The FDA Accelerated Approval Designation: A Primer

Picture1By Peter Martin, M.D.

As a response to the HIV/AIDS crisis of the 1980s the United States FDA developed guidelines for the Accelerated Approval designation in 1992. The purpose was to speed up the approval process and provide new treatments to the patients most in need. The program was an instant improvement, resulting in the approval of 80 drugs, including 29 cancer drugs, in the first decade, and was subsequently updated as part of the Food and Drug Administration Safety and Innovation Act in 2012. Under these guidelines the FDA can designate the Accelerated Approval label for new treatments that address a serious medical condition, and which are thought to offer a meaningful advantage over existing therapies.

The FDA’s criteria for making this designation is based on the scientific support for the measurement of surrogate or intermediate clinical endpoint in the treatment, and the likelihood it will predict a clinical benefit compared to available therapies in an area of unmet need. For example, in the past it may have been necessary for a new drug to prove a survival advantage compared to standard therapy in the context of a randomized phase III trial. It could take up to a decade to reach this benchmark for approval. Under the Accelerated Approval designation, a drug might be approved for an unmet need if it could demonstrate tumor shrinkage based on radiological imaging, which would likely be associated with a durable clinical benefit. Because the FDA requires a high degree of scientific support for the use of a surrogate endpoint, drugs that are approved under the Accelerated Approval program usually go on to receive full approval 3-4 years later on average, following the completion of confirmatory studies demonstrating clinical benefit.

This is not always the case, however, and some drugs that receive Accelerated Approval designation are subsequently withdrawn from the market when a confirmatory study fails to provide sufficient evidence of clinical benefit (e.g., bevacizumab for breast cancer). There is also the risk that a drug that had received accelerated approval will later demonstrate significant side effects during larger studies (e.g., this was part of the reason that gemtuzumab ozogamicin was withdrawn from the market in 2010). Other times, an application for accelerated approval might be denied, but the drug eventually receives full approval following completion of larger studies (e.g., TDM-1 for breast cancer). The definition of “unmet need” is another stumbling block to efficient drug development. Some developers might perceive an unmet need in settings where all available therapies have been exhausted, while the true need lies much earlier in the course of a disease where available therapies provide only limited benefit.

The Accelerated Approval program has provided access to dozens of drugs years earlier than they would otherwise have become available, improving the lives of countless patients with cancer and other conditions. However, the designation is not a panacea.  Physicians and patients should be aware of the evidence behind the designation of a given drug and should continue to follow the drug development process as new information comes to light.

Previous Entries in the Primer Series

The FDA Approval Process
The FDA Breakthrough Therapy Designation

The FDA Breakthrough Therapy Designation: A Primer

 

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By Peter Martin, M.D.

The Breakthrough Therapy Designation was introduced as part of the 2012 Food and Drug Administration Safety and Innovation Act and is designed to expedite the development of new treatments for serious conditions like lymphoma. If preliminary evidence from clinical trials demonstrates that a new drug represents a significant improvement over currently available therapies, the drug developer (also called the Sponsor) may request a Breakthrough Therapy Designation.

If the FDA agrees with the Sponsor and grants the designation, they will subsequently commit to providing additional resources to the development and review process.  Practically this means  more frequent meetings and communications with senior FDA officials, and aid in designing more efficient clinical trials. Although the Breakthrough Therapy Designation does not make a new drug available, early experience with the program suggests that it can shave years off of the typical development process.

Since 2012, the Sponsors of 342 treatments have applied for this status, with 111 receiving the designation. Of the treatments that have received the designation 42 have received full approval. In 2016 pembrolizumab received the designation for the treatment of patients with relapsed or refractory classical Hodgkin lymphoma and venetoclax received it in combination with rituximab to treat patients with relapsed/refractory chronic lymphocytic leukemia. Previously nivolumab, idelalisib, ofatumumab, obintuzumab, and ibrutinib all received the Breakthrough Therapy Designation for different lymphoma indications.

Despite the success of the program there are several points to keep in mind. The FDA’s definition of “breakthrough” is very different from its interpretation by lay persons and the media. The FDA’s definition refers to a drug that in the early stages of development has shown the potential for an improvement in patient care. It is not a guarantee of the approval or long-term success of the treatment.

As the FDA and Sponsors gain additional experience with the program we are likely to see some changes, including the number of applications and the cost of requesting a Breakthrough Therapy Designation. We are also likely to witness some unintended consequences, including investments by venture capitalists and opaque marketing strategies. When in doubt a patient should consult a physician about the usefulness of any treatment.

At the Weill Cornell Lymphoma Program, we are interested in any program that helps make promising new therapies available to patients as quickly as possible, and so we continue to follow this and other related programs closely. In the next post in the series we will discuss the Fast Track Designation.

Previous Entries in the Primer Series

The FDA Approval Process

New Clinical Trial: Phase 2B Open-label, Randomized Two-arm Study of Selinexor with Low Dose Dexamethasone in Patients with Relapsed/Refractory DLBCL

The Weill Cornell Lymphoma Program has recently opened a new clinical trial for men and women with relapsed/refractory diffuse large B-cell lymphoma (DLBCL). The study sponsor is Karyopharm, and the principal investigator at Weill Cornell is Peter Martin, M.D.. For more information about the study, please call Amelyn Rodgriguez, RN at (212) 746-1362 or e-mail Amelyn at amr2017@med.cornell.edu.

Key Eligibility

  • Men and women age 18 and older
  • Pathologically confirmed DLBCL whose disease is relapsed and/or refractory with documented evidence of disease progression after the most recently administered chemotherapy regimen and who in the opinion of the investigator are not candidates for high-dose chemotherapy with stem cell rescue
  • Patients must have received at least 2 but no more than 4 prior multi-agent therapies
  • Detailed eligibility reviewed when you contact the study team

Study Details

This clinical trial is for men and women with Diffuse Large B-Cell Lymphoma (DLBCL) and were previously treated for this disease.

For patients who are not cured with front-line therapy, DLBCL is a very difficult disease to manage with only limited treatment options. Selinexor has demonstrated anti-tumor activity in heavily pretreated patients with various subtypes of DLBCL. This study is designed to confirm selinexor activity with relapse and/or refractory DLBCL in patients who have had at least two but no more than four prior multi-agent therapies and are not eligible for high dose chemotherapy with stem cell rescue at the time of study entry.

This is a randomized, two-arm, multicenter, open-label Phase 2b study of the selinexor high (100 mg) and selinexor low (60 mg) doses with low dose dexamethasone given orally to patients with relapsed/refractory DLBCL who have no therapeutic options of demonstrated clinical benefit. Two hundred patients (100 per arm) with relapsed/refractory DLBCL who meet eligibility criteria will be enrolled and randomized in a 1:1 ratio of high (100 mg) to low (60 mg) selinexor doses.