PHUSE Data Transparency Workstream: A Global View of the ...

PHUSE Data Transparency Workstream: A Global View of the Clinical Transparency Landscape—Best Practices Guide

1 | PHUSE Deliverables

PHUSE Data Transparency Workstream:

A Global View of the Clinical Transparency

Landscape—Best Practices Guide

phuse.eu



Doc ID: WP-35 Version: v1.0 Working Group: Data Transparency


Contents

LIST OF IN-TEXT TABLES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1

LIST OF IN-TEXT FIGURES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1

Quick Navigation Guide 2

List of Abbreviations and Acronyms 3

DEFINITIONS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .4

Individual Patient Data/Patient-level Data 4

Protected Personal Data/Protected Personal Information/Personal Identifiable Information 4

Identifiers 4

Direct Identifier 4

Quasi Identifier (also known as Indirect Identifier) 4

Quasi Identifier Level 1 4

Quasi Identifier Level 2 4

Raw and Derived Data 5

Data Holder/Provider 5

Data Controller 5

Data Processing 5

Data Utility 5

Roles 5

Product 5

Study/Trial 5

Subject/Patient/Participant 6

Public Release/Disclosure 6

1. INTRODUCTION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .6

2. PLANNING ACROSS THE LIFECYCLE OF THE CLINICAL DEVELOPMENT PROGRAMME . . . . 7

2 1 Clinical Development Plan 7

2 2 Programme Level 7

2 3 Trial Level 8

2 4 Submission Level 9

3. DETAILED VIEW . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .9

3 1 Document Disclosure and Preparation 9

3 1 1 Categories of Document Disclosure 9

3 1 2 Project Plan 10

3 1 3 Document Content and Structure 11

3 1 3 1 Protected Personal Data 12

3 1 3 2 Commercially Confidential Information 12

3 1 3 3 Content Structure 14

3 1 4 Data Anonymisation 15

3 1 5 Document Anonymisation 15

3 1 5 1 Document Anonymisation Methodology 15

3 1 5 2 Document Anonymisation Technology 16

3 1 6 Document Quality and Metrics 17

3 1 7 Document Preparation—Summary 18

3 2 Protocol Registration and Summary Results Disclosure 18

3 2 1 Protocol Registration 18

3 2 1 1 ClinicalTrials gov and the Protocol Registration System 18

3 2 1 1 1 Quality Review 19

3 2 1 1 2 Registry Updates 19

3 2 1 1 3 Metrics 19

3 2 1 2 EU Clinical Trials Register and the Clinical Trial Application 20

3 2 1 2 1 Cross-functional Alignment 20

3 2 1 2 2 Registry Alignment 20

3 2 1 3 Data Sharing Statement 20

3 2 2 Summary Results Disclosure 21

3 2 2 1 Requesting Studies in EudraCT 22

3 2 2 2 Additional Data Needed 22

3 2 2 3 Document Requirements 22

3 2 2 4 Quality Review and Validation 23

3 2 2 5 Results Updates 23

3 2 3 Global Study Management 24

3 2 3 1 Acquisitions, Collaborations and Partnerships 24

3 2 3 2 Global Registry Tracking 25

Date: 22-May-20




3 3 1 Planning 26

3 3 2 Authoring 27

3 3 3 Delivery Process Best Practices 28

3 3 4 Review and Approval Process 29

3 3 4 1 Lay Review Panels 29

3 3 4 2 Data Provider Reviewers and Approvers 29

3 3 4 3 Institutional Review Boards and Ethics Committees 30

3 3 4 4 Regulators 30

3 3 5 Translations 31

3 3 5 1 Which Languages Should be Included? 31

3 3 5 2 Process 31

3 3 6 Disseminating Trial Result Summaries 31

3 3 6 1 Distribution Channels 32

3 4 Publications 33

3 4 1 Publication vs Clinical Trial Registration 33

3 4 2 Regulatory Aspects and Points to Consider 34

3 4 2 1 United States Labelling Definition 34

3 4 2 2 United States Guidance 34

3 4 2 3 European Requirements 35

3 4 3 Publication Planning and Management 35

3 4 3 1 Choice of Journal 36

3 4 3 2 How to Get Published 37

3 4 3 3 Publication: Open Access or Restricted? 37

3 4 3 4 Controlled Vocabularies 38

3 4 3 5 Timelines—When to Publish 38

3 4 3 6 Consequences of Release of Clinical Registry Results Prior to Peer Review Publication 39

3 4 3 6 Non-primary Publications 39

3 4 3 7 Authorship and Acknowledgements 39

3 4 4 Ethical Aspects: Privacy, Accuracy and Editors 40

3 5 Individual Patient Data Sharing 41

3 5 1 Value of Sharing Individual Patient Data 41

3 5 2 Embedding Processes 41

3 5 3 Preparation of Anonymised Data and Documents 41

3 5 4 Data Utility vs Data Privacy 42

3 5 5 Quantitative vs Qualitative Risk Assessment 43

3 5 6 How Does Data Sharing Fit in the Overall Landscape? 44

3 5 7 Individual Patient Data Sharing—Summary 44

3 5 8 Evolving Topics 45

3 5 8 1 Multi-platform, Multi-provider Sharing 45

3 5 8 2 Data Standards—FAIR Principles 45

3 5 8 3 Data Standards—CDISC 45

3 5 8 4 Data Modalities 46

3 5 8 5 Data Reuse Within a Data Provider’s Organisation 46

4. FUTURE VISION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 46

5. REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .47

6. APPENDICES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 53

6 1 Side-by-side Comparison of EMA and Health Canada Documents in Scope for Publication 53

6 2 Examples of Document Disclosure by Category 53

6 3 EMA Policy 0070 and Health Canada PRCI Process Flow 53

6 4 Health Authority-specific Practices for Protecting Personal Data in Clinical Documents Subject to Public Release 54

Doc ID: WP-35 Version: v1.0 Working Group: Data Transparency Date: 22-May-20

3 3 Trial Result Summaries 26




List of in-text tables

Table 1: Categories of Document Disclosure 9

Table 2: Best Practices: Project Plans 10

Table 3: Best Practices: Change the Paradigm for Authors 12

Table 4: Best Practices: Protected Personal Data 12

Table 5: Best Practices: Identifying Commercially Confidential Information 13

Table 6: Comparison of EMA and Health Canada Approaches to Justification of CCI Redaction 14

Table 7: Best Practices: Developing a Rationale for Redacted CCI 14

Table 8: Best Practices: Content Structure 14

Table 9: Best Practices: Side-by-side Comparison of Anonymisation Techniques 16

Table 10: Best Practices: Document Anonymisation Process 17

Table 11: Best Practices: Quality and Metrics 17

Table 12: Best Practices: Protocol Registration 20

Table 13: Validation Error Examples 23

Table 14: Best Practices: Results Disclosure 24

Table 15: Best Practices: Global Management 25

Table 16: Best Practices: Planning a Trial Result Summary 27

Table 17: Best Practices: Authoring a Trial Result Summary 27

Table 18: Best Practices: Delivering a Trial Result Summary 28

Table 19: Stakeholders to Consider for Reviewing a Trial Result Summary 30

Table 20: Best Practices: Review of a Trial Result Summary 30

Table 21: Best Practices: Translation of a Trial Result Summary 31

Table 22: Benefits and Risks Related to the Dissemination of a Trial Result Summary 31

Table 23: Potential Distribution Channels for a Trial Result Summary: Benefits and Risks 32

Table 24: Best Practices: Dissemination of a Trial Result Summary 33

Table 25: Aspects of Results Dissemination in Registries Compared to Publications 33

Table 26: Best Practices: General Publication Considerations 34

Table 27: Best Practices: Journal Selection 36

Table 28: Best Practices: How to Get Published 37

Table 29: SWOT Analysis—Open-access Publication 37

Table 30: SWOT Analysis—Restricted Access 37

Table 31: Best Practices: Vocabularies 38

Table 32: Best Practices: When to Publish 39

Table 33: Best Practices: Registry Publication Timing 39

Table 34: Best Practices: Authorship and Acknowledgements 40

Table 35: Best Practices: Individual Patient Data Sharing 45

List of in-text figures

Figure 1: Best Practices Associated With the 5 Key Aspects of Study-level Disclosure 6

Figure 2: Clinical Programme Development Stages 7

Figure 3: Clinical Development Plan Considerations 7

Figure 4: Trial Design Considerations 8

Figure 5: Balancing Data Utility and Privacy in Clinical Documents 11

Figure 6: Results Disclosure Timeline for Adult Study 21

Figure 7: Overall Process for Preparation and Dissemination of Trial Result Summaries 26

Figure 8: Publication Decision Tree 35

Figure 9: Considerations for Publication Planning 40

Figure 10: Pillars of Data Protection 43





Disclaimer

When considering changes to the structure or content of clinical documents, as suggested in this Guide, such as including information in an appendix or using relative days rather than dates, regional regulatory requirements or preferences should be carefully considered Scientific usefulness should consider the needs of the data provider, regulators, secondary researchers, and other data consumers who will subsequently utilise the data

The proposed best practices in this Guide look to support broad data utility Suggested best practices are based on data provider experience with structure and content of successful regulatory submissions that have been found to facilitate public disclosure of the clinical documents However, not all best practices may be accepted in each regulatory region and if there is any question, the proposed submission package to a health authority should be confirmed with them directly

Acknowledgements

The PHUSE core authoring team of Anne Cutting, George Allan, Rene Allard, Julie Holtzople, Liz Roberts, Nate Root and Wendy Wimmer would like to thank Nancy Sager [Division of Information Disclosure Policy (Center for Drug Evaluation and Research) at the FDA] and the PRCI team at Health Canada for providing valuable comments on earlier versions of Appendix 6 4, ‘Health Authority-specific Practices for Protecting Personal Data in Clinical Documents Subject to Public Release’, which greatly improved its content

The authors would also like to thank all internal and external reviewers who kindly provided comments on earlier drafts Incorporation of feedback comments and listing of names above does not imply respondents’ endorsement of this work

Section Links to Key Best Practices

3.1 Document Disclosure and PreparationThis section contains information on the types of disclosure for documents, best practices for writing with the end in mind, and subsequent management and preparation of documents for public release

Project PlansChange the Paradigm for AuthorsProtected Personal DataBest Practices: Identifying Commercially Confidential InformationDeveloping a Rationale for Redacted CCIContent StructureBest Practices: Side-by-side Comparison of Anonymisation TechniquesDocument Anonymisation ProcessQuality and Metrics

3.2 Protocol Registration and Summary Results DisclosureThis section contains information on registration and results disclosure

Protocol RegistrationResults DisclosureGlobal Management

3.3 Trial Result SummariesThis section contains information on the best practices for Trial Result Summaries (aka Lay or Plain Language Summaries) of clinical trials as defined under the European Union Clinical Trial Regulation

Planning a Trial Result SummaryAuthoring a Trial Result SummaryDelivering a Trial Result SummaryReview of a Trial Result SummaryTranslation of a Trial Result SummaryDissemination of a Trial Result Summary

3.4 PublicationsThis section contains information on the considerations when writing publications for clinical trials that also have other clinical disclosure requirements

General Publication ConsiderationsJournal SelectionHow to Get PublishedVocabulariesWhen to PublishRegistry Publication TimingAuthorship and Acknowledgements

3.5 Individual Patient Data SharingThis section contains information on approaches to Individual Patient Data sharing, provides best practices to consider related to data utility and participant privacy, and considers evolving topics, multi-platform, multi-data provider sharing, Findability, Accessibility, Interoperability, and Reusability Principles and the need for standards

Individual Patient Data Sharing

Quick Navigation Guide




List of Abbreviations and Acronyms

AE: Adverse eventANZCTR: Australian New Zealand Clinical Trials RegistryCBI: Confidential Business InformationCCI: Commercially Confidential InformationCDER: Center for Drug Evaluation and ResearchCDISC: Clinical Data Interchange Standards ConsortiumCMC: Chemistry, Manufacturing, and ControlsCSR: Clinical Study ReportCTA: Clinical Trial ApplicationCTIS: Clinical Trials Information SystemCTR: Clinical Trial RegulationEC: Ethics CommitteeeCTD: electronic Common Technical DocumentEMA: European Medicines AgencyEU: European UnionEudraCT: European Union Drug Regulating Authorities Clinical

Trials DatabaseFAIR: Findable, Accessible, Interoperable, ReusableFDA: Food and Drug AdministrationFDAAA: Food and Drug Administration Amendments ActFOIA: Freedom of Information ActGDPR: General Data Protection RegulationHIPAA: Health Insurance Portability and Accountability ActICF: Informed Consent FormICH: International Council for HarmonisationICMJE: International Committee of Medical Journal EditorsID: IdentifierIPD: Individual Patient Data (see also PLD)IRB: Institutional Review BoardLPLV: last-patient, last-visitMAH: Marketing Authorisation HolderMeSH: Medical Subject HeadingsNIH: National Institutes of HealthPDF: Portable Document FilePII: Personally Identifiable Information (see also PPD, PPI)PLD: Patient-level Data (see also IPD)PPD: Protected Personal Data (see also PII, PPI)PPI: Protected Personal Information (see also PPD, PII)PRCI: Public Release of Clinical InformationPRS: Protocol Registration SystemPSUR: Periodic Safety Update ReportQA: Quality AssuranceQC: Quality ControlSAE: Serious adverse eventSAP: Statistical Analysis PlanSWOT: Strengths, weaknesses, opportunities, threatsTLFs: Tables, listings, and figuresTRS: Trial Result SummaryUS : United StatesWHO: World Health OrganizationXML: Extensible Markup Language



DefinitionsNoting that there are different definitions across various publications for commonly used terms, and further noting that the PHUSE authors of this Best Practices Guide are not standards developers, below are the definitions used in this Guide, together with acknowledgement of related definitions used elsewhere

Individual Patient Data/Patient-level Data: Individual Patient Data (IPD) are defined in the Institute of Medicine report, "Sharing Clinical Trial Data: Maximizing Benefits, Minimizing Risk" 1 as, “Data that are collected from participants (e g the raw data) and then cleaned, abstracted, coded, and transcribed to become the analysable data ” Similarly, the European Medicines Agency (EMA) Policy 0070 2, defines IPD as “the individual data separately recorded for each participant in a clinical study ” As noted in "Protecting patient privacy when sharing patient-level data from clinical trials" 3, “Examples of patient-level data collected in clinical trials are patient identifier (ID), site ID, date of birth, gender, race, efficacy outcomes, laboratory test results, etc ”

For the purposes of this Guide, the terms IPD and Patient-level Data (PLD) will be used synonymously and denoted as IPD throughout

Protected Personal Data/Protected Personal Information/Personal Identifiable Information: Protected Personal Data (PPD) is any protected information relating to an identified or identifiable person

The European Union (EU) General Data Protection Regulation (GDPR) provides 4 the definition in Article 4 (1) that:“‘personal data’ means any information relating to an identified or identifiable natural person (‘data subject’); an identifiable natural person is one who can be identified, directly or indirectly, in particular by reference to an ID such as a name, an identification number, location data, an online ID or to one or more factors specific to the physical, physiological, genetic, mental, economic, cultural or social identity of that natural person ”

Personal data are not labelled or described consistently across different jurisdictions See further discussion of PPD and PII in the PHUSE White Paper “De-identification and Anonymisation of Individual Patient Data in Clinical Studies—A Model Approach” 5 Protected Personal Information (PPI) and Personally Identifiable Information (PII) are common acronyms that are conceptually similar to PPD; therefore, for simplicity, PPD will be the term used throughout this document

Identifiers: The following definitions of direct and quasi (indirect) IDs are provided per the PHUSE De-identification Standard for SDTM 3 2: Version 1 0, 15-May-2015 6:

Direct Identifier: One or more direct IDs can be used to uniquely identify an individual For example, Participant ID, Social Security Number, Telephone Number, Exact Address, etc It is compulsory to remove or de-identify any direct ID

Quasi Identifier (also known as Indirect Identifier): Quasi IDs are background information that can be used in connection with other information to identify an individual

with a high probability For example, Age at baseline, Race, Sex, Events, Specific Findings, etc

Quasi Identifier Level 1: Information that is not likely to change over time, be visible and available in other sources Typically demographic information For example, Sex, Age at baseline, Country, Body Mass Index, etc

Quasi Identifier Level 2: Longitudinal information that is likely to change over time For example, Measurements, Events, etc

These concepts align with definitions provided in the PHUSE “De-identification and Anonymisation of Individual Patient Data in Clinical Studies—A Model Approach” White Paper 5, which notes that

“For the purposes of this paper, we have defined de-identification and anonymisation as follows, although we acknowledge the definitions for these terms may differ across other guidance documents (i e industry, regulatory authorities), geographies and contexts

1 As noted in the PHUSE De-identification Standard for SDTM 3 2, “Data de-identification (verb: to de-identify) is the process by which a dataset is derived in such a way that the data subject is no longer identifiable”, ensuring that the risk of re-identifying a participant in a clinical trial, by all reasonably likely means to be used, is small Various techniques are applied to de-identifying direct as well as quasi IDs that, when combined together or with other data, could increase the risk of re-identification These techniques include removing or recoding IDs, generalisation of continuous data into categorical form, and removing or redacting free text verbatim terms Participants’ identification code numbers are de-identified by replacing the original code number with a new randomly generated code number

2 Anonymisation is defined in this paper as a step subsequent to de-identification that involves irreversibly destroying all links between the de-identified datasets and the original datasets This includes destroying the key code that was used to generate the new identification code number from the original, and destroying the deltas if dates were de-identified using the offset method Both the EU Data Protection Directive 7 and the GDPR 4 provide definitions of anonymisation As noted by the Article 29 Working Party in its 2014 publication on Anonymisation Techniques, 8 “Recital 26 signifies that to anonymise any data, the data must be stripped of sufficient elements such that the data subject can no longer be identified More precisely, the data must be processed in such a way that it can no longer be used to identify a natural person by using ‘all the means likely reasonably to be used’ by either the controller or a third party An important factor is that the processing must be irreversible ”

Note that the Article 29 Working Party definition above states that the processing must be irreversible From an operational perspective, data providers will usually have access to both the original pseudonymised datasets (see Section 3 1 4, Data Anonymisation) and the resultant anonymised datasets, although these can be stored on different, unconnected servers These original pseudonymised datasets are often required to be retained for regulatory reasons



As further noted in Tucker et al 3, “Guidance on implementation of the EMA Policy 0070 9 defines anonymisation as ‘the process of rendering data into a form which does not identify individuals and where identification is not likely to take place,’ and anonymised/de-identified data as ‘data in a form that does not identify individuals and where identification through its combination with other data is not likely to take place ’ The Health Insurance Portability and Accountability Act (HIPAA) 10 defines de-identified protected health information as “Health information that does not identify an individual…there is no reasonable basis to believe that the information can be used to identify an individual…”

Note that the terms ‘de-identification’ and ‘anonymisation’ are often used interchangeably in different contexts in the literature The definitions, as used in the PHUSE publications described above, will also be used in this Best Practices Guide

Note also that the terms ‘suppression’ and ‘redaction’ are often used interchangeably; however, they are separate methods and it is important to distinguish between them Redaction of information is when text is obscured by an opaque box, whereas suppression of information is when the text is removed (and potentially replaced with other text) Redaction does not allow for assessment of the information, as it is obfuscated according to a rules-based approach; suppression may still allow some information to be considered and assessed

Raw and Derived Data: As described in Tucker et al , “Raw data means patient-level data that have been directly collected during a clinical trial or study (e g weight and height of a patient) Derived data are data that are obtained from raw data and which have undergone a derivation or calculation (e g body mass index is derived from the weight and height of a patient) Patient-level data to be shared can include raw and/or derived data ”

These definitions of raw and derived data will also be used in this Best Practices Guide

Data Holder/Provider: Tucker et al define the data holder as the “Entity which holds the clinical trial data and has the ability and authority to share with third party researchers ” Likewise, the World Health Organization (WHO) 11 defines data providers as those “responsible for a database that is used by one or more registries Data providers provide data to WHO for inclusion in the ICTRP Search Portal ” Following this concept of the holder or provider being the party with the authority and ability to share/provide information, this Guide will describe such organisations (e g pharmaceutical sponsors and academic institutions providing data such as IPD and associated clinical trial documents/information) as data providers The term ‘sponsor’ has been used in this document when describing topics focused on pharmaceutical company data providers

Data Controller: As defined under GDPR 4 Article 4 (7),“‘controller’ means the natural or legal person, public authority, agency or other body which, alone or jointly with others, determines the purposes and means of the processing of personal data; where the purposes and means of such processing are determined by Union or Member State law, the controller or the specific criteria for its nomination may be provided for by Union or Member State law;”

Data Processing: As further defined under GDPR Article 4 (2), “‘processing’ means any operation or set of operations which is performed on personal data or on sets of personal data, whether or not by automated means, such as collection, recording, organisation, structuring, storage, adaptation or alteration, retrieval, consultation, use, disclosure by transmission, dissemination or otherwise making available, alignment or combination, restriction, erasure or destruction;”

Data Utility: When preparing anonymised IPD, data providers must sufficiently protect the trial participants’ privacy As noted in the guidance on implementation of the EMA Policy 0070 9, “Different anonymisation techniques will lead to different levels of data utility in the anonymised reports Applicants/MAHs should take into consideration the impact of the data transformations/redactions on the scientific usefulness of the data ”

Furthermore, as noted by the Organisation for Economic Co-operation and Development 12, data utility is described as, “A summary term describing the value of a given data release as an analytical resource This comprises the data’s analytical completeness and its analytical validity Disclosure control methods usually have an adverse effect on data utility Ideally, the goal of any disclosure control regime should be to maximise data utility whilst minimising disclosure risk In practice disclosure control decisions are a trade-off between utility and disclosure risk ”

Roles:

• Participant—A person who enrolls in a clinical trial; also known as a patient or subject of the trial (also see below)

• Disclosure Specialist—Subject matter expert who manages disclosures

• Product Team—General roles that make up a Product Team, including (but not limited to) representatives from clinical, statistics, pharmacology, nonclinical, regulatory affairs, and Chemistry, Manufacturing, and Controls (CMC)

Product: Within this document, the general term ‘product’ is used to describe a medicine (either an active medicine or placebo), biologic, vaccine, device or diagnostic

Study/Trial: Per the WHO definition 13,“For the purposes of registration, a clinical trial is any research study that prospectively assigns human participants or groups of humans to one or more health-related interventions to evaluate the effects on health outcomes Interventions include but are not restricted to drugs, cells and other biological products, surgical procedures, radiological procedures, devices, behavioural treatments, process-of-care changes, preventive care, etc ” Within this document, for deliverables such as IPD sharing where the scope does not include non-interventional studies, the term “trial” has been used In other sections, the words “study” and “trial” may have been used interchangeably to aid readability, though for deliverables that could contain non-interventional studies, the term “study” has been used

1 ICTRP: International Clinical Trials Registry Platform



Subject/Patient/Participant: Historically, the terms “subject” and “patient” have been used to describe people who provided informed consent to join a trial, the term “subject” often being used either as a blanket term for all people enrolled in trials or to describe healthy volunteers, i e people without the medical condition under study In alignment with such systems and references, these terms have also been used in places within this document to aid clarity The term “participant” has been used in this document to describe people who participated in the trial, i e as well as subjects/patients, this also includes for example, staff at the investigational site and the trial team within the data provider’s organisation As noted in the Clinical Data Interchange Standards Consortium (CDISC) glossary, 14 a participant is: “A person or entity with a role in a clinical study NOTE: Participant is used with growing frequency in some clinical and patient-facing documents like the informed consent form, Plain Language Summaries of study results, and publications Subject or patient are terms used in regulatory guidelines, databases, other clinical research documents, or systems to refer to study participants…”

Public Release/Disclosure: Within this document, ”public release” or “disclosure” refers to the distribution of information in data or documents to a person(s) or entity(ies) that is not bound to a confidentiality agreement directly with the owner of the information, though they may be subject to Terms of Use, which provides a possibility for the sponsor to take legal action in the case of data misuse Disclosures of documents can be to a single requestor, posting to a website (including mandatory disclosures to health authority sites), a press release, or the result of a voluntary disclosure

1. Introduction

The research community acknowledges that information and data sharing advance the generation of critical scientific knowledge Traditional methods of sharing are no longer adequate to support the rapid developments in healthcare and the need to make shared information and data digitally available and useful Globally, the proliferation of disclosure requirements and opportunities has resulted in a network of platforms and venues The public and researchers’ awareness of the various avenues of disclosure will enable insight into previous research to inform future research

This Guide builds upon and is complementary to “Clinical Trial Transparency and Disclosure: A Global View,” 15 which was developed by the same group of subject matter experts with the goal of highlighting the evolving global landscape of clinical trial transparency and disclosure

“Clinical Trial Transparency and Disclosure: A Global View” is a factual guide to regulatory requirements and voluntary disclosures at the individual trial and submission level existing at the time it was published In this Best Practices Guide, subject matter experts share recommendations with the aim of fostering a holistic approach to clinical data transparency and disclosure that provides accurate and complete information across multiple disclosure platforms Those in the role of a

data provider should consider its target audience and ensure the data are understandable and useful to them, whether researchers performing analyses to advance human healthcare, or participants in clinical trials wanting to understand the results of the trial in which they were involved What is critical is that data providers move from reactively preparing legacy data for availability, to proactively creating original data that is “easier” to share later while retaining scientific usefulness and compliance with regulatory requirements

The intention is that these tools can be used together or separately to assist in understanding a complex global landscape Due to the constantly evolving nature of clinical trial transparency, this Guide is intended to be a snapshot in time While the authors have included the best information available at the time of writing, it cannot be guaranteed that the Guide encompasses all requirements The authors welcome readers’ feedback via an FAQ Forum 16

The Guide begins with the initial clinical development plans for a product (medicine, vaccine or device for use in association with a product) and progresses through the entire lifecycle Best practices are described for the 5 key aspects of trial level disclosure (Figure 1) These best practices highlight opportunities for alignment through which regulators and researchers will be able to fully explore available information that may be used to help patients

Figure 1: Best Practices Associated With the 5 Key Aspects of Study-level Disclosure

Registries

Trial Result Summaries

Data Sharing

Document Disclosure

Publications



2. Planning across the lifecycle of the clinical development programme

This section focuses on the importance of planning for clinical transparency and disclosure at the same time as development of the clinical programme for a product and at each stage thereafter shown in Figure 2

2.1. Clinical Development Plan

The clinical development plan outlines the evidence that will be collected to demonstrate the clinical efficacy, safety and effectiveness of a product, which will support the marketing application, reimbursement negotiations and publications, plus any regulatory and other questions that might arise Questions addressed while developing the clinical programme (Figure 3) will also begin to indicate what sort of disclosures will be required

Figure 3: Clinical Development Plan Considerations

In addition to interventional clinical trials in healthy volunteers or patients, other types of observational study may be set up to better understand the product class and disease area Appropriate disclosure of these studies also needs to be considered

See Section 3, Detailed View, for best practices associated with each of the above disclosures

2.2. Programme Level

Disclosure should be considered during the development and updating of programme level documents such as the Investigator Brochure See Section 3 1, Document Disclosure and Preparation, for best practices to ensure transparency while protecting personal and commercially confidential information (CCI) Consideration should be given to whether commercial confidentiality changes during the lifecycle of an investigational product, e g details may be commercially confidential when contained in Investigator Brochures submitted with Phase I trials but no longer for Phase IV trials conducted after market authorisation

2.1 Clinical development plan 2.2 Programme level 2.3 Trial level 2.4 Submission level

• Healthy volunteers• Patients

What evidence is required?

• Clinical trials• Observational studies

• Trial medicines• Comparator• Device/other technology

• Regulatory submission• Re-imbursement• Publication• Regulatory questions

How will the evidence be used?

What medicines will be used?

Will participants be recruited?

Regulatory requirements

Registries: Registration required as part of Clinical Trial Application/trial initiation, with results posting after trial completion

Document disclosure: Required as part of registry posting, publication and marketing application

Recommended disclosures oftenrequired by data provider policy

Publication of manuscript in journal to facilitate scientific review

Data sharing to facilitate additional research

Lay Summaries: Summaries of results written for trial participants and the public

Figure 2: Clinical Programme Development Stages



• Adults only• Paediatrics

How will the evidence be used?

What endpoints are included?

• Regulatory submission• Re-imbursement• Publication• Regulatory questions

• Primary• Secondary• Exploratory• Post-hoc

• United States• Europe• Other

• Rare disease• Biomarkers• Genetic markers

• Healthy volunteers• Patients

• Randomised• Open label

How will participants be recruited?

Trial design?

Where will the trials be conducted?

Any specific considerations?

What ages of participants are

included?

Regulatory requirements

Registries: Which registries, primary completion vs trial end; expedited paediatric disclosure?

Document disclosure: How to minimize personal/confidential information contained in the original document to limit redaction required?

Recommended disclosures oftenrequired by data provider policy

Publication: Do journals recommend specific registry posting or data sharing statements?

Data sharing: what data will be shared & when?

Trial results summaries: Will they be produced for this trial, will participants be informed while in the trial, when will they be available?

2.3. Trial Level

The trial design phase will further impact the disclosure requirements for each of the trials in the clinical programme (Figure 4)

Figure 4: Trial Design Considerations

See Section 3, Detailed View, for best practices associated with each of the above disclosures



2.4. Submission Level

In addition to the trial-specific requirements already discussed, there are disclosure requirements following market approval or withdrawal of an application, depending on regional requirements An overview graphic that visually represents many of these topics is accessible on the PHUSE website 17

Each jurisdiction’s approach to document-access policies varies in both mechanics of delivery and what information is freely shared At a high level, sponsors should expect to be required to provide redacted/anonymised clinical documents that include Clinical Study Reports (CSRs), key clinical overview and summary documents and an anonymisation report This package must protect the privacy of participants while providing clinical utility to researchers and the public

Disclosure must be considered during the development of submission-level documents See Section 3 1, Document Disclosure and Preparation, for best practices to ensure transparency while protecting personal information and CCI

3. Detailed view3.1 Document Disclosure and Preparation

This section contains information on the types of document disclosure, best practices for writing with the end in mind, and subsequent management and preparation of documents for public release

The information and best practices outlined in this section of the paper are an overall view for preparing documents, recognising that there may be specific elements that would result in a different practice For further details regarding specific disclosure requirements, see Section 2 of “Clinical Trial Transparency and Disclosure: A Global View” 18

Any document that the marketing authorisation holder (MAH) submits to a health authority is in scope for Freedom of Information Act (FOIA) 20 or Access to Documents 21 requests In general, the most common types of document requested for disclosure, as defined in Section 3 1 1, Categories of Document Disclosure, include the following:

• Clinical components of the Common Technical Document

• Clinical components of the Clinical Trial Application (CTA)

• Safety reports: Periodic Safety Update Reports (PSURs) and Risk Management Plans

• Other miscellaneous reports and responses to health authority questions

For both EMA Policy 0070 and Health Canada Public Release of Clinical Information (PRCI), the documents in scope for publication of clinical information are similar 2, 19 See Appendix 6 1, Side-by-side Comparison of EMA and Health Canada Documents in Scope for Publication

Additionally, future implementation of the EU Clinical Trial Regulation (CTR) 536/2014 22 includes the public release of most information and documents contained in the CTA

3.1.1 Categories of Document Disclosure

To summarise the landscape for document disclosure where the MAH can review prior to release, there are 4 general categories that are grouped by the level of exposure to external parties along with the organisation that has final decision on the extent of the information released (Table 1)

Document Disclosure Categories Level of Exposure Final Decision for Release

Access to Documents—ad hoc requests from agencies Generally single requestor, though Health Canada will publish documents requested under the retrospective PRCI process

Health authority, often little consultation with MAH, though MAH will prepare documents for release under the Health Canada retrospective PRCI process

Health Authority Publication—scheduled public release of clinical information (documents) via a health authority portal

Public MAH, in some instances extensive consultation with Health Authority

Clinical Trial Data Sharing—external entities requesting (direct-to-data provider) access to documents

Single requestor Data providers

Voluntary Disclosure—external posting to other platforms (e g sponsor website)

Public Data providers

Table 1: Categories of Document Disclosure



Also see Appendix 6 2, Examples of Document Disclosure by Category, which contains a categorised list of common examples of document disclosure requests that may be submitted to an MAH consultation

When assessing the perceived risks for re-identification of an individual, the level of exposure due to disclosure is to be considered when deciding the anonymisation strategies applied to the documents See Section 3 1 5, Document Anonymisation, for best practices for document anonymisation

Likewise, the risk of releasing CCI may vary with the level of exposure and timing of release; a release plan should be discussed and agreed to by all team members See Section 3 1 3 2, Commercially Confidential Information, for related best practices

3.1.2 Project Plan

Not all requests for disclosure require a formal complex project plan in order to execute requests for the release of documents Disclosure Specialists should determine when a formal project plan should be initiated (e g project submission-level activities) and when the requests could be incorporated into other established processes as additional activities (e g trial-level activities) For complex submissions like EMA Policy 0070 and Health Canada PRCI, the expected milestones and deliverables can be outlined in a formal project plan Requests for access to documents are ad hoc with extremely short preparation times; therefore, there is rarely time to develop a full project plan In these cases, it is best practice to have a clear process in place that pre-defines cycle times for activities and those responsible For other, simpler activities such as preparing protocols and Statistical Analysis Plans (SAPs) for posting to ClinicalTrials gov (see Section 3 2 2 3, Document Requirements), the trigger for the start of processing of documents could be initiated by the Disclosure Specialist at the time of posting the trial results and does not need a formal project plan

See Appendix 6 3, EMA Policy 0070 and Health Canada PRCI Process Flow, for a high-level process flow for publication of clinical information

Table 2 is a list of best practices for planning a document disclosure project

Best Practices - Project Plans

1 Ensure Disclosure Specialists have access to documents in scope as well as submission archive repositories, as appropriate

2 Determine the scope of the content for submission (down to the exact version of a document) to inform appropriate Product Team members of upcoming disclosure submissions

3 If the product was a result of co-development, set up a spokesperson for each sponsor and agree on a disclosure route before starting any activities; plan who will lead discussions with the regulators and be the central contact

4 Create templates using either existing project plan tools or create a simple plan in a spreadsheet

5 Include key milestones such as: • Health authority dates, including (expected) approvals, notifications, consultation cycle times • Internal reviews, hand-offs • Product Team CCI release plan

6 Organise tasks to account for dependencies

7 Establish cycle times for: • Product Team review of CCI • Disclosure Specialist review of PPD, quality check and other deliverables as appropriate (e g justification tables)

Table 2: Best Practices: Project Plans



3.1.3 Document Content and Structure

Some documents contain extraneous information that is not relevant to the intent to summarise clinical trial results and conduct So, instead of being concise summaries of the trial information and data, CSRs may include all potential scenarios and trial conduct issues, i e they may have too much information There should be a concerted effort during authoring to describe the trial results and conduct without adding details of PPD and CCI that do not add scientific usefulness to the interpretation of the results or to the evaluation of trial conduct (Figure 5)

Minimise protected information (PPD/CCI) in documents rather than mitigate later For example, it is preferred to include statements that refer the reviewer to content that may reside in the trial master file rather than attach it to the CSR The medical writers and Product Teams should balance what is needed for regulatory approval vs the eventual publication risk For example, avoid summarising CMC details in Module 2 and instead refer to the appropriate CMC sections in Module 3 The goal should be to summarise the data concisely and qualitatively, cross-referencing as appropriate, only including trial participant-level information and CCI where required to appropriately describe the safety and efficacy of the investigational product as per International Council for Harmonisation (ICH) guidelines

The medical writer is in a unique position, as an authoring coordinator across functional areas, to identify protected information in early drafts of documents An early mitigation could be to inform medical writers to recognise protected information so they can spot potential issues early and coordinate conversations regarding alternate presentation of the information that are suitable for public release without having to transform or redact them later See Table 3 for best practices on changing the authoring paradigm

Data Utility

Protected Data

Transparency

Figure 5: Balancing Data Utility and Privacy in Clinical Documents



Best Practices - Change the Paradigm for Authors

1 Disclosure Specialists provide information to aid informing and training authors to recognise what may be protected information

2 Training can be formal, but informal sessions (e g lunch and learns) with targeted authors can be very effective and provide the opportunity for questions

3 Disclosure Specialists work with process and template owners to provide quick tips and reminders for avoiding the inclusion of non-essential protected information

4 The Product Team should consider having a briefing before authoring of a CSR for trials with a high risk of re-identification (due to a small population or rare indication) to strategise presentation of summary data that would decrease the risk of re-identification

5 The Product Team should write documents assuming they will be released or made available to the public

6 Disclosure Specialists can be inserted into the review process for draft documents to provide real-time feedback to authors prior to finalisation

Table 3: Best Practices: Change the Paradigm for Authors

The next few sections contain best practices to determine and identify protected information The information is presented as general definitions that may or may not be in alignment with local laws for a specific country Examples of these differences are presented in a side-by-side comparison of EMA, Health Canada, and Food and Drug Administration (FDA) country-specific guidances in Appendix 6 4, Health Authority-specific Practices for Protecting Personal Data in Clinical Documents Subject to Public Release A challenge for the Disclosure Specialist is to develop standard practices that meet most situations and to keep track of the exceptions to those rules

3.1.3.1 Protected Personal Data

PPD is any protected information relating to an identified or identifiable person (see DEFINITIONS) Data providers should consider the needs of the regulatory reviewer and scientific usefulness before changing processes for document writing around PPD See Table 4 for best practices for authors handling PPD

Best Practices - Protected Personal Data

1 Work with a de-identification expert who can appropriately assess the risks of re-identification for potentially numerous IDs 2 Ensure direct IDs have a consistent format and location in the document to allow effective identification and mitigation by anonymisation Consistency supports predictable

referencing across a submission

3 Proactively anonymise; if including participant-level details, DO use:• a consistent format throughout to ease later anonymisation• relative day instead of absolute date, wherever possible (consider in particular how to present dates related to medical history, as well as partial dates)• age of a participant rather than birth date• ‘participant’ rather than sex-specific pronouns

4 Avoid statements or mini-narratives in text and in table, listing, and figure (TLF) footnotes referring to a specific participant or including potential quasi IDs Avoid verbatim text (e g exact dates of trial visits, city in which the participant is located, procedure performed)

5 Avoid including participant IDs in table footers, table and figure titles (where they may show in a table of contents and bookmarks)

6 Include only essential direct IDs—i e patient IDs—to aid regulatory review by traceability of a participant through a document

7 Disclosure Specialists to consider country-specific exceptions and scientific usefulness when establishing rules and best practices for preparing documents for public release

Table 4: Best Practices: Protected Personal Data

3.1.3.2 Commercially Confidential Information

CCI is the terminology used in EU transparency policies and Confidential Business Information (CBI) is the equivalent terminology used by Health Canada 2, 19 The overall definitions are conceptually similar; therefore, for simplicity, CCI will be used throughout this document unless there is a specific difference for Health Canada, when CBI will be used It is important to note that while countries may have similar definitions and concepts for commercially confidential or trade secret information, there



are differences in thresholds for what is acceptable Tracking these differences will help in avoiding multiple rounds of consultation with a health authority

CCI means any information contained in the document that is not in the public domain or publicly available and where disclosure may undermine the legitimate economic interest of the owner of the information CCI (i e know-how that has not been registered as industrial property rights but that is actually or potentially valuable to its owner and not generally known or readily ascertainable by the public, and which the owner has made a reasonable effort to keep secret), such as a technology (e g novel assay information), a business or marketing strategy, a data compilation or a formulation, are valuable intangible assets of a sponsor

Appropriate review of documents for CCI must consider the timing of when the information will be available to the public (e g by prior release of clinical information, publications) The EMA categories of potential CCI along with the rationale for redaction can be found in Annex 3 of the “External guidance on the implementation of the European Medicines Agency policy on the publication of clinical data for medicinal products for human use” 9

Table 5 is a list of best practices for the identification of CCI

Table 5: Best Practices: Identifying Commercially Confidential Information

Best Practices - Identifying CCI

1 Disclosure Specialists meet with Product Team the first time they go through the process of preparing documents for public release and present an overview of the process and description of terms It is important to include representatives from the CMC, nonclinical and regulatory functional areas

2 All Product Team members are expected to know the product development stage and what has already been made public (e g via registries, abstracts, posters, presentations, patents, journals), as well as to be aware of identified CCI to avoid accidental disclosure later in development

3 Product Team focuses on identifying CCI while Disclosure Specialists focus on identifying PPD

4 Disclosure Specialists can guide teams as they identify CCI to be as specific in redactions as possible (i e redact words or phrases, and rarely whole sentences, paragraphs or sections); redact the minimum amount that allows protection of information

5 Product Team to consider the following questions when identifying CCI: a Is the information considered secret and has it not been previously disclosed ANYWHERE? b Specifically, how will the release of the information cause economic harm to the sponsor? c Is the team willing to take legal action if the health authority disagrees?

Prospectively:

6 Be knowledgeable and identify CCI while writing submission documents and carefully consider whether including it is essential (see Number 2 above)

7 If including CCI, consider cross-referencing other documents in the submission not subject to public disclosure (e g Module 3 [CMC information])

8 Use qualitative statements rather than quantitative values to minimise CCI (e g “high” rather than “300 units”)

9 Authors to avoid the following: • Forward-looking statements, such as future planned analyses • Speculative or exploratory statements (exploratory analyses should not be included in the protocol) • Chemical structure of a novel compound • Mention of development plans for the drug in other disease indications • Description of results from non-published trials • Unnecessary details of proprietary assays or test methodologies

For both EMA Policies 0043 (“Access to Documents” 21 ) and 0070 and Health Canada PRCI, there is a requirement to list by document the text that is considered CCI and the corresponding rationale for redaction See Table 6 for a side-by-side comparison of the EMA’s justification table and Health Canada’s PRCI control sheet deliverables 2, 19



Table 7 is a list of best practices for justifying redaction of CCI

CCI–EMA Policy 0043/0070—Justification Table CBI–Health Canada PRCI—Control Sheet

• EMA provides Microsoft Word template with specific naming conventions • Separate table required for each document• Does not require citation of regulations

• Health Canada provides Microsoft Excel template• One control sheet per submission• Rationale must cite associated regulations [C 08 009 2(2)(a); C 08 009 2(2)(b)]

Best Practices - Developing a Rationale for Redacted CCI

1 Use specific statements for justification of CCI, as provided in the guidelines (rather than general statements like those provided in the EMA external guidance) For example, ‘If competitors were to reconstruct production details from manufacturing specifics, the sponsor might lose 1 5 years of exclusivity and XXXM in sales due directly to premature release of data ’

2 For EMA submissions, review the extensive list of what is not considered CCI

3 Review public assessment reports and conduct internet searches; the information is not CCI if it is in the public domain (most frequent reason for EMA rejection)

4 Redaction of CCI requires a robust justification (second most common reason for EMA rejection); keeping track of rejections and successes will enable more acceptance in future submissions

Best Practices - Content Structure

1 Templates: • Remove unnecessary sponsor personnel information and signatories on pages subject to disclosure (separate wet signature pages as appropriate) • Ensure table of contents has clear demarcation of ‘like’ content: tabular summaries, narratives, individual participant-level listings, etc • Summarise information in report body and appropriately place comprehensive information in appendices that are out of scope for publication, e g list of lot numbers (16 1 6),

list of the administrative structure of the trial (16 1 4) • Consider both scientific usefulness and data privacy when including participant-level data in the body of the CSR Individual patient listings can be included in the

appropriate subheading of Appendix 16 2, as described in ICH E3, and cross-referenced in the body of the CSR • Use mock tables or table shells with no true trial details in SAPs • Minimal or no use of scanned documents and tables and figures

2 Submission Considerations:• Ensure documents are correctly placed in the electronic Common Technical Document (eCTD) modules Incorrectly placed documents are often difficult to claim as out of

scope once submitted to the health authority

3 Avoid including in future submissions:• Duplicate statements in multiple locations in the same document• Duplicate information across documents; refer to the source (e g bioanalytical data, CMC information)• Duplicate foreign-language content• Copyrighted material (or make sure it is appropriately cited for public release)• Clinical reports previously submitted as part of a marketing dossier• Reports or information for unrelated or discontinued compounds• Pages containing author information or signatures if not required• Identifying participant data in immutable content (e g graphs, images, scanned documents)

Table 6: Comparison of EMA and Health Canada Approaches to Justification of CCI Redaction

Table 7: Best Practices: Developing a Rationale for Redacted CCI

Table 8: Best Practices: Content Structure

3.1.3.3 Content Structure

With an understanding of the definitions of protected information, this section pulls together guidance that can be applied to templates and operational processes Decisions regarding how content is represented in documents start with the trial protocol Once Product Teams understand the disclosure requirements, they should write sections that are appropriate for disclosure and reuse across subsequent documents (e g Informed Consent Forms [ICFs], CSRs) Minimise repetition of data-heavy information, but reuse other text (e g trial methodology) without modification rather than mitigate later

To easily apply the guidance for disclosure of clinical information, it is best practice to follow as closely as possible the high-level heading structure of the CSR according to ICH E3 23 and clinical summaries (Modules 2 5, 2 7) according to ICH M4 24 The CSR synopsis, Sections 1 through to 15 (CSR body) and 3 appendices in Appendix 16 1 (protocols, sample case report forms and SAPs) are subject to public posting; therefore, the inclusion of CCI and PPD in a CSR must be carefully considered and discussed during the authoring of the CSR To decrease the need for subsequent document anonymisation activities, the guidance in Table 8 can be followed



3.1.4 Data Anonymisation

The anonymisation of data occurs when the level of detail for an individual is reduced, rendering a reverse compilation or re-identification of the individual difficult by plausible means The most conservative strategies for anonymisation are deleting all personal information in a data file and either “suppressing” or “masking” a selection of data so that the remaining information cannot be used to identify individuals It is important to note that pseudonymised data are not the same as anonymised data Pseudonymisation takes the most identifying fields (e g participant IDs) in a database and replaces them with artificial IDs, or pseudonyms (i e aliases) When data has been pseudonymised it still retains a level of detail that may allow tracking the data back to its original state and re-identification by reasonable efforts Therefore, this type of data is not considered anonymised data Once the document is anonymised, items that are pseudonymised can remain

Below are key references for privacy requirements and anonymisation methodologies that can be used to inform an anonymisation specialist:

• EU GDPR 4

• HIPAA (1996) 10 and subsequent guidance published by the Office for Civil Rights at the US Department of Health and Human Services 25

• Office of the Privacy Commissioner of Canada Privacy Act 26

Examples of key anonymisation standards are as follows:

• HIPAA Privacy Rule Section 164 514(b): (1) Expert Determination and (2) Safe Harbor methods 25

• Information and Privacy Commissioner of Ontario: De-identification Guidelines for Structured Data 27

• PHUSE: anonymisation of CDISC SDTM 3 2 datasets 6

• National Academies of Sciences, Engineering, and Medicine, Institute of Medicine: Sharing Clinical Trial Data: Maximizing Benefits, Minimizing Risk 1

It is recognised that anonymisation methodologies are an emerging area and multiple ways to achieve anonymisation can be used, and may depend on the structure of the data provider and scalability of the process The following publications provide useful guidance:

• El Emam: Guide to the de-identification of personal health information 28

• El Emam: Risky business: sharing health data while protecting privacy 29

• Arbuckle and El Emam: Building an anonymisation pipeline: Creating safe data 30

• Sweeney: k-anonymity: A model for protecting privacy 31

• Winpenny and Bamford: De-ID: ‘The What’ and ‘The How’ of de-identifying your clinical trial data 32

See also Section 3 5, Individual Patient Data Sharing

3.1.5 Document Anonymisation

Anonymisation methodology is a complex topic Most of the reference material for anonymisation is focused on electronic datasets of information, and there is little standardisation of document anonymisation Disclosure of documents, which were

previously considered confidential and containing identifiable participant data, has become a new norm and has required data providers to consider how to best anonymise them prior to release In many cases, documents to be released publicly have been written without forethought for public release, thereby requiring retroactive anonymisation of the document A key challenge to anonymisation of documents is the desire to retain the maximum amount of scientifically useful information or data utility

Based on the requirements for the release of clinical documents to public portals, best practices will focus on the EMA Policy 0070 and Health Canada PRCI guidances for anonymisation of documents The document anonymisation process involves the following steps:

1 Determining and classifying data elements as direct or quasi IDs, as outlined in Section 3 1 3 1, Protected Personal Data

2 Determining how to measure the risk of re-identification (qualitative or quantitative); refer to Section 3 1 5 1, Document Anonymisation Methodology

3 Determining how to implement anonymisation of the document (manual or technology-based); refer to Section 3 1 5 2, Document Anonymisation Technology

The key to developing a good anonymisation strategy is to ensure there is an anonymisation expert (i e Disclosure Specialist), as well as a privacy or data protection officer involved In the absence of an expert in the field of document anonymisation, a statistician who has previous experience in anonymisation of datasets can be consulted for developing strategies and rules for anonymisation of documents The privacy officer will be a resource for understanding the legal framework for privacy regulations and establishing processes using privacy-by-design concepts

3.1.5.1 Document Anonymisation Methodology

In all cases, direct IDs are expected to be removed or, if possible, participant IDs can be recoded rather than removed The determination of whether to remove or generalise quasi IDs may depend on the type of document disclosure request (Section 3 1 1, Categories of Document Disclosure) and the risk of re-identification against the determined threshold Alternatively, for efficiency, a common approach may be taken to anonymisation of documents for similar scenarios (large Phase III trials vs small Phase I trials) regardless of the type of disclosure, while allowing for retention of maximum data utility Evaluations of the risk of re-identification can be grouped into qualitative and quantitative approaches

A qualitative approach to risk assessment uses a set of rules (based on rarity of disease, single-site trials or other unique trial characteristics) or list of data elements that pose a risk for re-identification and uses a scale—high, medium, low—associated with each data element This is consistent with the Safe Harbor standard outlined in the HIPAA Privacy Rule 25 and is explored in more detail in the PHUSE White Paper “Protection of Personal Data in Clinical Documents—A Model Approach” 33



Side-by-side Comparison of Anonymisation Techniques

Manual—Personnel Automated Tool

Requires training and familiarity with IDs Requires training and familiarity with IDs, along with ensuring the tool applies the rules set forth

Second-person QC is best practice and may still include misses due to human error Machine learning and artificial intelligence are increasing in quality over time but still require human QC checks

Ability to detect non-standard presentations of data and one-off privacy concerns Unable to recognise new/different presentations of data and one-off privacy concerns; therefore, some human intervention is needed

Harder to utilise a pattern methodology to find IDs Easily finds all patterned IDs that are pre-programmed

Redaction of content; unable to do any transformation of information in a document Tools exist to autogenerate and transform information in a Portable Document File (PDF) and the level of anonymisation could be informed based on risk calculation Transformation (recoding, generalising, offsetting, etc ) can be done in a way that matches text presentation within the document

Cost associated with data provider’s personnel or contract cost for vendor to manually conduct anonymisation

Cost ranges depending on whether the tool is integrated into data provider infrastructure, hosted by a vendor, accessed via the cloud, or if there is contracting for full anonymisation services

Table 9: Best Practices: Side-by-side Comparison of Anonymisation Techniques

A quantitative approach to risk assessment uses the data from datasets or data extracted from the document (e g using natural language processing) or a combination of both to calculate the probability of re-identification and determine the amount of anonymisation that would result in the residual risk of re-identification being lower than a set threshold For both EMA and Health Canada the recommended risk threshold is 0 09 (9% probability) or lower for public disclosure The amount of anonymisation to be applied should be evaluated in consideration with the other pillars of patient privacy—procedural, legal and security protections—as discussed in Section 3 5 5, Quantitative vs Qualitative Risk Assessments, as well as consideration of the population and anonymisation approach A mixed approach could be taken to anonymise a set of documents, with quantitative, risk-based anonymisation performed for data-rich documents (CSRs, Module 2 summaries) vs masking of direct IDs alone (no quasi IDs present) for other documents (protocols, SAPs)

Due to the many types of disclosure for which a document (e g a protocol) may be used, when developing an anonymisation methodology, it is important to think holistically while also taking into consideration specific country guidance, e g rules for EMA PSUR transparency 34 Particularly challenging is the writing of participant narratives in a format that subsequently ensures anonymisation and promotes data utility For more detailed discussion of narratives, see the PHUSE White Paper “Retrospective vs Proactive Anonymisation of Narratives” 35 As with either approach for assessing risk, human quality control (QC) checks and interpretation are required to catch unique instances of combinations of quasi IDs and rare disease or sensitive information that are not anticipated Finally, the anonymisation methodology used for the documents that will be released for EMA Policy 0070 and Health Canada PRCI requires the completion of an anonymisation report (templates available) that outlines the chosen methodology These reports will be publicly posted along with the clinical information

3.1.5.2 Document Anonymisation Technology

Document anonymisation technology can be as simple as using software redaction tools for manual redaction to more complex quantitative, risk-based anonymisation software utilising artificial intelligence such as natural language processing and machine learning Technology can bring together the 2 methods for anonymising documents, removal (redaction) and data transformation See Section 3 5 3, Preparation of Anonymised Data and Documents, for additional information Tools for document anonymisation are available from vendor services or can be brought onto a data provider’s platform

It is understood that retrospective anonymisation of documents requires more processing time However, as described in Section3 5 3, the future best practice is to prospectively prepare anonymised documents as much as possible, thereby decreasing the amount of time spent on anonymisation later Table 9 is a comparison of manual and automated techniques



Best Practices Quality and Metrics

1 Involve legal counsel or privacy officer in setting up processes and looking at some documents to ensure effective identification of CCI

2 Assess ongoing and new transparency initiatives, evolving technology and other posted submissions for continuous quality improvement

3 Ensure there are resources to perform quality checks by document or across a submission

4 Establish a centralised model for discussing health authority feedback to ensure consistency, efficiency and future internal best practices

5 Establish a mechanism for tracking documents’ disclosure information (PPD, CCI, number of pages, etc )

6 Establish a mechanism to track quantity of deliverables (anonymised documents and data) in order to forecast future budget and resources (metrics)

Table 11: Best Practices: Quality and Metrics

3.1.6 Document Quality and Metrics

As a data provider develops procedures for document disclosure, it is important to also establish quality measures to ensure success and find early indicators for process improvement The EMA published its report on the 1st year of the implementation of the policy on publication of clinical data 36 Evaluating the report provides insight into the type of information a data provider should be collecting on the document level, which may include the following:

• Number of pages in each document

• Number of documents with PPD and CCI

• Category of CCI and reasons for rejection of CCI

Additionally, to understand all potential external sources of information for a given trial, the data provider may want to track documents released externally and the reason for the release (e g regulatory submissions, publications, conference materials, health authority-produced assessment reports)

Table 11 is a list of best practices for quality and metrics

Best Practices Document Anonymisation Process

1 Disclosure Specialists identify and work with anonymisation subject matter experts, who may include both a statistician and a privacy officer Consider expertise within the data provider’s organisation and the need for external relationships for success

2 Determine the anonymisation strategies for the different categories of document disclosure; try to establish a single strategy that can be used across all disclosure types

3 Determine whether the anonymisation criteria change for different situations, e g for country-specific rules

4 Determine a pre-defined template of information to be redacted if a qualitative approach is used Use a Deming continuous quality improvement approach, i e if new or different protected information is included in a trial report, extend the list of variables to be redacted

5 Conduct a pilot project with potential vendors; compare a non-complex and complex trial design; compare outcomes and give feedback to vendors

Table 10: Best Practices: Document Anonymisation Process

In evaluating document anonymisation technology, a data provider may consider the following:

• What is routinely expected to be anonymised (e g quantity, types of documents–simple vs complex, mainstream vs rare disease, controlled vs public data sharing, documents or datasets or both)?

• What available resources and expertise exist to prepare documents for disclosure?

• Is the data provider set up for a centralised or decentralised model (i e Disclosure Specialists that cross products vs Product Team members) for the preparation of documents for disclosure?

• Does the data provider have the time and resources to bring in new technology?

• Is there a desire to ensure consistency of anonymisation across structured data that is shared through a secure portal and associated documents that are publicly disclosed (i e maintaining the same random scrambled codes for participant IDs or date offsets, etc )?

• What kind of dataset does the tool use to calculate risk threshold? Can only CDISC-standardised data be used?

Table 10 is a list of best practices for establishing a document anonymisation process



3.1.7 Document Preparation—Summary

Medical writers and Product Team members need to consider that the submission documents are no longer just for health authority scientific review but will now likely be in the public domain; therefore, documents should be written and submissions prepared accordingly

Disclosure Specialists and medical writers alike should establish internal best practices and guidance that can be referenced across Product Teams as documents are written Consolidation of the best practices for preparing documents for disclosure in this Guide should serve as a reference towards efficiently navigating and operationalising the complex requirements for public release of documents

3.2 Protocol Registration and Summary Results Disclosure

Registering a clinical trial on a public registry, whether it be required or voluntary, helps to alleviate biases when it comes to disclosing the results of that clinical trial (i e journal publications, posters, presentations, press releases) It also helps to keep the public informed about the activity of ongoing trials, provides public access to summary results of trials, and allows fellow researchers to keep knowledge moving forward

With the growing demand for transparency in the pharmaceutical industry, as well as stricter regulations, there has been an upsurge in protocol registrations and results disclosures on public registries The importance of clinical trial registration and results disclosure is becoming more apparent and organisations are setting new standards, which introduces challenges to ensuring consistency and alignment between public registries Although there are over 90 public registries worldwide, this section will focus on best practices for 2 commonly used registries: ClinicalTrials gov and the EU Clinical Trials Register These are representative of 2 different processes for submitting information for protocol registration and results disclosure for interventional trials within the US and EU There are some mandatory registries for non-interventional trials and post-authorisation trials (see Reference 37), but the process for entering information will be similar in most cases Some data providers may also have their own clinical trial websites where information from their trials is posted, so the public can browse all trials the data provider is sponsoring rather than searching a public registry with multiple sponsors

It is important to note that the process for registering trials in the EU will change in the future when EU CTR 536/2014 22 (not to be confused with the EU Clinical Trials Register 38) is implemented and the EU Clinical Trials Information System (CTIS) 39 is launched Once this system is in place, the methodology for registering clinical trials in the EU will be similar to that of the Protocol Registration System (PRS), which is used to enter and submit information to ClinicalTrials gov 40 However, it is still useful to know both methods as several other countries manage the registration of information in both ways

3.2.1 Protocol Registration

The protocol registration processes for ClinicalTrials gov and the EU Clinical Trials Register are distinct and are likely managed by different internal groups with different processes (e g public disclosure vs regulatory affairs) ClinicalTrials gov is a data-entry system through an online portal (PRS), whereas information for the EU Clinical Trials Register is provided via the CTA, also known as the Annex 1 form

Whether a protocol registration is mandatory or voluntary (see “Clinical Trial Transparency and Disclosure: A Global View” 18), the required information tends to be similar However, there may be constraints, depending on the type of trial and the registry For example, early-phase trials and complex trial designs can be challenging to enter into a registry, since most were only designed for standard Phase I– IV interventional trials

The timing of protocol registration also varies per regulation, but it is typical to begin the registration process shortly after the protocol has been finalised (or, when necessary, a registration can be drafted from a protocol synopsis) Based on Section 801 and Final Rule of the Food and Drug Administration Amendments Act’s (FDAAA’s) 41 definition of trial start date and the requirement of the International Committee of Medical Journal Editors (ICMJE) 42, it is good practice to register a trial on or before the time of the first participant’s signed consent or first participant screened, whichever comes first

3.2.1.1 ClinicalTrials.gov and the Protocol Registration System

The PRS allows manual entry of information, an Extensible Markup Language (XML) upload, or a combination of both If performing a manual input of information, the PRS has step-by-step guidance for setting up a new trial Not all information is required to be entered at this time to create the record; the user can go back at any time to update the information The system will tell the user in red or blue text if a field is required and in what detail Some information may be omitted when submitting the initial registration (locations, Human Subjects Review, keywords, and others), depending on the status of the trial at the time of submission

The PRS also allows for the upload of information via an XML, which can be generated from system software or a customised macro It can be useful to have the trial information stored in a central location, as in disclosure software or an Excel document, but there is a risk of overwriting information when uploading to PRS Before executing an XML upload to PRS, it is a good idea to download the previous record in case of any errors, or to ensure the previous version is captured in an audit log Once the trial is loaded into the system, the user may edit within the system as well, but parallel changes should be made in any data provider records that are being maintained



3.2.1.1.1 Quality Review

When submitting a registration through the PRS, the system has several edit checks for the record before release (spelling and acronym review, warnings, notes), and the record will go through a PRS-managed quality review before being published to ClinicalTrials gov 43 The quality review will provide comments categorised as “advisory” or “major issue” An advisory comment does not require an update but would improve the quality of the record in the opinion of the reviewer, while a major issue is required to be updated before the record can be re-released

A record containing only advisory comments is considered accepted and will be made public on ClinicalTrials gov If the user decides to make updates to the record based on the advisory comments, this can be done at any time Any record with a major issue is required to be updated and re-released within 15 days of the initial review If it is not updated within 15 days, the record could be released “as is” with a note that corrections have been requested but not yet made It is useful to note that PRS and ClinicalTrials gov have an archive of all releases to PRS that are publicly available, so the user should ensure all updates are reviewed thoroughly

3.2.1.1.2 Registry Updates

ClinicalTrials gov requires updates to the posting by the responsible party within 30 calendar days of a change in any of the following:

• Individual site status

• Overall recruitment status

• Primary completion date

• Changes to trial design impacting any of the required registration fields (e g endpoints)

Other information must also be updated on ClinicalTrials gov within 15 or 30 days of a change (see Reference 43) For an ongoing trial, an update to the posting must be made at least every 12 months, but it is recommended that the Record Verification Date be updated at least every 6 months for trials that are not yet completed, even if there were no changes to the record

Some of these updates may come from a significant protocol amendment, which would require an update within 30 days of approval of the amendment by a human participant’s protection review board Since PRS has manual update capabilities, the data provider is responsible for making the updates within the system For this reason, it is important that a Disclosure Specialist be included in the review of a protocol amendment, or at least notified of a new protocol amendment to be aware of when it will be approved With only 30 days to review the amendment, update the registry, and go through any review and approval process; it can be a tight turnaround

The EU Clinical Trials Register 38 does not currently have the ability for a user to update information, unless there is a substantial CTA amendment, and even then, it is up to the national competent authority to enter the updated information into the registry With the implementation of the new EU CTIS 39, amendment updates will be manageable by a Disclosure Specialist at the data provider, and changes to the registration will be required within 15 days When this occurs, it will be even more important for a Disclosure Specialist to work closely with the teams that are drafting protocol amendments

When available, systems like a Clinical Trial Management System or project management system can be useful to the Disclosure Specialist for tracking updates and milestones to prepare for these kinds of updates There are also some disclosure systems that have the capability to link directly to a Clinical Trial Management System and feed information into the system

3.2.1.1.3 Metrics

The key to achieving a successful submission with either no comments from PRS, or only advisory comments, is to have a consistent registration drafting process, especially for outcome measure titles, outcome measure descriptions, and timeframes These fields are the most likely to receive a comment from PRS There are several methods that can lead to a higher success rate for submissions to PRS, which should start at the protocol development stage These include the following:

• Having guidance language embedded in the protocol template to help the teams at the drafting stage rather than at the review stage

• Utilising an endpoint library for commonly used endpoints for protocol authors to simply copy and paste pre-drafted endpoints (with minimal customisation needed)

• Working with the Product Team to ensure accurate and consistent endpoints are drafted in the protocol

A well-developed and designed protocol will not only help with ClinicalTrials gov submission success but will also alleviate inconsistencies between registries For endpoints and outcome measures that are atypical, searching ClinicalTrials gov for similar outcome measures in recently released trials will indicate what has already been accepted by PRS Technology-enabled protocol templates can also be implemented to help facilitate consistent disclosure, and there are tools available (either for purchase or created in-house) that can manage endpoint consistency

It is important to think about clinical documents with the end in mind as more of these documents now are required to be made public Eliminating information not crucial to a document that is publicly sensitive is best done at the authoring stage, rather than retrospectively by redaction



3.2.1.2 EU Clinical Trials Register and the Clinical Trial Application

As mentioned above, the information used to populate the EU Clinical Trials Register 38 is derived from the Annex 1 CTA The challenge is that the CTA is typically drafted by the regulatory affairs department and done so without considering the public release of information (e g exploratory endpoints) This is because the CTA is required to be submitted in each member state as part of trial start-up in that country and many times is drafted quickly, with only a small section dedicated to the information that will be made public (this process will be streamlined with only 1 submission for all member states upon application of EU CTR 536/2014 22) Because of this, there can be inconsistencies between public registries or the potential for CCI to be published

3.2.1.2.1 Cross-functional Alignment

To overcome this challenge, it is important that the Disclosure Specialist is aware of the group(s) that draft the CTAs, implements a process that allows for consistent drafting of information, and reviews the CTA along with other cross-functional stakeholders that approve registry material In combination with a well-developed protocol and properly developed endpoints, guidance documents and education about what information should (or should not) be included in the CTA will help align the information

Due to tight timelines for submitting the CTA, teams may be concerned that adding an additional reviewer will delay the overall review The Disclosure Specialist should assure the CTA author that review of Sections E and F will be timely and will not delay the overall review With guidance and education across functions, Product Teams should better understand the importance of this review

3.2.1.2.2 Registry Alignment

A major challenge with the alignment of ClinicalTrials gov 40 and the EU Clinical Trials Register 38 is that the CTA is sometimes drafted prior to the ClinicalTrials gov draft It is most efficient to simply send the ClinicalTrials gov registration draft to the team drafting the CTA and copy and paste the information, but if the former has not yet been drafted the Disclosure Specialist should work with the team drafting the CTA to align with the guidance for drafting the ClinicalTrials gov registration The CTA can then be used to draft the ClinicalTrials gov registration

3.2.1.3 Data Sharing Statement

Currently the ICMJE recommendations 42 state that a data sharing statement is required for all manuscripts published on or after 1 July 2018 Thereafter, for all trials starting on or after 1 January 2019, a data sharing plan is required to be published on a registry There is a function within PRS that has this capability, but it is currently the only registry with this field The ICMJE is highly supportive of data sharing but understands that in some situations—e g for a rare disease trial—a response of “No” to sharing data is acceptable, but it does not support an “Undecided” response

These data sharing plans should align, so cross-functional collaboration with the publications or communications teams is essential

Table 12 summarises best practices for protocol registration

Best Practices Protocol Registration

Challenge Best Practice

What trials should be registered and when? • All interventional trials should be registered prior to the first participant’s signed consent

Aligning information consistently between registrations • Update protocol template to include guidance on objectives and endpoints and how they will be disclosed

• Educate and work with cross-functional teams drafting applications and forms (like a CTA), adding a Disclosure Specialist to the review

• Create guidance documents for public registration • Use technology-enabled protocol templates

Entering information into PRS • If using manual input, ensure that there are site permissions and controls, to avoid accidental submission of unapproved information to ClinicalTrials gov

• If using an XML, ensure that the record being uploaded is the most up to date and save a copy of the current registration XML in case information is overwritten

Successful quality review and metrics

• Proper guidance for endpoint writing to ensure they are consistent, and create an endpoint library for commonly used endpoints in protocols

• Search for endpoints in recently accepted registrations • Establish templates and guidance for whomever is drafting and reviewing the

registration • Consult with PRS on a rejection that may not be clear and on how to improve

submissions moving forward

Registry updates • Review all active trials monthly for any updates needed • Insert a Disclosure Specialist into amendment reviews for awareness of and

preparation for any significant changes to a public registry

ICMJE data sharing statement • Register on ClinicalTrials gov where there is an IPD sharing section in compliance with ICMJE recommendations

Table 12: Best Practices: Protocol Registration



3.2.2 Summary Results Disclosure

While the protocol registration process differs between ClinicalTrials gov and the EU Clinical Trials Register, drafting of summary results is similar in both Both allow manual input of information and data, as well as XML uploads The PRS is still used for ClinicalTrials gov 40, while the European Union Drug-regulating Authorities Clinical Trials Database (EudraCT) system is used for input of results for the EU Clinical Trials Register 38 The major differences between the 2 registries are as follows:

• EudraCT requires a letter of request (from a primary user) for the responsible party to access trials in its EudraCT account

• PRS has a quality review step before publication, whereas EudraCT has an online validation process

• The XML format for EudraCT is slightly different from that for PRS

• EudraCT requires more information than PRS

• Although Phase I trials in adults will not be made public in the EU Clinical Trials Register (until the implementation of EU CTR 536/2014 22), they are still required to be submitted to EudraCT within the same timelines

In Figure 6, a high-level timeline is displayed for the process of finalising a CSR followed by drafting and submitting the summary results for an adult trial (paediatric trials in the EU are required within 6 months) Starting the process as early as possible is more efficient for many reasons, including the following:

• Releasing the results in a timely manner after a trial is completed is good transparency practice

• Study teams are still intact and recall the finer details of the trial

• There is less rush to review and approve

• It adds a buffer for technical difficulties, data requests, or other delays that may occur

Figure 6: Results Disclosure Timeline for Adult Study

QA: quality assurance

Results Disclosure Timeline

CSR Finalization

Within 12 months of study completion

If CSR is not finalized within two months of results due date, TLFs may be used

No later than 60 days prior to results due date

Sufficient time is needed to draft, review, approve, and finalize the results

30 day review time recommended

More team members are included on the results review and it may take several cycles to finalize

On or before results due date

A one or two day buffer is helpful in case of any technical difficulties – QA may take up to 30 days after submission

Initiate Drafting Team Review & Approval Submit + QA Review



There are instances when trial results will have to be disclosed on multiple registries at about the same time, and these can be prepared in parallel as there will be overlaps in the data With the help of technology, some systems are able to convert one XML format into another (as mentioned above, they differ slightly across registries) and all the relevant data can be uploaded easily into another registry

There are also times when information (e g adverse events [AEs] or locations) required across registries can be collated into 1 dataset Once this is validated, different programs and macros could read the dataset to create XMLs that are compliant with the different formats and containing the required information for each registry However, such automation is not possible for many results, and these would still require manual input into the various registries

Regardless, it is beneficial to draft all relevant registries in parallel when possible so that the source information aligns appropriately, and the reviewers will only need to perform 1 review A formal QC check of the data should be performed against sources to ensure all data has been entered accurately for all registry drafts

3.2.2.1 Requesting Studies in EudraCT

Before a Disclosure Specialist can start drafting summary results in EudraCT, the trial (or trials) must first be requested and assigned to the primary user The primary user must first have a EudraCT account and fill out the appropriate form to gain access to the system 44

The primary user will then log in to EudraCT, click on “Your Page”, and at the bottom of the page will find a hyperlink “request assignment” within the sentence ‘If you are required to prepare results for other clinical trials, you first need to request assignment to your user account ’ The timing of this process varies, so it is essential to prepare well in advance of the compliance due date for summary results in the EU Requesting large batches of trials on a quarterly or bi-annual basis is a common practice to ensure all trials are in the account and ready for results

3.2.2.2 Additional Data Needed

Both ClinicalTrials gov and EudraCT require additional AE information that is not typically a part of the standard TLF package For ClinicalTrials gov 40, this includes an “other adverse event” table that lists all non-serious adverse events (SAEs) with a frequency of greater than 5%, as well as an “all-cause mortality” table If there are no AEs within that frequency, it may be lowered (e g to greater than 2%), but it may not exceed 5%

EudraCT also includes this table, but additionally requires the number of events and occurrences for all deaths, SAEs, and AEs of frequency greater than 5%, as well as SAEs and deaths related to the investigational treatment Although 5% is the standard (and maximum) frequency used, a lower frequency percentage may be used to show lower-incidence AEs EudraCT also requires further breakdown of enrolment by country and of age categories If possible, work with the biostatistics team to incorporate these as part of the standard TLF package to avoid having to create them retrospectively

Manual entry of this AE information can be labour-intensive and prone to error Often, additional output tables may need to be produced by biostatistics to obtain these data To alleviate this burden, it is possible to implement technology that pulls the necessary AE data from raw datasets into an XML that can be directly uploaded to the registry Technology can also be used to format the data appropriately so that it can be more easily extracted It is important to also note that there are wording nuances between the different systems that need to be considered when drafting results for separate registries

3.2.2.3 Document Requirements

Currently there are no requirements to upload supplemental documents to EudraCT, but there are requirements for ClinicalTrials gov, depending on when the trial completed If a trial has a primary completion date on or after 18 January 2017, the full protocol (latest draft, including all amendments) and SAP (latest draft, including all amendments) must be uploaded to PRS and submitted along with the summary results (see the White Paper “Clinical Trial Transparency and Disclosure: A Global View” 18) The PRS also has the capability to upload the ICF as this is a US National Institutes of Health (NIH) requirement for US federally funded trials

The PRS requires a specific PDF/A format, which prohibits features unsuitable for long-term archiving, such as font linking (as opposed to font embedding) and encryption It is best to work with a document specialist to convert the file, ensuring that no information is lost or formatting issues occur in the process There is a checkpoint within the PRS that will tell the user if the file is in the correct format, and in some cases can convert the document itself

There are also some other instances where similar documents are required to be made public, such as for top-tier journals (New England Journal of Medicine, Journal of the American Medical Association, others), so it is useful to have the documents prepared consistently (whether at the drafting stage or when retrospectively redacting) See Section 3 4, Publications



3.2.2.4 Quality Review and Validation

The quality review of summary results in PRS is the same process as protocol registration, but because of the amount of data and the extent of the summary results the review will take significantly longer The ClinicalTrials gov PRS team has committed to either returning the findings of its quality review within 30 days or posting the summary results with a note that they have not yet been reviewed A typical set of summary results will go through 1 or 2 review cycles, but data providers are working to improve their processes to have a better initial success rate This leads back to what was mentioned in the protocol registration section regarding consistency and reviewing metrics to improve processes If there are any major issues found during PRS review, the responsible party must update and resubmit the data within 25 days of notification of findings

In the EudraCT system, instead of a manual quality review there is an online validation check This validation check only looks for missing fields and potential areas where numbers do not seem to add up, so the data should be fully QC checked internally before submitting If there are any findings, the system will provide these findings upon clicking “validate results” and provide the user with a chance to either correct the errors or enter a justification for the error Once the summary results are validated, the user is able to post the results

Table 13 displays common validation errors

3.2.2.5 Results Updates

For trials disclosed on ClinicalTrials gov 40, the primary completion date is used to measure the compliance due date for results However, the primary completion date may occur prior to overall trial completion This means that there will be 2 (or more) sets of results to be posted, unless there is a possibility to delay the posting or the overall trial completion date is shortly after the primary completion date Under the FDAAA Final Rule 41, once the initial results have been released based on the primary completion date, the additional secondary endpoints must be reported within 1 year of their independent completion dates (defined as the last-patient, last-visit [LPLV] date for data collection of that endpoint) This can be quite a challenge unless the secondary endpoint completion dates are consistently tracked, especially if there are multiple interim analyses

The first thing to consider is the possibility of delaying posting This is possible if the trial is investigating a drug for initial approval or to certify a new use, or the data provider may request an extension with a justification as to why it would be harmful to release the results at that time It is also important to check the mandates of the registry regarding when the trial is no longer required to be updated (i e all results updates have been completed)

See Table 14 for best practices for results disclosure

Validation Error Examples

ERROR – Subject Disposition: The number of fatalities causally related to treatment for serious adverse events is collectively larger than the number of deaths resulting from adverse events

WARNING – Arm: XX The number of subjects at this milestone seems inconsistent with the number of subjects in the arm It is expected that the number of subjects will be greater than, or equal to, the number that completed, minus those who left Either resolve this issue or provide a justification

WARNING—End Point: Percentage of Subjects with Treatment-Emergent Adverse Events (TEAEs)No statistical analyses have been specified for this primary endpoint It is expected there is at least one statistical analysis for each primary endpoint Either resolve this issue or provide a justification

Table 13: Validation Error Examples



Best Practices - Results Disclosure


Accessing trials in EudraCT for results input • Request batches of trials on a regular basis (quarterly or biannually) to ensure all trials are within the primary user’s account as there are sometimes delays in processing the request

Results disclosure process timeframe • Start as early as possible to allow for a buffer, but no less than 60 days prior to the compliance due date; this also helps for review by the trial team as the information is still fresh

• Use TLFs if necessary to get the draft going and reviewed by the team, then align with the CSR once available

• Allow at least 30 days for trial team review and ensure any relevant partners are included

• Allow a buffer of a day or 2 when submitting the results in case of technical difficulties

Multiple registries • Draft the summary results in parallel (preferably by the same author) or use XML to transfer the data to other registries when possible to ensure consistency

Additional data needed beyond normal data outputs • Work with the data processors and request the additional data be inserted into standard TLFs; if not possible, notify the data processors as soon as the trial is completed

Document requirements • For prospective studies, as mentioned previously, work on document templates with disclosure in mind, extracting unnecessary information

• For documents already in use, start to prepare the documents early, providing proposed redactions and justification for team review and ensuring the documents can be saved in the appropriate file format (PDF/A)

• Ensure that the information being redacted is not already public (poster, manuscript, presentation, etc )

• Work with biostatistics to incorporate additional data tables needed for public registries in the standard output

Quality review and validation • For PRS, ensure results have been entered consistent with previously accepted postings; for uniquely designed trials or if unsure how something needs to be entered into PRS, email register@clinicaltrials gov or submit a query within the PRS—the PRS team will help to resolve issues prior to QA review so findings are minimal

• EudraCT has a systematic validation and results are accepted or rejected instantly; this validation should be done prior to sending for internal team review to check for any data validation changes or explanations needed

Results updates • If a record has major findings in PRS and updates are needed, ensure all other applicable postings are also updated accordingly

• When disclosing results to PRS, consider if delayed certification is applicable for an unapproved product or new indication—this can help to align submission dates for summary results if submitting to multiple platforms

• If results were disclosed within 1 year of the primary completion date in PRS and the trial has lingering secondary outcome measures, it is crucial to track the data collection completion dates and post the secondary endpoint results as they are available

Table 14: Best Practices: Results Disclosure

3.2.3 Global Study Management

3.2.3.1 Acquisitions, Collaborations and Partnerships

When a product development programme changes or shares ownership, there are some challenges that ensue when it comes to public registration and who becomes the responsible party On ClinicalTrials gov 40, trials can be transferred to a new data provider simply by emailing register@clinicaltrials gov with information on a representative from each data provider and the National Clinical Trial numbers of the trials needing transfer Both parties have to agree to the transfer; the PRS team will then manage trial transfer

For the EU Clinical Trials Register 38, where information is submitted through a CTA form and updated by the national competent authority, changing ownership of trials can only be done by amending the application form (until the EU CTIS is implemented 39) This can create issues because, although trial ownership may have changed, the registry may not reflect the change and compliance may be impacted

The best practice for these kinds of transition is to work directly with the representative who previously managed the public registries and has all the information needed It is crucial to ensure that all trials are accounted for in all countries, and to obtain all data provider names, as there may be more than 1 data provider from previous acquisitions



3.2.3.2 Global Registry Tracking

Another challenge is managing global dates and status updates for all trials as there are different compliance due dates depending on the location and type of trial Depending on the number of global trials being managed within a data provider and how many employees are managing them, this can be very challenging ClinicalTrials gov uses the primary completion date as the compliance due date (as mentioned above), but it also allows for up to a 2-year delay in disclosing results if the drug is not yet approved in the US, or if it is being studied in a new indication for an approved product within the US This deferral date is cut short if the product becomes approved within that timeframe, in which case results are due within 30 days of FDA approval

EudraCT uses the overall trial completion date, but has 2 separate due dates based on whether a) the trial is in an adult or paediatric population or b) is part of a paediatric investigation plan A trial in a paediatric population or that is part of a paediatric investigation plan is required within 6 months of the trial completion date The compliance due date on EudraCT is also reliant on the national competent authorities entering the appropriate global end-of-trial date, and not the country-specific completion date The EU CTIS will help alleviate some of these issues, and EU CTR 536/2014 22 will also allow for deferral of publication of information based on the category of information in the CTA (see “Clinical Trial Transparency and Disclosure: A Global View” 18)

There are technologies available that can manage different compliance due dates based on the countries in which the trial is conducted, but they can be costly There is no single best practice for this process, but it is key to have a firm understanding of the different global regulations and compliance due dates (see Clinical Trial Transparency Country-level Worksheet 37) Also, categorise the trial to know which compliance due dates to track, as follows:

• countries• trial population• approval status• indication• any other requirements, such as for ICMJE, that may affect due

dates

Table 15 summarises best practices related to global management

Best Practices - Global Management


Acquisitions, collaborations and partnerships • Review all alliances, partnerships, collaborations, etc on a regular basis to ensure all trials have a responsible party • Transfer trials into the primary user’s account as soon as possible by working with relevant members of the other data

provider • For EU CTR 536/2014, contact the national competent authority to update the information within the system and avoid

compliance issues

Global due dates • Ensure all countries involved in the trial are tracked throughout the duration of the trial to know what regulations are to be followed and which due dates may differ, whether via a system or a trial tracker

• Priority items to track:• • study phase• • paediatric vs adult populations• • primary completion date vs overall trial completion date• • change in approval status• • substantial amendments and milestone changes

• Set up notifications as reminders for milestones; this can be done in Outlook, Notes, or using other technologies • Use software that automatically calculates due dates and sets reminders based on the countries entered • Prepare early, let trial teams know there may be multiple due dates and why, and develop a plan of execution from trial

initiation • Ensure the primary user has access to all global registries prior to initiating the drafting of results

Table 15: Best Practices: Global Management



3.3 Trial Result Summaries

The EU CTR 536/2014 22, which is currently expected to go live in 2022, calls for greater transparency and requires all sponsors of clinical trials to share with participants and the general public a summary of results written in non-scientific, easy-to-understand language This summary is referred to as Lay Summary in Europe, while in other jurisdictions it is referred to as a Trial Result Summary (TRS) or Plain Language Summary A TRS is required in the EU only and as best practice it is recommended to include it for all Phase I–IV interventional trials conducted globally

In this Guide, the summary will be referred to as a TRS The purpose of this section is to share lessons learned and identify best practices for sponsors of clinical trials when they decide to implement a process to create TRSs for their trials

Figure 7 illustrates the process for preparation and dissemination of a TRS In subsequent paragraphs each phase of the process will be discussed, focusing on key factors that need to be considered for successful completion of a summary

Data providers have already delivered hundreds of TRSs globally and learned best practices for delivering them at the end of a trial However, there is more to be determined with regard to complex trial designs and best practices associated with the dissemination of TRSs for trials with multiple endpoints Additionally, the authors note that there is a lack of experience in the development and delivery of a TRS for an observational study; therefore, there are no best practices to share for these studies at the time of preparation of this Guide

3.3.1 Planning

While creating a TRS, data providers should ensure that the summary includes results only of the single clinical trial for which it is created It is also important to remember that the content of the summary should be unbiased, non-promotional and consistent across all translations produced for a trial More details about the master version of a TRS are provided in Section 3 3 2, Authoring Successful upfront planning by the data provider is key

The decision to deliver a TRS should be made before the trial starts (until the point in time they are required by EU CTR 536/2014) Discussion of this decision should occur early in trial planning, such as during preparation of the initial ICF, and should be included in early trial information provided to trial participants and the investigational sites, such as ‘welcome cards’ and ‘thank you cards’ for trial participants The generation of a TRS must also be considered in trial budgeting and resourcing activities to ensure its successful delivery

Figure 7: Overall Process for Preparation and Dissemination of Trial Result Summaries

Planning

• ICF• Protocol• Patient Input

Authoring

• Templates• End Points• Safety Events

Review and Approve

• Roles• Process

Translations and Approvals

• Who and When• Cultural

Considerations

Dissemination

• Direct vs Indirect

• Electronic vs Not



Table 16 summarises best practices for planning a TRS

3.3.2 Authoring

A TRS should be written in plain language that is clear, concise, well-organised, and follows other best practices appropriate to the subject or field and the intended audience, in alignment with the US Plain Writing Act of 2010 (HR 946/Public Law 111-274) 45

In Europe, there is a recommended guideline 46 for authoring a TRS Implementing a standard template with required information to be included in a TRS will facilitate its development and help harmonise a data provider’s process As best practice, data providers should also consider variations for Phase I clinical trials, trials conducted in small populations, trials with participants with high mortality rates, and paediatric populations Key considerations for the template should also focus on which endpoints to select and on how to deal with variations in reporting safety events Two aspects are particularly challenging for a trial delivery team involved in the creation of a TRS

• Endpoints: In planning the components of a TRS, it is important to develop a plan that supports a non-promotional approach This means being specific and thoughtful about how to select endpoints consistently It is generally recommended to focus on primary endpoints, but to eventually consider additional secondary endpoints that may have significant value to participants, e g patient-reported outcomes or symptoms Authors must be conscious of the risk of perceived bias in selecting results It is advised to consider which additional endpoints will be reported in a TRS during protocol authoring and trial planning When the primary purpose of the trial is safety, authors should consider reporting AEs as the endpoints

• Safety Events: In the EU there is a focus on adverse (drug) reactions—i e AEs that the investigator has assessed have a possible causal relationship with the investigational medicinal product; whereas in the US, results usually report AEs—i e AEs for which causality has not been fully established Each data provider must decide how to resolve this difference in approach within its own organisation This discussion must include defining the right term for this section—AEs, adverse drug reactions, safety events, side effects, others—which is still a subject of debate The EU guideline requires adverse reactions to be reported, and the EMA has commented this is a purposeful decision Many data providers currently follow this guideline, reporting adverse reactions and using a simpler, easy-to-understand term to describe them, such as “medical problems” or ”unwanted problems”

By establishing these basic standards in templates, the data provider can create consistency across TRSs and help reduce the risk of perceived bias in selection of information Consideration should also be given to the amount of graphics vs text used in a TRS Generally, a well-designed graphic is considered best practice in communication Care should be taken to ensure that graphics do not become promotional and are focused on communicating relevant information in a non-biased way, following best practices on writing with non-promotional language

Finally, it is best practice to align with the terminology and definitions used in the ICF when creating a TRS Consider the way the disease and endpoints were defined in the ICF as the baseline of knowledge possessed by the reader of the document Should a complex term be used, it must be clearly and straightforwardly defined within the TRS to ensure understanding by trial participants and the public

Table 17 summarises best practices related to authoring a TRS

Table 16: Best Practices: Planning a Trial Result Summary

Table 17: Best Practices: Authoring a Trial Result Summary

Best Practices - Planning a Trial Result Summary

1 Include results of a single trial; language should be unbiased and non-promotional and should convey consistent information in all translations used for the trial 2 Use a template that complies with EU CTR 536/2014 3 Clearly communicate the plan for reporting the TRS in the ICF prior to trial start

Best Practices - Authoring a Trial Result Summary

1 A template helps drive a non-promotional, non-biased summary for all sponsored trials 2 Be consistent in the approach to handling endpoints and safety events 3 Consider graphics carefully based on the trial 4 Align with descriptions and terminology used in other participant-facing materials, such as the ICF



3.3.3 Delivery Process Best Practices

After a trial is completed, the trial team should start the process of development and delivery of the TRS These activities should be built into trial team delivery schedules The limited resourcing that is typically available at this stage of the clinical trial (within 12 months after the LPLV date for an adult trial, and 6 months for a paediatric trial), both in the data provider’s team and at the site for potential dissemination, must be considered in the planning Often there are not many individuals left assigned to the trial and at the sites; potentially there may be no one left working on the trial

It is recommended to create the TRS and have it available at the same time as the result summary (Section 3 2 2, Summary Results Disclosure), to be shared and uploaded on appropriate websites defined by the dissemination strategy Data providers should consider the publication location and ensure it is not published in collaboration with product marketing materials There is some concern within the industry that creating and sharing a TRS could be considered by some journals as a pre-publication There is some consensus starting to take shape against this position, and it is important to inform publication colleagues of the plan and timelines for development and sharing of the TRS to ensure broad and collaborative planning, since this timing is required by EU CTR 536/2014)

The traditional input documents required for authoring a TRS are as follows:

• CSR and protocol

• The ICF can be a good source for how the trial was described in easy-to-understand language at the start of the trial

• The TLFs may also be needed to support details of the adverse drug reactions or AEs if not included in the CSR

• Information such as AE results posting from public registries (when available)

• Internal standards/templates/glossaries/etc related to the process for development and delivery of the TRS

Given the input documents, it is understood that a TRS is one of the final documents created by the trial team It is recommended to plan for the English master TRS and for all translations to be completed within 1 year of the LPLV date for all adult trials to ensure readiness for EU CTR 536/2014 from a

process delivery perspective Paediatric trials have a 6-month delivery expectation This requires more complex planning and considerations on how to create the TRS and the paediatric CSR in parallel

Part of the authoring process includes several reviews This will be covered in detail in Section 3 3 4, Review and Approval Process The process of creating a TRS is time-consuming, especially during the early period of implementation in an organisation If internal and external reviewers are included, allow a minimum of 2 months for review, though that timeline will typically be tight

A sample timeline for completion of a TRS within 12 months after the LPLV date is shown below:

• Month 9—provide the CSR to the TRS writer

• 2 weeks—author first draft

• 2 weeks—internal reviews

• 2 weeks—update the draft

• 2 weeks—external reviews

• 2 weeks to finalise

• 2 weeks to translate, which should include back-translation by a native language speaker (this time may need to be expanded if there are many translations for review, depending on resourcing levels)

Initially the process may take longer Educating the organisation on the process, requirements and timelines should occur prior to starting work on the first TRS One of the benefits of early preparation of the organisation to deliver TRSs is assurance that the processes and resources are embedded in the trial delivery lifecycle prior to the time the EU CTIS goes live 39 The application deadline for the EU law that will drive requirement of the TRS is anticipated in 2022 During the early stage of implementation, leadership should be prepared for the typical change management challenges encountered when initiating a new process, e g explaining the committment to preparing these new documents (in the EU or globally), addressing resource challenges, and reinforcing the requirements, as well as agreed processes and templates, throughout the organisation

Table 18 summarises best practices for delivery of a TRS

Best Practices - Delivering a Trial Result Summary

1 Align the availability of the TRS with the publication of trial results 2 The development cycle for a TRS usually takes several months 3 Broad education across the data provider’s organisation will increase ease and speed of delivery of the TRS 4 First develop an English master version, then use it to drive any necessary translations

Table 18: Best Practices: Delivering a Trial Result Summary



3.3.4 Review and Approval Process

To ensure a high-quality master TRS, time should be spent identifying the key stakeholders responsible for reviewing and approving the document Consideration should also be given to identifying who is responsible for ensuring all key goals are met The following must be accounted for in the review and approval process:

• Accuracy: The content of the summary is accurate, reflects the conclusion of the trial correctly and is consistent with other trial presentations disclosed so far

• Non-promotional: The summary should not be written in a way that describes the results in a promotional way There are guidelines available for this in Reference 47

• Commercially Confidential Information (CCI): The summary does not contain any CCI

• Regulatory requirements: The summary adheres to all global regulatory requirements

• Participant privacy: The summary does not create any individual privacy concerns This is particularly important when reporting safety events and providing a TRS for a rare disease

• Targeted reading level: The summary is written in an easy-to-understand language and is targeting the right reading age (approximately that of an average 12 year old, with additional considerations needed for younger paediatric populations)

When considering required reviewers, consider all stakeholders across the trial delivery lifecycle—data provider leadership, clinical trial team, site personnel or healthcare providers, and patients or individuals with the same disease or condition As with other deliverables, it is not recommended that all reviewers be approvers As the trial owner, the clinical trial team is responsible for providing final approval for the content of the TRS

3.3.4.1 Lay Review Panels

It is an industry-wide best practice to ensure that the TRS is reviewed by individuals who are considered end users of the document Lay review panels can test both the accuracy of the information in the TRS and its success in communicating to the targeted level of reading To achieve this, it is recommended to have review of the document performed by a lay panel before it is approved This panel should include individuals who were either in the trial or have a similar or the same condition tested in the trial Additionally, the lay review panel should include healthcare providers who are familiar with the condition that was being studied and have experience discussing it with the participants impacted by the disease or condition researched in the trial These individuals are best positioned to test the level of understanding of the information provided, as well as whether the information shared matters to the individuals with the condition and their caregivers

Conduct of the lay review panel is often best managed by a third party and not the data provider This is especially the case if individuals from the trial population are included on the panel If no trial participants are included but individuals with a similar condition are, then potentially the review could be managed by the data provider directly

A proposed version of the TRS should be provided to lay review panel participants Their feedback should be collected either verbally or in writing and shared with the TRS writers The TRS authors should ensure all necessary clarifications are made to the document before it is presented to the approvers for final review

3.3.4.2 Data Provider Reviewers and Approvers

Depending on the structure of a data provider’s organisation, reviewers and approvers will vary widely It is recommended that data providers look to similar roles who are already reviewing and approving trial summary results and other transparency deliverables (such as results posted on ClinicalTrials gov and EudraCT) as a starting set of appropriate reviewers and approvers of the TRS Decisions regarding which role is an approver vs a reviewer will be data provider-specific

Table 19 provides stakeholder roles to consider for review, together with the potential expertise they offer



Table 19: Stakeholders to Consider for Reviewing a Trial Result Summary

Table 20: Best Practices: Review of a Trial Result Summary

Role Review Point of View

Clinical trial lead Accuracy and consistency with all publications, including technical results postedParticipant privacyDisease knowledge

Statisticians (or delegate) Accuracy and sense of the results when summarised and presented in the TRSConsistency of results with other publications

Legal CCIParticipant privacy

Regulatory Regulatory requirements Non-promotionalParticipant privacy

Physician—either trial or local AccuracyParticipant privacy

Medical Affairs Non-promotionalDisease knowledge

Disclosure Specialist Participant privacyCCI

Medical writing Accuracy of the dataClarity of meaningGrammar/syntaxOverall style, per established guidesCompliance with established standard operating procedures and reporting guidelinesTargeted reading level

Lay panel reviewers (i e participants with the targeted disease)

Understanding/accuracyTargeted reading level

Health literacy experts Understanding/accuracyTargeted reading level

3.3.4.3 Institutional Review Boards and Ethics Committees

Institutional Review Boards (IRBs) and Ethics Committees (ECs) review the materials provided to participants during the clinical trial Since a TRS is typically made available to the public and participants after the trial has completed and the sites have closed, the IRB and local ECs should not be involved in the review and approval process

A TRS is another form of results posting, like those disclosed on ClinicalTrials gov and EudraCT These results disclosed after trial completion are not reviewed by IRBs and ECs The IRB and ECs should be informed that the TRS will be made available to trial participants and they should have an opportunity to review how the TRS will be made available to them This can easily be included during the trial start-up phase through the ICF review process The process a data provider plans to use to make the TRS available to participants should be clearly stated in the ICF The ICF is reviewed by the IRB and local ECs Additionally,

if another communication is used to explain to participants the process for receiving or retrieving their TRS, this should be reviewed by the ECs as best practice

In the case where a TRS is made available during the trial, it is recommended that it only be made available via a public website If a data provider were to give the TRS to participants during an ongoing trial, the IRB/EC would need to review it as it would be considered participant-facing material delivered directly to the trial participants during the trial

3.3.4.4 Regulators

To date, health authority regulators have not indicated a need to review and approve a TRS As details of the EU CTIS become clearer, this may change

Table 20 summarises best practices for review of a TRS

Best Practices - Delivering a Trial Result Summary

1 Include review by a group of potential users of the summary This should include participants with similar conditions and a health professional familiar with caring for participants with the condition being studied

2 First develop an English master version, then use it to complete all reviews 3 The summary should be reviewed by data provider reviewers Ideally, similar roles who are reviewing trial results should be involved in review of the TRS, to ensure consistent information is shared publicly 4 Be clear on the role of each reviewer and on what they should focus in the summary 5 Regulators do not review and approve the content of the TRS 6 The IRB/EC does not review or approve the TRS when it is delivered after the trial is completed



Table 21: Best Practices: Translation of a Trial Result Summary

Table 22: Benefits and Risks Related to the Dissemination of a Trial Result Summary

3.3.5 Translations

3.3.5.1 Which Languages Should be Included?

It is best practice to ensure that a TRS is available in the same languages in which the data provider created the ICF when enrolling trial participants This ensures that all trial participants can obtain the information easily Generally, a translation is not required in a particular language if a participant was not enrolled who speaks that language

At a minimum, the summary is expected by the regulation to be provided in the local language of each of the EU countries in which the trial took place However, this is not an agreed data provider best practice at the time of publication of this Guide Data providers are typically focused on the audience of the trial participants as a primary target, and the general public as a secondary audience

3.3.5.2 Process

As best practice, it is recommended to finalise the English version of the TRS and treat it as a master version Then, the master version should be used to generate identified translations All translations should include 3 key review steps:

• Translation by a native language speaker• Back-translation by a native language speaker• Certification that the translation has complied with all best

practices in translation

Inserting a local review (e g trial or site staff) of the translated document has both risks and benefits It is recommended that any local site trial team members who review translations of the TRS be involved in preparing and finalising the master English template, to minimise variances globally This will ensure data are accurate If local trial or site staff review and comment on the translated versions, there is a risk of having an evolved version of the summary that communicates variations, such as preferential changes in results or other information contained within the summary It is also recommended to provide a copy of the translated ICF to support the reviews

If data providers decide to include a local review, it is recommended to establish principles defining what kind of feedback will be acted on For example, errors will be corrected, but language preferences will not be updated Local reviewers need to be trained to avoid subtle changes in meaning that impact translations Any content errors identified during local reviews will need to drive an update to the master version and potentially other translated documents

Table 21 summarises best practices related to the translation of a TRS

3.3.6 Disseminating Trial Result Summaries

Data providers must consider how and when a TRS will be shared with both trial participants and the general public As mentioned above, it is recommended that this is planned and communicated using the ICF It is generally recommended that distribution in TRSs in advance of the EU CTIS is best practice

There are typically 2 ways to communicate this information:

• Direct delivery of the information to individuals through targeted delivery, e g via investigators

• Indirect delivery via publicly available websites, e g Reference 48

Table 22 lists the benefits and risks of both approaches

The expected timing for dissemination of the TRS (per EU CTR 536/2014) is 1 year after LPLV There is a current debate within the industry around whether the publication of a TRS counts as a pre-publication to a scientific journal The data provider should consider this in its overall planning

Best Practices - Translation of a Trial Result Summary

1 Translate into the same languages used for translation of the ICF for trial participants globally 2 Use the approved English master version as the source for all translations and require translation certificates by translators 3 Follow standard best practices for translation of other trial materials, such as the ICF 4 If local reviews are relied on, be aware that any local changes can change the content of the results Therefore, to minimise the risk of creating discrepancies among translations, set clear expectations for local reviewers with regard to the review process

Benefits Risks

Direct dissemination • Targeted at trial participants• Effective at ensuring the data provider meets commitments to

and expectations of trial participants

• May need IRB/EC review, especially if done during the trial before site closure

• Could expose others to the fact someone was involved in a clinical trial if they intercept the communication (e g via mail), creating a privacy issue for trial participants

Indirect dissemination • No need for IRB/EC review as it is posted publicly like other trial results

• Effective distribution globally and lower costs to both trial participants and the public

• Often requires a technology solution, which may mean that some participants without access to technology or familiarity with technology feel left out or are missed from the distribution channel



3.3.6.1 Distribution Channels

There are several distribution channels available beyond the EU CTIS 39 (which is not yet available as of 2020); some are technology-based and some are print-based It is possible that multiple communication channels may make sense for some data providers, given that they do not have direct access to participants

Table 23 outlines potential distribution channels and their associated benefits and risks

Distribution Channel Direct or Indirect Benefits Risks

Printed and presented on site (when added to site agreement responsibilities)

Direct • Targeted way to get the document to trial participants

• Some research shows that people appreciate physical receipt of the TRS

• Will need another channel for the public• The site staff must be committed to this time-intensive effort and

trained on how to successfully and safely communicate results consistently in a verbal way

• Direct communications generally need IRB review, especially if delivered before the site closes

Printed and mailed from site to trial participants

Direct • Targeted way to get the document to trial participants

• Some research shows that people appreciate physical receipt of the TRS

• Will need another channel for the public• The site must be committed to the resources needed to complete

the mailing• Direct communications generally need IRB review, especially if

delivered before the site closes• Will require recipients who need more information to proactively

reach out to investigator or data provider separately with questions

Emailed PDFs to trial participants

Direct • Targeted way to get the document to trial participants in a cost-effective way

• Will need another channel for the public• Must be resourced by someone outside data provider purview?• Must consider a way to communicate with population that does

not use email• Will require recipients who need more information to proactively


Interactive discussion with trial participants on site when handing the printed copy of the TRS to the participant

Direct and Indirect • Some trial participants in the patient advocacy space advocate this approach

• This is an uncontrolled delivery of information• Conversation leaves open trial result interpretation, and this

creates overall risk• Will need another channel for the public• The site staff must be committed to this time-intensive effort• Only possible in situations where there is an ongoing

relationship with site doctor and participant after the trial

Posted to data provider’s website

Indirect • No need for IRB/EC review as it is posted publicly like other trial results


• Could be viewed as promotional by being posted on the same site as information about a data provider’s product

• Data provider needs to find a way to communicate to participants how and when results will be made available to them

• Not a good solution where internet access is limited• Not a good solution if the website is not available in local languages• Will require recipients who need more information to proactively


Posted to an industry consortium portal such as trialsummaries com

Direct • No need for IRB/EC review as it is posted publicly like other trial results


• Non-promotional by posting on a site that is not associated with data provider’s products

• Easy access for most individuals via global use of mobile phones

• Can provide access in local languages through translation of the website

• Risk that some journals may consider this a pre-publication exercise

• Data provider needs to find a way to communicate to participants how and when results will be made available to them

• Not a good solution where internet access is limited (mitigated by sign-up/email option)

• Will require recipients who need more information to proactively reach out to investigator or data provider separately with questions

Printed summary posted to a patient advocacy website

Indirect • Effective distribution globally and lower costs to individuals in specific therapeutic areas

• Non-promotional by posting on a site that is not associated with data provider’s products

• This would not be a solution for the general public or all trial participants; if this is selected, an additional distribution channel is needed

• Will require recipients who need more information to proactively reach out to investigator or data provider separately with questions

Videos posted for access by trial participants

Indirect • Some trial participants in the patient advocacy space have advocated this

• Resource-intensive• Need to consider additional communication channel for public• Translations will likely be dubbed with subtitles and require

additional reading for recipients • Potentially need multiple videos to consider cultural implications

globally• Will require recipients who need more information to proactively


Videos posted for access by general public and participants

Indirect • Some trial participants in the patient advocacy space have advocated this

• Resource-intensive• Translations will likely be dubbed and require additional reading for

recipients • Potentially need multiple videos to consider cultural implications

globally• Will require recipients who need more information to proactively


Table 23: Potential Distribution Channels for a Trial Result Summary: Benefits and Risks



Table 24: Best Practices: Dissemination of a Trial Result Summary

Table 25: Aspects of Results Dissemination in Registries Compared with Publications

Table 24 summarises best practices related to the dissemination of a TRS

Best Practices - Dissemination of a Trial Result Summary

1 Distribution beyond EU CTR 536/2014 requirements is recommended It is recommended to consider both direct and indirect distribution channels to reach all stakeholders 2 A single distribution channel is not recommended Instead, consider which important risks to mitigate and focus on communication channels that support risk mitigation goals

3.4 Publications

3.4.1 Publication vs Clinical Trial Registration

Historically, access to the results of a trial has been through a publication in a peer review journal 49 In 2006, a year before the FDAAA ClinicalTrials gov 40 results requirement, the Board on Health Sciences Policy stated that “A clinical trial registry is not intended to replace the advice of a healthcare professional regarding benefits and risks nor is it intended to replace the comprehensive information on a product label as required by the relevant regulatory authorities It is also not intended to replace peer-reviewed publication” 50

The online Oxford dictionary 51 defines publication as “the action of making something generally known” Because of the numerous synonyms for publication, data providers are advised to define which activities fall under the scope of a publication and to define how other information made public is processed Thus, not only medical information but data provider press releases to inform shareholders, as per Securities and Exchange Commission regulations, and country-specific legal interpretations such as labelling (see Section 3 4 2 1, United States Labelling Definition and Misbranding Implications) need to be considered

The Council of Biology Editors in 1968 proposed the following definition of a primary scientific publication 52:“An acceptable primary scientific publication must be the first disclosure containing sufficient information to enable peers 1) to assess observations, 2) to repeat experiments, and 3) to evaluate intellectual processes; moreover, it must be susceptible to sensory perception, essentially permanent, available to the scientific community without restriction, and available for regular screening by one or more of the major recognised secondary services (e g currently, Biological Abstracts, Chemical Abstracts, etc in the United States and similar facilities in other countries) ”

In 2000, the Council of Biology Editors became the more encompassing Council of Science Editors 53 The Council of Science Editors is aligned with the ICMJE regarding the rejection of publications for failure to register a clinical trial 54 (See also Section 3 2 1, Protocol Registration )

Table 25 summarises aspects of results dissemination in registries compared with publications

Parameter Background Registry Publication

Context Clinical background of the trial and the clinical development programme in general

Discussion of the indication and the aims of the clinical trial

Previously not foreseen and most likely to be difficult due to copyright restrictions If implemented, could be viewed as too much information, requiring constant updating with new knowledge Exception since 2017 is the uploading of protocols to ClinicalTrials gov

Publications normally target a specialist audience for the indication for which the therapy was developed; may span several years to decades of knowledge

Target audience May be general and dictated by law or may be specific and written in a technical manner that the specialist can understand

Multiple1) Participants2) Regulators3) Investigators4) Medical and scientific community5) Payers6) Publishers, etc

Specific target audience based on the route and method of communication, e g scientific peer review or (potential) shareholder information via press release or financial statements

Methods The methods used in the planning of a clinical trial are essential to minimise bias

Essential information is entered for endpoints to explain the result variables reported

Broad statistical information made available; exception is the uploading of protocols and SAPs to ClinicalTrials gov from 2017 onwards

Some publications focus on the methods employed

Other publications are based on well-established methods and reference these There are well known to specialists in the field

Discussion Discussion of trial results, i e placing results in context of the medical condition and the defined population

Registries do not foresee the discussion or interpretation of clinical trial results

One of the main aims of peer review publication is to discuss and place results into context

Conclusions A clinical trial is part of a clinical development programme

Registries do not foresee drawing of conclusions as most clinical trials are part of an eCTD with integrated summaries of efficacy and safety, which together are the basis for a marketing authorisation

The conclusions of a publication put the results of a clinical trial in context with previous clinical findings for the same indication or within the clinical development programme

References Publication referencing foreseen by the Australian New Zealand Clinical Trials Registry (ANZCTR), ClinicalTrials gov and EU CTR 536/2014 in their results sections

Addition of the PubMed identifier or of the reference to the registry

Publications cite the most relevant available knowledge and place the clinical trial results, with their findings and limitations, in context



Table 26: Best Practices: General Publication Considerations

3.4.2 Regulatory Aspects and Points to Consider

When setting out to publish, there are additional considerations in addition to the journal editor and target audience The primary goal of peer review publications is to disseminate clinical trial results The findings of the clinical trial intervention and the potential impact on participants with the medical condition need to be subjected to scientific debate However, the advertising of a medical product or intervention is subject to regulation An editorial published by the American Medical Association in 1900 informed its readers that publications related to drugs whose ingredients were not disclosed or that were advertised directly to the public would not be accepted 55 Lawmakers were forced by commercial entrepreneurs to enact laws and establish regulatory authorities to prevent misbranding and false claims 56

Table 26 summarises best practices for general publication considerations

3.4.2.1 United States Labelling Definition

The United States Federal Food, Drug, and Cosmetic Act defines “Brochures, booklets, mailing pieces, detailing pieces, file cards, bulletins, calendars, price lists, catalogues, house organs, letters, motion picture films, film strips, lantern slides, sound recordings, exhibits, literature, and reprints and similar pieces of printed, audio, or visual matter descriptive of a drug and references published (e g the “Physicians’ Desk Reference”) for use by medical practitioners, pharmacists, or nurses, containing drug information supplied by the manufacturer, packer, or distributor of the drug and which are disseminated by or on behalf of its manufacturer, packer, or distributor are hereby determined to be labelling as defined in section 201(m) of the act” 57

3.4.2.2 United States Guidance

In January 2006, the Center for Drug Evaluation and Research (CDER) and the Center for Biologics Evaluation and Research issued guidance 58 to assist data providers in deciding

• what trials should be included in the clinical trials section of prescription drug labelling,

• how to describe individual trials, and• how to present trial data

In 2009, the US NIH required researchers in receipt of federal funding to deposit their final, peer-reviewed manuscripts in PubMed Central 59, and the Omnibus Appropriations Act made the NIH public access policy permanent 60

Best Practices - General Publication Considerations

Best Practice Publication Planning

Do Do Not Alignment with eCTD M4

Ensure publication of clinical trials that are the basis for the marketing authorisation

Publish interim analyses of trials pertinent to the claimed indication where not all participants have had their final assessment for the primary endpoint

Make multiple submissions to different journals

Publication of endpoints that have been agreed with the regulatory authorities for the label and will be CSRs in Module 5 3 5 1, and the trials used to support the prescriber information referred to in the Clinical Overview

Ensure publication of uncontrolled clinical trials Take for granted that target audience will guess contextual relationship of these trials to Module 5 3 5 1

Reports of uncontrolled clinical trials will be in Modules 5 3 5 2 to 5 3 5 4

Submit for peer review publication an integrated manuscript for all trials of human pharmacokinetic and pharmacodynamic investigations

Limit manuscript to a single submission attempt or submit a series of publications, unless the active ingredient or the pharmacokinetics and pharmacodynamics are unique and have specific scientific or clinical outcomes

Module 2 5, Section 6, Benefits and Risks Conclusions



Figure 8: Publication Decision Tree

3.4.2.3 European Requirements

In Europe, there are requirements that the dissemination of clinical trial results cannot be unnecessarily delayed Publication policies and procedures should be part of the clinical trial protocol National laws address the restrictions that a data provider may or may not implement with regards to the publication of clinical results Examples include the Swiss Clinical Trial Ordinance on Clinical Trials 61 and the Dutch Directive on the Assessment of Clinical Trial Agreements 62

3.4.3 Publication Planning and Management

Publication management is an integral part of the eCTD and drug application process The detailed clinical summaries (Module 2 7) have been described as analogous to the results section of a research publication In addition, the Integrated Summary of Efficacy in Module 5 provides the sponsor with an opportunity to highlight and discuss data from different trials that are supportive of a drug’s clinical utility 63

A decision tree for publication is shown in Figure 8

DDD: defined daily dose; SmPC: summary of product characteristics

Pharmaceutical sponsors often use software tools or internal databases for publication planning and management Resources for these can be found on the websites of the International Society for Medical Publication Professionals 64, the European Medical Writers Association 65 and the American Medical Writers Association 66

The pharmaceutical industry and the International Society for Medical Publication Professionals founded a unique collaborative venture in 2008: the Medical Publishing Insights & Practices initiative This initiative supported development of an Authors’ Submission Toolkit to compile best practices for the preparation and submission of manuscripts describing sponsored research 67

Clinical Development & Publication Policy

Planning and Interrelated Activities

Decision to publish in peer review journal

Pre-marketing Non-promotional publications

Individual Study Clinical Trial Registry Record

One publication for Multiple Clinical Trial Registry Records

SmPCPhysician Labelling Rule (US)Patient Report Outcome (US) Spoke and Wheel Validation

Clinical Trial Registry Record

SmPC Updates Physician Labeling Rule (US) - UpdatesEMA Good Pharmacovigilance Practice (EU)

Clustering of Studies

Phase of Development

Non-Clinical Studies

Disease background, Diagnosis & Epidemiology

Post-marketing Clinical Studies

Health Technology Assessment Evidence Reports/Studies/WHO DDD

Patient Case Study

Summary of Safety

Confirmatory/Pivotal Clinical Studies

Methodology

Post-marketing

Potential reasons:1 Organisations interpretation of publication2 Patent not yet granted3 Patent public but under dispute4 Commercially confidential information (CCI)5 Restricted due to Strategic Defence Issues6 Publication of clinical studies will be in Portals,

e g Clinical Study Data Request (CSDR) EMA clinical data website & freely available clinical trial registry

Decision not to publish in peer review journal



Table 27: Best Practices: Journal Selection

3.4.3.1 Choice of Journal

The author’s choice of journal is based on the target audience This should be planned at the time that the first CTA is submitted or before ClinicalTrials gov registration is finalised The clinical indication, a newly validated outcome or another methodological aspect are usually the primary determinants of the choice of journal Secondary aspects include geography (e g if a product is for a national market); in this case it is possible that the publication would appear in a non-English journal

The editors of 12 journals are currently official members of the ICMJE, and a large number of non-member journals follow the committee’s recommendations 42, 68 A journal editorial board may have individual interpretations of and implementation practices for ICMJE recommendations This is highlighted by the difference in opinions regarding prospective clinical trial registration requirements and whether they should be mandatory 69, 70

Table 27 summarises best practices for journal selection

There is consensus within the ICMJE that the reporting of clinical trial results in registries does not affect the submission of a manuscript for publication 73 It has been argued that publications are only validly published if they are published in the right place 52 With the publication of CSRs on the EMA Clinical Data website 2,

74, an extreme argument would be that this constitutes publication in the right place as the clinical trials were primarily performed for a marketing authorisation and have been reviewed by experts Therefore, at the marketing authorisation submission stage, the publication team should be actively planning product lifecycle publications

Best Practices - Journal Selection

Criteria to Consider Rationale

Objectives of trial protocol are aligned with the journal’s aims and scope Accuracy and consistency with all publications, including technical results postedParticipant privacyDisease knowledge

PubMeda or MEDLINEb listed? Accuracy and sense of the results when summarised and presented in the TRSConsistency of results with other publications

Journal has editorial policy CCIParticipant privacy

Journal describes its policy for publication ethics Code of conduct and best practice guidelines for journal editorsc

Journal contacts all authors upon submission and requires declaration of conflict of interest

All authors are aware that the corresponding author has submitted their approved manuscript

Journal has public peer review guidelines Authors’ work will be subject to a review of their intellectual processes

Journal has clear instructions for authors Authors can prepare a suitable manuscript

Journal enables authors to comment on pre-publication proofs Authors retain oversight and ownership of data and clinical and scientific interpretation

Journal is transparent with respect to article charges Authors and data providers can plan budget; target audience and public can assess potential conflicts of interest

Journal is open access Depending on the target audience, the open-access publication route may be an option

Beware of predatory journals They charge but do not provide services that are consistent with a stringent scientific process

aReference [59]; bReference [71]; cReference [72]



Table 28: Best Practices: How to Get Published

Table 29: SWOT Analysis—Open-access Publication

Table 30: SWOT Analysis—Restricted Access

3.4.3.2 How to Get Published

Many publishers and journals have instructions and guidelines for authors on how to publish research It is recommended that the journal most appropriate for the target audience is consulted on how to prepare the manuscript A description of the scope, aims and types of research that are published can be obtained in the “Instructions to Contributors” section on the journal’s web page A look at the journal’s editorial board might also provide a good idea of a journal’s theoretical approaches, philosophical orientation, and research interests 75

Table 28 summarises best practices related to how to get published

3.4.3.3 Publication: Open Access or Restricted?

The following types of scientific communication on a clinical trial are possible:

1 Open access is a means of accelerating scientific discovery by providing free and unrestricted access of scientific knowledge via the internet This would be an extension of the WHO and ICMJE philosophy of clinical trials being registered and reported in freely accessible clinical trial registries

2 Restricted access to research findings and scientific discovery through subscription and pay-per-view journals

The European Commission has published 83 trends for open access to publications from 2009

Table 29 and Table 30 summarise benefit-risk analyses (strengths, weaknesses, opportunities, threats [SWOT]) of the open-access and restricted routes of publication

Best Practices - How to Get Published

Identify appropriate journal by deciding upfront who the target audience will be for the clinical trial results As there are length restrictions, consider publishing the primary manuscript based on the primary endpoint and key secondary endpoints Secondary manuscripts can address findings from the clinical trial for which the clinical trial was not statistically powered at the protocol finalisation stage

Journal scan based on:- clinical indication- journals that have been used as references for clinical and scientific content in the regulatory documentation- if in doubt, consider making use of internet-available abstract submission tools for potential journal selectiona

Key message Align with Target Product Profileb

Implement appropriate standards in manuscripts ICMJE; Ann Int Med GPP3; CONSORT; EQUATOR networkc

Does the journal publish a lay version of the publication, i e a lay publication?(Note: This is different from a TRS per EU CTR 536/2014 )

Plan alignment with regulatory and data provider requirements Numerous journals require or allow a lay version of the publication to be published with the peer-reviewed publication

Strengths Weaknesses

Prescribers have free access to the publications of clinical trials for a marketed product No control over third-party use of publications once published

Opportunities Threats

Interact with a broad base of stakeholders who have unrestricted access to the same information

Dedicate resources for tracking and interactions with external groups to ensure that no false or misleading information is generated

Strengths Weaknesses

Prescribers do not have free access to publications for a product that does not have marketing approval; thus, article is less likely to be classified as promotional Restricted access does not hamper access to information to the academic community, whose institutions have licence agreements with publishers

Participants may not be able to access information and give input into the design of Module 5 3 5 1 trials

Opportunities Threats

After marketing authorisation, consider open access to documents and data Negative perception in the community

a References [76, 77, 78]; b Reference [79]; c References [42, 80, 81, 82]



Table 31: Best Practices: Vocabularies

3.4.3.4 Controlled Vocabularies

Index Medicus was a bibliographic index introduced in the late 19th century to help catalogue publications and assist readers to find them 84 Medical Subject Headings (MeSH) has replaced Index Medicus; it is a comprehensive controlled vocabulary used by ClinicalTrials gov and PubMed 85

Table 31 summarises best practices for vocabularies

3.4.3.5 Timelines—When to Publish

Journal editors have acknowledged the changing climate around results registration and reporting There is a conflict of interest in that time-critical regulatory requirements require submission of results within 6 to 12 months after the end of the clinical trial (or its primary endpoint) and journal editors want the key messages from a trial to appear first in their publication 49

Under US law (21 Code of Federal Regulations 201 57), the MAH is accountable for the content and correctness of information brought into the public domain for the product under development These regulations are in place to ensure fair commercial practice and ensure balanced reporting on a medical product It is unethical and, in some countries, illegal not to publish clinical trial results The best practice for pharmaceutical sponsors is to strive for peer review of clinical trials The United Kingdom House of Commons Science and Technology Committee stated in 2004 that “peer review gives the lay reader an indication of the extent to which they can trust each article” 86 A peer-reviewed publication, especially in early clinical development, allows feedback from the clinical and scientific community on aspects that the data provider may wish to plan for at the time of marketing authorisation submission Furthermore, a peer-reviewed publication in a journal has an advantage of introducing the clinical trial, placing it into context, and discussing the results from the clinical trial Three important aspects of the scientific process—assessment of observations, repetition of experiments, and evaluation of intellectual processes—cannot be implemented in any of the currently available clinical trial registries

Product Teams that have followed scientific exchange best practices are better prepared for an FDA Advisory Board Hearing as the information has been evaluated interactively by peer review journals and readers How FDA Advisory Board meetings impact data providers’ development plans is described in detail elsewhere 87

Best Practices - Vocabularies

Use MeSH terminology in manuscript submissions that match the keywords in ClinicalTrials gov

The National Library of Medicine may add keywords to the ClinicalTrials gov record Consider which keywords and MeSH terms best identify the clinical trial

Include the keyword “clinical trial”/“study” in the manuscript submission if it is not in the title of the manuscript

PubMed searches will not find clinical trial publications if at manuscript submission the TRIAL REGISTRATION data field is left blank



Table 32: Best Practices: When to Publish

Table 32 summarises best practices regarding when to publish

Table 33: Best Practices: Registry Publication Timing

Best Practices - When to Publish

Submission of a primary clinical trial manuscript should be around the time (12-week period) of CSR finalisation

All contributing experts and authors are focused on the clinical trial and the interpretation of results Coordination of information and consistency of clinical results reporting are easier

Consider publication of a clinical trial even if only an abbreviated or synopsis report will be written, and clinical development will be placed on hold or terminated

The results and interpretation are available and team members may leave the data provider or be seconded to other projects There is a narrow window of opportunity for the data provider to have feedback from the community that may shed light on aspects not considered by the data provider’s team with respect to clinical development

Consider submission of the primary publication before the CSR is made public by the regulatory authority

The publication of the CSR may jeopardise the acceptance by a journal as the information is no longer novel

Data providers whose healthy volunteer studies are rejected by a journal should consider publishing them in a manuscript that covers the clinical pharmacology aspects of the clinical development project

Data providers whose manuscripts are rejected should not waste resources or consider further demotivating a clinical team by forcing peer review publication and should consider whether the posting of an ICH E3 synopsis (on the data provider’s clinical trial website) and results posting in a registry suffices

Once the journal has accepted the publication and a PubMed identifier is available, it should be shared with the Disclosure Specialist so that the clinical trial record in the registry can be updated

Registries serve as an ideal platform for clinical data stewardship and permit knowledge curation of the primary and secondary analyses

Reference and respect copyright issues, including the submission of publications of secondary analyses of clinical data on the EMA clinical data website to the EMA before publication of the manuscript

Required as per EMA Policy 0070 and conditions/terms of use of other registries, such as ANZCTR and ClinicalTrials gov

34.3.5.1 Consequences of Release of Clinical Registry Results Prior to Peer Review Publication

If a data provider, or the publication team of contributing authors, does not plan a peer review publication for a clinical trial that is about to have results released on a clinical trial registry, the data provider may miss the opportunity to place a clinical trial in context and discuss the results The data provider must expect that the registry results will be cited by non-data provider authors The use of clinical trial data from clinical trial registries in secondary publications is referred to as “grey literature” Grey literature has been reported to represent almost half of the references cited in reports on new and emerging nondrug health technologies The 3 main sources for grey literature were found to be manufacturers’ websites, ClinicalTrials gov, and the FDA 88 “Grey Literature is a field in library and Information science that deals with the production, distribution, and access to multiple document types produced on all levels of government, academics, business, and organization in electronic and print formats not controlled by commercial publishing, i e where publishing is not the primary activity of the producing body” (GreyNet website) 89

Table 33 summarises best practices related to the timing of registry publications

3.4.3.6 Non-primary Publications

Most journals have a 5000-word limit It may therefore not be feasible to publish and discuss all protocol endpoints in a single manuscript In addition, exploratory analyses—such as the tolerability profile in different age groups and the influence of genes on the metabolism of a medication—may only be performed at the end of a clinical development programme These post-hoc analyses would thus be a separate publication and probably in a different journal as the target audience may be different The ICMJE refers to this as an “Acceptable Secondary Publication” 42

In recent years, numerous journals have offered the opportunity or requested that authors of peer review manuscripts consider writing a lay summary of their publication for a broader audience This differs from the TRS that is required by EU CTR 536/2014 From a planning point of view, synergies between these 2 types of lay summary should be explored

3.4.3.7 Authorship and Acknowledgements

The ICMJE recommendations with regards to authorship 42

are that non-authors should be acknowledged Medical writers that are involved in the concept and throughout the manuscript process can be listed as authors All authors have to disclose conflicts of interest, including potential financial relationships

Figure 9 summarises some ICMJE considerations for publication planning Best Practices - Registry Publication Timing

Clinical trial registries do not foresee the discussion of results publications, and it is therefore essential to share interpretations of the results and to place them into clinical context The citation of clinical trial results from registries and non-peer-reviewed sources is an internet-age development that requires caution and additional skills



Figure 9: Considerations for Publication Planning

Table 34: Best Practices: Authorship and Acknowledgements

Planning for publication• Requirements by funding agency (even if partial)• Clinical Trial Registration• Publication agreement/plan• May be enshrined in national law

• • The Netherlands, Switzerland• Potential conflicts of interest of authors & contributors

• • Availability• • Public Responsibility

• Best practice • Acceptance/Rejection• Open access

Primary publication• Not necessarily first disclosure

• • Often oral, poster or abstract • First full disclosure allows:

• • Assessment of observation• • Evaluate conclusions• • Permit repeat

Industry Commitments• 2010 EFPIA Statement and

IFPMA "Industry Commits to Submit for Scientific Journal Publication the Results of all its Phase III Clinical Trials"

• 2013 PhRMA and EFPIA "Principles for responsible clinical trial data sharing"

• 2017 PhRMA "Clinical Trial Data Transparency"

• 2019 EFPIA Reaffirmation

Prerequisites Author and contributors must• Meet 21 CFR 201 & 208, sNDA

and 21 CFR 314 70• Have full access to study data

before writing the article• Strive for a scientific debate

rather than promotion• NOT be an off-label promotion

(Section 401 FDAMA)

Secondary publication• ICH E3 synopsis if after primary

peer-review publication• Post-hoc analyses • Exploratory data analysis • Meta-analysis

Duplicate publication• Certain circumstances to allow

widest possible audience • If journal of original article

approves, due to copyright issues• Title should mark duplicate

publication• Fulfilment of legal requirements,

e g, result posting in ClinicalTrials gov, does not constitute pre/publication

• Requires that an abstract at a conference or a poster by internal definition are not "primary publication"

3.4.4 Ethical Aspects: Privacy, Accuracy and Editors

In the Basic Principle section of the 1975 version of the Declaration of Helsinki, it was stated that “[e]very precaution should be taken to respect the privacy of the subject” and that “[i]n publication of the results of his or her research, the doctor is obliged to preserve the accuracy of the results Reports of experimentation not in accordance with the principles laid down in this Declaration should not be accepted for publication ” In the 2018 version of the Declaration, research registration and publication and dissemination of results are discussed 95

With increasing financial transparency requirements—e g the US act on payments to medical professionals 94—data providers should consider acknowledging contributing investigational sites by name on a publication Authorship must be decided before any publication planning starts

Table 34 summarises best practices for authorship and acknowledgements

Best Practices - Authorship and Acknowledgements

Authorship and publication policy should be clearly stated in the clinical trial protocol that is submitted prior to trial start-up to the IRB/EC and the regulatory authorities

CFR: Code of Federal Regulations; EFPIA: European Federation of Pharmaceutical Industries and Associations; IFPMA: International Federation of Pharmaceutical Manufacturers

and Associations; FDAMA: FDA Modernization Act; PhRMA: Pharmaceutical Research and Manufacturers of America; sNDA: supplemental New Drug Application

References [90, 91, 92, 93]

Correspondingauthor

Coordinates

PublicationTeam

Lead authorWriting & Managing

Guarantor Integrity

Chief Medical Officer,Data Protection Officer,

Compliance, Legal, Regulatory Affairs, Patent?

Contributors Support

Medical Writers, Editors, Investigators, Vendors?

Authors Substantial contribution

Project Team, Investigators?

Journal and Target Audience



3.5 Individual Patient Data Sharing

At the time of writing, there are no active, mandatory requirements to share IPD, although the EMA has noted the topic as a future activity—namely “Part 2” of its Policy 0070 process 2 The EMA also hosted a workshop in late 2017 together with the Multi-Regional Clinical Trials Center of Brigham and Women’s Hospital and Harvard At this 2-day workshop the topic of ‘Data anonymisation—as a key enabler for clinical data sharing’ was explored 96 Pre-dating this meeting, in 2016, the United Kingdom Anonymisation Network published an anonymisation decision-making framework 97 that considered challenges to confidentiality in the context of data sharing

Additionally, there are principles, guidelines and ranking tables related to IPD sharing, as follows:

• The Institute of Medicine published “Sharing Clinical Trial Data: Maximizing Benefits, Minimizing Risk” on 14 January 2015, which included a series of recommendations for stakeholders 1

• One of the components of several published trade association guidances 93, 98, 99, 100 relates to enhancing data sharing with researchers

• Since 1 July 2018, ICMJE recommendations 42 have required data sharing statements to be provided in any manuscripts submitted to its journals, and since 1 January 2019, data sharing plans need to be provided at the time of trial registration

• The AllTrials Transparency Index 101 assesses 4 disclosure categories, one of which is the sharing of IPD

• The Good Pharma Scorecard ranks performance related to transparency and data sharing 102

In adherence with these principles and guidelines, and in line with many data providers’ voluntary processes, there are a growing number of pathways through which anonymised IPD (and associated trial documentation) can be shared These pathways can support both appraisal of trial outcomes and novel analyses

3.5.1 Value of Sharing Individual Patient Data

As with any disclosure or sharing activity, the value of the activity must be considered from the perspective of the intended audience In the case of IPD sharing, the primary audience is the secondary research community that submits research proposals to further analyse clinical data

It is important to consider how to maximise the utility of anonymised IPD for these researchers, providing them with the richest data possible Indeed, the value is not in the sharing per se, but in the new scientific insights that researchers can identify as a consequence of this sharing As such, there needs to be a balance between enabling transparency, protecting trial participant privacy and maximising clinical utility However, there are various views in the research community, and while some researchers are actively requesting, pooling and analysing trial data from data providers, there are others who see greater

value in first focusing on disclosure activities such as trial registration and results reporting—“All trials registered, all results reported” 103—before researchers can fully benefit from IPD sharing Registering and reporting results of all trials is a gold standard to pursue, though it can be challenging for trials that were completed many years earlier This is a strong reason for ensuring that trials are disclosed in a timely manner Data providers need to balance this with other disclosure activities that may often compete for the same budget

3.5.2 Embedding Processes

As noted above, a data sharing plan is now required to be posted (e g on ClinicalTrials gov 41) prior to trial initiation for any trials for which a manuscript is planned to be submitted to an ICMJE journal 42 The process required to support this activity can connect departments within a data provider who perhaps have not worked closely before For example, some staff will be responsible for registry activities, others for publications, others for IPD and document anonymisation, and others for processing data sharing requests These colleagues will all be subject matter experts for a newly defined process, working with the trial level experts required to produce the planned disclosure material The most appropriate process to follow will depend to some extent on a data provider’s organisational structure; an efficient process will be one that includes all the appropriate stakeholders at the appropriate time For example, a trial team needs to decide at the trial planning stage whether data are planned to be subsequently shared for that trial This is so that the appropriate data sharing plan can be specified, e g in the ClinicalTrials gov registration record 104 All team members who are part of the process should be aware of this plan, and any changes subsequently made to it, so that they can coordinate appropriately within their departments—e g to provide the appropriate statement in any subsequent manuscripts—and to schedule anonymisation either proactively or in line with other disclosure requirements, such as EMA Policy 0070 or Health Canada’s PRCI

3.5.3 Preparation of Anonymised Data and Documents

When sharing anonymised IPD with researchers, the datasets are often shared together with associated trial documentation such as the protocol, SAP, sample case report form, and CSR including tables and graphs In 2015, PHUSE published a set of de-identification rules to aid the anonymisation of direct and quasi IDs within CDISC SDTM 3 2 datasets 6 that complemented White Papers published at the time by TransCelerate, and which are now PHUSE assets 5, 33

An initial question for a data provider to consider is ‘Who should prepare the anonymised deliverables?’ Some data providers have the capability and resources to prepare the anonymised IPD and documents in-house, whereas others utilise the expertise of vendors The choice will depend on factors such as the data provider’s operational model—e g whether non-core activities are outsourced—as well as resources, budget, expertise, and the scope and volume of deliverables to be anonymised

Documents need to be reviewed for PPD, as well as CCI, and when document disclosure first became common, a redaction approach was usually followed prior to disclosure As the landscape has advanced, and in line with the preferred



approach of some regulators, it is now possible to anonymise documents (see Section 3 1 5, Document Anonymisation) This means that documents and IPD can have the same anonymisation process applied to certain variables, such as trial participant ID numbers and ages, so that the resultant IPD and documents remain consistent in their anonymised forms For example, Trial Participant 123 in the original trial would have the same new randomly generated ID number (e g to Trial Participant 456) in both the anonymised datasets and anonymised documents This contrasts with other types of variables where the same approach cannot be followed across both datasets and documents For example, verbatim text can be redacted in a document but the variable containing that text must either be set to blank or deleted from the dataset Note: sometimes partial redaction is applied to particular variables of interest, e g if there is a free text field (with no coded variable equivalent) that contains information important to an analysis

This combined “IPD and document” approach can lead to greater utility for the researcher, who can now connect the anonymised trial participant ID number from a narrative in a CSR and link back to all the (anonymised) data for that trial participant within the various IPD datasets However, when following this approach, the anonymisation needs to be applied considering other sources of data available to the recipient The sharing of IPD under strict contractual restrictions in a controlled environment will likely allow more permissive methods—i e less data perturbation; however, public sources of data also need to be considered, e g EMA Policy 0070 or ClinicalTrials gov Thus, a CSR publicly available under EMA Policy 0070 may retain full details related to the country and age of trial participants Subsequent sharing of the equivalent (anonymised) IPD datasets may have necessitated elevating country to region and age to age bands to result in an acceptable risk when sharing that IPD However, in practice, the recipient would now have access to the partial age (from the anonymised IPD) and full details of the participant’s country (from the disclosure under EMA Policy 0070), which may result in a higher than acceptable risk of re-identification

As the landscape moves forward, data providers need to look for additional ways in which the anonymised data can be shared in increasingly useful ways with the researcher community, as well as being cognisant of the increasing amount of information now in the public domain (once released, information must be considered to be available forever), to ensure that the risk of re-identification of a trial participant is not increased above an acceptably low level

Data providers need to consider how to proactively approach IPD anonymisation Documents may need to be anonymised or redacted for other disclosure requirements such as ClinicalTrials gov results disclosure 41, EMA Policy 0070 2 or Health Canada PRCI 19, but the datasets are currently only shared per trade association principles (if the data provider has certified compliance to them), the ICMJE process 42 (if so stated in the data sharing plan), or through voluntary data sharing processes such as the Yale University Open Data Access (YODA) Project 105, Vivli Center for Global Clinical Research Data 106, SOAR DATA 107, ClinicalStudyDataRequest com 108, Project Data Sphere 109, etc

Since the documents will likely need to be disclosed in additional places, the data provider may consider anonymising

the IPD for a trial at the same time as the documents, and thus have the option to utilise a higher-utility anonymisation approach across documents and IPD However, given the cost of anonymising IPD, should this activity only be performed on request? The answer to this question will vary depending on the data provider’s processes, including whether the anonymisation is performed in-house or by an expert vendor, and how many IPD sharing requests are anticipated If choosing to anonymise IPD proactively, there are additional considerations such as how to manage changing requirements over time—i e if, in the future, mandatory regulations come into application regarding the sharing of anonymised IPD, would the data provider’s process be compliant with those requirements, or would the IPD (and documents) need to be anonymised again?

Another consideration for data providers is that, given the increasing amount of data now made public, as well as the increasing number of privacy threats (more tools and more data available to adversaries), it is increasingly necessary to review anonymisation processes at regular intervals to ensure they are still meeting all requirements 5 The appropriate review cycle will depend on the anonymisation methods used and the speed at which the landscape is evolving

Since the level of CCI can also reduce over time—i e after information has been disclosed publicly anywhere in the world—another consideration is whether such documents should be re-reviewed and information that is no longer considered to be CCI can now be made visible However, if documents are updated in this way, it could lead to a misalignment between the information presented in the datasets and the documents, or a perceived misalignment in the audit trail associated with the overall anonymisation process As such, consideration should be given to whether the datasets also require re-anonymisation An instance of a document type in which the amount of CCI would decrease over time is the Investigator Brochure, which will be required to be disclosed under EU CTR 536/2014 22

3.5.4 Data Utility vs Data Privacy

Many data providers are looking to evolve from a document redaction approach to one of anonymisation, which brings opportunities for connections to remain between documents and IPD, and thus for greater utility of the data shared with the research community

Such a process needs to remain in compliance with all privacy regulations, the most well known of late being the EU GDPR 4 Many understand this regulation to require the data key code to be destroyed after de-identification, which is a step further than many data providers performed previously, preferring instead to store the code in a separate, secure location so that the anonymisation could be re-run if, for example, a main trial needed to be anonymised again at the time when an extension trial had completed

In addition, there are certain types of trials that require special consideration, e g Phase I trials, trials in rare disease populations, and trials that collect photographic, genetic or biomarker data These can be very challenging to anonymise—indeed, it can be questioned whether it is possible to successfully anonymise genetic data (though this can depend



on how much data are planned to be shared) At the time of writing of this Guide, it is not common practice to share these types of data (especially genetic data) due to the challenges associated with their anonymisation

The type of data and type of trial may influence the choice of anonymisation method, as well as the approach taken to assess the risk of re-identification For data requiring additional anonymisation steps to sufficiently protect trial participant privacy, there will be an impact on the clinical utility of that data Many data providers are still exploring that balance, and not yet able to anonymise such data while retaining sufficient clinical utility With continued advances in this field, it is expected that solutions will be identified for many of these challenges, thus enabling the responsible sharing of these rich data sources in the future

3.5.5 Quantitative vs Qualitative Risk Assessment

Some regulatory agencies have expressed a preference for anonymisation (of PPD within documents) over redaction, and for quantitative risk assessment over qualitative 9, 19, with the maximum risk threshold being recommended not to exceed 0 09 for public data releases Many data providers are looking to move towards an anonymisation approach to fulfil the requirements of EMA Policy 0070 and Health Canada PRCI, often utilising the skills of expert vendors This contrasts with the FDA’s approach to its 2018 pilot 110 and FOIA process 20, as well as EMA Policy 0043 21, in which only redacted documents are shared

When IPD are anonymised together with documents, as those documents are being prepared in compliance with various global disclosure requirements, the appropriate risk level for re-identification of trial participants must be considered The threshold selected will be trial dependent and must be determined based on the sensitivity of the data and, for data shared under the legal basis of consent, the potential invasion of that informed consent For example, it may be appropriate that since both EMA and Health Canada recommend (default) risk threshold not to exceed 0 09 for documents that are publicly available, the anonymisation process can be run once to produce compliant outputs for both regions In the future, if additional regions stipulate different risk thresholds, the data provider will need to consider carefully whether to produce different versions for different regions, each below the respective specified risk thresholds, which may risk confusion or erode trust by disclosing multiple versions of the same information An alternative approach, in the hypothetical example of needing to navigate multiple different regional requirements in a worldwide setting, is to produce 1 version for global use according to the strictest (most conservative) risk threshold accepted at the time and publish this version in all regions; however, this will result in documents having less

clinical utility than may have been possible in some regions It should also be noted that it will not always be possible to exactly achieve a defined risk threshold For example, when preparing documents for public disclosure according to EMA Policy 0070 or Health Canada PRCI processes, in which the risk threshold is not to exceed 0 09, data providers will aim to get as close to (but not exceed) that threshold, but it may not be possible to deliver all documents with a risk of re-identification of exactly 0 09, especially, but not exclusively, when the clinical trial contains a small number of participants

The risk of re-identification is an interesting topic in its own right Documents contain mainly aggregate data, with some individual trial participant information in narratives and listings, and these documents are published on various public websites and portals The IPD datasets contain more complete trial participant records In recent years (2013 onwards), data providers have made these anonymised data available only to qualified researchers and only after other protective steps have been put into place, e g process protections such as requiring the submission of a research proposal to an independent review panel that assesses the scientific merit of the proposal, and legal protections such as requiring the execution of a Data Sharing or Data Use Agreement prior to the data being shared Furthermore, such data are often only shared in secure, password-protected locations from which only the analysis of the data can be downloaded, and not the IPD datasets themselves When anonymising documents and IPD together, the location where, and the audience with whom, the data are planned to be shared need to be considered when calculating the risk of re-identification The Institute of Medicine report 1 also discusses the different probabilities of re-identification attempt (deliberate attack, acquaintance and breach) that must be evaluated and factored into risk calculations

Applying data protection algorithms to IPD is one way to protect the privacy of trial participants Other approaches include procedural, legal and security protections, and, together, these approaches can be considered “Pillars of Security” (Figure 10) Such approaches are to be considered holistically For example, IPD shared publicly with no terms and conditions of use will require more in-depth data protection algorithms to be applied than if the same data were to be shared in a secure environment that required a Data Sharing Agreement to be in place The risk threshold in the public setting will likely need to be more conservative than in a secure setting Similarly, before IPD from clinical trials in rare diseases can be shared, more conservative risk thresholds than the commonly used 0 09 threshold may be necessary in order to reduce the risk of re-identification of a person living with a rare disease

2 Prior to this approach to data sharing, data providers may have shared data with

academic researchers through processes considered secure at the time, but in

recent years processes have become more transparent and utilise additional security

measures

Figure 10: Pillars of Data Protection

Data Protection:Data Anonymization

Procedural Protection: Research Proposals

reviewed by IRPs

Legal Protection: Data Sharing Agreements

Security Protection: Password-protected secure environments



The calculation of the risk of re-identification depends on the denominator selected When determining the denominator to use, there are generally 3 populations to consider: the trial population, the population of similar trials, and the population in the same geographic area Further discussion of this topic is provided in the Health Canada PRCI guidance document 111

Further information related to quantitative risk assessment is considered in the upcoming PHUSE White Paper “De-Identification and Risk Analysis Automation”

3.5.6 How Does Data Sharing Fit in the Overall Landscape? The sharing of IPD cannot be considered a standalone exercise as it connects with other disclosure activities For example:

• Publications (to ICMJE journals and to journals that follow ICMJE recommendations) need to provide a data sharing statement 42 This statement will explain if, and if so, how, the IPD that was used to generate the analyses described in the publication can be requested by interested parties As best practice, such a statement could be included in all publications, regardless of whether submission is to an ICMJE journal or another source

• When registering a trial on ClinicalTrials gov, there are now fields in which to capture the data sharing plan for that trial

104 These fields similarly include a description of if, and if so, how, the IPD from that trial can be requested by interested parties Information in this data sharing plan and the data sharing statement described above needs to be consistent As best practice, data providers could define the scope of their anticipated sharing (e g all Phase I–IV trials, or Phase II–IV clinical trials in specific regions or globally), and this could then be applied consistently as new trials are registered The data sharing plan would then need to be updated in rare circumstances where anticipated data sharing could no longer occur, e g if for some reason it was not possible to anonymise the IPD as required

• Trial documents are shared as part of current and upcoming regulatory requirements 2, 19, 22, following trade association principles 90, 91, 92, 98, 99, 100, and for voluntary activities such as posting trial protocols, SAPs, and full CSRs on data provider and custom websites Many of these documents are also provided as part of a data sharing request, and so data providers need to consider how best to fulfil all requirements holistically, in an efficient, complete, consistent and accurate way This decision needs to be made with the understanding that there are different levels of risks of trial participant re-identification depending on whether the documents are disclosed publicly or via secure systems This is due to the varying threat scenarios that will be applicable depending on the use of public vs secure disclosure Data providers should consider ‘risk’ holistically across both IPD and documents, reflecting the elements that could be anonymised consistently across both media

3.5.7 Individual Patient Data Sharing—Summary

The sharing of IPD is an important part of the interconnected clinical transparency landscape As noted earlier, it complements and connects with other clinical transparency activities such as trial registration and results reporting,

publications and document disclosure There have been more than 500 research proposals submitted to ClinialStudyDataRequest com and the YODA Project alone since the launch of those platforms around 2013 112, 113 Many projects are ongoing, and so the expected high volume of manuscripts and potential new scientific insights therein are still being generated It is incumbent on those sharing data to continue to explore ways in which to modify this process to be as researcher-friendly as possible, while also being mindful of protecting the privacy of trial participants The sharing process needs to be further improved to speed up cycle times (e g time to delivery of datasets), and solutions need to be identified for multi-platform, multi-provider sharing The researchers can also support these improvements by moving administrative steps (such as the execution of a Data Sharing Agreement) through their organisations as promptly as possible It would also be beneficial for researchers to consult as early as possible with the appropriate platforms to confirm that all the requested data can be shared on 1 platform for their pooled analyses It currently takes a lot of time to navigate custom solutions, and this is best handled off the critical path so that there are no or few delays to data access for the researcher requesting the data

In summary, data providers need to remember why data from clinical trials is being shared It is to support the identification of new scientific insights that can bring new solutions and advance human healthcare With this in mind, collaboration must continue to progress that goal as promptly as possible

Table 35 summarises best practices related to IPD sharing



3.5.8 Evolving Topics

3.5.8.1 Multi-platform, Multi-provider Sharing

There are multiple platforms through which data providers can fulfil data sharing requests From a researcher’s perspective, it can be challenging to request data from different data providers who happen to use different platforms—how can the anonymised IPD be pooled when it cannot be downloaded from each originating platform?

Data providers and platform administrators are aware of this challenge and have taken a collaborative approach to identifying tailored solutions on a case-by-case basis, though they have not been successful every time A more durable solution is required, and this is being explored by some data providers who are assessing the qualification of multiple platforms via which the data from their trials can be shared Other data providers are exploring how to allow secure download of their anonymised datasets by the researcher into other locations while ensuring that appropriate data security measures remain

It should be noted that even if all required data are located on a single common platform, researchers may still experience challenges when pooling the data, since different anonymisation algorithms may have been used by different data providers These different algorithms may result in, for example, different age bands being applied to data from different trials, and thus limit the ability to pool these data across trials

3.5.8.2 Data Standards—FAIR Principles

Not only do those wanting to share data need to be clear about the scope of their data sharing policies, they also need to ensure that researchers are able to find the information they need Findable, Accessible, Interoperable, Reusable (FAIR) Principles 114, 115 are useful to consider for this purpose

As noted in the FAIR Principles, “The first step in (re)using data is to find them Metadata and data should be easy to find for both humans and computers Machine-readable metadata are essential for automatic discovery of datasets and services, so this is an essential component of the FAIRification process Once the user finds the required data, they need to know how they can be accessed, possibly including authentication and authorisation The data usually need to be integrated with other data In addition, the data need to interoperate with applications or workflows for analysis, storage, and processing The ultimate goal of FAIR is to optimise the reuse of data To achieve this, metadata and data should be well-described so that they can be replicated or combined in different settings The principles refer to three types of entities: data (or any digital object), metadata (information about that digital object), and infrastructure ”

To comply with FAIR Principles, some data providers are looking to associate Digital Object IDs with the trials and datasets, with the aim that Digital Object IDs would also be associated with the secondary researcher’s datasets and outputs, so that both this primary and secondary source of data could be FAIR for future researchers

3.5.8.3 Data Standards—CDISC

Another important consideration is the standards applied to shared IPD For example, datasets shared by pharmaceutical sponsors are generally in CDISC format 14, 116, but those shared by academic research institutions often are not Even considering data in CDISC format, if the datasets are from legacy trials, there could be differences between the CDISC versions applied to the various trials Having different standards and different dataset structures is another hurdle for researchers wanting to combine data from different trials and different data providers

Best Practices - Individual Patient Data Sharing

Take a holistic approach: Consider all forms of disclosure for documents and data and map out within an organisation how best to connect related activities to define an efficient process

Start with the end in mind: • It is good practice to expect that every document will be disclosed somewhere at some time When authoring new documents, be mindful to not include unnecessary (based on

scientific usefulness and regulatory requirements) information that will subsequently need to be protected • Before preparing IPD for sharing, define upfront the approach that will be taken to manage and measure the risk of re-identification of IPD Consider the environment in which the

IPD will be shared (i e public or secure), as well as any procedural protections (e g research proposals) and legal protections (e g Data Sharing/Use Agreements) Ensure that the risk of re-identification does not exceed the pre-defined threshold

Consider the audience: When preparing anonymised IPD for sharing, consider the primary stakeholders, i e the researchers It can often be helpful to discuss certain topics with them ahead of the IPD being shared For example:

• If the data provider can custom anonymise the IPD, are some variables more important to the researcher’s planned analyses than others? If so, can these be preserved with greater granularity (e g narrower age bands) while still appropriately anonymising the datasets?

• Understand the full scope of the data being requested by the researcher (i e understand who all the data providers will be) so that any possible issues related to multi-platform, multi-provider sharing can be addressed as early as possible

How to be helpful:• Identify what information is helpful to researchers before they submit a request, e g trial protocols Provide easily navigable information so researchers can identify all relevant

trials within the scope of their research • Standardise wherever possible to ensure pooling is as straightforward as possible

Collaborate with others: The landscape is fast evolving; connect with others, whether multi-provider platforms or special-interest groups within—e g the Drug Information Association, PHUSE—to keep abreast of advancements in the area, and identify how these can best be brought into the organisation

Informed consent: Understand the scope of the informed consent used in the original clinical trial—what did it cover and what did it not? Also understand the legal basis under which data are shared (which may not be informed consent) to ensure compliance with all relevant regulations

Defined processes: Clearly define the process through which anonymised IPD will be shared:• Share data with qualified researchers, i e the research team includes a person with statistical qualifications • Utilise independent review panels to assess the scientific merit of submitted research proposals • Ensure the anonymisation algorithm protects the privacy of trial participants appropriately (i e the data cannot be re-identified by all reasonably likely means) while still

maintaining sufficient clinical utility for the research team • Share data only after appropriate legal safeguards (e g Data Use Agreement) have been fully executed • Where possible, align the anonymisation of datasets and documents

Table 35: Best Practices: Individual Patient Data Sharing



3.5.8.4 Data Modalities

This section has focused on the sharing of IPD as clinical trial datasets that contain structured data For many data providers who share anonymised IPD, this type of structured data often forms the majority or sole format of what is shared However, there are other data sources, including X-ray images, computed tomography scans, photographs, sensor data, and ‘-omics’ data With these data modalities, there are additional challenges to preparing anonymised data in which trial participant privacy is appropriately protected while clinical utility is retained This topic is planned to be re-visited in later versions of this Guide, once the approaches to sharing such data have been developed further and are more widely used

3.5.8.5 Data Reuse Within a Data Provider’s Organisation

Secondary sharing of data is often seen as the sharing of anonymised data with a third party, external to the data provider’s organisation However, there are often times when a data provider would like to reuse the data collected in its own clinical trials Data providers may find it helpful to document the types of reuse that are, and are not, allowed For example, if the scope of sharing with an external researcher requires that the researcher’s proposed research must be in the same broad therapeutic area as the original clinical trial, then should this also define the scope of further research allowed by the data provider themselves? There is currently not a single generally accepted opinion on this topic, with some data providers only allowing themselves a narrow window for secondary research, while others allow a broader interpretation

4. Future Visions

Global clinical trial transparency and disclosure requirements and opportunities have expanded dramatically over the past 10 years, from the exchange of medical knowledge published in books and journals, to implementation of regulated clinical trial registries, to clinical document publication and participant-level data sharing Further developments are set to continue with the forthcoming EU CTR 536/2014, which requires the publication of additional documents such as Investigator Brochures and non-technical ‘lay’ summaries Other countries and regions are moving forward with their own plans for data transparency through a variety of mechanisms

During this period, data providers have been building capabilities to stay abreast of these increasing demands and deliver quality disclosures in a timely manner, while ensuring the protection of participant privacy and commercial confidentiality This Guide highlights opportunities for data providers to proactively prepare for these disclosures utilising emerging best practices to ensure common messages across all information disclosed and to build in efficiencies while maximising data utility

Looking to the future, further debate is encouraged and opportunities should be sought for global harmonisation, as far as possible, of clinical trial transparency and disclosure Steps in the right direction are already being seen through agencies aligning their approaches, e g through participant ID

anonymisation becoming the globally accepted norm Health Canada’s PRCI process has taken the approach of accepting clinical documents that have already been published by the EMA under Policy 0070 This not only reduces workloads for the data provider and regulator but limits possible confusion that could be caused by publishing a document in multiple places

Our vision for global harmonisation is to have:

• a single global registry of records that is also used for technical results posting

• accurate, complete and clear information that is meaningful to the intended audience

• harmonisation of privacy and confidentiality laws and regulations

• globally accepted anonymisation standards that maximise clinical utility while protecting participant privacy, thereby adding value for the intended audience

To reap the greatest benefit, the data disclosure and transparency community needs to aspire to developing a global platform for clinical trial transparency and disclosure, with common standards applied to the provision of ‘one version of the truth’ Through exploration of such a TRUSTED source, regulators and researchers will be able to more fully explore available information to advance human healthcare, benefitting patients globally



References

1 National Academies of Sciences, Institute of Medicine Sharing Clinical Trial Data: Maximizing Benefits, Minimizing Risk Washington, DC: National Academies Press, 2015, accessed at: https://doi org/10 17226/18998 (last accessed 24 April 2020)

2 EMA Policy 0070, accessed at: https://www ema europa eu/human-regulatory/marketing-authorisation/clinical-data-publication (last accessed 24 April 2020)

3 Tucker K, Branson J, Dilleen M, et al Protecting patient privacy when sharing patient-level data from clinical trials BMC Med Res Methodol 2016;16 Suppl 1:77, accessed at: https://doi org/10 1186/s12874-016-0169-4 (last accessed 24 April 2020)

4 EU General Data Protection Regulation (GDPR), accessed at: https://eur-lex europa eu/legal-content/EN/TXT/PDF/?uri=CELEX:32016R0679&from=EN (last accessed 24 April 2020)

5 PHUSE: De-Identification and Anonymisation of Individual Patient Data in Clinical Studies—A Model Approach, accessed at: https://www phuse eu/white-papers (last accessed 24 April 2020)

6 PHUSE: De-Identification Standard for SDTM 3 2 Version 1 0, 15 May 2015, accessed at: https://www phuse eu/documents/working-groups/data-transparency/de-identification/PHUSE-de-identification-standard-for-sdtm-32-version-101-21300 xls https://www phuse eu/phuse-references (last accessed 24 April 2020)

7 EU Data Protection Directive (Directive 95/46/EC), accessed at: https://eur-lex europa eu/legal-content/EN/TXT/?uri=celex:31995L0046 (last accessed 24 April 2020)

8 Article 29 Working Party Opinion 05/2014 on Anonymisation Techniques: WP216 10 April 2014, accessed at: https://iapp org/media/pdf/resource_center/wp216_Anonymisation-Techniques_04-2014 pdf (last accessed 24 April 2020)

9 EMA External guidance on the implementation of the European Medicines Agency policy on the publication of clinical data for medicinal products for human use (Policy 0070), accessed at: https://www ema europa eu/en/human-regulatory/marketing-authorisation/clinical-data-publication/support-industry/external-guidance-implementation-european-medicines-agency-policy-publication-clinical-data (last accessed 24 April 2020)

10 Health Insurance Portability and Accountability Act of 1996, accessed at: https://aspe hhs gov/report/health-insurance-portability-and-accountability-act-1996 (last accessed 24 April 2020)

11 World Health Organization International Clinical Trials Registry Platform (ICTRP) Data Providers, accessed at: https://www who int/ictrp/search/data_providers/en/ (last accessed 24 April 2020)

12 Organisation for Economic Co-operation and Development, Glossary of Statistical Terms, accessed at: https://stats oecd org/glossary/detail asp?ID=6905 (last accessed 24 April 2020)

13 World Health Organization International Clinical Trials Registry Platform (ICTRP) Clinical Trial, accessed at: https://www who int/ictrp/en/ (last accessed 24 April 2020)

14 National Cancer Institute, CDISC Terminology, accessed at: https://www cancer gov/research/resources/terminology/cdisc (last accessed 24 April 2020)

15 PHUSE: Clinical Trial Transparency and Disclosure: A Global View, accessed at: https://www phuse eu/white-papers (last accessed 28 April 2020)

16 PHUSE Feedback Forum, accessed at: https://www phuse eu/ctt-feedback-forum (last accessed 28 April 2020)

17 PHUSE: Global View of Clinical Trial Transparency and Disclosure Events for a Single Study and Product Submissions, accessed at: https://www phusewiki org/docs/Deliverables/SupportingDocs/Global%20View%20of%20CTT%20and%20Disclosure%20Events%20Version%202_May2020 pdf (last accessed 29 April 2020)

18 PHUSE: Clinical Trial Transparency and Disclosure: A Global View Version 1 0, 11 December 2018, accessed at: https://www phuse eu/white-papers (last accessed 29 April 2020)

19 Health Canada Public Release of Clinical Information 12 March 2019, accessed at: https://www canada ca/en/health-canada/news/2019/03/health-canada-finalises-regulations-to-provide-public-access-to-clinical-information-on-drugs-and-medical-devices html (last accessed 29 April 2020)

http://https://doi.org/10.17226/18998

https://www.ema.europa.eu/human-regulatory/marketing-authorisation/clinical-data-publication

https://doi.org/10.1186/s12874-016-0169-4

https://eur-lex.europa.eu/legal-content/EN/TXT/PDF/?uri=CELEX:32016R0679&from=EN

https://eur-lex.europa.eu/legal-content/EN/TXT/PDF/?uri=CELEX:32016R0679&from=EN

https://www.phuse.eu/white-papers

https://www.phuse.eu/documents/working-groups/data-transparency/de-identification/PHUSE-de-identification-standard-for-sdtm-32-version-101-21300.xls

https://www.phuse.eu/documents/working-groups/data-transparency/de-identification/PHUSE-de-identification-standard-for-sdtm-32-version-101-21300.xls

https://www.phuse.eu/phuse-references

https://www.phuse.eu/phuse-references

https://eur-lex.europa.eu/legal-content/EN/TXT/?uri=celex:31995L0046

https://eur-lex.europa.eu/legal-content/EN/TXT/?uri=celex:31995L0046

https://iapp.org/media/pdf/resource_center/wp216_Anonymisation-Techniques_04-2014.pdf

https://iapp.org/media/pdf/resource_center/wp216_Anonymisation-Techniques_04-2014.pdf

https://www.ema.europa.eu/en/human-regulatory/marketing-authorisation/clinical-data-publication/support-industry/external-guidance-implementation-european-medicines-agency-policy-publication-clinical-data



https://aspe.hhs.gov/report/health-insurance-portability-and-accountability-act-1996

https://aspe.hhs.gov/report/health-insurance-portability-and-accountability-act-1996

https://www.who.int/ictrp/search/data_providers/en/

https://www.who.int/ictrp/search/data_providers/en/

https://stats.oecd.org/glossary/detail.asp?ID=6905

https://stats.oecd.org/glossary/detail.asp?ID=6905

https://www.who.int/ictrp/en/

https://www.who.int/ictrp/en/

https://www.cancer.gov/research/resources/terminology/cdisc


https://www.phuse.eu/ctt-feedback-forum

https://www.phusewiki.org/docs/Deliverables/SupportingDocs/Global%20View%20of%20CTT%20and%20Disclosure%20Events%20Version%202_May2020.pdf

https://www.phusewiki.org/docs/Deliverables/SupportingDocs/Global%20View%20of%20CTT%20and%20Disclosure%20Events%20Version%202_May2020.pdf



https://www.canada.ca/en/health-canada/news/2019/03/health-canada-finalises-regulations-to-provide-public-access-to-clinical-information-on-drugs-and-medical-devices.html





20 US FDA, Freedom of Information, accessed at: https://www fda gov/regulatory-information/freedom-information (last accessed 4 May 2020)

21 EMA Policy 0043 on Access to Documents, accessed at: https://www ema europa eu/en/documents/other/policy/0043-european-medicines-agency-policy-access-documents_en pdf (last accessed 29 April 2020)

22 EU Regulation 536/2014 of the European Parliament and of the Council of 16 April 2014 on clinical trials on medicinal products for human use, and repealing Directive 2001/20/EC, accessed at: https://ec europa eu/health/sites/health/files/files/eudralex/vol-1/reg_2014_536/reg_2014_536_en pdf (last accessed 29 April 2020)

23 International Council for Harmonisation: E3 Structure and Content of Clinical Study Reports, 1995, accessed at: https://www ich org/page/efficacy-guidelines (last accessed 29 April 2020)

24 International Council for Harmonisation: M4, The Common Technical Document, 2016, accessed at: https://www ich org/page/multidisciplinary-guidelines (last accessed 29 April 2020)

25 Office for Civil Rights, US Department of Health and Human Services, Guidance Regarding Methods for De-identification of Protected Health Information in Accordance with the Health Insurance Portability and Accountability Act (HIPAA) Privacy Rule, 26 November 2012, accessed at: https://www hhs gov/sites/default/files/ocr/privacy/hipaa/understanding pdf (last accessed 29 April 2020)

26 Office of the Privacy Commissioner of Canada Privacy Act RSC, 1985, c P-21 13 December 2018, accessed at: https://laws-lois justice gc ca/eng/acts/P-21/ (last accessed 29 April 2020)

27 Information and Privacy Commissioner of Ontario, De-identification Guidelines for Structured Data June 2016, accessed at: https://www ipc on ca/wp-content/uploads/2016/08/Deidentification-Guidelines-for-Structured-Data pdf (last accessed 29 April 2020)

28 El Emam K Guide to the De-Identification of Personal Health Information Auerbach Publications 2013

29 El Emam K Risky Business: Sharing Health Data While Protecting Privacy Trafford 2013

30 Arbuckle L, El Emam K Building an Anonymization Pipeline: Creating Safe Data O’Reilly 2020

31 Sweeney L k-anonymity: A model for protecting privacy Int J Uncertainty, Fuzziness Knowledge-based Syst October 2002, 557-70

32 Winpenny G, Bamford S De-ID: ‘The What’ and ‘The How’ of de-identifying your clinical trial data PHUSE 2015 Annual Conference, accessed at: http://www phusewiki org/docs/Conference%202015%20SD%20Papers/SD06 pdf (last accessed 29 April 2020)

33 PHUSE: Protection of Personal Data in Clinical Documents – A Model Approach Version 1 0, 10 June 2019, accessed at: https://www phuse eu/white-papers (last accessed 30 April 2020)

34 EMA Heads of Medicines Agencies Recommendations on Transparency; Recommendations on the handling of requests for access to Periodic Safety Update Reports (PSURs), 2009, accessed at: https://www ema europa eu/en/documents/regulatory-procedural-guideline/heads-medicines-agencies/european-medicines-agency-recommendations-transparency-recommendations-handling-requests-access_en pdf (last accessed 30 April 2020)

35 PHUSE: Retrospective vs Proactive Anonymisation of Narratives Version 1 0, 10 June 2019, accessed at: https://www phuse eu/white-papers (last accessed 30 April 2020)

36 EMA, Clinical data publication (Policy 0070) report Oct 2016-Oct 2017, accessed at: https://www ema europa eu/en/documents/report/clinical-data-publication-policy-0070-report-oct-2016-oct-2017_en pdf (last accessed 30 April 2020)

37 PHUSE: Clinial Trial Transparency Country-level Worksheet, accessed at: https://www phuse eu/documents//working-groups/deliverables/data-transparency/phuse-white-paper-country-oversight-update-12-may-2020-29701 xlsx (last accessed 30 April 2020)

38 EU Clinical Trials Register, accessed at: https://www clinicaltrialsregister eu/ctr-search/search (last accessed 30 April 2020)

39 EU Clinical Trials Information System, information for stakeholders, accessed at: https://www ema europa eu/en/human-regulatory/research-development/clinical-trials/clinical-trial-regulation#the-clinical-trials-information-system--section (last accessed 30 April 2020)

https://www.fda.gov/regulatory-information/freedom-information

https://www.ema.europa.eu/en/documents/other/policy/0043-european-medicines-agency-policy-access-documents_en.pdf

https://www.ema.europa.eu/en/documents/other/policy/0043-european-medicines-agency-policy-access-documents_en.pdf

https://ec.europa.eu/health/sites/health/files/files/eudralex/vol-1/reg_2014_536/reg_2014_536_en.pdf

https://ec.europa.eu/health/sites/health/files/files/eudralex/vol-1/reg_2014_536/reg_2014_536_en.pdf

https://www.ich.org/page/efficacy-guidelines

https://www.ich.org/page/efficacy-guidelines

https://www.ich.org/page/multidisciplinary-guidelines

https://www.ich.org/page/multidisciplinary-guidelines

https://www.hhs.gov/sites/default/files/ocr/privacy/hipaa/understanding.pdf

https://laws-lois.justice.gc.ca/eng/acts/P-21/


https://www.ipc.on.ca/wp-content/uploads/2016/08/Deidentification-Guidelines-for-Structured-Data.pdf

https://www.ipc.on.ca/wp-content/uploads/2016/08/Deidentification-Guidelines-for-Structured-Data.pdf

http://www.phusewiki.org/docs/Conference%202015%20SD%20Papers/SD06.pdf



https://www.ema.europa.eu/en/documents/regulatory-procedural-guideline/heads-medicines-agencies/european-medicines-agency-recommendations-transparency-recommendations-handling-requests-access_en.pdf





https://www.ema.europa.eu/en/documents/report/clinical-data-publication-policy-0070-report-oct-2016-oct-2017_en.pdf


https://www.phuse.eu/documents//working-groups/deliverables/data-transparency/phuse-white-paper-country-oversight-update-12-may-2020-29701.xlsx

https://www.phuse.eu/documents//working-groups/deliverables/data-transparency/phuse-white-paper-country-oversight-update-12-may-2020-29701.xlsx

https://www.clinicaltrialsregister.eu/ctr-search/search

https://www.ema.europa.eu/en/human-regulatory/research-development/clinical-trials/clinical-trial-regulation#the-clinical-trials-information-system--section

https://www.ema.europa.eu/en/human-regulatory/research-development/clinical-trials/clinical-trial-regulation#the-clinical-trials-information-system--section



40 US National Library of Medicine, ClinicalTrials gov, accessed at: https://clinicaltrials gov/ (last accessed 30 April 2020)

41 US National Library of Medicine, 42 CRF Part 11, FDAAA 801 and the Final Rule, accessed at: https://clinicaltrials gov/ct2/manage-recs/fdaaa (last accessed 30 April 2020)

42 ICMJE Recommendations for the Conduct, Reporting, Editing, and Publication of Scholarly Work in Medical Journals Updated December 2018, accessed at: http://www icmje org/icmje-recommendations pdf (last accessed 30 April 2020)

43 US National Library of Medicine, ClinicalTrials gov “How to Edit Your Study Record”, accessed at: https://clinicaltrials gov/ct2/manage-recs/how-edit (last accessed 30 April 2020)

44 EudraCT Primary User Request Form, accessed at: https://eudract ema europa eu/docs/guidance/EudraCt%20Request%20March2019 pdf (last accessed 1 May 2020)

45 US Office of Personnel Management, Information Management, Plain Language, accessed at: https://www opm gov/information-management/plain-language/ (last accessed 1 May 2020)

46 Summaries of Clinical Trial Results for Laypersons, accessed at https://ec europa eu/health/sites/health/files/files/eudralex/vol-10/2017_01_26_summaries_of_ct_results_for_laypersons pdf (last accessed 1 May 2020)

47 TransCelerate Recommendations for Drafting Non-Promotional Lay Summaries of Clinical Trial Results, accessed at: http://www transceleratebiopharmainc com/wp-content/uploads/2015/04/TransCelerate-Non-Promotional-Language-Guidelines-v10-1 pdf (last accessed 1 May 2020)

48 TrialScope Trial Results Summaries, accessed at: https://www trialsummaries com/Home/LandingPage (last accessed 1 May 2020)

49 Ghersi D, Clarke M, Berlin J, et al Reporting the findings of clinical trials: a discussion paper Bull WHO, June 2008;86(6),492-3

50 National Academies of Sciences, Institute of Medicine Developing a National Registry of Pharmacologic and Biologic Clinical Trials: Workshop Report Washington, DC: The National Academies Press, 2006, accessed at: https://doi org/10 17226/11561 (last accessed 2 May 2020)

51 Oxford English Dictionary, accessed at: https://www lexico com/definition/publication (last accessed 2 May 2020)

52 Day R What is a scientific paper? In: How to Write and Publish a Scientific Paper, Page 2 iSi Press Philadelphia, 1983

53 Altman PL The Council from 1957 to 1991: CBE Foundations for CSE Sci Ed 2007;30:111-3, accessed at: https://www councilscienceeditors org/wp-content/uploads/v30n4p111-113 pdf (last accessed 2 May 2020)

54 Council of Science Editors, Clinical Trial Not Registered, accessed at: https://www councilscienceeditors org/resource-library/editorial-policies/sample-correspondence-for-an-editorial-office/clinical-trial-not-registered/ (last accessed 2 May 2020)

55 Editorial: Secret nostrums and the journal JAMA 1900;XXXIV(22):1420, accessed at: https://jamanetwork com/journals/jama/article-abstract/477331 (last accessed 2 May 2020)

56 Donohue J A history of drug advertising: the evolving roles of consumers and consumer protection Milbank Q 2006;84(4):659-99

57 US Electronic Code of Federal Regulations, Part 202, Prescription Drug Advertising, accessed at: https://www ecfr gov/cgi-bin/retrieveECFR?gp=&SID=7fc2dee8601af5e15f743b542ee3f47c&mc=true&r=PART&n=pt21 4 202 (last accessed 2 May 2020)

58 US FDA, Clinical Studies Section of Labeling for Human Prescription Drug and Biological Products—Content and Format, Guidance for Industry January 2006, accessed at: https://www fda gov/RegulatoryInformation /Guidances/ucm127509 htm (last accessed 2 May 2020)

59 US NIH National Library of Medicine PubMed Central, accessed at: https://www ncbi nlm nih gov/pmc/ (last accessed 2 May 2020)

60 US NIH Office of Extramural Research Omnibus Appropriations Act March 2009, accessed at: http://www grants nih gov/grants/guide/notice-files/NOT-OD-09-071 html (last accessed 2 May 2020)

61 Switzerland Federal Council, Ordinance on Clinical Trials in Human Research, Chapter 2, Section 2, Article 25, accessed at: https://www admin ch/opc/en/classified-compilation/20121176/index html#a25 (last accessed 2 May 2020)

62 Netherlands Central Committee on Research Involving Human Subjects, CCMO Directive on the Assessment of Clinical Trial Agreements, accessed at: https://english ccmo nl/investigators/publications/directives/2011/08/30/ccmo-directive-on-the-assessment-of-clinical-trial-agreements (last accessed 2 May 2020)

https://clinicaltrials.gov/

https://clinicaltrials.gov/ct2/manage-recs/fdaaa

https://clinicaltrials.gov/ct2/manage-recs/fdaaa

http://www.icmje.org/icmje-recommendations.pdf

https://clinicaltrials.gov/ct2/manage-recs/how-edit

https://clinicaltrials.gov/ct2/manage-recs/how-edit

https://eudract.ema.europa.eu/docs/guidance/EudraCt%20Request%20March2019.pdf

https://eudract.ema.europa.eu/docs/guidance/EudraCt%20Request%20March2019.pdf

https://www.opm.gov/information-management/plain-language/

https://www.opm.gov/information-management/plain-language/

https://ec.europa.eu/health/sites/health/files/files/eudralex/vol-10/2017_01_26_summaries_of_ct_results_for_laypersons.pdf

https://ec.europa.eu/health/sites/health/files/files/eudralex/vol-10/2017_01_26_summaries_of_ct_results_for_laypersons.pdf

http://www.transceleratebiopharmainc.com/wp-content/uploads/2015/04/TransCelerate-Non-Promotional-Language-Guidelines-v10-1.pdf

http://www.transceleratebiopharmainc.com/wp-content/uploads/2015/04/TransCelerate-Non-Promotional-Language-Guidelines-v10-1.pdf

https://www.trialsummaries.com/Home/LandingPage

https://doi.org/10.17226/11561

https://www.lexico.com/definition/publication

https://www.councilscienceeditors.org/wp-content/uploads/v30n4p111-113.pdf

https://www.councilscienceeditors.org/wp-content/uploads/v30n4p111-113.pdf

https://www.councilscienceeditors.org/resource-library/editorial-policies/sample-correspondence-for-an-editorial-office/clinical-trial-not-registered/

https://www.councilscienceeditors.org/resource-library/editorial-policies/sample-correspondence-for-an-editorial-office/clinical-trial-not-registered/

https://jamanetwork.com/journals/jama/article-abstract/477331

https://jamanetwork.com/journals/jama/article-abstract/477331

https://www.ecfr.gov/cgi-bin/retrieveECFR?gp=&SID=7fc2dee8601af5e15f743b542ee3f47c&mc=true&r=PART&n=pt21.4.202

https://www.ecfr.gov/cgi-bin/retrieveECFR?gp=&SID=7fc2dee8601af5e15f743b542ee3f47c&mc=true&r=PART&n=pt21.4.202

https://www.fda.gov/RegulatoryInformation /Guidances/ucm127509.htm

https://www.ncbi.nlm.nih.gov/pmc/

http://www.grants.nih.gov/grants/guide/notice-files/NOT-OD-09-071.html

http://www.grants.nih.gov/grants/guide/notice-files/NOT-OD-09-071.html

https://english.ccmo.nl/investigators/publications/directives/2011/08/30/ccmo-directive-on-the-assessment-of-clinical-trial-agreements

https://english.ccmo.nl/investigators/publications/directives/2011/08/30/ccmo-directive-on-the-assessment-of-clinical-trial-agreements



63 Roth RI Preparing the Common Technical Document for registration of pharmaceuticals for human use (CTD)—insights and recommendations Drug Inf J 2008;42:149-59, accessed at: https://regulatoryaffairsblog files wordpress com/2013/04/ectd pdf (last accessed 2 May 2020)

64 International Society for Medical Publication Professionals, accessed at: https://www ismpp org/ (last accessed 2 May 2020)

65 European Medical Writers Association, accessed at: https://www emwa org/ (last accessed 2 May 2020)

66 American Medical Writers Association, accessed at: https://www amwa org/ (last accessed 2 May 2020)

67 Chipperfield L, Citrome L, Clark J, et al Authors' Submission Toolkit: A practical guide to getting your research published Curr Med Res Opin 2010;26:8:1967-82

68 ICMJE membership list, accessed at: http://www icmje org/about-icmje/faqs/icmje-membership/ (last accessed on 2 May 2020)

69 Smith SM, Dworkin RH Prospective clinical trial registration: not sufficient, but always necessary Anaesthesia 2018;73(5):538-41

70 Pandit JJ, Klein AA Journal response: prospective clinical trial registration—desirable, but not necessary Anaesthesia 2018;73(5):535-48

71 US NIH National Library of Medicine MEDLINE, accessed at: https://www nlm nih gov/bsd/medline html (last accessed 2 May 2020)

72 Committee on Publication Ethics, Code of Conduct and Best Practice Guidelines for Journal Editors, accessed at: http://publicationethics org/files/Code_of_conduct_for_journal_editors_Mar11 pdf (last accessed 2 May 2020)

73 ICMJE FAQ on clinical trials registration, accessed at: http://www icmje org/about-icmje/faqs/clinical-trials-registration/ (last accessed 2 May 2020)

74 EMA Clinical Data, Online access to clinical data for medicinal products for human use, accessed at https://clinicaldata ema europa eu/web/cdp/home (last accessed 2 May 2020)

75 Resta RG, McCarthy Veach P, et al Publishing a Master’s Thesis: A Guide for Novice Authors J Genet Counsel (2010);19:217–27

76 Elsevier JournalFinder, accessed at: https://journalfinder elsevier com/ (last accessed 3 May 2020)

77 Springer Nature Journal Suggester, accessed at: https://journalsuggester springer com/ (last accessed 3 May 2020)

78 Taylor & Francis Author Services, accessed at: https://authorservices taylorandfrancis com/how-to-choose-a-journal/ (last accessed 3 May 2020)

79 US FDA Guidance for Industry and Review Staff, Target Product Profile—A Strategic Development Process Tool, Draft Guidance, March 2007, accessed at: https://www fda gov/media/72566/download (last accessed 3 May 2020)

80 Annals of Internal Medicine, Good Publication Practice for Communicating Company-sponsored Medical Research: GPP3, accessed at: https://annals org/aim/fullarticle/2424869/good-publication-practice-communicating-company-sponsored-medical-research-gpp3 (last accessed 3 May 2020)

81 CONSORT Transparent Reporting of Trials, Statement, accessed at: http://www consort-statement org/ (last accessed 3 May 2020)

82 EQUATOR Network, Enhancing the QUAlity and Transparency Of health Research, accessed at: http://www equator-network org/ (last accessed 3 May 2020)

83 European Commission, Trends for open access to publications, Research journal policies, accessed at: https://ec europa eu/info/research-and-innovation/strategy/goals-research-and-innovation-policy/open-science/open-science-monitor/trends-open-access-publications_en#journalspolicies (last accessed 3 May 2020)

84 Backus JEB, Davidson S, Rada R Searching for patterns in the MeSH vocabulary Bull Med Libr Assoc 1987;75(3):221–7

85 US National Library of Medicine, Bibliographic Services Division, accessed at: https://www nlm nih gov/bsd/bsdhome html (last accessed 3 May 2020)

86 House of Commons Science and Technology Committee, Scientific Publications: Free for all? Tenth Report of Session 2003-04, published 20 July 2004, accessed at: https://publications parliament uk/pa/cm200304/cmselect/cmsctech/399/399 pdf (last accessed 3 May 2020)

https://regulatoryaffairsblog.files.wordpress.com/2013/04/ectd.pdf

https://www.ismpp.org/

https://www.emwa.org/

https://www.amwa.org/

http://www.icmje.org/about-icmje/faqs/icmje-membership/

https://www.nlm.nih.gov/bsd/medline.html

http://publicationethics.org/files/Code_of_conduct_for_journal_editors_Mar11.pdf

http://publicationethics.org/files/Code_of_conduct_for_journal_editors_Mar11.pdf

http://www.icmje.org/about-icmje/faqs/clinical-trials-registration/

https://clinicaldata.ema.europa.eu/web/cdp/home

https://clinicaldata.ema.europa.eu/web/cdp/home

https://journalfinder.elsevier.com/

https://journalsuggester.springer.com/http://

https://authorservices.taylorandfrancis.com/how-to-choose-a-journal/

https://www.fda.gov/media/72566/download

https://annals.org/aim/fullarticle/2424869/good-publication-practice-communicating-company-sponsored-medical-research-gpp3

https://annals.org/aim/fullarticle/2424869/good-publication-practice-communicating-company-sponsored-medical-research-gpp3

http://www.consort-statement.org/

http://www.equator-network.org/

https://ec.europa.eu/info/research-and-innovation/strategy/goals-research-and-innovation-policy/open-science/open-science-monitor/trends-open-access-publications_en#journalspolicies



https://www.nlm.nih.gov/bsd/bsdhome.html

https://publications.parliament.uk/pa/cm200304/cmselect/cmsctech/399/399.pdf



87 Cox V, Scott MC FDA Advisory Committee Meetings: What they are, why they happen, and what they mean for regulatory professionals Regul Rapp 2014;11(11):5-8, accessed at: http://www 3dcommunications us/wp-content/uploads/2014/11/14-11-regulatory-rapporteur-FDA-advisory-committee-meetings-cox-scott pdf (https://embed topra org/sites/default/files/regrapart/1/5988/14-11-regulatory-rapporteur-fda-advisory-committee-meetings-cox-scott pdf (last accessed 3 May 2020)

88 Farrah K, Mierzwinski-Urban M Almost half of references in reports on new and emerging nondrug health technologies are grey literature J Med Libr Assoc 2019;107(1):43-8

89 GreyNet International 2019, accessed at: http://greynet org/home/aboutgreynet html (last accessed 4 May 2020)

90 IFPMA, New industry position requires submission for journal publication of all phase III clinical trials, accessed at: https://www ifpma org/resource-centre/new-industry-position-requires-submission-for-journal-publication-of-all-phase-iii-clinical-trials/ (last accessed 4 May 2020)

91 PhRMA, Clinical Trial Data Transparency, accessed at: https://www phrma org/fact-sheet/clinical-trial-data-transparency (last accessed 4 May 2020)

92 EFPIA, Sharing clinical trial information, accessed at: https://www efpia eu/about-medicines/development-of-medicines/regulations-safety-supply/clinical-trials/sharing-clinical-trial-information/ (last accessed 4 May 2020)

93 PhRMA/EFPIA, Principles for Responsible Clinical Trial Data Sharing, accessed at: https://www efpia eu/media/25189/principles-for-responsible-clinical-trial-data-sharing pdf (last accessed 4 May 2020)

94 US Centers for Medicare & Medicaid Services, Open Payments, accessed at: https://www cms gov/openpayments/ (last accessed 4 May 2020)

95 World Medical Association Declaration of Helsinki, Ethical Principles for Medical Research Involving Human Subjects, accessed at: https://www wma net/policies-post/wma-declaration-of-helsinki-ethical-principles-for-medical-research-involving-human-subjects/ (last accessed 4 May 2020)

96 EMA, Data anonymisation workshop, 2017, accessed at: https://www ema europa eu/en/events/data-anonymisation-workshop (last accessed 4 May 2020)

97 Elliot M, Mackey M, O’Hara K, et al The Anonymisation Decision-Making Framework, 2016, accessed at: http://ukanon net/wp-content/uploads/2015/05/The-Anonymisation-Decision-making-Framework pdf (last accessed 4 May 2020)

98 Biotechnology Industry Organization, BIO Principles on Clinical Trial Data Sharing, accessed at: https://www bio org/sites/default/files/legacy/bioorg/docs/BIO%20Principles%20on%20Clinical%20Trial%20Data%20Sharing pdf (last accessed 4 May 2020)

99 IFPMA, Principles for Responsible Clinical Trial Data Sharing, accessed at: https://www ifpma org/wp-content/uploads/2010/11/IFPMA-Principles_Data-Sharing-FINAL-w-QA-vF pdf (last accessed 4 May 2020)

100 EFPIA/IFPMA/PhRMA/Japan Pharmaceutical Manufacturers Association, Joint Position on the Disclosure of Clinical Trial Information via Clinical Trial Registries and Databases, November 2008, accessed at: http://www jpma or jp/event_media/release/pdf/090416_shishin_e pdf (last accessed 4 May 2020)

101 AllTrials Transparency Index, accessed at: http://policyaudit alltrials net/ (last accessed 4 May 2020)

102 Bioethics International, Good Pharma Scorecard, accessed at: https://bioethicsinternational org/good-pharma-scorecard/ (last accessed 4 May 2020)

103 AllTrials, accessed at: http://www alltrials net/ (last accessed 4 May 2020)

104 US National Library of Medicine, ClinicalTrials gov, IPD Sharing Statement, accessed at: https://prsinfo clinicaltrials gov/definitions html#IPDSharing (last accessed 4 May 2020)

105 Yale University, The Yale Open Data Access (YODA) Project, accessed at: https://yoda yale edu/ (last accessed 4 May 2020)

106 Vivli Center for Global Clinical Research Data, accessed at: https://vivli org/ (last accessed 4 May 2020)

107 Duke Clinical Research Institute, SOAR DATA, accessed at: https://dcri org/our-work/analytics-and-data-science/data-sharing/soar-data/ (last accessed 4 May 2020)

108 ClinicalStudyDataRequest com, accessed at: https://clinicalstudydatarequest com/Default aspx (last accessed 4 May 2020)

http://www.3dcommunications.us/wp-content/uploads/2014/11/14-11-regulatory-rapporteur-FDA-advisory-committee-meetings-cox-scott.pdf

http://www.3dcommunications.us/wp-content/uploads/2014/11/14-11-regulatory-rapporteur-FDA-advisory-committee-meetings-cox-scott.pdf

https://embed.topra.org/sites/default/files/regrapart/1/5988/14-11-regulatory-rapporteur-fda-advisory-committee-meetings-cox-scott.pdf

https://embed.topra.org/sites/default/files/regrapart/1/5988/14-11-regulatory-rapporteur-fda-advisory-committee-meetings-cox-scott.pdf

http://greynet.org/home/aboutgreynet.html

https://www.ifpma.org/resource-centre/new-industry-position-requires-submission-for-journal-publication-of-all-phase-iii-clinical-trials/

https://www.ifpma.org/resource-centre/new-industry-position-requires-submission-for-journal-publication-of-all-phase-iii-clinical-trials/

https://www.phrma.org/fact-sheet/clinical-trial-data-transparency

https://www.efpia.eu/about-medicines/development-of-medicines/regulations-safety-supply/clinical-trials/sharing-clinical-trial-information/

https://www.efpia.eu/about-medicines/development-of-medicines/regulations-safety-supply/clinical-trials/sharing-clinical-trial-information/

https://www.efpia.eu/media/25189/principles-for-responsible-clinical-trial-data-sharing.pdf

https://www.efpia.eu/media/25189/principles-for-responsible-clinical-trial-data-sharing.pdf

https://www.cms.gov/openpayments/

https://www.wma.net/policies-post/wma-declaration-of-helsinki-ethical-principles-for-medical-research-involving-human-subjects/

https://www.ema.europa.eu/en/events/data-anonymisation-workshop

http://ukanon.net/wp-content/uploads/2015/05/The-Anonymisation-Decision-making-Framework.pdf

http://ukanon.net/wp-content/uploads/2015/05/The-Anonymisation-Decision-making-Framework.pdf

https://www.bio.org/sites/default/files/legacy/bioorg/docs/BIO%20Principles%20on%20Clinical%20Trial%20Data%20Sharing.pdf

https://www.bio.org/sites/default/files/legacy/bioorg/docs/BIO%20Principles%20on%20Clinical%20Trial%20Data%20Sharing.pdf

https://www.ifpma.org/wp-content/uploads/2010/11/IFPMA-Principles_Data-Sharing-FINAL-w-QA-vF.pdf

https://www.ifpma.org/wp-content/uploads/2010/11/IFPMA-Principles_Data-Sharing-FINAL-w-QA-vF.pdf

http://www.jpma.or.jp/event_media/release/pdf/090416_shishin_e.pdf

http://www.jpma.or.jp/event_media/release/pdf/090416_shishin_e.pdf

http://policyaudit.alltrials.net/

https://bioethicsinternational.org/good-pharma-scorecard/

http://www.alltrials.net/

https://prsinfo.clinicaltrials.gov/definitions.html#IPDSharing

https://prsinfo.clinicaltrials.gov/definitions.html#IPDSharing

https://yoda.yale.edu/

https://vivli.org/

https://dcri.org/our-work/analytics-and-data-science/data-sharing/soar-data/

https://dcri.org/our-work/analytics-and-data-science/data-sharing/soar-data/

https://clinicalstudydatarequest.com/Default.aspx



109 CEO Life Sciences Consortium, Project Data Sphere, accessed at: https://www projectdatasphere org/projectdatasphere/html/home (last accessed 4 May 2020)

110 US FDA, Clinical Data Summary Pilot Program, accessed at: https://www fda gov/drugs/development-approval-process-drugs/clinical-data-summary-pilot-program (last accessed 4 May 2020)

111 Health Canada, Guidance document on Public Release of Clinical Information, accessed at: https://www canada ca/en/health-canada/services/drug-health-product-review-approval/profile-public-release-clinical-information-guidance html (last accessed 4 May 2020)

112 ClinicalStudyDataRequest com, Metrics, accessed at: https://www clinicalstudydatarequest com/Metrics aspx (last accessed 4 May 2020)

113 The YODA Project, YODA Project Metrics, accessed at: https://yoda yale edu/yoda-project-metrics (last accessed 4 May 2020)

114 GO FAIR, FAIR Principles, accessed at: https://www go-fair org/fair-principles/ (last accessed 4 May 2020)

115 Jauregui B, Lynn D, Hudson LD, Becnel LB, et al The turning point for clinical research: global data standardisation App Clin Trial 22 January 2019, accessed at: http://www appliedclinicaltrialsonline com/turning-point-clinical-research-global-data-standardization (last accessed 4 May 2020)

116 CDISC: CDISC Standards in the Clinical Research Process, accessed at: https://www cdisc org/standards (last accessed 4 May 2020)

https://www.projectdatasphere.org/projectdatasphere/html/home

https://www.projectdatasphere.org/projectdatasphere/html/home

https://www.fda.gov/drugs/development-approval-process-drugs/clinical-data-summary-pilot-program

https://www.fda.gov/drugs/development-approval-process-drugs/clinical-data-summary-pilot-program

https://www.canada.ca/en/health-canada/services/drug-health-product-review-approval/profile-public-release-clinical-information-guidance.html

https://www.canada.ca/en/health-canada/services/drug-health-product-review-approval/profile-public-release-clinical-information-guidance.html

https://www.clinicalstudydatarequest.com/Metrics.aspx

https://yoda.yale.edu/yoda-project-metrics

https://www.go-fair.org/fair-principles/

http://www.appliedclinicaltrialsonline.com/turning-point-clinical-research-global-data-standardization

http://www.appliedclinicaltrialsonline.com/turning-point-clinical-research-global-data-standardization

https://www.cdisc.org/standards



6. Appendices

6.1 Side-by-side Comparison of EMA and Health Canada Documents in Scope for Publication

In scope

• Clinical overviews (submitted in Module 2 5) • Clinical summaries (submitted in Module 2 7) • Clinical trial reports (submitted in Module 5), including:

• • CSR or ‘report body’,• • 16 1 1 (protocol and protocol amendments), • • 16 1 2 (sample case report form), and • • 16 1 9 (documentation of statistical methods)

• Previously submitted cross-referenced clinical reports:• ALL reports for extension/modification of indications for paediatric population• Only pivotal reports for other extensions/modifications of indications/line

extensions

• Clinical overviews (submitted in Module 2 5) • Clinical summaries (submitted in Module 2 7) • Clinical trial reports (submitted in Module 5), including:

• • CSR or ‘report body’ (including 14.3.4),• • 16 1 1 (protocol and protocol amendments), • • 16 1 2 (sample case report form), and • • 16 1 9 (documentation of statistical methods)

• Medical Class III/IV devices:• International Medical Device Regulators Forum—Table of Contents, Chapter 4,

and includes the summaries, reports, and evidence• Implementation delayed until the adoption of International Medical Device

Regulators Forum—Table of Contents

Out of scope

• CSR Section 14.3.4, Abnormal Laboratory Value Listing• Modules 2 7 5, 2 7 6, 5 1, 5 2, 5 3 1 3, 5 3 1 4, 5 3 6, 5 3 7, 5 4

• Modules 2 7 5, 2 7 6, 5 1, 5 2, 5 3 1 3, 5 3 1 4, 5 3 6, 5 3 7, 5 4

Blue bold is unique to the EMA Green bold is unique to Health Canada

6.2 Examples of Document Disclosure by Category

6.3 EMA Policy 0070 and Health Canada PRCI Process Flow Publication of Clinical Information

Health Authority Publication• AusPAR—Australian Public Assessment Reports • DE PharmNet.Bund—Germany BfArM (Federal Institute for Drugs and Medical

Devices)• EPAR—European Public Assessment Report • ES REec—Spanish Clinical Studies Register• EU CDP—European Clinical Data Publication (Policy 0070) • EU CTIS—Clinical Trials Information System (CTA)• EUDAMED—European Database on Medical Devices • EudraCT—EU Clinical Trials Register (Interventional trials)• EU PAS Register—European Union Post-Authorisation Studies Register (ENCePP—

European Network of Centres for Pharmacoepidemiology and Pharmacovigilance) (Observational trials)

• EU PRAC/PSUSA—Pharmacovigilance Risk Assessment Committee (PRAC)/PSUR, single assessment (PSUSA)

• HC PRCI—Health Canada Public Release Clinical Information • JP PMDA—Japan Pharmaceuticals and Medical Devices Agency • US NLM—US National Library

Access to Documents*• BE AtD—Belgium Access to Documents (AtD) • DK FOI—Denmark Freedom of Information• EU AtD—EMA Access to Documents (Policy 0043) • NL AtD—Netherlands Access to Documents • UK FOI—United Kingdom Freedom of Information

Clinical Trial Data Sharing

• External Publisher/Journal • External Researcher or Partner • WHO PQVAR—World Health Organization Prequalified Vaccine Annual Report

*The US FDA processes the requests for Freedom of Information without MAH consultation; therefore, they are not included in the list above

• Cover Letter; (EMA-List of Documents)

• Proposed redaction M2 5, 2 7 Summaries & M5 Reports

• Anonymization Report• Justification Table or Control

Sheet

• Cover Letter• Proposed redaction M2 5,

2 7 Summaries & M5 Reports• Revsied anonymization report

(if applicable)

• EMA Clinical Data Portal• Health Canada Public Release

of Clinical Information

Redaction Proposal Package

Consultation

Final Redaction Package

Agency Posting



6.4 Health Authority-specific Practices for Protecting Personal Data in Clinical Documents Subject to Public Release

The document disclosure and preparation section of this Best Practices Guide outlines the best practices for writing with the end in mind, and subsequent management and preparation of documents for public release Specifically, a challenge for data providers is to develop a single set of practices that optimise operational efficiency while complying with various health authority regulations and guidance Ideally, a well-planned approach should create a regulatory submission that:

• provides the information that is necessary to support regulatory review in multiple regions,

• minimises information that needs to be anonymised (redacted or recoded) prior to public disclosure of the submission documents, and

• standardises the format of any remaining protected information, to the extent practicable, to facilitate anonymisation (redaction or recoding)

The laws, regulations, and policies that guide public disclosure of clinical documents and determine what constitutes personal privacy information vary among regions An understanding of these differences may allow the writing and formatting of clinical documents to avoid inclusion of information that is released in one region and protected in another, thus supporting a holistic and efficient approach to protecting personal privacy information

The tables below are side-by-side comparisons that summarise the current anonymisation and release practices for specific personal data or personal privacy information elements (participant and data provider level) within clinical documents used in submissions that may be subject to disclosure by:

• the EMA under Policy 0070 [Ref A1],

• Health Canada under PRCI [Ref A2], and

• the US FDA CDER under FOIA [Ref A3] for information in approved marketing applications in response to FOIA requests or proactive public disclosure by the health authority

Given the increasing amount of data now made public, as well as the increasing number of privacy threats (i e more tools and data available to adversaries), it is increasingly necessary to review anonymisation processes at regular intervals to ensure they are still meeting all requirements [Refs A4, A5, A6] When creating clinical documents for submissions it is important to think holistically and to take into consideration specific health authority guidance When assessing risk, it should be kept in mind that statistical support and human review and interpretation are often required to identify unique instances of combinations of quasi identifiers and rare disease or sensitive information

Disclaimer: Anonymisation TechniquesBoth redaction (removal) and recoding (modification) can be used to protect private and confidential information, and both are considered forms of anonymisation The preferred technique will depend on the health authority, on whether the anonymisation is being performed by the health authority or data provider, and on the programme/legal authority under which the disclosure is being made Sponsors should consult with the health authority if there are any questions about the preferred anonymisation technique

3 The US does not currently have a programme to proactively disclose clinical

documents from marketing applications However, these documents may be publicly

disclosed in response to FOIA requests, and information excerpted from these

documents is routinely included in US FDA CDER reviews proactively posted on the

FDA’s website shortly after an application is approved The same clinical documents

are frequently submitted to the US FDA CDER, the EMA, and Health Canada For

this reason, US FDA CDER practices are included and compared to the EMA and

Health Canada programmes for publicly disclosing clinical documents Regardless

of the programme under which US FDA CDER prepares documents for public

disclosure (e g FOIA requests, proactive disclosure programmes, litigations), the

same anonymisation technique (redaction) is used and the same information is

exempt from public disclosure



Personal Privacy—Participant Level

Data Element EMA—Policy 0070 Health Canada—PRCI FDA/CDER—FOIA

Anonymise Release Anonymise Release Anonymise Release

Participant name, contact information or other typical ID (e g social security number, initials in participant ID)

X X X

Aligned Aligned Aligned

Participant ID(also includes clinical trial SAE case ID, treatment randomisation ID)

X X X


Participant demographic information/physical characteristics (age, sex, race, weight, etc )

X X X

Risk-based anonymisation of quasi IDs until acceptable risk threshold is achieved

Population (disease vs trial) impacts the outcome of risk calculations and therefore the

degree of anonymisation required

Aligned with the EMA Released with limited exceptions For example, when the population for the disease studied is extremely small—i e “ultra-orphan”—this

information would be reviewed holistically, and further redactions may be considered

Medical personnel and healthcare facilities (including site/laboratory ID) associated with details of an individual participant in a clinical trial

X X X


Participant date of birthX X X

Aligned; full participant date of birth should no longer be collected Age or age range

recommended instead If date is present, prefer year to be retained, day/month can be redacted

Age would be retained unless anonymised to achieve the risk threshold (see above)

Aligned Aligned Age is released

Participant date of deathX X X

Routinely anonymise whole date of death; alternatively, follow rules as per participant

dates of birth above

Routinely anonymise whole date of death Relative day (i e day of death relative to anchor date for that participant, e g Day 10) is released

Participant dates of hospitalisation/ treatment

X X X

The EMA expresses a preference for anonymisation

Routinely anonymise whole date Note: relative day is released

Any additional information that could lead to determining the participant’s identity For example, sensational AEs such as murder/suicide and other sensitive events (e g legal situations) that might have been newsworthy

X X X

Aligned; case-by-case evaluation to assess risk with consideration as to whether document will

be released publicly

Aligned Aligned; FDA regulations state to delete names and any other information that would identify

research participants See 21 US Code of Federal Regulations § 20 63(a) [Ref A6]

Genetic information: limited For example, limited genetic information assessing disease state of individual participant (tumour cell, viral, bacterial mutation) or general characteristics of some participants in the trial (e g slow metaboliser, participants for whom the treatment was not effective)

X

Limited experience Consult with health authority


Genetic information: more extensive For example, significant portions or multiple portions of a participant’s genome

X



Photographs, images and X-rays

X



Exception: withheld if unable to remove identifying information from the photographs,

images or X-rays



Personal Privacy—Data Provider Level

Data Element EMA—Policy 0070 Health Canada—PRCI FDA/CDER—FOIA

Anonymise Release Anonymise Release Anonymise Release

Sponsor employees: high-level/responsible officials For example, employees with signatory/approval authority or oversight responsibilities

X X X

Exception: data provider signatory is released Considered personal information under HC Privacy Act [Ref A7]

Sponsor employees: low level For example, secretaries, laboratory technicians, etc

X X X


Clinical investigator names and their affiliations (i e clinical site) in the context of a general list

X X X

Principal investigator names are released Exception: other investigator names are

anonymised

XConsidered personal information under HC Privacy Act Any information that is considered

personal information and not directly identifying is assessed on a case-by-case basis This includes

the roles and titles of individual investigators

Generally, both principal investigator and sub-investigator names and affiliations are released

(21 U S Code of Federal Regulations § 20 63(d)) [Ref A6]

Clinical investigator names in the context of an individual participant (i e anonymise the investigator’s name to protect the privacy of the participant rather than the investigator)

X X X

Aligned Considered personal information under HC Privacy Act

Aligned

Role/title, e g statistician, physician

X X X

Generally, all released Considered personal information under HC Privacy Act Exception: trial role, e g statistician role may be released, whereas organisational

titles would be anonymised

Exception: anonymised if the role/title would identify the low-level individual or other

individual whose name would be redacted

Contractor employees X X X

Contracted employee names redacted unless considered a responsible official

Considered personal information under HC Privacy Act [Ref A7]

Exception: When the contractual relationship has been publicly disclosed by the data

provider/contractor, apply the same practices as per data provider employees, i e information

identifying high-level employees is released, whereas information identifying low-level

employees would be redacted

Contract organisations X X X

Exception: name and location of contract organisation can be redacted if justified as CCI

Exception: name and location of contract organisation can be redacted as CBI if justified

Exceptions: (1) When the contractual relationship has been publicly disclosed by the data provider/contractor, the FDA CDER would release the name of the contract organisation; (2) information relating to contracts involving

the federal government (funding, participation) is often releasable

Business contact information for individuals listed above whose names have been disclosed For example, business email, telephone, fax and mobile phone numbers

X X X

Redact all email addresses and telephone, fax and mobile phone numbers Exception:

release general data provider numbers and non-personal email addresses

Not clarified in PRCI guidance

Personal contact information For example, home telephone numbers, personal email addresses

X X X

Considered personal information under HC Privacy Act

SignaturesX X X

All signatures and handwritten initials are redacted

Considered personal information under HC Privacy Act and redacted

Exception: redacted if name is redacted

HC: Health Canada



References

A1 EMA: Clinical data publication (Policy 0070) report Oct 2016-Oct 2017 accessed at: https://www ema europa eu/en/documents/report/clinical-data-publication-policy-0070-report-oct-2016-oct-2017_en pdf (last accessed 29 April 2020)

A2 Health Canada Public Release of Clinical Information 12 March 2019, accessed at: https://www canada ca/en/health-canada/news/2019/03/health-canada-finalises-regulations-to-provide-public-access-to-clinical-information-on-drugs-and-medical-devices html (last accessed 29 April 2020)

A3 United States Food and Drug Administration, Center for Drug Evaluation and Research (US FDA CDER) under the Freedom of Information Act 5 (FOIA)United States Code U S C § 552 accessed at: https://www fda gov/regulatory-information/freedom-information (last accessed 29 April 2020)

A4 Luc Rocher, Julien M Hendrickx & Yves-Alexandre de Montjoye Estimating the success of re-identifications in incomplete datasets using generative models Nature Communications, 10: 3069 (2019), accessed at: https://doi org/10 1038/s41467-019-10933-3 (last accessed 29 April 2020)

A5 PHUSE: Protection of Personal Data in Clinical Documents—A Model Approach Version 1 0, 10 June 2019, accessed at: https://www phusewiki org/docs/WorkingGroups/TransCelerate pdf (last accessed 29 April 2020)

A6 United States Food and Drug Administration Code of Federal Regulations Title 21, accessed at: https://www accessdata fda gov/scripts/cdrh/cfdocs/cfCFR/CFRSearch cfm?fr=20 63 (last accessed 29 April 2020)

A7 Office of the Privacy Commissioner of Canada Privacy Act R S C , 1985, c P-21 13 December 2018, accessed at: https://laws-lois justice gc ca/eng/acts/P-21/ (last accessed 29 April 2020)








https://doi.org/10.1038/s41467-019-10933-3

https://doi.org/10.1038/s41467-019-10933-3

https://www.phusewiki.org/docs/WorkingGroups/TransCelerate.pdf

https://www.phusewiki.org/docs/WorkingGroups/TransCelerate.pdf

https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfCFR/CFRSearch.cfm?fr=20.63

https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfCFR/CFRSearch.cfm?fr=20.63



Date post:	25-Nov-2021
Category:	Documents
Upload:	others
View:	2 times
Download:	0 times