Intro:

 

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.


Key Strategic Points:


  • Pursuing an expedited program requires even greater attention to the features of any malignancy being studied, trial design, and regulatory requirements.

  • The agency’s new pilot programs are already popular and shaving additional months off approval times, especially when they are granted in conjunction with other expedited programs.

  • Companies pursuing any of these pathways are encouraged to have early and regular discussions with FDA personnel, including about clinical trial design.

  • Two major recently published studies reported that cancer drugs approved based on response rate (RR) have a low rate of conversion to regular approval, raising skepticism about the Accelerated Approval pathway, in which trials often depend on RRs.

  • Despite recent criticism from academic authors, expedited programs remain a vital avenue for new cancer drugs to reach the market as speedily as possible and drug development programs should not be deterred from making application to one a core element of their regulatory strategy. In fact, not doing so could see a program fall behind its competition, receive approval late and lose important market share that may be difficult to regain.

The Backdrop


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.)


The FDA Has Four Established and Two Pilot Expedited Programs


Each of the FDA’s expedited programs are summarized below.


Established Programs:

  • Fast Track designation facilitates development and expedites review of drugs to treat serious conditions and fill an unmet medical need. A Fast Track designation can be requested as early as during the Investigational New Drug (IND) application. However, the agency advises that the request not be submitted later than the pre-Biologics License Application (BLA) or pre-NDA meeting.

  • Breakthrough Therapy designation applies to drugs for treatment of serious conditions that show a “large” early clinical effect. Breakthrough drugs may be able to skip portions of the usual FDA review process. This program was implemented in 2012.

  • Accelerated Approval is a pathway specifically intended for drugs with long-term end points, such as increased survival or decreased morbidity, which are hard to measure in clinical trials. It also allows approval based on surrogate end points (e.g., tumor shrinkage). Post-market clinical trials are required, and such drugs can be subject to expedited withdrawal. 

  • Priority Review cuts the FDA review period of a drug from 10 to 6 months. This designation should be requested with the submission of a BLA or NDA. Drugs that qualify for Fast Track, Breakthrough Therapy, and Accelerated Approval are also eligible for Priority Review.

Pilot Programs:

  • The Real-Time Oncology Review Pilot Program (RTOR) began in mid-2018. It is designed for drugs that are “likely to demonstrate substantial improvements over available therapy” and are undergoing “straightforward study designs.” It allows the FDA access to key data prior to the official application for approval. This program has been extremely popular, as discussed further in “Strategic Considerations.”

  • The Assessment Aid Pilot Project (AAid) is a voluntary submission to support assessment of the NDA/BLA. The aim of the program is to focus the FDA’s review on critical thinking (i.e., assessment) while increasing review efficiency and consistency, as well as to decrease review time spent on administrative tasks such as formatting. The AAid template is sent to the applicant during the IND stage and submitted with the NDA/BLA. AAid and ROTR can be pursued simultaneously.

 

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. 

Continuing Media Controversy

 

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:

  • One study, whose lead author is Emmerson Y. Chen, reported on 59 cancer drugs for 85 indications, 38% of which received regular approval and the rest of which were approved via the Accelerated Approval pathway. According to the authors, “Drugs with accelerated approval pending confirmatory data had lower RR[s] compared with drugs that have completed most post-marketing efficacy requirements.” Twenty-nine drugs (55%) on the Accelerated Approval pathway were later converted to regular approval. But only six of these drugs (21%) demonstrated overall survival benefit, 16 (55%) established progression-free survival benefit, and seven (24%) continued to use RR but gained regular approval. The authors concluded, “Many cancer drugs approved on the basis of response rate offer numerically low or modest response rates.” They further advised that “some of these drugs could potentially be tested in premarket randomized clinical trials.”

  • The other paper, whose lead author is Bishal Gyawali, reviewed 93 cancer drug indications that were granted Accelerated Approval by the FDA between December 1992 and the end of May 2017. They found that confirmatory trials for 19 cancer drug approvals (20%) reported an improvement in overall survival, 20 (21%) reported improvement in a different surrogate measure, and 19 (20%) reported improvement in the same surrogate measure used in pre-approval trials. The authors concluded, “Few cancer drugs approved via the accelerated FDA approval pathway were judged to have verified benefits based on improvement in survival reported in confirmatory trials.”

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.”

Selected Recent Expedited Reviews Granted

 

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: 

  • In November 2018, the FDA granted Accelerated Approval to larotrectinib (Vitrakvi), a cancer treatment for adults and children with tumors that have a specific genetic biomarker—a neurotrophic receptor tyrosine kinase gene fusion without a known acquired resistance mutation. It was only the second time that the FDA approved a cancer treatment based on a common biomarker across multiple tumor types. In a press release, the agency reported: “The approval marks a new paradigm in the development of cancer drugs that are tissue agnostic.”

  • SCLC has an overall 5-year survival rate of only 6%. In February 2019, the FDA granted Priority Review designation to an sBLA for pembrolizumab (Keytruda) in treatment of patients with advanced SCLC that has progressed following two or more lines of therapy. The application is based on findings from cohorts of the Phase II KEYNOTE-158 and Phase Ib KEYNOTE-028 studies. Patients with advanced and extensive-stage SCLC showed overall response rates of 19% and 33%, respectively, to pembrolizumab.

  • Also, in February 2019, ado-trastuzumab emtansine received Breakthrough Therapy designation for adjuvant treatment of patients with HER2-positive early breast cancer who have residual disease after neoadjuvant treatment. Ado-trastuzumab (Kadcyla) is an antibody–drug conjugate (ADC) of two anticancer agents (trastuzumab and the chemotherapy DM1) connected by a stable linker. The FDA is currently reviewing the application under the RTOR and AAid pilot programs.

  • In March 2018, the FDA granted Fast Track designation to the investigational anti-HER2 ADC [vic-]trastuzumab duocarmazine (SYD985). This ADC is designed for patients diagnosed with HER2-positive metastatic breast cancer that has either 1) progressed during or after at least two HER2-targeting treatment regimens for locally advanced or metastatic disease, or 2) progressed during or after ado-trastuzumab emtansine treatment. Fast Track designation was granted based on promising data obtained in patients with heavily pretreated last-line HER2-positive metastatic breast cancer who were participating in a two-part Phase I clinical trial (SYD985.001). Clinical results to date suggest that this HER2-targeting ADC is efficacious and safe. These patients do not have any other treatment options.

  • Eli Lilly saw its fortunes turn when the company had to withdraw olaratumab (Lartruvo) in April 2019 after the drug failed to prolong overall survival in a clinical trial (ANNOUNCE) with more than 500 patients. Olaratumab is a platelet-derived growth factor receptor–α antagonist. It was being evaluated in combination with doxorubicin and was on the Accelerated Approval pathway. In 2016, the regimen was approved for treatment of soft-tissue sarcoma based on a study of 133 patients. The study showed that the combination helped patients live an average of nearly 1 year longer. The drug had generated global sales of $350 million in 2018, up 50% from the prior year.

Strategic Considerations

 

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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