Shifting Landscape of Oncology Drug Development and Approvals

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Future oncology drug development and approvals will be faster and more efficient as well as take the patient experience more into account, said Richard Pazdur, MD, Director of the Oncology Center of Excellence at the U.S. Food and Drug Administration (FDA). The Center was established as part of former Vice President Joe Biden’s National Cancer Moonshot Initiative.

At JADPRO Live, the annual meeting of the Advanced Practitioner Society for Hematology and Oncology (APSHO), Dr. Pazdur described the changing landscape within the FDA’s oncology center, which regulates approximately 40% of all new drugs developed in this country.

From Then to Now

“This is my 18th year at the FDA. When I began, we had 10 to 15 medical oncologists. Now we have 80. When I began, the oncologists were ‘jacks of all trades,’ reviewing multiple types of malignancies without any specialization. Today, we have disease-specific teams,” he said. “In 1979, when I started in oncology, we had only about 35 oncology drugs. Today, about 40% of all drugs in development are in oncology, and approximately 50% of all breakthrough therapies are in oncology. So not only are there many drugs being developed, but the drugs have the chance of offering substantial improvements over available therapies.”

Our thinking at the FDA about the clinical endpoints and data required for drug approval has evolved over the years. The same criteria we used in the 1960s and 1970s would be considered inflexible today.
— Richard Pazdur, MD

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The need to make some structural changes became clear as the field of oncology began to explode. The most recent is the creation of the Oncology Center of Excellence, for which Dr. Pazdur is the inaugural Director. The center is aiming for a more comprehensive evaluation of oncology drugs, one that starts at “conception” of the drug and considers more flexible approval pathways, and incorporates the patient’s voice.

“Patients have said they want an FDA that represents how they are actually treated,” Dr. Pazdur said. “The agency has begun thinking of alternative ways of looking at what constitutes benefit to them.”

Oncology Is a Different Entity

To expedite the drug development and approval process, a number of current and emerging initiatives are in place. They all take into account the many ways in which oncology is different from other therapeutic areas. These differences impact how the FDA looks at drugs, he said.

Cancer drugs treat severe and life-threatening diseases. These aspects create a sense of urgency with regard to the drug’s availability and also a greater tolerance for risk that patients are willing to accept. “We feel a need to approve drugs in a timely fashion because lives are at stake,” he said.

The increasing complexity of cancer—its causes, diagnosis, and treatment—also sets this field apart. For example, biomarkers are now selecting patients and driving treatments, and this has implications in both the clinics and in clinical trials. The public’s heightened interest in cancer, as well as the active participation of the advocacy community seeking a voice in drug approvals, also makes oncology a different entity, Dr. Pazdur noted.

New Endpoints and Considerations

“Our thinking at the FDA about the endpoints to use in clinical trials and information required for approval has evolved over the years. The same criteria we used in the 1960s and 1970s would be considered inflexible today,” he said.

The FDA is looking beyond the traditional endpoints that focus on how to measure clinical benefit—how a patient “feels, functions, or survives.” The challenge to find alternative endpoints began around the year 2000, after the dramatic effects observed with imatinib in the treatment of patients with chronic myeloid leukemia. By molecularly targeting abnormalities in tumors, unprecedented response rates began to be observed in selected populations across a variety of tumor types.

“There is no perfect clinical trial endpoint. For example, the interpretation of objective response rates has to take into consideration the magnitude of the response, the duration of the response, the location of the tumor, and the bulk of metastatic disease, he continued. Even the interpretation of ‘overall survival’—the gold standard of endpoints—in randomized trials can be confounded by subsequent treatment and crossover of patients from the standard treatment to the investigational arm. Also, with patients living longer, the evaluation of overall survival may be impractical if it would take many years to evaluate and potentially deny patients important drugs. Also, there may be a lack of clinical equipoise, which may render randomized trials not feasible. This would occur when we have early recognition of substantial improvement in response rates compared with standard treatments, and randomization to prove a survival benefit may be impractical, if not unethical, to many people. It’s no longer a cookie-cutter approach of having a randomized trial show a survival advantage. We have to rethink, with each application, what makes sense for the approval of a particular drug,” Dr. Pazdur said.

Determining the best endpoints to show the benefit of new agents remains a challenge.

New and Future Programs

New approval pathways are helping move drugs into the clinic, including Fast Track, Breakthrough Therapy, Priority Review, and Accelerated Approval. These new pathways are the result of “retooling and rethinking of how to evaluate drugs,” he said. The new processes enable the FDA to “marshal all its forces” to expedite drug development and approval, including early involvement of the FDA, sponsors, investigators, and patients in the discussion of clinical development plans, he said.

The Moonshot Initiative has led to changes, among them the “seamless design” of clinical trials in with expansion cohorts that represent what were previously considered distinct phases I, II, and III trials. With these seamless designs, there are no discrete breaks between the “phases” of these drug developments—leading to a “more natural, expeditious” evaluation process that escalates resources and reduces the development time, he explained. “The strategy has been adapted and eagerly used by the pharmaceutical industry.”

We also encourage “large, simple” trials in which investigators focus on a more real-world evaluation of the drug, with fewer data being collected. In addition, we need to think how electronic medical records, the use of easily measured endpoints reflecting in daily practice, and the incorporation of the -real-world experience will influence drug development and approval. We are also re-evaluating eligibility criteria, enabling clinical trial populations to better reflect the patients who will eventually use the drugs. “Rather than cutting and pasting from one protocol to another, we should be asking whether the eligibility criteria make sense for the specific drug and population,” he said.

Other components of the Moonshot Initiative are the expanded use of patient-reported outcomes and tumor site–agnostic indications. Recently, pembrolizumab (Keytruda) was approved for the treatment of patients whose tumors show microsatellite instability (ie, are microsatellite instability–high). “We are getting away from specific sites of disease to approval based on our understanding of how the drug works,” he said.

‘In an Impossible Situation’

Dr. Pazdur concluded: “Our job at the FDA will never make every stakeholder happy. In the end, the FDA is in an impossible situation—some people may believe we are either approving drugs too quickly; others believe we are approving drugs too slowly. Some believe we are approving the wrong drug. Others believe we are overly conservative, and still others believe we are overly liberal. Patients and other stakeholders have different points of view and evaluate evidence differently.”

The overarching aim remains consistent: to balance safety and efficacy, understanding that patients with cancer have a greater tolerance for risk than individuals with other illnesses. Manufacturers also take risks in that many investigational compounds ultimately fail. “We have to balance risks and benefits in all the regulatory decisions we make. If every decision the FDA made was correct, and we never took a drug off the market or revised the product label, my thinking is we would be overly conservative,” Dr. Pazdur commented. “We cannot have perfection be the enemy of the good.” ■

DISCLOSURE: Dr. Pazdur reported no conflicts of interest.