Regulations and Guidances EHR Integrationkhuri/SMPD_287/CDM/SJSU_Regulatory_6perslide_2015.pdf ·...

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e-Clinical Regulatory Standards

Bioinformatics in Medical Product Development

April 27, 2015

Future Possibilities

Agenda

• Regulations and Guidances

• EHR Integration

• EDC Demo


Software in a Regulated Environment •  What do the regulators care about? o  Data integrity o  Patient privacy o  Fraud

•  What do life science companies care about? o  Data integrity o  Confidentiality o  Acceptance of data by regulatory authorities

•  What do software vendors care about? o  Data integrity o  Passing sponsor audits


Data Integrity - ALCOA Test

•  A -- Attributable (who did it?)

•  L -- Legible (can I read it?)

•  C -- Contemporaneous (when did they do it?)

•  O -- Original (has it changed?)

•  A -- Accurate (is it right?)


Data Regulations and Guidances

•  21 CFR Part 11

•  Guidance for Industry – Computerized Systems Used in Clinical Trials

•  General Principles of Software Validation; Final Guidance for Industry and FDA Staff


eSource Guidances

•  Guidance for Industry – Electronic Source Data in Clinical Investigations (FDA)

•  Reflection Paper on Expectations for Electronic Source Data and Data Transcribed to Electronic Data Collection Tools in Clinical Trials (EMA)

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Regulation

•  Legally binding as statutory law

•  Published in Federal Register

•  Title 21 pertains to FDA regulations


Guidance •  Not legally enforceable

•  Describe FDA’s current thinking

•  The word “should” used in a guidance means it is suggested or recommended, but not required


21 CFR Part 11 - Overview •  Two Components o Electronic Records o Electronic Signatures

• Released 1997

•  Brief, vague and often over-interpreted

• Multiple Guidances – latest: August, 2003


21 CFR Part 11 – Subpart A General Provisions •  Scope o Conditions by which FDA considers electronic

records and signatures to be equivalent to paper o Applies to electronic records that are “created,

modified, maintained, archived, retrieved or transmitted”

o Does not apply to electronically transmitted paper records

o Hardware, software and documentation are subject to FDA inspection


21 CFR Part 11 – Subpart A General Provisions •  Implementation o  For records not submitted to the FDA, electronic

records and signatures can be used if they conform to Part 11

o  For records submitted to the FDA, electronic records and signatures can be used if they conform to Part 11 and have been identified as documents the FDA will accept electronically

o  FDA departments specify the format of the electronic records


21 CFR Part 11 – Subpart A General Provisions •  Definitions o Biometrics – identification of an individual based

on physical trait or repeatable action o Closed system – an environment where access

is controlled by persons responsible for the content

o Open system – an environment where access is not controlled by persons responsible for the content

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21 CFR Part 11 – Subpart A General Provisions •  Definitions o Electronic signature – a computer data

compilation of any symbol or series of symbols executed, adopted or authorized by an individual to be the legally binding equivalent of the individual’s handwritten signature

o Digital signature – an electronic signature based on cryptographic methods of originator authentication using a set of rule and a set of parameters such that the signer and the integrity of the data can be verified


21 CFR Part 11 – Subpart A General Provisions •  Definitions o Electronic record – any combination of text,

graphics, data, audio, pictorial or other information representation in digital form that is created, modified, maintained, archived, retrieved or distributed by a computer system


21 CFR Part 11 – Subpart B Electronic Records •  Controls for Closed Systems o Procedures and controls to ensure integrity,

authenticity, confidentiality and non-repudiation of records

o Validated system to ensure accuracy, reliability, consistent intended performance and ability to discern invalid or altered records

o Ability to generate accurate records in human-readable format

o Protection of records during retention period o Access limited to authorized personnel


21 CFR Part 11 – Subpart B Electronic Records

•  Controls for Closed Systems o Audit trail § Time stamp § Cannot obscure previous data § Retained as long as record itself § Available for FDA inspection

o System checks to ensure permitted sequencing o Authority checks to ensure use only by

authorized persons o Device checks to ensure validity of data source


21 CFR Part 11 – Subpart B Electronic Records •  Controls for Closed Systems o Determination that persons who develop,

maintain or use the system are properly trained o Written policies that hold individuals accountable

for actions done under their electronic signature (SOPs)

o Adequate controls over documentation (SOPs) ü System operation and maintenance ü Revision and change control procedures to

maintain audit trail of modification to system documentation


21 CFR Part 11 – Subpart B Electronic Records •  Controls for Open Systems

•  Procedures for ensuring: –  Authenticity –  Integrity –  Confidentiality (if appropriate)

•  Document encryption

•  Digital signatures

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21 CFR Part 11 – Subpart B Electronic Records

•  Signature Manifestations o Printed name of signer o Date and time stamp o Meaning associated with signature o All of the above must be available in

human-readable format


21 CFR Part 11 – Subpart C Electronic Signatures

•  General Requirements o Unique to one individual – cannot be reassigned o  The organization must verify the identity of the

individual before assigning individual’s electronic signature

o Persons using electronic signature must certify that they agree to be legally bound by signature

o Certification must be submitted by paper to FDA o  FDA may request additional certification


21 CFR Part 11 – Subpart C Electronic Signatures •  Sample Certification from FDA – included in

Guidance for Industry – Computerized Systems Used in Clinical Trials “Pursuant to Section 11.100 of Title 21 of the Code

of Federal Regulations, this is the certify that [name of organization] intends that all electronic signatures executed by our employees, agents, or representatives, located anywhere in the world, are the legally binding equivalent of traditional handwritten signatures.”


21 CFR Part 11 – Subpart C Electronic Signatures •  Signature Components and Controls o  Non-biometric signatures:

ü Employ at least 2 distinct components, i.e., username and password

ü In a continuous session, first signature requires both components, subsequent signings only require 1 component

ü Non-continuous sessions require both components ü Used only by genuine owners ü Administered such that unauthorized use requires

collaboration of 2 or more people


21 CFR Part 11 – Subpart C Electronic Signatures

•  Signature Components and Controls

o Biometric signatures shall be designed so they cannot be used by others


21 CFR Part 11 – Subpart C Electronic Signatures •  Controls for Identification Codes /

Passwords o Combination of identification code and password

must be unique o Passwords must expire o Procedures to handle deauthorization and

reissue of identification codes and passwords o  Transaction safeguards to prevent unauthorized

use o Periodic testing of tokens (if used) to ensure

proper operation.

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Computerized Systems Used in Clinical Trials •  Introduction o Primary focus is computer systems used at the

clinical sites o Also applies to systems used at CROs and

sponsors o Not intended for computerized medical devices,

diagnostic laboratory instrumentation or instruments used in analytical labs

o Does not address electronic submissions o Applies to hard copy source documents entered

into electronic records or direct entry into computer by a human or machine


Computerized Systems Used in Clinical Trials •  Key Definitions o  Commit – a action that creates, modifies or deletes an

electronic record. (The record does not exist until it is committed.)

o  Direct Entry – recording data where the electronic record is the original capture of data

o  Software Validation – confirmation by examination and provision of objective evidence that software specifications conform to user needs

o  Source Documents – original documents and records, including hospital records, clinic charts, subjects diaries, pharmacy records and recorded data from automated instruments


Computerized Systems Used in Clinical Trials •  Key General Principles o  Study protocol should identify at which steps computerized

system will be used o  Documentation should identify hardware and software

used for study o  Documentation should enable reconstruction of the trial o  When original observations are entered directly into a

computer system, the electronic record is the source doc o  Investigators must retain original or certified copies of all

source documents o  Audit trails including reason are required


Computerized Systems Used in Clinical Trials •  Recommended Standard Operating

Procedures o System Setup / Installation o Data Collection and Handling o System Maintenance o Data Backup, Recovery and Contingency Plans o Security o Change Control


Computerized Systems Used in Clinical Trials •  Data Entry o Electronic signature required at beginning of

session o User’s name must be displayed o All entries are attributable to user o Users cannot work under another user’s access o Passwords should expire regularly o Systems should have an access timeout


Computerized Systems Used in Clinical Trials •  Audit Trails o  Time stamped audit trails required o Audit trials must be retained o End-users cannot modify audit trails o  Investigators must retain original or certified

copies of audit trails o  FDA should be able to read audit trails at study

site and other locations where records are maintained

o Audit trails should be maintained chronologically and not overwrite previous information

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Computerized Systems Used in Clinical Trials

• Date and Time Stamps o Date and time cannot be changed by end-

users o Dates and time should be local to the

activity o Local time stamps can be derived from a

remote server


Computerized Systems Used in Clinical Trials •  System Features o  Prompts should be used alert users to out-of-range data o  Automatic entry of bypassed data by the system is not

allowed o  Annotations should be allowed o  Data tags should identify data that has been changed or

deleted o  Sponsors should retain the ability to retrieve data from

legacy systems (maintain old systems or transcribe data to new system

o  Transcription to new system must be validated and documented


Computerized Systems Used in Clinical Trials •  Reconstruction of Study o  FDA should be able to reconstruct study

including how data was obtained or managed o Sponsor/vendor should maintain: o Software o Operating system o Software development tools o  FDA recognizes the limitations of this

requirement



•  Physical Security o Access to system is restricted to

authorized personnel o SOPs should be in place for preventing

unauthorized access


Computerized Systems Used in Clinical Trials •  Logical Security o  All access to data should be through protective system

software o  User access log should be maintained o  Sponsor-provided systems should remain dedicated to

clinical trials •  If computer is used for other purposes:

ü Study software must be physically and logically isolated from other software

ü Changes to other software should trigger evaluation of integrity of study software

•  Virus protection is required



•  System Dependability o  Sponsor should ensure computer system conforms to their

requirements: ü Original validation documents or on-site vendor audit

documents o  Systems documentation should be available at clinical sites o  FDA may inspect software validation documentation o  Validation documentation should include:

ü Design specification ü Test plans ü Test results

o  Written procedures required for change control to software

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•  System Controls o System used should match documentation o Written contingency plans should be in place in

case of system failure o SOPs for backup and recovery procedures should

be written o Backups kept separate from original records



•  Training o  Training required for: ü Users who enter or process data ü Study monitors

o  Training should be ongoing and cover updates to system

o Personnel education, training and experience should be documented



•  Records Inspection o  FDA may inspect all records intended to support

submissions to the agency o Systems should be able to generate human-

readable and electronic forms of the data for review and copying

o Sponsor should provide hardware and software as necessary for FDA to inspect electronic records and audit trail at the site of the FDA inspection



•  Certification of Electronic Signatures o Users must agree to be legally bound by

electronic signature o Certification must be submitted by paper to FDA

with a handwritten signature o One certification letter can cover entire

organization o Sample text of letter and FDA address provided


FDA eSource Guidance

•  Guidance issued September 2013

•  Defines eSource documents / eSource data: –  Data that are initially recorded in electronic format –  Examples of entry directly into EDC and EHR

•  Protocol should describe computerized systems to be used



Data Originators

•  Clinical staff

•  Study participants

•  Medical devices

•  Central laboratories

•  EHR

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Source Data Capture

•  Transcription into eCRF* – Worst Case!

•  Direct entry into eCRF**

•  Automatic transmission from device**

•  Transmission from ePRO device**

•  Direct Transmission from EHR***

*Original doc is source **eCRF is source ***EHR is source


FDA eSource Guidance •  Audit trail required

•  Data originator should be identified –  Name –  Type

•  Investigators should be able to comment on data

•  Investigators need to sign off on data

•  Investigators must retain records or certified copies



Data from EHR

•  Must be identified as such

•  EHR must be available during an FDA inspection

•  FDA does not assess EHR compliance with 21CFRPart 11


EMA eSource Guidance •  Based on CDISC Working Group Recommendations

•  Publication: CDISC Standards and Electronic Source Data within Clinical Trials

•  Applies to: –  eCRFs –  ePRO –  Automated clinical equipment, i.e., blood pressure, ECG –  Analytical equipment –  EHR


EMA eSource Guidance

•  A – Accurate

•  L – Legible

•  C – Contemporaneous

•  O – Original

•  A – Attributable

•  C – Complete

•  C – Consistent

•  E – Enduring

•  A – Available When Needed


EMA eSource Guidance Creation and Modification of Systems

•  Instrument used to collect data (eCRF, ePRO) should be accurate representation of the protocol

•  Location of source data identified

•  Need to maintain: •  Records of system validation •  Training •  Access

•  Audit trail required

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EMA eSource Guidance Control

•  Investigator should control source document or certified copy

•  Source should not be modified without investigator knowledge

•  Sponsor should not have exclusive control of source document

•  A service provider can provide control

•  Access to source documents must be controlled


EMA eSource Guidance

Copying

•  Source document should allow for copies

•  Copies should contain metadata: –  Formats –  Context –  Layout –  Electronic signature –  Audit trail


EMA eSource Guidance Storage

•  Easily retrievable –  Available during and after active trial –  Direct access to systems should be provided to monitor,

auditors and inspectors

•  Protected from destruction –  Back-ups –  Archival


EMA eSource Guidance Electronic Health Records

•  Sponsor should assess EHR for suitability

•  Mitigation to meet requirements: –  Absence of investigator control okay with adequate audit

trail or signed printouts –  Presence of site staff can ensure monitors and auditors do

not access non-trial patients

•  Copies of EHR records should be verifiable that they are accurate and complete


General Principles of Software Validation

•  Applies to medical device software or validation of software used to design, develop or manufacture medical devices

•  The sponsor is responsible for assessing validation of off-the-shelf software

•  Very detailed – 43 pages

•  Provides insight to FDA’s view of sufficient software validation


Conclusions

•  Sponsor carries burden of responsibility for meeting regulations

•  Sponsor manages responsibility through vendor audits and internal testing

•  Focus on 21 CFR Part 11

•  Make sure all stakeholders, particularly clinical sites, understand the regulations

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References

21CFR Part 11

http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfCFR/CFRSearch.cfm?CFRPart=11


References

Guidance for Industry – Computerized Systems Used in Clinical Trials

http://www.fda.gov/OHRMS/DOCKETS/98fr/04d-0440-gdl0002.pdf


References

Guidance for Industry – Electronic Source Documentation in Clinical Investigations

http://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm328691.pdf Future Possibilities

References

Reflection Paper on Expectations for Electronic Source Data and Data Transcribed to Electronic Data Collection Tools in Clinical Trials

http://www.ema.europa.eu/docs/en_GB/document_library/Regulatory_and_procedural_guideline/2010/08/WC500095754.pdf


References

General Principles of Software Validation; Final Guidance for Industry and FDA Staff

http://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/GuidanceDocuments/ucm085281.htm EHR Integration

A New Research Paradigm

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A great hockey player plays where the puck is going to be.

A good hockey player plays where the puck is.

Wayne Gretsky


Paradigm Shift in 4 Domains

•  Protocol Feasibility

•  Site Selection & Patient Recruitment

•  Pharmacovigilance

• Clinical Data Collection


Protocol Feasibility

• Compare protocol eligibility with real patient population

•  Examine outcomes in target patients

•  Avoid costly protocol amendments

•  EHR4CR Pilot – 10 sites

• Mayo / Centerphase - 7M patients


Site Selection & Pt Recruitment

• Determine # of pts at site that meet inclusion/exclusion criteria

•  Alert PI to eligible patients

•  Pilots – Mayo: one of first to implement – Penn: increased referrals 87% – Geisinger: identified 5,000 pts for study


Pharmacovigilance

•  Safety events are underreported

•  >15 minutes to complete CIOMS form

•  >30 minutes to complete MedWatch form

•  Pfizer ASTER Pilot – All but 2 fields auto-populated – Safety reporting increased


Clinical Data Collection Today

•  92% of sites report >80% of trial data is entered in both EHR and EDC

•  Error rate between source and EDC >4%

•  Burden on sites

•  SDV is expensive

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Benefits of EHR Integration •  Eliminate unnecessary duplication of data

•  Reduce the possibility for transcription errors

•  Encourage entering source data during a subject’s visit, where appropriate

•  Eliminate transcription of source data prior to entry into an eCRF

•  Facilitate remote monitoring of data

•  Promote real-time data access for review

•  Facilitate the collection of accurate and complete data


Benefits of EHR Integration

Source: Guidance for Industry – Electronic Source Data in Clinical Investigations, September 2013


Benefits to Sponsor

• Reduction in SDV – SDV is 25-35% of Phase III budget – Enables remote SDV – Part of Risk Based Monitoring plan

•  Faster Decision Making – Sites enter data faster – Supplements Nextrials real-time ad hoc

reporting tool


EHR – State of the Industry

•  70-80% of of family physicians have EHR

•  >90% will have EHR by 2019

• US adoption driven by ARRA – $11B incentives – Medicare penalties started January 2015 – Meaningful use will require interoperability


Compatible EHR Systems

•  ~60% of Hospital Market – Epic – Allscripts – Cerner – Greenway – Tiani Spirit / Cisco – eMDs – GE


Implementation • Multiple EHR systems and EDC

– Same database

• Minimal site responsibilities – Enable communication to EDC –  Identify study in EHR

• Nextrials – Map fields in database definition – Validate

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Data Collection - NextGreen Study •  4 sites / 40 patients retrospective study

•  Integrated with Greenway EHR

•  Based on CDISC/IHE standards

•  >75% of data was auto-populated from EHR

•  Site: “The ease of data capture within our system is amazing!”


Extensions – “Never Leave the EHR”

•  Patient enrollment from EHR system

•  Edit checks run in EHR

• Query resolution within EHR

•  Filter and select from multiple data points


Extensions – “Never Leave the EHR”

•  Flags for EDC/EHR data mismatch

•  Variations in mapping incorporated

•  Start sites with EDC – switch to EHR Future Possibilities

Nextrials EHR Integration Today •  7 consecutive years at Connectathon and HIMSS

InterOperability Showcase

•  Demonstrations at DIA, SCDM and CDISC meetings

•  Awarded first EHR integration project on regulated clinical trial –  Multi-site, multi-EHR, and EDC-only prospective study –  Supported by CDISC and FDA


RFD – EHR Integration Standard

Process Description Future Possibilities Form Receiver (Nextrials) Form Manager (Nextrials)

Form Filler (EHR – Cerner, Allscripts, Greenway, Epic, GE, E-MDS, TS)

Form Archiver (Nextrials , Abnology, or other 3rd party archive solution)

Request Form Submit Form Archive Form

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Future Possibilities Future Possibilities

Data Repository Archive System

Patient Care (EHR) System

Clinical Research System

Patient comes in for study visit.

EHR system submits pre pop patient data and a

request to Clinical system for specific form(s). A copy is

submitted to Archive at the same time.

Medical professional at site brings up patient record in EHR system.

Data Repository or Archive System stores each transaction as an entire component in its

database.

Future Possibilities Clinical system collects pre-pop data and pre-fills form with patient

data already collected in the EHR system.

Clinical system submits pre-filled form to the

EHR system to be displayed within the

EHR interface.









User reviews data and enters additional

information as needed into the embedded

Clinical form.

When complete the Medical professional at site submits the form which is immediately

transmitted to the Clinical system.

Data Repository or Archive System stores each transaction as an entire component in its

database. Future Possibilities

Conclusions for EHR Integration • Cleaner Data

• Reduced SDV costs

•  Faster Decision Making

•  Supported by FDA and EMA

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Jim Rogers

CEO

Nextrials, Inc.

[email protected]

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