Approximately 40% of recently approved cancer drugs have gone through one of four established FDA expedited programs. These treatments account for billions of dollars in sales and help create a thriving, industry-wide pipeline. The FDA has also recently approved the first New Drug Application (NDA) under one of its new pilot programs intended to speed cancer drug review, leading to optimism that these programs will also help speed delivery of more drugs to patients. But there has also been fresh criticism about results of the Accelerated Approval pathway and whether post-market trials support approval of most of these drugs. Will concerns about overuse lead to curtailment of these programs? Or do these concerns just reflect the age-old tension between getting drugs approved faster and knowing more about them before they are approved? Have criteria for what makes a good candidate for an expedited program changed? Here, we review the latest developments with insights and comments from Dr. William (Bill) Slichenmyer, a partner at Alacrita and an oncologist with more than 20 years of experience in the biopharma industry.
The Accelerated Approval pathway was adopted by the FDA in 1992 in the context of perceived regulatory delays in the face of very high unmet medical needs as well as significant activist pressures. It has delivered rapid regulatory assessment and market launch of significant medicine, with bicalutamide (Casodex) being one of the earliest examples of an oncology drug to take this pathway, in 1995, for the treatment of prostate cancer. The Accelerated Approval pathway set a new record for imatinib mesylate (Gleevec), in May 2001, for the treatment of chronic myeloid leukemia where the FDA’s review and approval took approximately 2.5 months. There are other excellent examples of drugs that have vastly improved outcomes for patients with hitherto few, if any, therapeutic options that have been brought to market via this highly efficient regulatory pathway and this has clearly delivered considerable value at a societal level.
More recently, the FDA granted Accelerated Approval for the immunotherapy atezolizumab (Tecentriq) in combination with chemotherapy for initial treatment of advanced triple-negative breast cancer. This is the first FDA-approved regimen for breast cancer that includes an immunotherapy. Shortly afterward, the drug received approval for treatment of small-cell lung cancer (SCLC), another condition that is notoriously difficult to treat. (The role of atezolizumab in SCLC will be further discussed below).
These examples represent exactly the type of drug candidates that regulators were thinking of when these expedited programs were developed—products that address major unmet needs and that seem to offer a significant advantage over current treatments. Although types of products being studied have greatly expanded, those features remain the keys to receiving expedited review.
“The Accelerated Approval system was adopted to expedite the approval of new therapies for patients with no good treatment alternatives. In particular, AIDS activists drew attention to this issue. Many of the early Accelerated Approvals were for new HIV drugs and are good examples of the FDA responding to a public health need. Subsequently, Accelerated Approval has been used for new drugs in a variety of disease areas, including oncology. Accelerated Approval remains an important mechanism for making new therapies available quickly for patients in need,” says Dr. Slichenmyer.
Although the expedited programs may seem similar, they each have important distinctions. In addition, some of them can be used together. Finally, the attention most recently has been largely on Accelerated Approval, as discussed further in “Continuing Media Controversy.” (The FDA Guidance on Expedited Programs is available here.)
Each of the FDA’s expedited programs are summarized below.
Established Programs:
Pilot Programs:
Each of these programs was started in response to the fundamental tension faced by both the FDA and drug developers: How to get truly safe and effective drugs to patients as quickly as possible. Because of the profound unmet need in oncology and often rapid progression of cancer, expedited programs have become particularly popular in this field.
A 2018 study by the FDA examined malignant hematology and oncology Accelerated Approvals from the program’s inception in December 1992 to the end of May 2017. The authors found that the FDA granted Accelerated Approvals to 64 such products for 93 new indications. Fifty-three of these approvals were for new molecular entities. The FDA team reported that 55% of products fulfilled their post-marketing requirements and verified benefit in a median of 3.4 years after their initial Accelerated Approval. The authors surmised that, over the past 25 years, “Only a small portion of indications under the Accelerated Approval program fail to verify clinical benefit.”
Two studies published more recently (in May 2019) dispute that conclusion. Both were reported in JAMA Internal Medicine, and both found that a high percentage of drugs approved based on RR, which is common among Accelerated Approvals, did not fulfill their promise after completion of required confirmatory testing:
These conclusions, whilst earning media-grabbing headlines, represent an oversimplified view of the real world drug approval process where, for each individual drug, a careful assessment of the risk-benefit balance is warranted. Each accelerated approval is predicated on the likelihood that benefits outweigh the risks and, importantly, that this will be further tested in confirmatory studies. The fact that some confirmatory studies did not yield a positive result simply illustrates the uncertainties inherent in drug development. Using the “retrospectoscope” as a blunt instrument for regulators’ inability to predict with near 100% accuracy the outcome of a confirmatory study is rather harsh. In reality, this is not a net new issue: since the dawn of the current regulatory era, there has been continued debate about where the threshold for evidence needed to support drug approval should lie.
“These publications provide high-level summaries of data that served as the basis for FDA approval for various cancer drugs,” explains Dr. Slichenmyer. “One challenge inherent in such an approach is that it necessarily lumps together different diseases such as acute lymphoblastic leukemia and metastatic colorectal cancer, which have distinct clinical manifestations and approaches to treatment. Summary statistics for such a heterogeneous group of diseases are less meaningful than a detailed assessment of each application. There are other limitations of these publications. The study by Gyawali et al. is critical of various clinical trial end points, such as RRs and progression-free survival. The limitations of these endpoints are widely acknowledged in our field. Yet Gyawali et al. recommend the use of other end points related to quality of life and overall survival without a critical discussion of their potential limitations. The publications devote little (Gyawali et al.) or no (Chen et al.) discussion to the historical perspective on development of the Accelerated Approval pathway or the societal and scientific tradeoffs that policy makers and regulators must consider in setting and implementing approval standards. This is a complex process with numerous stakeholders, requiring a nuanced understanding of the needs of patients who lack good treatment alternatives and how our society chooses to serve them.”
A review of recent expedited reviews suggests that there are considerable benefits to patients generated through rapid regulatory assessment and new regulatory paradigms even though a number of confirmatory studies fail to subsequently demonstrate the anticipated level of efficacy:
There is substantial evidence that expedited programs are speeding drugs to market. Although there may be controversy about the Accelerated Approval program, a 2018 review by the FDA found that only 5% (five of 93) Accelerated Approvals had been withdrawn or revoked over the last 25 years. A 2016 review of cancer drugs that received Breakthrough Therapy designation found that 12 were approved between 2012, when the program started, and the end of 2015. Eight of these drugs were approved based on Phase I or II data, all received Priority Review, and three-quarters were on the Accelerated Approval pathway. A more recent review, published in 2018, found that by 2017, the FDA had approved 58 new cancer drugs, 25 (43%) of which had received Breakthrough Therapy designation. The median time to first FDA approval was 5.2 years for Breakthrough Therapy–designated drugs versus 7.1 years for non-Breakthrough Therapy–designated drugs.
There is also encouraging news about the new pilot programs launched in mid-2018. Thanks to these programs (RTOR and AAid), approval for the breast cancer treatment alpelisib (Piqray) was granted more than 3 months before its PDUFA deadline and a little more than 5 months after it was submitted. Alpelisib was approved in May 2019 for use in combination with fulvestrant and with a companion diagnostic (therascreen). Several sNDAs or sBLAs have also been approved or are in process. In November 2018, through the pilot programs, Seattle Genetics was granted an sNDA in less than 2 weeks. The approval was for brentuximab vedotin (Adcetris) in combination with CHP chemotherapy (cyclophosphamide, doxorubicin, prednisone) for treatment of systemic anaplastic large cell lymphoma or other CD30-expressing peripheral T-cell lymphomas. The drug , which netted its first approval (for two other types of lymphoma) in 2011, had also received Breakthrough Therapy designation and Priority Review for this new indication.
Some argue that expedited programs also lead to a higher number of post-marketing safety-related label modifications. Although deferring the need to perform randomized controlled trials can substantially shorten the time to regulatory approval, they say, it shifts a substantial amount of drug evaluation into routine clinical practice where there is less attention to collecting patient outcomes data. However, well-designed pharmacovigilance programs have long been used in oncology, particularly with novel types of therapies. In any case, the developing regulatory frontier concerning use of “real world data” has made limited impact in oncology to date.
Expedited drug development is still very attractive, and it can be argued that much of the current media attention is a confected controversy that brings nothing new to the complexities of drug approval decision making. “Almost all of my clients are considering ways to use expedited pathways in their interactions with the FDA,” says Dr. Slichenmyer. He points out that many patients in oncology trials have either received standard therapy and not responded to it, or they cannot tolerate it. So, they do not have any other treatment options. “The classical approach to clinical development was Phase I, followed by Phase II, which then led to Phase III. In oncology clinical development today, development plans are more fluid. If a new drug demonstrates durable responses in patients for whom all reasonable treatment options have failed, that is a signal that an expedited development pathway should be considered.”
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