Earlier this week, Energy and Commerce Committee Chairman Frank Pallone, Jr. (D-NJ) introduced the Accelerated Approval Integrity Act, which would improve the Food and Drug Administration’s (FDA) ability to ensure that drugs that receive accelerated approval are providing a proven clinical benefit to patients
About the Accelerated Approval program (AAP)
In 1992 the FDA instituted its Accelerated Approval Program to allow for earlier approval of drugs that treat serious conditions, and that fill an unmet medical need based on a surrogate endpoint.
A surrogate endpoint is a marker, such as a laboratory measurement, radiographic image, physical sign or other measure that is thought to predict clinical benefit, but is not itself a measure of clinical benefit. The use of a surrogate endpoint can considerably shorten the time required prior to receiving FDA approval.
Pharmaceutical companies are still required to conduct phase 4 confirmatory trials to confirm the anticipated clinical benefit. If the confirmatory trial shows that the drug actually provides a clinical benefit, then the FDA grants traditional approval for the drug. If the confirmatory trial does not show that the drug provides clinical benefit, FDA has regulatory procedures in place that could lead to removing the drug from the market.
However, as multiple witnesses at a February Health Subcommittee hearing testified, these existing tools are cumbersome, resource-intensive, and seldom used.
Why was this bill was introduced?
According to Frank Pallone, Jr:
“The Accelerated Approval Program allows patients to access innovative new drugs while the manufacturer and FDA conduct additional studies to confirm the product’s clinical benefit, However, under the current system, some products have been allowed to stay on the market for far too long without clinical trials that demonstrate a real clinical benefit for patients. Patients deserve to know that the drugs they are taking are safe and effective. I’m introducing the Accelerated Approval Integrity Act to protect patients and provide FDA with the authority it needs to ensure approved drugs provide a clinical benefit. The bill would also streamline the process for taking products off the market if no clinical benefit is proven in a timely manner.”
House Committee on Energy and Commerce
Some potential areas of concern about the AAP
A July 2021 White paper1 by Kaltenbrock et al states that:
- the reliance on surrogate endpoints seems to have become more common, even as guidance about the magnitude of change needed to plausibly suggest long term patient benefit remains largely absent.
- the confirmatory evidence required for conversion of AAP to full approval is often slow to materialise. In some instances, study sponsors fail to conduct or publish required studies at all.
- the magnifying the impact of both of these areas of concern, is the issue of the high prices of drugs launched through the AAP. Drugs coming to market with accelerated approval often arrive with very high price tags, with no apparent discount for the uncertainty surrounding their effectiveness
Yet another White paper2 from August 2021 also by Kaltenbrock et al states:
However other patient groups and many policymakers view the AAP and its implementation as having lost the balance needed to ensure overall benefits to the patients and society. Strongly worded condemnations claim that the FDA’s use of the AAP has now fully succumbed to a gradual erosion in the standard of evidence deemed adequate for approval. In addition, there are longstanding concerns that the regulatory mechanism to ensure that drug sponsors perform high-quality confirmatory trials is ineffective, undermined by the lack of financial incentives and the apparent lack of will within the FDA to exercise their existing powers to withdraw approval when trials are not conducted expeditiously or fail to confirm the intended clinical benefit. Compounding the concerns of many stakeholders is the high price of most drugs approved through the AAP, a reflection of the lack of any mechanism to modulate pricing despite the greater uncertainty regarding clinical benefits for patients.
How is the Accelerated Approval Integrity Act expected to improve the AAP?
It is expected that the Accelerated Approval Integrity Act will provide FDA with additional authority to ensure products that receive accelerated approval are providing a clinical benefit to patients in a timely manner, including:
- Codifying requirements for manufacturers to conduct post-approval studies on drugs that receive accelerated approval;
- Requiring manufacturers to enter into an agreement with FDA on how the studies will be conducted before the agency can grant accelerated approval, which may include details like enrollment targets, milestones, and study design;
- Allowing FDA to require studies to be underway at the time of approval;
- Requiring more frequent updates on post-approval studies, including updates on enrollment targets, milestones, and study design;
- Outlining expedited procedures for withdrawing approval, which would include due notice and opportunity for a written appeal to FDA, an opportunity for public comment, and may include FDA convening and consulting an advisory committee;
- Specifying additional instances in which an accelerated approval can be withdrawn including if a manufacturer fails to achieve agreed upon enrollment targets, milestones, or timely study completion;
- Automatically expiring accelerated approval status one year after post-approval studies are scheduled to be complete, and in no case later than five years after approval, unless the post marketing study has been completed and verified the clinical benefit, or the Secretary of Health and Human Services determines that adequate progress has been made. In that case, those studies can continue;
- Requiring additional information on accelerated approval drugs’ labels; and
- Making failure to submit reports or act with due diligence on post-approval studies prohibited acts subject to penalties.
Further information
You can read more about the FDAs Accelerated Approval pathway here.
References
- Strenghtening the Accelerated Approval Pathway: An analysis of potential policy reforms and their impact on uncertainty, access, innovation and costs (White Paper Institute for Clinical and Economic Review, Anna Kaltenboeck et al, April 2021)
- Potential policy reforms to strengthen the accelerated approval pathway (White paper, Journal of Comparative Effective Research, Anna Kaltenboeck et al,, August 2021)