James Valentine, MHS, JD CandidateProgram Manager, FDA Patient Network

FDA Office of Special Health Issues

FDA and Patient Interactions on Benefit-Risk Determinations

July 25, 2012Regulatory Education and Action for Patients

(REAP)

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

Traditional Patient Interactions in FDA Regulatory Decision-Making

http://www.fda.gov/ForConsumers/ByAudience/ForPatientAdvocates/PatientInvolvement/default.htm

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FDA’s Patient Advocacy Programs

Office of Special Health Issues• Patient Representation Program• Patient Network (forthcoming)

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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

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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/patientinvolvement/ucm123858.htm

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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

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Food and Drug Administration Safety and Innovation Act – “Patient Provision”

Office of Special Health Issues

(OSHI)

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.

Patient-Focused Drug Development

Center for Drug Evaluation and Research (CDER)

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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

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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

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?

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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?

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“Valley of death”

Drug Development and Review

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Patient input on effectiveness & tolerability of currently available therapy (unmet medical need)

Patients identify important dimensions of benefit not adequately captured in current studies; need for PRO tool(s)

PRO tool development and qualification

Drug Developers

FDA

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

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Patient Risk Tolerance Survey for Obesity Devices

Center for Devices and Radiological Health (CDRH)

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• 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

Patient Risk Tolerance Survey Overview

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• 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

Why Weight-Reduction Devices?

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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

Patient Risk Tolerance Survey Participants

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1. Study design and development of survey instrument2. 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

Survey instrument has been jointly developed by the CDRH and Research Triangle Institute, Health Solutions (RTI – HS)

Survey Instrument Development

Four phases

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Risk

EffectivenessWeight Loss

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isk

Benefit-Risk Trade-off

Curve

Device AMaximum

Acceptable Risk

Quantitative Approach: Assessing Patient’s Benefit-Risk Preferences

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• 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

Stated Choice Methods

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• 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)

The Survey Instrument: Stated Choice Question

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Feature Device A Device B

Type of operation Endoscopic surgery

Recommended diet restriction Wait 4 hours between meals

On average, how much weight is lost

30 lbs. 60 lbs.

On average, how long the weight loss lasts

Weight loss lasts 5 years Weight loss lasts 1 year

Average reduction in dose of prescription drugs for diabetes at the lower weight

Eliminates the need for prescription drug

On average, how long side effects last

(Remember that side effects will limit your ability to do daily activities several times a month.)

Last 1 month Last 1 year

Chance of a side effect requiring hospitalization

None

Chance of dying from getting the weight loss device

10%

(10 out of 100)

1%

(1 out of 100)

Which weight-loss device do you think is better for people like you?

Device A

Device B

Choice Question Example: Judgment

Call

Questions?James Valentine, MHS, JD Candidate

FDA Office of Special Health Issues

301-796-8458

james.valentine@fda.hhs.gov

AcknowledgmentsCDER 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

Appendix A: CDER’s Benefit-Risk Framework

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

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”

Benefit-Risk Assessment Framework

Decision Factor Evidence and Uncertainties Conclusions and Reasons

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

Summary of evidence: Conclusions (implications for decision):

Benefit-Risk Summary and Assessment

The Rows: Key Benefit-Risk Considerations

Information on the Therapeutic Area Analysis of Condition Unmet Medical Need

Product-Specific Information Benefit Risk

Risk Management

Provide clinical context for weighing benefits and risks

Use all information available to make judgments on the benefits and risks to the population

Describes risk management plan (if required) and its expected impact to reduce or further characterize safety concerns

Provide clinical context for weighing benefits and risks

Use all information available to make judgments on the benefits and risks to the population

Describe risk management plan (if required) and its expected impact to reduce or further characterize safety concerns

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

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

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

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

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

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

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.

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

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

Factors FDA Considers When Making Benefit-Risk Determinations

Factors FDA Considers When Making Benefit-Risk (B-R) Determinations

• Factors that characterize benefit• Factors associated with risks• Additional factors to be considered

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

• 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.

Benefit factors in B-R determinations (cont.)

• 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

Risk factors in B-R determinations

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

Worksheet