In their 2015 industry report, the Pharmaceutical Research and Manufacturers of America (PhRMA) estimated over 800 cancer therapies were in the industry pipeline—citing that approximately 80% of these drugs have the potential to be first-in-class medicines. One of the most groundbreaking areas in oncology today is checkpoint inhibitor immuno-oncology (I-O) treatments, with the American Society of Clinical Oncology (ASCO) naming immunotherapy as its 2016 Advance of the Year. Checkpoint inhibitor I-O treatments unlock immune system cells, allowing the cells to recognize and fight cancer tumors, and have shown early efficacy gains that have given hope to many oncology researchers, physicians, and patients. An exciting breakthrough that raises the question—what is the fastest and safest way to get these new treatments to patients?
FDA Accelerated Approval Program
Traditionally, it can take years of clinical trials to gather sufficient evidence to gain approval from the U.S. Food and Drug Administration (FDA). For its part, the FDA has sought opportunities to accelerate speed to market for treatments that fill unmet medical needs. The Accelerated Approval Program, initiated in 1992, permitted approval based on the use of surrogate endpoints. In 2012 the Food and Drug Administration Safety Innovations Act (FDASIA), amended the prior act to "allow approval for drugs for serious conditions that fill an unmet medical need on whether the drug has an effect on a surrogate or intermediate clinical endpoint." Drugs that are granted accelerated approval are required to submit postmarketing confirmatory trials "to verify and describe the anticipated effect on irreversible morbidity or mortality (IMM) or other clinical benefit." Associated with the treatment of long course disease conditions, checkpoint inhibitor I-O treatments are ideal candidates for the Accelerated Approval Program.
Acceleration of Checkpoint Inhibitor I-O Approvals
Currently, there are four FDA approved checkpoint inhibitor I-O drugs to treat six types of cancer for 15 total indications. Three out of four of the FDA-approved checkpoint inhibitor I-O drugs received approval under the Accelerated Approval Program for eight indications:
- KEYTRUDA® – melanoma (second line); non-small cell lung cancer (NSCLC) (second line); head and neck squamous cell carcinoma (HNSCC) (second line)
- OPDIVO® – melanoma (first line); melanoma (second line); Hodgkin's lymphoma (second line); bladder cancer (second line)
- TECENTRIQ® – bladder cancer (second line)
YERVOY®, the first checkpoint inhibitor approved, was assessed on the basis of overall survival (OS) data, a hard clinical trial endpoint, in a normal FDA review. In contrast, the three checkpoint inhibitor I-O drugs (KEYTRUDA, OPDIVO, and TECENTRIQ) launched after YERVOY were submitted and received initial approval through the Accelerated Approval Program based on the surrogate endpoints of progression-free survival (PFS) and objective response rate (ORR). Most of these approvals were based on non-comparative trial data.
While it may not always be appropriate, non-comparative ORR results can be collected much more quickly than comparative OS data. This opportunity for faster market access has been widely used by the industry. KEYTRUDA, for example, used accelerated approvals in three out of the five indications for which it has been approved. To date, the FDA's requirement for confirmatory evidence appears to be sufficient to ensure the necessary burden of evidence is met. No checkpoint inhibitors that have been approved under the Accelerated Approval Program have been subsequently withdrawn.
How do accelerated regulatory approvals affect reimbursement approvals? While the evidence may be sufficient for regulatory approval by the FDA, is it—or should it be—sufficient for the EMA as well? In most countries, market access is determined by reimbursement organizations. A drug must receive both regulatory and reimbursement approval in order to reach patients. Could this level of evidence be sufficient for reimbursement approval as well? Tune in for our March Webinar where we will discuss this and other challenges to market access for the checkpoint inhibitor I-O drugs.