PHILADELPHIA—The most vital component of avoiding drug shortages is early communication, officials from the U.S. Food & Drug Administration (FDA) said in a session at ACR Convergence 2022 in November.
“Early notification is key in order to prevent and mitigate shortages,” said Hyun Son, PharmD, a member of the Drug Shortage Staff with the FDA Center for Drug Evaluation and Research.
The session also included a review of the FDA’s “extrapolation of efficacy” approach to approving drugs for pediatric rheumatic diseases, in cases when there is enough similarity to adult care that a standard, randomized controlled trial isn’t necessary.
In her presentation, Dr. Son emphasized how important the FDA considers drug shortages to be.
“There’s always a sense of urgency when it comes to any drug shortages, but, ultimately, we want to maintain an availability while minimizing risk to the patients,” she said.
She said that if her office gets a notification from a manufacturer that it is having issues with a product, the FDA will look at the overall market and contact other suppliers of that product to see whether they can meet any increased demand.
There are steps within the power of the FDA, and steps that are not, she said. The FDA requires manufacturers to notify officials when there are supply disruptions, discontinuations or other issues that could harm supply, even if a given manufacturer has a relatively small share of the market. But the FDA can’t require a company to start making a drug, make more of a drug or mandate how a drug is distributed.
What Can Be Done
The FDA can work with review divisions on expediting reviews.“As a last resort, we will exercise temporary importation of a product from outside the U.S.,” she said, as with triamcinolone hexacetonide injections during the current shortage.
In another recent example, there was a shortage of tocilizumab injections because of increased demand, and the FDA worked with manufacturers and the manufacturers were able to increase the supply. The shortage resolved in March 2022.
Asked about continuing issues with availability of triamcinolone hexacetonide injections, Dr. Son said, “If any institutions or hospitals or providers are having issues, you can definitely send us an email”—at [email protected]—“and we can forward all that information to Medexus,” the company authorized to import the drug. “We definitely would like to have an approval for a product instead of importing, but as of now, the imported product is the only product available for our U.S. patients.”
Pediatric Concerns
Amit Golding, MD, PhD, medical officer with the FDA Division of Rheumatology and Transplant Medicine, said the “extrapolation of efficacy” concept has been growing in importance in pediatric rheumatology.
“It has been the basis for a number of recent pediatric approvals in rheumatology,” he said.
Approvals follow a continuum, according to this philosophy. When indications in pediatrics are considered essentially distinct, without a matching adult counterpart, well-controlled clinical studies are required. On the other end of the spectrum are pediatric conditions that are considered highly similar to the adult condition. In these cases, approval might only require simple pharmacokinetic safety studies evaluating a single dose level that matches adult exposures, Dr. Golding said.
For conditions with partial similarities, approval may rely on controlled or descriptive efficacy studies, using biomarkers, if available and appropriate, as a bridge from adults to pediatrics and using statistical inferences.
Belimumab, approved for pediatric lupus nephritis in July 2022—the first for this population of patients—is an example of how the extrapolation approach is used. The components of this approval, Dr. Golding said, were similarity of the disease between adults and pediatric patients, a pharmacokinetic bridge study, extrapolation of efficacy in pediatric patients from that in adult patients with lupus nephritis, and a justification that safety data on patients with systemic lupus erythematosus was relevant to this group of patients.
FDA officials were asked about the value of enrolling younger patients in trials.
Nikolay Nikolov, MD, director of the Division of Rheumatology and Transplant Medicine, encouraged the enrollment of adolescents, when possible. This, he said, can “inform extrapolation to smaller age groups.”
“As long as there is data to support the prospect of direct benefits, which usually comes from a phase 2 clinical study data or from earlier development of the product in adults, that’s sort of a fundamental requirement for us to allow pediatric patients to be studied,” he said.
“We’ve heard from the community that this is challenging to coordinate, and to do that practically, but we have seen proposals and programs including adolescents successfully.”
Thomas R. Collins is a freelance medical writer based in Florida.
