AC Meetings - , where they offer the patient perspective, ask questions, and give comments to assist the committee in making recommendations. Consultants – assist the clinicians and scientists who review data submitted to determine whether the product’s benefits outweigh the potential risks
Webiste: Medical Product Development 101 Library of Written & Multimedia Educational Resources Updates on FDA actions, upcoming meetings, opportunities to comment (i.e. dockets) Interactivity
Today I am going to discuss the guidance document entitled, Factors to Consider When Making Benefit-Risk Determinations in Medical Device Premarket Approval and De Novo Classifications. This guidance document was published in its final form on March 27, 2012.
This guidance document was developed to provide greater clarity for FDA reviewers and Industry regarding the factors FDA considers when making benefit-risk assessments in PMA applications and de novo premarket submissions for medical devices. FDA believes that the appropriate application of the factors listed in this guidance will help FDA believes that the full implementation of the guiding factors described in this guidance will facilitate transparency, consistency, and predictability of the premarket review process.
This guidance addresses two main avenues for a sponsor to gain market entry for a new medical device: PMAs and de novo petitions. Under Section 513(a) of the Federal Food, Drug & Cosmetic Act, or the “FD&C Act,” FDA determines whether PMA applications provide a “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.” Other factors also apply. FDA reviews the valid scientific evidence submitted in the application to determine whether it supports the intended use of the device. This evidence may come from a range of information sources, such as clinical data, animal studies, and non-clinical data. Scientific data reviewed by FDA includes clinical studies, non-clinical studies, and the intended use of the device. Wherever eligible, the Sponsor may submit a de novo classification petition in order to gain market entry for a new medical device. For de novos, FDA considers the risk profile of a device to make a classification determination for the device under Section 513(a)(1) of the FD&C Act. FDA makes a risk-based classification determination after consideration of all risks of the device, such that the risks may appropriately be mitigated through the general and/or special controls. A complete benefit-risk assessment is then carried out as part of the assessment of device's safety and effectiveness. . Devices that reach the market via a de novo classification petition serves as predicates for future submissions through the 510(k) program.
This guidance was developed by the benefit-risk working group, made up of FDA Staff from the Office of Device Evaluation (ODE), the Office of Surveillance and Biometrics (OSB), the Office of In Vitro Diagnostics (OIVD), and the Office of Science and Engineering Laboratories (OSEL). This group’s effort led to the issuance of the draft guidance in August 2011, which was published and available for public comment The comment period was open until November 15, 2011, at which time the docket closed and comments were collated, addressed, and incorporated as appropriate into the final guidance. The final version of the guidance was published on March 27, 2012.
The guidance document addresses and defines multiple factors FDA considers important in making benefit-risk determinations. Several examples are included within the guidance document to demonstrate how the factors are applied in making benefit-risk determinations. A worksheet is provided at the end of the guidance. This worksheet is intended to capture how reviewers consider the factors described within the guidance when making benefit-risk assessments.
The factors I will now describe are considered within the intended use of the device when assessing the benefit-risk profile. I will present each factor, followed by examples of questions the FDA reviewers consider for each factor described. The guidance document contains a worksheet that provides additional questions for each factor.
This guidance characterizes the benefit-risk determinations into three primary categories: the factors that characterize the benefits of the device; the factors associated with the risks of the device; and, finally, additional factors that FDA considers while weighing the probable benefits and risks.
The guidance document helps FDA reviewers assess the extent of the probable benefit using several factors, including the type of benefits, the magnitude of the benefits, the probability of the patient experiencing one or more of the benefits, and the duration of the benefits. These factors are considered individually and in the aggregate. The type of benefit can be measured directly, or by using endpoints or surrogate endpoints. Knowing what primary endpoints or surrogate endpoints were evaluated and what value physicians and patients place on the benefit are important considerations. Additionally, understanding the impact of the benefit to public health may be helpful for therapeutic devices and early diagnosis of a disease. FDA often assesses magnitude of benefits along a scale or according to specific endpoints or criteria, or by evaluating whether a pre-identified health threshold was achieved.
Another measure of benefit is the probability of the patient experiencing one or more benefits. Based on the data provided, does the study predict the which patients will experience a benefit or the probability that a patient will experience a benefit. Understanding the variation in public health benefits for different subgroups is important because different patient subgroups may experience different benefits or different levels of the same benefit. A final measure of benefit is the duration of the effect of the benefit. A treatment whose benefit lasts longer is more desirable than a treatment that must be repeated to preserve the benefit.
FDA determines the Risk profile of the device by taking into the severity, types, number and rates of harmful events; the probability of a harmful event; the duration of each harmful event; and the risk from false positive or false negative results, as in the case of diagnostic devices. These factors are considered individually and in the aggregate. The severity, types, number and rates of harmful events refers to events that result directly from the patient’s use of the device. Examples of questions considered by the reviewer include: what are the device-related serious adverse events? What are the device-related non-serious adverse events? And, what other procedure-related or indirect complications to which a patient be subjected? The probability of a harmful event can be assessed by understanding what the probability is that a patient in the intended population will experience a harmful event. Reviewers also consider the question, “are patients willing to accept the probable risk of the harmful event, in exchange for the probable benefits of the device?”
Another factor FDA considers when making benefit-risk determinations is the availability of alternative treatments or diagnostics. FDA takes into account how effective these other treatments are and the risks they pose to patients. The use of risk mitigation strategies, when appropriate, can minimize the probability of a harmful event occurring. The reviewer will determine if the sponsor has identified ways to mitigate risks through product labeling or education programs. For in vitro diagnostics, risks may be mitigated by the use of complementary diagnostic tests.
FDA and Patient Interactions On Benefit-Risk Determinations
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)
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-Makinghttp://www.fda.gov/ForConsumers/ByAudience/ForPatientAdvocates/Patien 3
FDA’s Patient Advocacy ProgramsOffice of Special Health Issues• Patient Representation Program• Patient Network (forthcoming) 4
FDA Patient Representative ProgramRole 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
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
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
Food and Drug Administration Safety and Innovation Act – “Patient Provision” Office of Special Health Issues (OSHI)
Patient Participation inMedical 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)
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
Patient-FocusedDrug 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
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
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
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-Riskundefined ~5-10 years ~5-10 years Assessment ongoing Framework in drug review
Patient-focused developmentFor 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)
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
Patient Risk Tolerance Survey for Obesity DevicesCenter for Devices and Radiological Health (CDRH)
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
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
Patient Risk Tolerance Survey ParticipantsSurvey 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
Survey Instrument DevelopmentSurvey instrument has been jointly developed by the CDRH andResearch 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
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
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
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
Feature Device A Device B ChoiceQuestion Type of operation Endoscopic surgeryExample: Recommended diet restriction Wait 4 hours between mealsJudgment 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
Questions?James Valentine, MHS, JD CandidateFDA Office of Special Health Issues301firstname.lastname@example.orgAcknowledgmentsCDER Benefit-Risk Framework: Patrick Frey, Director, Office of Planning and Analysis, CDERCDER Patient Focused Drug Development: Theresa Mullin, PhD, Director, Office of Planning and Informatics, CDERCDRH Benefit-Risk Guidance: Peper Long, Associate Director for External Relations, CDRHPatient Risk Tolerance Survey for Obesity Devices: Martin Ho, MS, Division of Biostatistics, Office of Surveillance and Biometrics, CDRH
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 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
The Rows:Key Benefit-Risk ConsiderationsInformation on the Therapeutic Area Analysis of Condition Provide clinical context for weighing Unmet Medical Need benefits and risksclinical context for Provide weighing benefits and risksProduct-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
The Columns:Evidence and ConclusionsEvidence 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 considerationBenefit Risk Summary & AssessmentA balanced written analysis of the factors and their tradeoffs thatsummarizes 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 35
Guidance for Industry and FDA Staff:Factors to Consider When Making Benefit-Risk Determinations in MedicalDevice Premarket Approval and De Novo ClassificationsDate 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 MakingBenefit-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
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.
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
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