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ASCO Post – FDA Helps Streamline Approval Process for Supplemental Drug Indications

ASCO Post – FDA Helps Streamline Approval Process for Supplemental Drug Indications

As researchers learn more about the natural history of cancers, as more drugs are effective for more types of the disease, and as the number and complexity of combination therapies increase, the more important it is that new drugs and permutations of old ones be available to patients.


The U.S. Food and Drug Administration (FDA) has been making efforts over the past several years to expedite drug approvals. How to streamline the review-and-approval process and, in turn, create more and better treatment options for patients was the overarching question posed recently in a panel discussion at the Friends of Cancer Research Annual Meeting held earlier this year in Washington, DC.

We need constant updates about how drugs and devices are performing, and we need to incorporate more real-world evidence into the regulatory process. — Scott Gottlieb, MD

FDA Commissioner Scott Gottlieb, MD, said the agency and all its stakeholders have to think differently about how to apply regulations to new products. “We need constant updates about how drugs and devices are performing, and we need to incorporate more real-world evidence into the regulatory process.”


He added that the FDA’s Oncology Center of Excellence, headed by Richard Pazdur, MD, is applying new ways of thinking about drug development and regulation. The Center attempts to expedite oncology and hematology drugs and devices and to support an integrated approach in their clinical evaluation. “We have a dynamic regulatory environment,” said Dr. Pazdur. “There’s lots of back and forth with sponsors.”

What Happens to a New Indication

Every time a biopharmaceutical company (as a “sponsor”) seeks approval of a new indication for an already-approved drug, the FDA requires a supplemental new drug application (NDA) that consists of the same quality and content as the drug’s original new drug application. Its review and assessment are similar to the original dossier, but the process may not add much value to what the agency already knows about the drug’s safety and efficacy.

We have a dynamic regulatory environment. There’s lots of back and forth with sponsors. — Richard Pazdur, MD

Panel members agreed that the wealth of high-quality data amassed for the original new drug application, plus what has been learned from postmarketing experience, should be considered when the drug is presented to the FDA for an additional indication.

How to Accomplish the Goals

George D. Demetri, MD, Quick Family Chair in Medical Oncology, Dana-Farber Cancer Institute, noted that the FDA approval is the gold standard for drugs all over the world. “We want to preserve that position while at the same time expand what that approval means and how it is accorded.”


More and more approved drugs are being used in multiple indications, and increasingly, supplemental new drug applications are being submitted using an intermediate endpoint as clinical benefit because the need is so critical.


“A supplemental new drug application can entail either a regular or accelerated approval,” said Amy McKee, MD, Supervisory Associate Director, FDA Office of Hematology and Oncology Products. “The agency may now grant full approval to a supplemental new drug application using an intermediate endpoint on a case-by-case basis. One reason is because we weigh the urgency of an unmet clinical need.”


For example, said Dr. McKee, daratumumab (Darzalex) was first approved for multiple myeloma in November 2015; a supplemental new drug application for another indication showed similar response rates, resulting in a second approval 1 year later—and a third only 7 months after that. “We were very comfortable with the speed at which all this happened. All the approvals were based on excellent response rates or progression-free survival.”


The panel discussed a framework that could analyze the characteristics that have led to full approval of drugs based on intermediate endpoints for a new indication.


Shanthi Ganeshan, PhD, Vice President and U.S. Head of Oncology Regulatory Affairs, Novartis, listed the benefits of using intermediate endpoints for drug approval: It streamlines and systematizes the process; there may be no need for confirmatory studies; preclearance for promotional materials is not necessary; and it encourages more supplementary applications.

Unmet Clinical Need

Urgency for filling a medical gap is a primary reason to approve a new indication. That is, how serious or life-threatening is the disease in question? How rare is it? What are the current treatment options, and how effective are they?


For example, a single-arm trial of the combination of daratumumab with pomalidomide (Pomalyst) and dexamethasone resulted in its approval for patients with refractory multiple myeloma who had received at least two prior therapies including lenalidomide (Revlimid) and a protease inhibitor such as bortezomib (Velcade). Of patients in the study, 89% were refractory to lenalidomide and 71% were refractory to bortezomib, with 64% of the group refractory to the combination of those two drugs. These patients were about out of treatment options. However, 59% of patients in a single-arm trial of the daratumumab-based combination achieved a response, with a median duration of 13.6 months, demonstrating a significant efficacy outcome.

Natural History of Disease

Understanding the natural history of a specific disease is critical when attempting to expand the use of an approved drug in a new setting. New molecular technologies can help in this effort because genomes, epigenomes, and transcriptomes can be unique to a single tumor type or shared across several tumors driven by the same or related pathogenic mechanisms.


For example, multiple oncogenic driver mutations and rearrangements have been identified in lung cancers and are currently targeted with different therapies, such as kinase inhibitors that have produced greater clinical benefit than platinum-based chemotherapy.

Drug Actions in Different Diseases

To expand a drug’s use, one must understand its pharmacokinetics, pharmacodynamics, and interactions with other drugs—as a single agent and in combinations. For example, dabrafenib- -(Tafinlar) and trametinib (Mekinist) are kinase inhibitors that modulate two independent targets in a particular pathway. Together they have been successful in treating BRAF V600–mutant metastatic melanoma and metastatic non–small cell lung cancer (NSCLC). However, when the combination was used in BRAF-mutant metastatic colorectal cancer, it conferred a poor prognosis and only a modest response rate, according to the panel.


Thus, although the mechanism of action of these kinase inhibitors was well understood and efficacy had been demonstrated in previous controlled trials, a more detailed preclinical investigation of the drug’s pharmacodynamics and tissue-unique mechanisms of resistance showed how the drugs performed in a new indication.

Safety Issues

Supplemental new drug applications require sponsors to submit a safety profile in the new population as well as provide comparisons with previously approved indications. A supplemental new drug application is more likely to be approved when safety data mirror the original indication, thus demonstrating that the drug behaves similarly in both settings.


Dabrafenib and trametinib, used in combination, was granted full approval in metastatic NSCLC, in addition to metastatic melanoma, in part because of the similar safety profile observed in both diseases.…