Presented to the Regulatory Education and Action for Patients (REAP) Coalition on 7/25/12

1. FDA and Patient Interactions on
Benefit-Risk Determinations
James Valentine, MHS, JD Candidate
Program Manager, FDA Patient Network
FDA Office of Special Health Issues
July 25, 2012
Regulatory Education and Action for Patients
(REAP)

2. Overview
• Traditional Patient Interactions
– FDA Patient Representative Program
– FDA Patient Network
• New Opportunities
– FDASIA “Patient Provision”
– CDER’s Patient-Focused Drug Development
– CDRH’s Patient Risk Tolerance Survey for Obesity Devices
• Appendices
– Appendix A: CDER’s Benefit-Risk Framework
– Appendix B: CDRH/CBER’s Benefit-Risk Guidance

3. Traditional Patient Interactions in
FDA Regulatory Decision-Making
http://www.fda.gov/ForConsumers/ByAudience/ForPatientAdvocates/Patien
3

4. FDA’s Patient Advocacy Programs
Office of Special Health Issues
• Patient Representation Program
• Patient Network (forthcoming)
4

5. FDA Patient Representative Program
Role of the FDA Patient Representative:
• Provide FDA with the unique perspective of patients and
family members directly affected by serious or life-
threatening disease.
• Serve in several ways, including:
– On Advisory Committees
– As Consultants to Review Divisions
5

6. FDA Patient Representative Program (cont.)
The Program’s Activities:
• Recruitment of New Patient Representatives
• Selection of Patient Representatives for:
– Advisory Committees
– Consultation with Review Division
• Conducts Training For Patient Representatives
– Individual FDA 101 Training
– Monthly Webinars
– Annual Workshop for Newly Recruited Patient Representatives
• More information:
http://www.fda.gov/forconsumers/byaudience/forpatientadvocates/pati
6

7. FDA Patient Network
• New Program
• Goals:
– Scale up current educational and advocacy activities
– Proactive approach to patient advocacy
– Primary FDA educational and advocacy resource
• Network Activities:
– Biweekly Email Newsletter
– Annual Conference
 Inaugural Meeting: May 18, 2012 “FDA Working with Patients to Explore
Benefit/Risk: Opportunities and Challenges”
– Multifaceted Website
7

8. Food and Drug Administration Safety and
Innovation Act – “Patient Provision”
Office of Special Health Issues
(OSHI)

9. Patient Participation in
Medical Product Discussions under FDASIA
• Provision will assist the agency in developing and
implementing strategies to solicit the views of patients
during the medical product development process and
consider their perspectives during regulatory discussions.
• This will include:
– Fostering participation of FDA Patient Representatives as Special
Government Employees in appropriate agency meetings with
medical product sponsors and investigators; and,
– Exploring means to provide the identification of FDA Patient
Representatives who do not have any, or have minimal, financial
interest in the medical products industry.
• FDASIA. Title XI. Subtitle C. Section 1137.

10. Patient-Focused Drug Development
Center for Drug Evaluation and Research
(CDER)

11. Understanding the Patient Perspective:
Patient-Focused Drug Development
• Assessment of a drug’s benefits and risks involves analysis of
severity of condition and current state of the treatment
armamentarium
• Patients who live with a disease have a direct stake in drug
review process and are in a unique position to contribute to
drug development
• However, current approach to patient input generally relies on
feedback received at FDA Advisory Committee meetings
• Review process could benefit from broader and more systematic
approach to obtaining patient perspective on disease severity
and unmet medical need by therapeutic or disease areas
11

12. Patient-Focused
Drug Development in PDUFA V
• PDUFA V includes dedicated resources to expand activities
that will provide review divisions with patient input
• FDA will convene meetings with stakeholders focused on
specific disease areas during PDUFA V
– Four public workshops per year—a total of 20 meetings over 5
years
– Each meeting will feature a different disease area, reviewing the
armamentarium for that indication, and identifying areas of
unmet need
– Participants will include FDA review staff, the relevant patient
advocacy community, and other interested parties
12

13. Analysis of Condition:
Sample Questions FDA Considers
• What is the treated (or prevented) condition?
• What are its clinical manifestations (i.e., symptoms that are either
reported or observed)?
• What is known about the natural history and progression of the
condition, including in specific subpopulations?
• How severe is the condition for those who have it?
– How does severity vary across the sub-populations we have defined?
(Note specific subpopulations and nature of differences.)
• What is the basis for our assessment of the condition and its severity?
(Note any relevant literature, clinical experience, expert opinion, etc.)
• What are the major uncertainties in the available information? What
are their implications?
13

14. Unmet Medical Need:
Sample Questions FDA Considers
• What other pharmacological therapies are approved for this
condition?
• How effective and well-tolerated are these alternative therapies?
– How does their effectiveness and tolerance vary by sub-population?
• What off-label pharmacological therapies or non-pharmacological
might be considered?
– How effective and how well tolerated are they reported/believed to be?
• What kinds of evidence are available about the use of alternative
treatments for this condition?
• What is the strength of evidence in each case?
• What are the major uncertainties in the evidence? What are the
implications of any uncertainty?
14

15. Drug Development and Review
FDA
Basic Research/Discovery
Drug Developers
Post-marketing
Pre-IND NDA/BLA Review
“Valley of death”
Translational Gap
NDA/
Translational IND Clinical BLA
Ph 1 Ph 2 Ph 3 Ph 4
Use of Benefit-Risk
undefined ~5-10 years ~5-10 years Assessment ongoing
Framework in drug
review

16. Patient-focused development
For a specific disease area
FDA
Basic Research/Discovery
Drug Developers
Post-marketing
Pre-IND
PRO tool development and
NDA/BLA Review
qualification
NDA/
Translational IND Clinical BLA
Ph 4
Patients identify important Patient input on
dimensions of benefit not effectiveness &
undefined
adequately captured in years
~5-10 ~5-10 years
tolerability of currently ongoing
current studies; need for PRO available therapy (unmet
tool(s) medical need)

17. Next Steps:
Planning for PFDD in PDUFA V
• Summer 2012:
– Develop preliminary list of 20 disease areas for public comment
– Develop basic roadmap that could be used by any patient group interested
in helping to identify important but unaddressed aspects of their disease,
potentially leading to development of PRO measures used in evaluating
new therapies
• September 2012
– Publish FR notice with preliminary list of 20 disease areas for public
comment
• October 2012
– Plan to hold public meeting to:
 Discuss the proposed list of disease areas for the PDUFA meetings
 Discuss strategies for getting broader and representative public input
 Discuss basic roadmap for identification of important patient outcomes and
strategies for collaborative development of PRO measures
17

18. Patient Risk Tolerance Survey
for Obesity Devices
Center for Devices and Radiological Health
(CDRH)

19. Patient Risk Tolerance Survey Overview
• CDRH has been exploring new ways to seek inputs from
patients and their advocates
• The patient risk tolerance survey for obesity devices is
FDA’s first attempt to collect quantitative data on
patient preferences
• The survey conducted using scientifically valid methods
can complement anecdotal feedbacks that FDA
currently receives through existing channels
• Survey data collected systematically will provide
valuable information about patient preferences
19

20. Why Weight-Reduction Devices?
• Obesity is a condition with high prevalence
• Treating obese patients has a high public health impact
• Obesity treatments offer difficult tradeoffs to be made
• Broad array of potential devices with diverse benefit-risk
profiles
• This pilot survey may identify challenges and
opportunities of incorporating survey results into CDRH
decision making process
20

21. Patient Risk Tolerance Survey Participants
Survey obese subjects willing to lose weight
• 450 obese respondents with BMI ≥ 30 kg/m2(self-
reported weight and height in the last 3 years)
• Recruited from nationally representative Internet
panel
• Administered via the Internet
• Target between 100 and 150 respondents who
underwent prior weight reduction procedures (gastric
bypass or banding) to capture “before and after”
experiences 21

22. Survey Instrument Development
Survey instrument has been jointly developed by the CDRH and
Research Triangle Institute, Health Solutions (RTI – HS)
Four phases
1. Study design and development of survey instrument
2. Pre-testing of survey instrument
• 9 Face-to-face cognitive interviews
• Improvement and validation of survey instrument
• Federal Register Notice published on April 19, 2012
3. Administration of the survey to 450 respondents
4. Analysis of results
22

23. Quantitative Approach:
Assessing Patient’s Benefit-Risk Preferences
Risk
Benefit-Risk
Trade-off
Curve
Device A
Risk
Acceptable
Maximum
Δ Risk
Weight Loss
Effectiveness
23

24. Stated Choice Methods
• Capture respondent’s willingness to accept tradeoffs among
features or attributes of different treatment alternatives
• Alternatives consists of different combinations of attributes
such as benefits, side effects, and other features
• Respondents state their choices in a series of pairs of
hypothetical alternatives
• The observed pattern of respondents’ choices reveals the
relative importance of attributes and levels in their minds
• Example result: Patients would be willing to accept 2 more
months of mild-to-moderate side effects to achieve an
additional weight loss of 25 pounds
24

25. The Survey Instrument:
Stated Choice Question
• Respondents will indicate their choices between pairs
of hypothetical obesity devices
• Each treatment is defined by its features (attributes)
• Each attribute has a set of levels (values)
25

26. Feature Device A Device B
Choice
Question Type of operation Endoscopic surgery
Example: Recommended diet restriction Wait 4 hours between meals
Judgment On average, how much weight is
lost
30 lbs. 60 lbs.
Call On average, how long the weight
Weight loss lasts 5 years Weight loss lasts 1 year
loss lasts
Average reduction in dose of
prescription drugs for diabetes at Eliminates the need for prescription drug
the lower weight
On average, how long side effects
last
Last 1 month Last 1 year
(Remember that side effects will limit your
ability to do daily activities several times a
month.)
Chance of a side effect requiring
None
hospitalization
Chance of dying from getting the
weight loss device
10% 1%
(10 out of 100) (1 out of 100) 26
Which weight-loss device do you
think is better for people like you? Device A Device B

27. Questions?
James Valentine, MHS, JD Candidate
FDA Office of Special Health Issues
301-796-8458
james.valentine@fda.hhs.gov
Acknowledgments
CDER Benefit-Risk Framework: Patrick Frey, Director, Office of Planning and Analysis, CDER
CDER Patient Focused Drug Development: Theresa Mullin, PhD, Director, Office of Planning and
Informatics, CDER
CDRH Benefit-Risk Guidance: Peper Long, Associate Director for External Relations, CDRH
Patient Risk Tolerance Survey for Obesity Devices: Martin Ho, MS, Division of Biostatistics, Office
of Surveillance and Biometrics, CDRH

28. Appendix A:
CDER’s Benefit-Risk Framework

29. A Benefit-Risk Framework:
What problem are we trying to address?
• CDER identified the need for a more structured benefit-
risk assessment in the review process
 Better communicate the reasoning behind CDER’s decisions
o Which benefits/risks or other factors were considered?
o How was evidence interpreted?
o How were risks and benefits weighed?
 Ensure the “big picture” is kept in mind during a complex, detailed
review
• This effort was initiated in 2009 and has continued with
the support of internal and external decision science and
drug regulatory experts

30. Framework Development
• Developed and tested a conceptual framework
 Explored 6 case studies of past regulatory decisions to “tease out” the
range of benefits and risks considered
 One-on-one interviews of key review disciplines painted the picture of the
relevant issues for each decision
• Road-tested in more recent regulatory decisions
 Explored 2 additional case studies using a focus group process
 Framework revised as a result
• Overall process and development guided by senior management
 Office of New Drugs, Office of Surveillance and Epidemiology, Office of
Biostatistics
 Recognized that effective decision support must begin with an
understanding of how the decision-makers think, i.e., you must bring them
along for the “ride”

31. Benefit-Risk Assessment Framework
Decision Factor Evidence and Uncertainties Conclusions and Reasons
Summary of evidence: Conclusions (implications for decision):
Analysis of
Condition
Summary of evidence: Conclusions (implications for decision):
Unmet Medical
Need
Summary of evidence: Conclusions (implications for decision):
Benefit
Summary of evidence: Conclusions (implications for decision):
Risk
Summary of evidence: Conclusions (implications for decision):
Risk Management
Benefit-Risk Summary and Assessment

32. The Rows:
Key Benefit-Risk Considerations
Information on the Therapeutic Area
 Analysis of Condition Provide clinical context for weighing
 Unmet Medical Need benefits and risksclinical context for
Provide
weighing benefits and risks
Product-Specific Information
 Benefit Use all information available to to
Use all information available
make judgments on the benefits and
make judgments on the benefits
 Risk risks to the population population
and risks to the
Describes risk management
Describe risk management plan (if
plan (if required) and its
 Risk Management required) and its expectedreduce orto
expected impact to impact
reduce or further characterize
further characterize safety
concerns
safety concerns

33. The Columns:
Evidence and Conclusions
Evidence and Uncertainties
• What you know (facts)
• What you don’t know (uncertainties and underlying assumptions)
• How good are the data?
Conclusions and Reasons
• What do you make of the data and uncertainties?
• Analysis of the information and its clinical relevance
• Drawing conclusions within each key consideration
Benefit Risk Summary & Assessment
A balanced written analysis of the factors and their tradeoffs that
summarizes the resulting regulatory recommendation or action

34. B-R Framework designed to
“tell the story” of the regulatory decision
• What is the problem?
 Analysis of the Condition
• What other potential interventions exist?
 Unmet Medical Need
• What is the benefit of the proposed intervention?
 Benefit
• What am I worried about?
 Risk
• What can I do to mitigate/monitor those concerns?
 Risk Management

35. Benefit-Risk in PDUFA V:
FDA’s Commitments
• Publish a 5-year plan that describes FDA’s approach to
implement a structured benefit-risk framework by
December 31, 2012 and begin execution by September 30,
2013
• Conduct two public workshops on benefit-risk from the
regulator’s perspective that will begin by December 31,
2013
• Develop an evaluation plan to ascertain the impact of the
benefit-risk framework
• Revise review templates, decision memo templates and
MaPPs as appropriate to incorporate FDA’s approach
35

36. Appendix B:
CDRH/CBER’s Benefit-Risk Guidance

37. Guidance for Industry and FDA Staff:
Factors to Consider When Making Benefit-Risk Determinations in Medical
Device Premarket Approval and De Novo Classifications
Date of Publication: March 27, 2012

38. Purpose
• To identify and clarify the factors FDA considers when making
benefit-risk determinations during our approval decisions
• To facilitate transparency, consistency, and predictability of
the premarket review process for benefit-risk assessments

39. Background
• §513(a) of the Federal Food, Drug & Cosmetic Act
– FDA determines if PMA applications provide “reasonable assurance of safety and
effectiveness” by “weighing any probable benefit to health from the use of the device
against any probable risk of injury or illness from such use,” among other relevant factors
– FDA reviews valid scientific evidence to determine if data support claims made by
Sponsor
• Clinical data
• Non-clinical data
• Intended use/Indications for Use
– For de novo classification petitions [513(f)(2)], FDA also makes a classification
determination after consideration of all risks and whether they can appropriately be
mitigated through general and/or special controls.

40. Development Process
• Contributing Team:
– Benefit-risk working group from CDRH
• Chronology of Key Milestones:
– August 2011: Draft issued for public comment
– November 15, 2011: Docket closed
– Final published on March 27, 2012

41. Content of Guidance
• Addresses factors FDA considers important as part of the
benefit-risk determination
• Provides examples of how FDA uses the factors in making
benefit-risk determinations
• Includes worksheet, which reviewers will use in making
benefit-risk determinations as part of the premarket process

42. Factors FDA Considers When Making
Benefit-Risk Determinations

43. Factors FDA Considers When Making Benefit-Risk
(B-R) Determinations
• Factors that characterize benefit
• Factors associated with risks
• Additional factors to be considered

44. Benefit factors in B-R determinations
• Type of benefit
– device’s impact on clinical management, patient health, and patient
satisfaction in the target population,
• Magnitude of the benefit(s)
– change in subjects’ condition or clinical management

45. Benefit factors in B-R determinations (cont.)
• Probability of experiencing one or more benefit(s)
– which patients may experience a benefit?
• Duration of effect
– A treatment whose benefit lasts longer is more desirable than a treatment that
must be repeated.

46. Risk factors in B-R determinations
• Severity, types, number and rates of harmful events
– device-related serious adverse events
– device-related non-serious adverse events
– procedure-related complications
• Probability of harmful event
• Duration of harmful events
• Risk from false-positive or false-negative results for
diagnostics

47. Other Factors in B-R Determinations (Cont’d)
• Availability of alternative treatments or diagnostics
• Risk mitigation
• Postmarket data
• Novelty of technology addressing an unmet medical need

48. Worksheet