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Oncology Times – FOCR Meeting Highlights Modernization of Expedited FDA Drug Approvals

Oncology Times – FOCR Meeting Highlights Modernization of Expedited FDA Drug Approvals

The Friends of Cancer Research (FOCR) held the first of a two-part virtual annual meeting, which focused on ways of updating expedited drug approvals at the FDA. Modernization of expedited approval pathways is especially important for oncology, because since 2012 the vast majority of oncology drugs have used an expedited FDA approval program. While these have been very successful, speakers said it is time to take a look at harmonizing them, such as coordinating the use and timing of expedited pathways with clinical need and the appropriate drug development stage.

The Biden administration is likely to be receptive to such modernization to speed new drugs to patients safely. President-Elect Joe Biden’s son Beau died of glioblastoma; Biden led the Biden Cancer Initiative before campaigning for the presidency. Vice President-Elect Kamala Harris’ mother, Shyamala Gopalan Harris, PhD, was a cancer researcher who died of colon cancer.

In opening remarks at the virtual annual meeting, FDA Commissioner Stephen Hahn, MD, assured meeting attendees that, while the agency is hard at work on issues related to the COVID-19 pandemic, that has not stopped the FDA from continuing to approve drugs for cancer patients. He said one of the questions currently under study at the FDA is whether cancer patients diagnosed with COVID-19 have worse outcomes than cancer patients without the virus.

Hahn noted that the FDA has issued guidance on the conduct of clinical trials during the pandemic. He said the agency encourages pharmaceutical sponsors to work collaboratively on biomarker and companion diagnostic drug development.

“We recognized very early that we had to be there for cancer patients,” said Richard Pazdur, MD, Director of the FDA’s Oncology Center of Excellence. While COVID-19 took the spotlight away from cancer patients, he reiterated: “We are committed to making sure our patients with cancer do not feel forgotten in this pandemic…we marshaled our forces.”

In a fireside chat with FOCR Founder and Chair Ellen Sigal, PhD, Pazdur said that on a personal level he fully understands how difficult it must be for cancer patients during the challenging time of a pandemic, since his wife died of cancer 5 years ago.

FOCR released a new white paper developed by a working group which explores ways of updating expedited pathways for new drug approvals. Currently, the agency uses five pathways to safely speed the development of promising new medicines aimed at treating serious diseases for patients with unmet needs: 1) Fast Track; 2) Breakthrough Therapy; 3) Regenerative Medicine Advanced Therapy (RMAT); 4) Priority Review; and 5) Accelerated Approval.

The white paper evaluates the current use of these expedited approval pathway designations and makes recommendations to clarify and simplify them.

“To be honest, there’s a lot of overlap that exists,” said Pazdur of these pathways. “The designation means nothing unless one actually executes it.”

He stressed that what happens to an expedited drug after its approval—the processes and actions—is just as important as its designation. For example, he said, “I don’t think we’ve done a really good job in dosing of oncology drugs.”

Pazdur noted there are different “pain points” in drug development, and sometimes it is good to step back and look at the big picture. He said one of the most challenging issues in cancer drug development and expedited review today is that, with the subsetting of patient groups due to specific molecular diagnoses, drug studies will get smaller and smaller. He said there are clearly a number of differences between a 50-patient study and one with thousands of patients, and thus “everyone needs to be on the same page” in conducting drug reviews.

The white paper on expedited reviews states, “In situations where substantial benefit over existing therapies is observed in early clinical studies addressing unmet need, expedited drug development pathways help balance the need to provide individuals with serious diseases or conditions with expedited access to breakthroughs while also maintaining the rigorous standards established for approving drugs.”

In oncology, between 2012 and 2019, more than 90 percent of initial oncology drug approvals used an expedited FDA-approval program versus only 55 percent of new non-oncology drug approvals, said panel moderator Amy McKee, MD, Vice President of Regulatory Consulting Services at Parexel International Corp., a former FDA staffer, and a member of the working group that wrote the white paper. The paper states, “Accelerated Approval, Breakthrough Therapy designation, and Priority Review are overwhelmingly used more for oncology products than non-oncology products…. Expedited development programs at the FDA have had a positive impact on ushering new drugs through clinical development to reach patients more quickly.”

In fact, expedited programs in oncology have resulted in new drug approvals 2 years earlier on average than occurs with new drugs not on an expedited program, said Harpreet Singh, MD, Division Director in the Division of Oncology 2 at the FDA and a member of the working group that wrote the white paper.

However, she noted there is some redundancy in the expedited drug approval programs. The white paper said this redundancy “can make it difficult to understand when to apply for one or all in a particular development program.” Singh said the expedited programs were put together in a bit of a “patchwork” fashion and, while they have been successful, now is the time to ask how they can be made better.

It is not surprising that these expedited approval pathways have some redundancy, since they evolved over time, said Scott Korn, MD, Vice President for Global Regulatory Affairs at Merck and a member of the FOCR working group that wrote the white paper. He noted it would be more efficient if a drug sponsor could submit one application rather than bunches of paperwork at different times. He stressed that drug sponsors need advice along the way from the FDA to help them manage “the uncertainties inherent in our business.”

The paper notes that enabling new trial designs or approaches using new elements, such as real-world evidence, circulating tumor DNA (ctDNA), in vitro diagnostics, the impact of COVID-19, and decentralization of trials, could help to accelerate clinical drug development, more rapidly advance the knowledge base, and harmonize expedited approval pathways.

For example, Real-Time Oncology Review, an FDA pilot program, allows the agency to review much of the data earlier, after the clinical trial results become available and the database is locked, before the information is formally submitted to the FDA.

The working group’s recommendations include the following:

1. Maximize the intent of and modernize expedited approval programs in the pre-New Drug Application (NDA)/Biologics License Application (BLA) stage.

This recommendation suggests a more simplified approach with a common entry point for drugs intended to treat a serious or life-threatening condition. “One approach could be to reimagine expedited development programs utilized in the pre-NDA/BLA space by condensing them into a single pathway where the application requirements associated with Fast Track and RMAT are bundled into a pre-Breakthrough Therapy designation pathway,” states the white paper.

2. Codify a process for utilizing expedited programs.

The white paper envisions a process “beyond breakthrough,” which specifies the follow-up obligations for sponsors and the FDA once a drug qualifies for an expedited program. The paper states, “A structured process should be defined that enables early and frequent feedback/dialogue in a more standardized way with shorter timelines than currently available with formal interactions to address early-stage questions in a development program…” Currently, the paper states, “Much attention is given to whether a product is a breakthrough therapy or not, but little focus is given to the processes that follow a Breakthrough Therapy designation; identifying scenarios where earlier and more frequent interaction would have benefited a program, especially where it was less successful at expediting development, could help elucidate best practices.”

This recommendation also addresses best-practice actions for late-stage development and post-approval interactions between the FDA and drug sponsors. It cites actions that may need to occur, including those linked to manufacturing site inspections, strategies for associated diagnostic test development or design of potential post-market commitments, and a “holistic multidisciplinary approach to begin to map out various processes and the necessary interactions that should occur with different groups within FDA.”

3. Facilitate the development of emerging therapies and complex development programs.

The white paper states, “Dedicated and more frequent meetings for emerging therapies, such as cell and gene therapies and next-generation immunotherapies, in a pre-Breakthrough Therapy designation setting may be necessary to keep key development components in sync to get these potentially transformative therapies to patients quickly and safely.”

The recommendation suggests a pilot program to accelerate key aspects of development for products with complex innovative manufacturing processes: chemistry, manufacturing, and controls (CMC). “Establishing a dialogue very early in the process (Phase I or earlier) between the sponsor and the FDA would help sponsors devise an efficient development plan,” states the white paper.

These early dialogues should acknowledge the complexity of global development, states the white paper. Project Orbis, an initiative of the OCE, provides a framework for concurrent submission and review of oncology products among international partners. This initiative may allow cancer patients in other countries to receive earlier access to new drugs.…