The FDA's accelerated approval pathway, intended to provide quicker access to potentially life-saving treatments, is under increasing scrutiny as concerns rise about the actual clinical benefits and high costs of some drugs approved through this route. This process, which allows the licensing of drugs based on surrogate markers of effectiveness rather than proven clinical outcomes, has led to debates over the validity of these stand-ins and the overall value of the approved medications.
Ocaliva: A Case Study in Accelerated Approval
Ocaliva, prescribed for primary biliary cholangitis, highlights the complexities of accelerated approvals. Dr. Steven-Huy Han, a UCLA liver specialist, notes that while Ocaliva effectively lowers alkaline phosphatase levels, a surrogate marker, its long-term impact on preventing liver cancer or cirrhosis remains uncertain. "I have no idea if the drug will make them better," he stated, emphasizing the years it could take to determine its true efficacy. Approved in 2016, Ocaliva carries a list price of around $100,000 per year, adding to the financial burden on patients.
Concerns Over Surrogate Markers and Clinical Benefit
Dr. Aaron Mitchell, an oncologist at Memorial Sloan Kettering Cancer Center, argues that truly game-changing drugs don't require surrogate markers for proof of effectiveness. He suggests that the accelerated approval process contributes to the availability of "marginally effective, not clinically meaningful, more expensive drugs." The debate centers on whether these surrogate markers accurately predict long-term patient outcomes and justify the high costs associated with these medications.
The Role of User Fees and Industry Influence
The FDA's reliance on user fees paid by pharmaceutical companies, which accounted for $2.9 billion of the agency's $6.5 billion 2022 budget, raises questions about potential industry influence. Senator Bernie Sanders has expressed concern that these fees may incentivize the FDA to prioritize industry interests over patient access to affordable drugs. The user fee agreements, negotiated between the FDA and industry, have expanded communication and streamlined the approval process, but critics worry about the balance between regulatory efficiency and rigorous evaluation.
Calls for Stricter Confirmatory Trials
To address these concerns, there are increasing calls for stricter requirements for confirmatory trials after accelerated approval. The FDA's cancer branch has considered demanding that drugmakers initiate these trials before receiving accelerated approval. However, challenges remain, as evidenced by Intercept Pharmaceuticals' difficulty in enrolling enough patients for a confirmatory trial for Ocaliva. The use of "real-world evidence" for post-market reviews is also being debated, with concerns about the reliability of data collected outside of controlled clinical trials.
Balancing Innovation and Patient Benefit
Despite the criticisms, many doctors and patients express gratitude for having access to drugs like Ocaliva, especially when other treatment options are limited. Dr. Renumathy Dhanasekaran of Stanford University School of Medicine acknowledges the dilemma: "As a scientist, the accelerated approval process concerns me, but as a physician treating patients with a very challenging disease, translating some of these drugs to the clinic faster is attractive." The challenge lies in striking a balance between fostering innovation and ensuring that approved drugs provide meaningful and lasting benefits to patients.
