FDA’s standards for approving generics are questioned



– The Food and Drug Administration’s standards for demonstrating pharmacokinetic bioequivalence between two inhaled products, which allow for single batch comparisons of approved and generic candidate products, need to be revised to address batch to batch variability, suggested a presenter at the CHEST annual meeting.

Marketing approval of a new generic drug in the United States, including orally inhaled products, generally requires a demonstration of pharmacokinetic bioequivalence to a reference listed product. The standard criterion for statistical bioequivalence applied by the FDA requires the pharmacokinetics of the generic to be within about 10% of the branded product.

In early pharmacokinetic bioequivalence studies, Elise Burmeister Getz, PhD, and her colleagues compared single batches of their generic candidate OT329 Solis 100/50 to single batches of Advair Diskus 100/50 in five individual studies and single batches of Advair Diskus 100/50 to single batches of the same drug. The investigators found greater than 10% differences between some single batches of Advair Diskus 100/50 and some single batches of OT329 Solis 100/50. They also found Advair Diskus 100/50 batches that were more than 30% different from each other.

Dr. Elise Burmeister Getz, director of clinical pharmacology at Oriel Therapeutics

Dr. Elise Burmeister Getz

“When patients differ from one another, we put many patients in the trial. And when batches differ from one another, we should be putting many batches in the trial,” Dr. Burmeister Getz, director of clinical pharmacology at Oriel Therapeutics, said at the CHEST meeting. “If we want a robust assessment of bioequivalence and not just a check the box exercise, we really need to have product sampling that’s aligned with product variability.”

When the researchers combined the data in a meta-analysis, bioequivalence was demonstrated, but the pooled analysis could not be used for FDA registration because of its retrospective nature.

They later conducted a prospective study with multiple batches of both the generic and branded drugs. This multiple-batch bioequivalence study involved 96 healthy subjects using 16 batches each of Advair Diskus and Oriel’s OT329 Solis 100/50. A single inhalation was administered to healthy adult subjects in a randomized crossover design and blood samples were collected pre dose and up to 48 hours after inhalation.

With the FDA’s definition of bioequivalence, the generic candidate fell within the bioequivalence goalposts, Dr. Burmeister Getz noted.

The issue of pharmacokinetic variance is not unique to Advair Diskus, but she and her colleagues don’t understand why different batches show such wide variability, Dr. Burmeister Getz noted.

“The advantage of this multibatch approach is that the results of the bioequivalence assessment aren’t dependent on the single batch that happened to be chosen for the study. They are generalizable to the product because the product has been robustly represented in the study,” Dr. Burmeister Getz told attendees.

Oriel makes OT329 Solis 100/50, a fully substitutable generic to Advair Diskus 100/50, which is indicated for treating asthma. Both are multidose dry powder oral inhalation products containing fluticasone propionate, to reduce inflammation in the lungs, and salmeterol, to relax muscles in the airways, for the maintenance treatment of asthma. Advair Diskus at higher doses is indicated for asthma and COPD.

An FDA response?

Asked what the FDA makes of the batch-to-batch variability data, Dr. Burmeister Getz answered simply, “We don’t know.” Before she and her colleagues ran the 16 batch per product study, they submitted their protocol to the FDA for review, but 1 year later, they still hadn’t heard any response.

“Sponsors are apparently allowed to simply pick their batch in a careful and, dare I say manipulative way, to gain the result they want. With a single batch study the selection of batch will absolutely determine the outcome of the study.”

In vitro bioequivalence studies are already required to use multiple batches, she noted.

This research was funded by Oriel Therapeutics, an indirect wholly-owned subsidiary of Novartis AG.


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