During the last week of April 2021, the FDA’s accelerated approval process took centre stage for three days as its Oncologic Drugs Advisory Committee (ODAC) considered the future of so called “dangling” indications that have failed to substantiate clinical benefit. The Accelerated Approval process has been an important regulatory pathway for almost 30 years. It was created by the US Food and Drug Administration (FDA) to allow faster approval of drugs for serious life-threatening conditions with a high unmet medical need. Based upon surrogate endpoints and post approval confirmatory studies, patients can get access to promising new medicines much faster.
In the first of two articles covering this important regulatory event, we look at the history, the importance, and the challenges of the Accelerated Approval program.
Any new drug must provide evidence of a therapeutic effect and the clinical benefit may take many years to establish. Before a regular approval is granted the sponsor company must complete the lengthy process of drug discovery, preclinical and several phases of clinical research, demonstrating that the clinical benefit outweighs the risks. If granted Accelerated Approval, the drug must instead demonstrate effect on a surrogate endpoint, which allows the FDA to approve the drug faster under the condition that the clinical benefit must be further established post approval in phase 4 confirmatory trials.
The need for speed
Accelerated Approval was created in response to the urgency of new therapeutic needs during the HIV/AIDS epidemic during the 1980s in the United States. As a result of the unmet medical needs for the people living with AIDS, patient advocacy groups steadily challenged the FDA to speed up the availability of new therapeutic options. In 1987, FDA issues the treatment IND regulations, expanding the access to promising new experimental medications. Through better planning and closer consultations with the agency, the timeline of the regulatory process was shortened. The first AIDS medicine AZT was approved in March 1987 (only 25 months after it was first demonstrated active against HIV in a laboratory).
Dr. Smaldone Alsup, CMO and CSO at NDA was facing these historical regulatory challenges from the developer’s perspective.
“In the early days of the AIDS epidemic there was only AZT to treat this severe disease”, she explains. “People were dying, and we had nothing to combat the virus. The technology to assess the disease was also relatively primitive as accurate measurements of viral load came much later. It was in this environment of significant unmet need where health authorities in US, Europe and around the world demonstrated flexibility in accepting a laboratory marker of disease, as a surrogate for efficacy. Long term trials were conducted in collaboration with cooperative groups to demonstrate long term benefit. As expected, the pivotal programs were brought before an FDA advisory committee to assess the benefit /risk of the available data to support approval. These were critical moments in advancements in regulatory science and cross stakeholder collaboration of FDA, industry, academia, and patient groups working together to find a way to bring products to patients in need as soon as possible”.
When the FDA issued the Accelerated Approvals in 1992, it allowed drugs for serious conditions that filled an unmet medical need to be approved based on a surrogate endpoint that was most likely to predict a clinical benefit. A surrogate endpoint is an indirect marker such as a laboratory measurement, radiographic image or a physical sign that is considered reasonably likely to predict the clinical benefit of a drug, such as an effect on irreversible morbidity and mortality (IMM).
The surrogate endpoint for HIV therapies was the number of CD4 positive T cells in patient’s blood. Loss of these immune cells is a result of the viral infection which damages the immune system, creating an immune deficiency allowing severe secondary infections. CD4 counts appeared to predict duration of survival, suggesting a correlation between CD4 counts and life expectancy. However, new discoveries and methodologies led scientists to determine the amount of active and quiescent HIV virus stored in tissues, and ‘viral load’ was recognised as a more accurate surrogate endpoint than CD4 counts.
As in the case of CD4 counts, surrogate endpoint may correlate with a real clinical effect but does not necessarily guarantee causality. Choosing the right surrogate endpoint and proving that it can predict the intended clinical benefit within the scope of the targeted disease is not always straightforward. The surrogate marker must show sufficient evidence for being reasonably likely to predict a drug’s intended clinical benefit to be used for accelerated approval (1).
Cancer treatments moving forward
During the second half of the 1990s there was a new national initiative which included applying accelerated approval also to cancer drugs. In cancer, the approval of new therapies was based on clinical endpoints such as longer patient survival, decreased recurrence rate, longer disease-free intervals and/or improved quality of life. Instead of waiting to learn if a drug extends survival for cancer patients, an approval based on surrogate endpoints such as tumour shrinkage is considered reasonably likely to predict a true clinical benefit. However, the drug developer must still conduct studies to confirm that this is actually the case.
For measuring efficacy, overall survival (OS) and progression-free survival (PFS) are the most common endpoints in oncology trials. The tumour objective response rate (ORR) is determined by tumour assessments from radiological tests or physical examinations and is an important parameter to demonstrate the efficacy of a treatment in oncology (2).
After accelerated approval, the drug developer must perform confirmatory trials to prove that the medicine is effective in meeting a definitive clinical endpoint, at which time the approval is converted to a standard, unconditional approval. If the trials fail to verify clinical benefit or do not demonstrate sufficient clinical benefit to justify the risks associated with the drug, the product may be withdrawn from the market (3,4).
The first accelerated approval for an oncology drug was granted in 1995. In the 30-year history of the program, a total of 253 drugs have been approved (Dec 2020). Twelve of these products or indications have been withdrawn, the majority (seven) for oncology indications (5). A renowned example took place in 2011 when the FDA announced its decision to withdraw the marketing approval of bevacizumab (Avastin®) for the treatment of advanced breast cancer. ODAC re-evaluated the approval from 2008 by examining the results of two confirmatory clinical trials and voted 12 to one to recommend removing the indication as the studies did not demonstrate a difference in outcome and showed an increased risk of serious adverse effects.
Can we go back?
The withdrawal process provoked reactions from patients, consumer organisations, health professionals, healthcare policy makers and the pharmaceutical industry, and the decision generated major media coverage. The case illustrated the vast differences between the stakeholder’s interest, and although the purpose of regulatory decisions is to protect public health and safety, it may conflict with the individual patient need for reasons beyond the proven effect.
Today, immunotherapy has established itself as one of the pillars of cancer treatment. Anti–PD-1/PD-L1 antibodies are checkpoint inhibitors, and by blocking these checkpoints, the immune cells can more effectively terminate cancer cells. However, recently the drug companies announced voluntary withdrawal for this type of immunomodulatory treatment in four so called ‘dangling’ indications, which despite showing early promise, failed to demonstrate a survival benefit in confirmatory trials.
During the 3-day public hearing, another six indications for immune checkpoint inhibitors granted under the FDA’s accelerated approval process were reassessed by ODAC after the confirmatory trials failed to verify their clinical benefit. After this advisory meeting, ODAC made final decisions regarding continuing approval of each indication.
The treatment of these indications, by industry, committee, and agency, indicates a maturation of the process and the commitment of each stakeholder to stick to the principles laid out. It is vital for the system and its credibility that confirmation of benefit/risk is achieved, or the product removed from the market. But to achieve this is more than a matter of policy – it’s a matter of strong engagement by everyone involved and clear and continual communication to patients, physicians and relevant parts of the health care community.
More about the committee’s discussions and decisions in our upcoming article: Accelerated Approvals - Making the right decisions.
Dr Ingela Loell