The FDA’s accelerated approval pathway has a potentially prominent champion — Robert Califf, the scientist President Biden has nominated to lead the FDA.
This pathway opens the door to earlier approval of drugs aimed at serious conditions that fill an unmet medical need based on a surrogate endpoint, which can considerably shorten the time required to submit data to the FDA and expedite the agency’s review process.
At his confirmation hearing in December, Califf said he is “a fan of accelerated approval for the right conditions.”
Six weeks later, Senator Ron Wyden (D-Ore.), who chairs the U.S. Senate’s Committee on Finance, sent Califf a letter asking him to clarify his position on accelerated approval. He asked Califf five important questions:
- What standard will you use to determine whether a company has failed to comply with confirmatory evidence requirements?
- How do you expect to hold laggard companies accountable? Which of the existing FDA authorities will you use?
- How will you measure compliance with clear enforcement standards?
- If these actions do not lead to success, will you request additional authorities from Congress?
- How will you use your position to prioritize policy reforms that use existing authority to fix the problems for drugs with accelerated approval when they have yet to provide evidence for confirming their effect?
All excellent, timely, thoughtful and, most importantly, fair inquiries. Dr. Califf’s brief response is a start.
A more potent and progressive way to address the issue would be for Congress to pass the Promising Pathways Act. Its premise and specific recommendations respond directly to Wyden’s questions and the broader regulatory science and public health issues they raise. Its sponsor, Senator Mike Braun (R-Ind.), sits on the Senate’s Committee on Health, Education, Labor, and Pensions. That means he will be part of the Senate’s hearings to reauthorize the Prescription Drug User Fee Act, and could propose that the pathways act becomes part of this “must pass” legislation.
The Promising Pathways Act would require the FDA to establish a priority review system to create a pathway for provisional approval applications. “Provisional” here means that a drug could become available to patients with limited data, but that the manufacturer would be required to continue collecting data until full FDA approval is granted. The FDA would consider new therapies seeking review under this pathway on a rolling basis and evaluated within 90 days of receiving a completed application. The act would also require the agency to evaluate provisional approval applications related to epidemics or pandemics, including Covid-19, within three weeks of submission.
Under the act, a drug may be eligible for provisional approval if it is intended for the treatment, prevention, or medical diagnosis of a serious or life-threatening disease or condition in which there is a reasonable likelihood that premature death will occur without early medical intervention; for a disease or condition that poses a threat of epidemic or pandemic; or for a disease or condition associated with morbidity that substantially affects day-to-day functioning.
The Promising Pathways Act would allow the FDA to approve applications for provisional approvals that demonstrate substantial evidence of a drug’s safety along with relevant early evidence establishing that it improves therapeutic outcomes and that the benefits are consistent with or greater than currently marketed on-label therapies, with equal or fewer side effects. The act also requires the agency to establish protocols to enable sponsors to submit a rolling, real-time, mid-trial application for provisional approval while preserving the integrity of any ongoing trials. It also requires the FDA to allow sponsors to include real-world evidence and scientifically substantiated surrogates to support applications for provisional approval.
FDA watchers might ask: Doesn’t the agency already have the expedited pathways that allow approvals under similar circumstances? The short answer is “Yes.” The longer answer is “Yes but …”
All of the FDA’s various pathways for drug review overlap by design. They’re iterative. The one outlined in the Promising Pathways Act would specifically give the agency added potency in the measures it can take to drive sponsors to deliver what they have committed to deliver. To Wyden’s questions about authority, accountability, and enforcement, the act is both targeted and innovative.
The Promising Pathways Act would require the establishment of patient registries for all provisionally approved drugs. These registries — which could be run by third-party governmental, for-profit, or nonprofit entities — would track the therapeutic effect of provisionally approved drugs on patients. Disaggregated and de-identified, this database must be accessible for approved researchers and medical professionals for public health research. The costs of the registry would be funded by drug sponsors or, in the case of an epidemic or pandemic, the government. The FDA would be required to submit an annual report to Congress on drugs granted provisional approval status.
The act would require patients who use a provisionally approved drug to participate in the registry and consent to the sponsor’s collection of their data and submission of to the FDA. A drug sponsor with less than 90% of patients receiving a provisionally approved drug participating in the registry would be penalized $100,000 and, if the violation is not corrected within 30 days, the sponsor would be penalized $10,000 every day it continues to violate this requirement. If patient participation is not at or above 90% within six months, provisional approval would be withdrawn.
Withdrawal of provisional approval
The Promising Pathways Act would require the FDA to withdraw provisional approval of a drug if the agency determines that patients are experiencing more adverse effects compared to other available currently marketed on-label therapies for the disease or condition. If provisional approval is withdrawn, the sponsor may not give the drug to any new patients, though it may continue to give it to those who had started taking the drug before it was withdrawn, for a period of time based on patient need, as determined by the Secretary of Health and Human Services (HHS).
Post-market controls and labeling
Under the Promising Pathways Act, the FDA would be required to rescind provisional approval for drugs in which the patient registry data show that the drug is less beneficial than other drugs with full approval or the side effects do not outweigh the benefits.
The act would also require sponsors of a provisionally approved drug to ensure that all of its labeling and promotional materials include the statement “provisionally approved by FDA pending a full demonstration of effectiveness under (the application number assigned by the Secretary).” All promotional, educational, and marketing materials for provisionally approved products must be reviewed and approved by the HHS secretary.
Applying for full FDA approval
The FDA would allow the sponsor of a provisionally approved drug to apply for full approval at any point. If real world data establishes a 15% improvement in an important endpoint, including scientifically substantiated surrogates, it would automatically receive full approval status.
Advancing the power of the patient voice
Implicit in Wyden’s letter to Califf is the need to advance patients’ access to new therapies while enhancing safety protocols. The Promising Pathways Act would require the FDA to establish (within six months of its passage) an Office of Patient Advocate General within the Office of the Commissioner. That office would provide assistance to patients and their families who use provisionally approved drugs and other FDA reviewed or approved drugs. Such assistance would include providing information about maintaining health, delivery of proper informed consent, participating in clinical investigations, and completing required documentation to participate in various clinical programs.
To avoid a repeat of the Aduhelm reimbursement imbroglio, one section of the Promising Pathways Act would amend the Public Health Service Act and the Social Security Act to prevent commercial and federal payers from denying coverage of any drug provisionally approved on the basis that the drug is experimental. Payers must treat a provisionally approved drug in the same manner as drugs that have received full FDA approval.
Wyden wants the FDA to be both an innovation accelerator and a more robust regulator. The Promising Pathways Act would help facilitate that complicated double play by providing innovators with incentives to pursue exciting new science through progressive and pragmatic 21st-century approaches. Provisional approvals forge a partnership between patients, developers, and the FDA, sharing acceptable risks and promising benefits for serious and life-threatening diseases.
With a healthy dose of bipartisanship, Wyden can help accelerate a promising pathway for expanded access along with a Califf confirmation.
Peter J. Pitts is president of the Center for Medicine in the Public Interest, a visiting professor at the University of Paris Medical School, a former member of the United States Senior Executive Service, and a former FDA associate commissioner.
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