Benefit-Risk Guidance: Impact on FDA Decision-Making CRT 2013 CAPT Brian Lewis, MD, USPHS Implantable Electrophysiological Devices Branch Division of Cardiovascular Devices Office of Device Evaluation CDRH/FDA First Presentation: FIRST IN THE USA: EARLY FEASIBILITY STUDIES (EFS) INCLUDING FIRST-IN-MAN WORKSHOP 8:14AM 9:45AM David E. Kandzari, MD (Moderator) Ron Waksman, MD (Moderator) Bram D. Zuckerman, MD (Moderator) Empire Ballroom Lewis Presentation: Benefit-Risk Guidance: Impact on FDA Decision-Making 10:30AM 10:40AM Brian M. Lewis, MD Empire Ballroom Good morning. My name is Dr. Brian Lewis. I’m a Medical Officer in Pacemakers, Defibrillators and Leads Pre-Market Review for the Office of Device Evaluation in the Center for Devices and Radiological Health at FDA. Last year the Center for Devices implemented a Benefit-Risk Guidance document. I’m going to try to give you an overview of the guidance, what it applies to, and discuss some of the factors FDA considers in making a Benefit-Risk determination. I hope none of this is totally new to you, but I think some of the concepts in the BR guidance are a little different than how we’ve typically approached reviews in the past, and I’ll try to highlight those areas for you. February 26, 2013

I have no real or apparent conflicts of interest to report. Brian Lewis, MD I have no real or apparent conflicts of interest to report.

Acknowledgements Randall Brockman, MD Elias Mallis Acting Chief Medical Officer Office of Device Evaluation Center for Devices and Radiological Health, FDA Elias Mallis Director Division of Small Manufacturers, International and Consumer Assistance Office of Communication and Education Center for Devices and Radiological Health, FDA I’d like to acknowledge the help of colleagues in preparing this talk, Dr. Randy Brockman, Acting Chief Medical Officer, Office of Device Evaluation at CDRH and Elias Mallis, Director, Division of Small Manufacturers, International and Consumer Assistance, Office of Communications and Education at CDRH

Why do we need this Benefit-Risk Guidance? “This guidance clarifies this process for industry, which will provide manufacturers with greater predictability, consistency and transparency in FDA decision-making while allowing manufacturers and the FDA to use a common framework for benefit-risk determinations,”* Jeffrey Shuren, M.D., J.D. CDRH Director Here you see our Center Director, Dr. Shuren’s perspective on the B-R G: From an FDA News Release http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm297411.htm The B-R G clarifies this process for industry provide manufacturers with greater predictability, consistency and transparency in FDA decision-making while allow manufacturers and the FDA to use a common framework for benefit-risk determinations,”* *http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm297411.htm

What does the Guidance apply to? Premarket approval applications (PMAs) De Novo applications Note: Guidance does not apply to premarket approval notifications (510ks) The guidance specifically identifies PMA and de novo submissions as covered files. Although HDEs are not explicitly cited in the scope of the guidance document, the principles apply to HDEs as well. But the concepts discussed in this guidance are applicable to the medical device development process from design to market. So, the benefit-risk factors presented could really be considered (and we think should be considered) during earlier stages such as a Pre-Submission, and IDE phases as well.

What does this new Guidance do? Summarizes factors the FDA considers when making the benefit-risk determination Provides standardized method for making decisions and documenting in consistent manner Also contains several hypothetical examples to illustrate the process Appendices to the Guidance include the worksheet the FDA uses during review to summarize its analysis and sample worksheets based on hypothetical examples This guidance represents a formal way to consistently document the factors that go into our decisions for PMAs and De Novos. That’s not to say that we hadn’t previously been making benefit risk decisions - we did, and continue to do that all the time. But this formalized method helps us to more consistently apply the same criteria for the decisions that we make.

What constitutes an “appropriate benefit-risk determination”? Does not refer to device being “OK” to approve or clear Utilizes consistent methods to conduct premarket reviews of benefit and risk Considers both valid clinical and non-clinical data Supported by data analysis which demonstrates whether or not probable benefits of a device outweigh probable risks Includes completion of Worksheet for Benefit-Risk Determinations Takes into consideration applicable factors described in the following slides What constitutes an “appropriate benefit-risk determination”? First let me say that this does not refer to the device being “OK” to approve or clear. The BR assessment informs that decision, but the BR assessment is a process. The process [read slide beginning with] Utilizes consistent methods to conduct premarket reviews of benefit and risk Considers both valid clinical and non-clinical data Supported by data analysis which demonstrates whether or not probable benefits of a device outweigh probable risks Includes completion of Worksheet for Benefit-Risk Determinations Takes into consideration applicable factors described in the following slides

Factors FDA considers in assessing benefit Type of benefit(s) Magnitude of benefit(s) Probability a patient will experience benefit(s) Duration of benefit(s) Here are factors FDA considers in assessing benefit The type of benefit(s) – this will of course vary depending on the device and the clinical study The magnitude of the benefit(s) The probability a patient will experience the benefit(s) The duration of the benefit(s) Pretty staightforward

Factors FDA considers in assessing risk Severity, types, number and rates of harmful events associated with use of device, including: Device-related serious adverse events Device-related non-serious adverse events Complications from procedures Probability of a harmful event; Duration Risk of false-positive or false-negative results for diagnostics Factors FDA considers in assessing risk: Severity, types, number and rates of harmful events associated with use of device, including: Device-related serious adverse events Device-related non-serious adverse events Complications from procedures Probability of a harmful event; Duration Risk of false-positive or false-negative results for diagnostics I hope none of the factors I’ve listed on these last two slides surprise you.

Additional factors FDA takes into account But there are additional factors FDA considers that might not be as familiar to you. Degree of certainty deals with issues such as study design, data analysis, repeatability and generalizability of results. FDA understands that there is never 100% certainty when making these assessments. But understanding the degree of uncertainty of the benefits and risks of a device can be critical to making benefit-risk determinations. Risk mitigation includes issues such as appropriate Indications, warnings, etc. as well as appropriate Instructions for Use, training, etc. We have Patient tolerance for risk and perspective on benefit, and availability of alternative treatments and novel technology addressing unmet needs These last several items may be a little different than you’re used to having FDA consider. These aren’t brand new issues for us, but one of the goals of this effort is to improve the consistency with which we consider these aspects when relevant. Degree of certainty of benefits and risks of a device Risk mitigation Post-market data Patient tolerance for risk and perspective on benefit Availability of alternative treatments or diagnostics Novel technology addressing unmet medical need

Patient Tolerance for Risk & Perspective on Benefit So let’s look at a simple hypothetical example … and think about it in terms of a patient’s tolerance for risk and perspective on benefit. While considering the patient’s perspective is not totally new to FDA, it is something that we may not have consistently taken into account in the past, but something we would like to do more consistently in the future. The patient population to be treated has a serious medical condition with advanced symptoms. These patients are highly symptomatic with substantial limitation in their ability to perform routine activities. Consider a device that is a permanent implant, with all of the entailed risks of such. The mechanism of action is not clearly defined, but based on the clinical trial, the device appears to improve symptoms but increase mortality. I hope you can understand that this is a pretty challenging situation for FDA. Increased mortality is obviously a very concerning signal for us. But rather than simply make a risk-based decision, the BR guidance asks us to consider the patient’s perspective in the benefit-risk assessment. This is a hypothetical example, but I can envision a survey of affected patients, done in a rigorous fashion, that asks patients for their opinion regarding what they think of the benefits of the device vs. risks. If quality patient perspective data were to indicate patients (or at least a reasonable subset of patients) would accept the risks of the device (in this case, that they would specifically accept the risk of increased mortality, and the more specific this survey were to be in terms of hard numbers, the better), … So if patients would accept the risks of the device in exchange for the benefits in terms of symptomatic improvement, then it’s possible FDA could find such a device approvable. Patients with serious disease, advanced sx’s Permanent implant Mechanism of action unclear Data indicates Improved symptoms Increased mortality Patient preferences survey

Novel Technology and Unmet Medical Need This next example is intended to give you an idea of how we could use the Benefit-Risk framework to help us work through an issue regarding a clinical trial. As I mentioned at the beginning, while the BR guidance specifically applies to certain marketing applications, the concepts can often be used in making BR assessments earlier in the process. The other point I hope to make is that FDA is trying to be more consistent in considering the role of a device in terms of addressing an unmet medical need. Consider a device intended to treat a medically-refractory condition. Importantly, when inadequately treated, this medical condition is associated with high morbidity and mortality. The device is a permanent implant placed around a vascular structure. Bench testing raises a safety concern, that, long-term, there might be a risk of damage to, or erosion into, an artery. One path we could take is to require a long-term animal study, to look at this specific issue, prior to starting a clinical trial. The point of the animal study is to better understand the risk of vascular injury prior to exposing patients to the device. While not unreasonable, another way to look at this is to understand the risk of NOT allowing a clinical trial to start. The device is intended to treat a medically-refractory population suffering from a condition that’s associated with high morbidity and mortality. So the risk of NOT allowing a clinical trial to start is that the population to be studied, who has failed conventional therapy, may experience the morbidity and mortality associated with the uncontrolled underlying disease process. Viewed from that perspective, the benefits vs. risks of allowing a clinical trial to start, may be considered acceptable, as long as the animal study is conducted. The BR assessment, therefore, may favor allowing the clinical trial to start, running the long-term animal study concurrently. Medically refractory condition High morbidity and mortality Permanent implant Around vascular structures Bench testing safety concern Potential for damage/erosion into artery Long-term animal study needed Prior to clinical study or run concurrently?

Internal FDA Training Premarket review staff received training prior to implementation Periodic “Grand Rounds” ODE and OIR (previously OIVD) Led by Chief Medical Officers Discuss current PMA and de novo applications I’ll wrap up with just a brief comment on efforts FDA is undertaking to train our own staff on this effort. We held a series of training sessions for the staff and managers that are impacted by this guidance. Examples include members of the Office of Device Evaluation (or ODE), Office of In-vitro Diagnostics and Radiological Health (OIR which was formerly OIVD), and the Office of Surveillance and Biometrics (or OSB). This training occurred about the time the BR guidance became effective. Since then, ODE and OIR have been holding joint BR Grand Rounds in which typically one file is presented as a springboard for discussion, and attendees (who can come from any Office) can discuss the benefits and risks of the device, ask questions, and hear how others in the Center view the same information. One of the goals is to share knowledge and learn from each other in order to improve our consistency in making these assessments. The rounds have been pretty well attended, and I have to say the discussion is often quite spirited. The good news is that there’s a lot of interest in this effort on our part, so I hope you see value in it, as well.

Useful Links This is a link to the guidance document. http://www.fda.gov/downloads/MedicalDevices/DeviceRegulationandGuidance/GuidanceDocuments/UCM296379.pdf This is a link to a CDRH Learn module.  http://fda.yorkcast.com/webcast/Viewer/?peid=bac3f2698df14fa98388409da5cba6831d The 1st link is to the BR guidance itself. In case you haven’t read it, you can see it here. The 2nd bullet is a link to on online training module that discusses the BR guidance which you may find useful. So that’s all I had in terms of a formal presentation. I’ll be happy to take questions if you have any.

Here is what you will find at CDRH Learn on the topic, a video explaining more than I’ve had time to outline.

Providing Industry Education and Assistance – CDRH Resources CDRH Learn – Online Regulatory Training Tool Over 50 Medical device and Radiological Health modules Video, PowerPoint presentations available 24/7 (some Chinese / Spanish) Certificate of completion upon passing post-tests http://www.fda.gov/Training/CDRHLearn/ Device Advice – Online Regulatory Information Searchable by Topic http://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/ Division of Small Manufacturers, International, and Consumer Assistance (DSMICA) – Live Regulatory Assistance Technical Assistance for the Medical Device Industry Available 8:00 am – 5:00 pm EST @ 800-638-2041 or 301-796-7100 DSMICA@fda.hhs.gov Here are some facts about CDRH Learn and additional learning resources.

Thank You