Are Higher Standards for Expedited FDA Approvals Needed?

Sanket Dhruva, MD, MHS

Although expedited pathways have allowed for faster availability of novel drugs and medical devices, many clinicians have reported a lack of understanding of the FDA approval process and expressed a desire for strong premarket evidence to support these approvals, according to findings from a national survey published in Health Affairs.¹

“Physicians are generally looking for greater rigor when drugs and devices are coming to the market compared with how often the standards are used to support approvals,” Sanket Dhruva, MD, MHS, an assistant professor of medicine at the University of California San Francisco (UCSF) and lead author of the survey study, said in an interview with OncologyLive. “They’re looking for greater rigor in the evidentiary standards and are looking for regulatory action when postapproval trials are either not conducted, not conducted meeting timelines, or conducted and show that a drug or device doesn’t work.”

Board-certified physicians in internal medicine, medical oncology, or cardiovascular medicine who were surveyed regarding the approval process of new drugs (n = 489) and high-risk medical devices (n = 479) self-reported that they understood the FDA approval process extremely well (7% and 4%, respectively), moderately well (34% and 13%), somewhat well (35% and 24%), slightly well (13% and 20%), and not at all well (12% and 39%). When allowed to respond more than once, physicians reported that they believed newly approved FDA drugs vs medical devices were more effective than other available treatments for the same condition (39% vs 43%; P < .001), more effective than placebo (91% vs 66%; P < .001), and safer than other treatments available for the same condition (31% vs 37%; P < .001), respectively. The survey focused on 4 domains regarding approvals: physicians’ perception of FDA approval, characteristics that physicians think are important among studies supporting FDA approval, views about expedited FDA development or review, and views about moderate-risk devices.¹

When a postapproval trial for an accelerated approval drug or breakthrough medical device fails to demonstrate clinical benefit upon completion, approximately 95% of surveyed clinicians felt the FDA should withdraw the agent from market, and approximately 89% believed the medical device should be withdrawn. Moreover, approximately 50% of physicians believed that the FDA should work with the manufacturer to continue testing to identify an effective indication for drugs compared with approximately 60% for devices in this situation. When the postapproval trial for an accelerated approval drug or medical device was delayed or not conducted, approximately 60% of clinicians thought the agent should be withdrawn and approximately 70% thought the device should be withdrawn; approximately 80% responded that the FDA should work with the manufacturer to expedite trial completion for both agents and devices. However, Dhruva noted that “we know that the FDA extremely infrequently [withdraws indications].”

Additional results from the survey revealed that clinicians believed the following conditions should be mandated for the FDA to approve drugs and medical devices: 2 or more randomized controlled trials (57% and 60%, respectively), a single randomized controlled trial (43% and 39%), only data from registries (0.2% and 0.8%), and only case reports and expert opinion (0.2% and 0.4%).¹

Dhruva also explained that “physicians overwhelmingly felt randomization, the use of blinding, and the use of comparators were very important. [They felt] these trials should all have at least 1 primary end point [and] meet that primary end point to support FDA approval, among other characteristics. This is a particularly important finding because it contrasts with the evidence standards that are sometimes used for FDA approvals of drugs and high-risk medical devices.”

He added that “there’s not as much as 90% use of randomization, even though [approximately] 90% of physicians felt that should be an important characteristic in the FDA’s approval decision. The use of blinding, for example, in medical device clinical trials is very infrequent, even though more than 70% of physicians felt that this should be an important characteristic. We’re seeing that there is some disconnect between what physicians expect and what the actual realities are of the trials that are used to support FDA approvals of drugs and medical devices.”

Beginning in 2015 as a transparency initiative launched by the FDA recognizing agents used in various medical conditions, the Center for Drug Evaluation and Research has released annual Drug Trials Snapshots summary reports on novel therapies approved.2 In 2022, there were 10 novel therapies approved in the oncology space. Of all novel therapies approved in 2022 spanning additional diseases, 24 of 37 novel drug approvals used at least 1 expedited approval pathway.1 Dhruva and the study authors recommend that the Drug Trials Snapshots could be extended to medical devices to help improve understanding of device regulation.

Breaking Down Fast Track and Breakthrough Therapy Designations

Per the FDA Safety and Innovation Act of 2012, breakthrough therapy designation was created to expedite drug development.3 To receive the designation, preliminary evidence must show via a clinically significant end point that a drug may provide substantial benefit vs available therapies to treat a serious condition.4 In this instance, a clinically significant end point encompasses an end point measuring an effect on irreversible morbidity or mortality as well as on symptoms that are serious consequences of the disease; this can also include findings that the new drug has a significantly improved safety profile vs available therapies or has an effect on a surrogate end point, intermediate clinical end point, or pharmacodynamic biomarker that does not meet criteria for an acceptable surrogate end point but suggests potential for a clinically meaningful effect.⁴

Additionally, when an agent receives breakthrough therapy designation, it is then eligible for fast track designation features, guidance on a drug development program starting with phase 1, and organizational commitment with senior managers.⁴

Dhruva noted that the word breakthrough has affected how patients and clinicians view agents, with study findings showing the perception of drugs is impacted for both clinicians and patients who then believe that breakthrough correlates with effectiveness.

“There’s something naturally about this term breakthrough that makes it more likely that physicians and patients are going to use or recommend use of this device, even though the breakthrough designation actually means that there are more flexible study designs,” Dhruva explained. “It’s particularly important that the connotation of the word breakthrough is affecting patient and physician perceptions.”

To receive fast track designation, an agent must either fill an unmet need or demonstrate benefit vs available therapies, and following this designation, the drug has eligibility for accelerated approval and priority review if relevant criteria are met, according to the FDA. Additionally, rolling review may then occur along with more frequent meetings as well as written communication with the FDA.⁵

Diving Into Priority Review, Accelerated Approvals, and Device Approvals

Under the Prescription Drug User Fee Act of 1992, priority review and standard review were written into law to improve drug review time. Following standard review protocol, the goal of the FDA is to act on a drug application within 10 months, and priority review decreases this period to 6 months.⁶

Significant improvements regarding the efficacy or safety of an agent vs standard therapies in the treatment, diagnosis, or prevention of serious conditions must be demonstrated via evidence of increased efficacy, evidence of efficacy and safety in a new patient population, reduction/elimination of a treatment-limiting drug reaction, or enhancement of patient adherence that may lead to improvements. Then, priority review will be granted; the FDA states they will grant the designation within 60 days of receiving the original biologics license application, new drug application, or efficacy supplement.⁶

“Expedited pathways have been increasingly used in FDA regulatory decision-making, and in general, these pathways allow for the use of earlier-stage data [from] smaller clinical trials, shorter trials, and trials that are focused on surrogate end points, such as laboratory tests or imaging tests, as opposed to clinical end points such as how patients live or feel,” Dhruva said. “This is important, and the reasoning behind this is to get drugs and devices to patients more quickly if there is promise, but that needs to then be matched in the postapproval setting [with] information about risks and benefits and postapproval trials conducted verifying safety and effectiveness.”

Accelerated approval designation, which was first introduced in 1992, allows for approvals of agents based on a surrogate end point. Following the FDA Safety and Innovation Act of 2012, accelerated approvals occur when agents that fill an unmet need to treat serious conditions affect a surrogate or intermediate clinical end point. The FDA said that scientific support on the surrogate or intermediate end points impacts their decision on whether to accept the end point.⁷

Regarding device approvals, when seeking approval, device developers file an application based on the device’s class. The Humanitarian Device Exemption; Premarket Notification 510(k), indicating that a class II device is similar to others on the market; and Premarket Approval Application for Class III Devices are the 3 categories that investigators may file an application under. Humanitarian category devices treat or diagnose a disease/condition affecting fewer than 4000 people, and when a new application is submitted, there must be proof provided that no similar legally approved devices exist and that there is no other way to bring the device to market.⁸

Class III devices represent less than 1% of all medical devices marketed a year, according to the study investigators, and although this class often requires clinical trial evidence to be approved, class II devices most likely can be approved without clinical data if they are similar to other legally marketed devices. Additionally, class I devices can emerge on the market if good manufacturing practices are followed and no misbranding or adulteration occurs.¹

Steps to Ensure Knowledge of Agents/Devices

“We think that covering these topics in medical education would be important, that this should be a part of medical school so that physicians are able to understand the basics of medical product approvals and medical product regulation,” Dhruva said. “We also believe that there should be more tailored training during subspecialty.”

Dhruva also noted that CME could have a role in including information on evidence the FDA reviewed to support the approval decision. “There is a real need and emphasis on postmarket evidence generation, and having that in CME could be important,” he said.

“It would be very helpful to tell patients, ‘We’re recommending this drug because we think that it’s going to help you.’ However, we should acknowledge there is uncertainty based on [certain] factors and there is also ongoing postapproval evidence generation,” he explained. “That is very different and can help patients make more informed decisions based on the totality of evidence rather than the absence of that information or saying, ‘We have a breakthrough drug that we’re going to recommend to you.’ It’s important that patients are provided relevant, meaningful information to be able to inform decisions in their care, [and we must] honor the ethical principle of patient autonomy.”

A follow-up to the physician survey study is also in progress, Dhruva said. He also noted that they are surveying medical, pharmacy, and dental students from UCSF on what they learned regarding drug and medical device regulation.

“Hopefully, this will help to provide further information and inform strategies to help close these gaps in physician understanding and, depending on what we find, health professional understanding of drug and device regulation,” Dhruva said.

References

1. Dhruva SS, Kesselheim AS, Woloshin S, et al. Physicians’ perspectives on FDA regulation of drugs and medical devices: a national survey. Health Aff (Millwood). 2024;43(1):27-35. doi:10.1377/hlthaff.2023.00466
2. Center for Drug Evaluation and Research. Drug Trials Snapshots Summary Report 2022. FDA. 2022. Accessed January 31, 2024. https://www.fda.gov/media/168662/download?attachment
3. Puthumana J, Wallach JD, Ross JS. Clinical trial evidence supporting FDA approval of drugs granted breakthrough therapy designation. JAMA. 2018;320(3):301-303. doi:10.1001/jama.2018.7619
4. Breakthrough therapy. FDA. Updated January 4, 2018. Accessed January 31, 2024. https://www.fda.gov/patients/fast-track-breakthrough-therapy-accelerated-approval-priority-review/breakthrough-therapy#:~:text=Breakthrough%20Therapy%20designation%20is%20a,clinically%20significant%20endpoint(s)
5. Fast track. FDA. Updated January 4, 2018. Accessed January 31, 2024. https://www.fda.gov/patients/fast-track-breakthrough-therapy-accelerated-approval-priority-review/fast-track
6. Priority review. FDA. Updated January 4, 2018. Accessed January 31, 2024. https://www.fda.gov/patients/fast-track-breakthrough-therapy-accelerated-approval-priority-review/priority-review
7. Accelerated approval. FDA. Updated February 24, 2023. Accessed January 31, 2024. https://www.fda.gov/patients/fast-track-breakthrough-therapy-accelerated-approval-priority-review/accelerated-approval
8. Step 4: FDA device review. FDA. Updated January 4, 2018. Accessed January 31, 2024. https://www.fda.gov/patients/device-development-process/step-4-fda-device-review