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MEDICAL RESEARCH – PART I

RESEARCH REQUIREMENTSRESEARCH PLANNING

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THE MEANING OF INFORMATION Requirements

, needs

Planning, direction

Collection

ProcessingAnalysis production

Dissemination

Re-evaluation

SCIENTIFIC PUBLICATIONS ARE A SPECIALIZED FIELD OF INTELLIGENCE

Need for high quality

decisions

Work within available

timeNeed for

Consensus

Trade offs

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RESEARCH REQUIREMENTS

• S.W.O.T. analyses• Project pipeline review, in-project reviews• Internal safety and benefit:risk assessments• Mandatory literature screening and regulatory reports• Study of disease, treatment guidelines, comparison of therapies • Efficacy and cost-effectiveness of new treatments • Review of new available evidence

REQUIREMENT The need for answers to pressing questions in healthcare spans from the requirement to identify best available treatment options to direction of resources and effort to research projects which are likely to succeed.

Identifying requirements means defining policy issues within an organization or areas to which information support is expected to make a contribution, as well as decisions as to which of these issues has priority over the others, also with respect to intelligence capabilities which are always limited.

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RESEARCH REQUIREMENTS

Positive/negative questions (similarities v. differences) Speculative questions What if questions Disagreement with source Answer to a question which can’t be plausibly disproved is pointless Screen materials for research questions posed but not answered

LIST OF EXPLORATORY QUESTIONSWhat is the purpose of the research? What is the client’s objective? What is the scope? What is the larger context (functional, geographical, economic)?

REFINE RESEARCH QUESTION

Validity, quality, certainty, and accuracy of answer to a research question directly depends on quality of available evidence.

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RESEARCH REQUIREMENTS

REFINE RESEARCH QUESTION TO FIT CONTEXT, SCOPE, PURPOSE AND OBJECTIVE

Is answer to the research question as asked RELEVANT? Is the answer CRITICAL for a specific DECISION?

WHAT IS THE OBJECTIVE?• Obtain funding for a project?

• Decide between multiple competing projects? • Weed out projects that are unlikely to succeed? • Select the most viable/economic project/solution?

• Identify critical points in a project to plan resources, funding and timing?• Screen the datascape for opportunities in certain therapeutic area? • Develop/amend managed care treatment guidelines? • Develop state-of-art treatment options regardless cost? • Review novel treatments for safety, efficacy and cost-effectiveness?

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RESEARCH REQUIREMENTS

RESEARCH QUESTION DEFINED IN REGULATIONS/GUIDELINES

WHAT IS THE OBJECTIVE?• Comply with regulations and prove due diligence?

SCREENING MEDICAL LITERATURE FOR REGULATORY PURPOSES WRITING STANDARD REGULATORY REPORTS

PBRERsDSURs RMS

Pharmacovigilance Medical literature screening Medical writing

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RESEARCH REQUIREMENTS

FORMAT of RESEARCH OUTPUT • Research report adapted to a specific project • Template • Standard regulatory report (PBRER, DSUR, RMP)• Academic writing styles• Presentation delivered F2F or online, live or recorded

SCOPE• Limitation on cost of data collection • Limitation on cost of data processing and analysis• Time constraints for researcher• Time constraints for customer to achieve consensus

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PERFORMANCE

COST TIME

Need for high quality decisions

Need for consensus Work within available time 5/4/2015

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THE MEANING OF INFORMATION Requirements

, needs

Planning, direction

Collection

ProcessingAnalysis production

Dissemination

Re-evaluation

SCIENTIFIC PUBLICATIONS ARE A SPECIALIZED FIELD OF INTELLIGENCE

Need for high quality

decisions

Work within available

timeNeed for

Consensus

Trade offs

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RESEARCH REQUIREMENTS

OUTLINE v. STORYBOARD

WORKING ANSWERS:• Confirmed negative is a valuable outcome which saves time and resources

spent on exploration of a dead end. • Plausible working hypotheses can be tested against each other

• Search for evidence that supports the hypothesis• Search for evidence that disproves the hypothesis What kind of evidence is required?

• Outline preferred for shorter projects • Outline can specify too much too soon • Storyboard offers more space especially if there are more working hypotheses

and conflicting evidence • Storyboard offers more flexibility for presentation of reasoning

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PLANNING, DIRECTION• Medical journals • Case histories • Published studies • Reviews, articles, meta-analyses• Patents• Regulatory information • Legal cases, litigation• Press releases• Customer communications• Clinical trial registries • Press, media, tabloids • Disease registries • Treatment guidelines • Safety databases • Industry reports • Competitors’ pipeline assessments • Geopolitical development• Regional / local sources • Social networks

OBJECTIVE PURPOSESCOPE

• MANDATORY SCREENING• DUE DILIGENCE EFFORTS• INTERNAL DECISION-MAKING• PROJECT REVIEWS• BUSINESS DECISIONS• RESEARCH STRATEGIES• RISK EVALUATION• KNOWN KNOWNS• KNOWN UNKNOWNS• KNOWLEDGE GAPS• KNOWN PAST FAILURES • CONFIRMED NEGATIVES

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PLANNING, DIRECTION

• To identify findings relevant for the research subject of interest as well as means and methods which are unlikely to yield a positive result (negative studies)

• To determine the extent of current knowledge already developed in order to identify known knowns, known unknowns, and make a qualified estimate of unknown unknowns

• To identify the definition of concepts and variables which have already been established in the literature

• To examine the research designs and methods, and analytical techniques used by previous researchers and make predictions for methods and research designs which are likely to accomplish the desired outcome

• To become aware of difficulties experienced by others and methods used to overcome them, both successful and unsuccessful

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PLANNING, DIRECTION OBJECTIVITY: Does it avoid mirror imaging, cultural bias, and prejudicial judgments?

RELEVANCE: Does it relate directly to the end user’s area responsibility and mission?

ACCURACY: Did the producer clearly articulate the level of confidence in its accuracy?

PRECISION: Does it have the required level of detail to satisfy the needs of the end user at his or her operational level?

COMPLETENESS: Were all of the user’s requirements addressed in the level of detail necessary to satisfy his or her needs?

USABILITY: Did it arrive in a format that the end user can easily understand and assimilate into his or her decision-making process?

AVAILABILITY: Was it readily accessible to the user at the appropriate security classification or accessibility?

ANTICIPATION: Does it anticipate the intelligence needs of the customer?

GOOD QUALITY RESEARCH OBJECTIVE, RELEVANT, COMPLETE within SCOPE, ACCURATE and PRECISE, USABLE, AVAILABLE and ACCESSIBLE.

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PLANNING: SOURCESPRIMARY:

• Raw data from observation and experiment • Adverse reaction reports from healthcare professionals and patients • Interviews conducted using reliable methods for eliciting and recording information • Data from clinical trials typically not availableSECONDARY:

• Monographs, review articles, special focus journal articles, theses • Specialized encyclopedias and textbooks, books• Regulatory documents, reports and announcements, and public records• Used often for screening of current situation in the field; contain opinions and views TERTIARY:

• Based on secondary sources, usually written for non-specialists • Popular press, newspapers

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<2 years1 year1.5-2.5 years

1-2 years

Target Identification & Validation

Lead Generation

Lead Optimization

Pre-clinical Development

Clinical Development

NDAIND* Compartmentalized data sets/intellectual property

1-3 years 4-8 years

Approval

Thorough understanding of the disease mechanisms and the role of enzymes, receptors or proteins within the disease pathology. simple experiments carried out to confirm regulation of the target and development of assay

Identification of chemical start points for drug discovery projects. Identification of related compounds with improved potency, reduced off-target activities (undesirable activities at other biological targets), and physiochemical/metabolic properties suggestive of reasonable in vivo pharmacokinetics.

Optimise potency against the enzyme target, cellular and toxicity assays as well as those that govern good oral absorption, slow metabolic clearance in vivo and display activity in an animal model of the disease.

Toxicology in vitro and in vivo ADME studies pharmacokinetics Pharmacodynamics Chronic toxicity, Acute toxicity, Safety pharmacology

Phase 0: Very limited human exposure to the drug, with no therapeutic or diagnostic goalsPhase 1: Healthy volunteers , emphasize safety. What the drug's most frequent and serious adverse events are and, often, how the drug is metabolized and excreted. Phase 2: Data on effectiveness (whether the drug works in people who have a certain disease or condition). The drug may be compared with placebo or a different drug. Safety continues to be evaluated. Phase 3: Data on safety and effectiveness by studying different populations and different dosages and by using the drug in combination with other drugs.

Phase 4: Studies occurring after launch. Additional information about a drug's safety, efficacy, or optimal use.

PRIMARY SOURCES

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ClinicalTrials.gov: 175,013

Non-U.S. Only 79,372 (45%)

U.S. Only 69,535 (40%)

Not Specified* 15,545 (9%)

Both U.S. and Non-U.S. 10,561 (6%)

DATA FROM FOREIGN STUDIES Inconsistent acceptance around the world- Quality of data - Applicability of results (populations)- Ethical concerns

PRIMARY SOURCES

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ARETE-ZOE, LLC 17Source: EudraCT Statistics 3/2015

Developed countries keep 78 % of the sites and 65 % of the patients Emerging regions capture 22 % of the clinical trial sites and 35 % of the patients

5,028 in 2007

4,629 in 2008 4,619 in 2009

4,400 in 2010 3,490 in 2011

EU Clinical Trial applications

EU clinical trials rules are too BUREAUCRATIC and lack harmonized SCIENTIFIC DISCUSSION

PLATFORM for DATA EXISTS, INDUSTRY PROVIDES DATAREGULATORS UNABLE TO RECORD AND ANALYZE DATAAND DRAW VALID COCLUSIONS

Clinical trials in the EudraCT Database

PRIMARY SOURCES

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1997: Congress Passes Law (FDAMA) Requiring Trial Registration2000: NIH Releases ClinicalTrials.gov Web Site 2000–2004: FDA Issues Guidance for Industry Documents2005: International Committee of Medical Journal Editors Requires Trial Registration 2006: World Health Organization Establishes Trial Registration Policy 2007: Congress Passes Law (FDAAA) Expanding ClinicalTrials.gov Submission Requirements2008: ClinicalTrials.gov Releases Results Database2008: Declaration of Helsinki Revision Promotes Trial Registration and Results Dissemination2009: Public Meeting Held at the National Institutes of Health2013: European Medicines Agency Expands Clinical Trial Database to Include Summary Results2014: Notice of Proposed Rulemaking (NPRM) for FDAAA 801 Issued for Public Comment2014: NIH Draft Policy on Registration and Results Submission of NIH-Funded Clinical Trials Issued for Public Comment2015: National Cancer Institute Issues Clinical Trial Access Policy

LONG RECOGNIZED NEED: REGISTRATION OF TRIALS AND AVAILABILITY OF RESULTS

PRIMARY SOURCES

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– 2,021 (42%) business entities sponsored only 1 clinical trial– 3,773 (78%) business entities sponsored ≤ 5 clinical trials– 4,300 (89%) business entities sponsored ≤ 10 clinical trials– 53 (1%) business entities sponsored more than 100 clinical trials– 8 business entities sponsored more than 1000 clinical trials

Lead sponsor: The organization or person who oversees the clinical study and is responsible for analyzing the study data. Collaborator: an organization other than sponsor that provides support for a clinical study. This may include funding, design, implementation, data analysis, or reporting.

Highly consolidated and concentrated globalized industry, but: • 50,194 industry-sponsored clinical trials identified on the database • Lead sponsors for these clinical trials: 4,854 different business entities

Daughter/parent companies typically not linked (with few exceptions)

PRIMARY SOURCES

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PUBLICATION BIAS

PUBLICATIONS

Medline

Embase

Derwent Drug File

BIOSIS Previews

SciSearch

IMS R&D Focus

Adis R&D Insight

CLINICAL TRIALS

ClinicalTrials.gov

EU CT register

National registries

WHO registry

• Unpublished studies• Studies published multiple times• Missing study ID (linking

publication to study)• Selective publication of data • Fewer than half of published trials

are registered • Fewer than half of registered trials

are ever published in peer-reviewed journals

Trials reporting positive findings are more likely to be published, and to be published faster, than those reporting negative findings.

Publication of a single study multiple times works like an amplifier which makes anecdotal findings appear more relevant than they really are.

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PLANNING: EVALUATION

I. RELEVANCE, USEFULNESS, ACCURACY, CORRECTNESS

II. EVALUATION OF SOURCES• Source reliability assessment (competency and past behavior based)• Bias assessment (motivators, interests, funding, objectives)• Conflicts of interest • Sources of funding, important business relationships

Methodology for grading of individual itemsCriteria for exclusion of irrelevant, incorrect, and useless information

PLAN FOR EVALUATION OF SOURCES

CRITERIA for GRADING, INCLUSION and EXCLUSION

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MEDICAL RESEARCH – PART I

Contact: 1334 E Chandler Blvd No 5, Box A-19Phoenix 85048, AZ, USAT: +1.480.409.0778Email: veronikav@arete-zoe.comWebsite: http://aretezoe.com/

THANK YOU

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