NBCC’s first priority has been guaranteed access to quality healthcare for all. To achieve its mission to end breast cancer, everyone must have equitable access to interventions that work and are safe and affordable. The Food and Drug Administration (FDA) plays a vital role in achieving that goal. We need an FDA that approves drugs with clinically meaningful benefits for patients. Among a number of critical reforms, NBCC seeks to address systemic deficiencies in FDA regulation of the drug and biologic approval process, including accelerated approval.
A key responsibility of the FDA is to protect the public by ensuring the safety and efficacy of new drugs and other medical interventions that enter the market. Patients assume they are receiving that when they are offered an FDA-approved drug/biologic. Unfortunately, this expectation is not met in many cases.
In 1992, the FDA instituted its Accelerated Approval Program to allow for earlier approval based on surrogate endpoints of drugs/biologics that treat serious conditions and fill an unmet medical need. A surrogate endpoint is an intermediate endpoint (e.g., tumor shrinkage) “reasonably likely to predict clinical benefit” that is a substitute for a direct measure of clinical benefit, such as how a patient feels, functions, or survives. When properly validated, surrogate endpoints are reasonable to use as endpoints in clinical trials, but many surrogates currently in use today have failed to correlate with clinical benefit.
Current Federal law grants FDA the authority to require drug sponsors to conduct confirmatory trials after accelerated approval to verify that the drug or biologic provides the predicted clinical benefit. At the time of accelerated approval, FDA and sponsors agree on the timeline for completing the confirmatory study and other milestones. Upon completion, if the confirmatory trials demonstrate true clinical benefit, the accelerated approval is converted to regular approval. The FDA also can withdraw an accelerated approval if the drug manufacturer fails to conduct the post-approval studies with due diligence, if the studies fail to verify the predicted effect or demonstrate that the product is not safe or effective under the conditions of use, or if the manufacturer disseminates false or misleading promotional material. However, rescinding or withdrawing a drug or biologic that has received accelerated approval is cumbersome and can take many months to years. This creates a drug approval system that allows drugs to come to market and stay on the market without evidence of clinical benefit. These drugs all carry toxicities, and many also have an extraordinary financial cost.
Clinical benefit has not been confirmed in a significant majority of the drugs granted accelerated approval. The FDA often permits drug sponsors ridiculously long timelines to complete post-approval trials. While these trials are meant to show whether clinical benefit exists, the trials frequently use the same or other surrogate endpoints rather than clinically meaningful ones. This makes no sense if the goals are to show clinically relevant outcomes and to save lives. In some cases, toxic drugs without any evidence of clinical benefit remain on the market for years.
Congress must consider reforms to the accelerated approval pathway to ensure that the drugs given to patients are safe and have actual clinical benefits (improved survival and/or quality of life). The FDA should impose strict timelines for the initiation of confirmatory trials and require the use of clinically meaningful endpoints. Additionally, the FDA should have the authority to quickly withdraw an accelerated approval if a confirmatory trial has not been initiated or timely completed and/or the drug fails to confirm clinical benefit.
While surrogate endpoints may allow for shorter trials and easier measurement, they usually do not yield useful information about how well an intervention improves or prolongs lives. Yet all drugs carry toxicities. That means most of the time, patients are being harmed with no clinical benefit. Individuals should be able to make healthcare decisions based on the highest possible quality of evidence. For that to happen, we need well-designed clinical trials that use valid and meaningful outcome measures. We recognize that the selection of the ideal experimental endpoint is not always possible or practical. On the other hand, designing a trial with practical but inadequate outcome measures will only result in harm to patients, wasted resources, and delays in identifying the most effective healthcare.
The goal should not be to push more drugs to market quickly. Rather, it should be to adhere to a system that approves drugs that clinically benefit patients in an expeditious and scientifically rigorous manner.
NBCC believes that the drug/biologic approval process must bring drugs to market that have been proven to confer significant clinical benefits with minimum harm. In the breast cancer context, the clinical benefit should be a significant increase in overall survival or quality of life.