I’ve Got My Eye on You – FDA May be More Closely Evaluating Generic Products

Earlier this month, the Food and Drug Administration issued a funding request for further studies of metoprolol succinate, generic versions of AstraZeneca’s extended release Toprol XL. (http://grants.nih.gov/grants/guide/rfa-files/RFA-FD-14-024.html). The request for additional studies was prompted by thousands of complaints from doctors and patients about the generic version of the product. This is only the latest example of generic versions of extended release products potentially not performing as well as the innovator products they allegedly copy. In 2012, the FDA withdrew approval for Teva’s generic version of Wellbutrin XL after patients complained of headaches and returning depression when they switched to the generic version. Studies found that Teva’s extended release formulation was not releasing drug in the same manner as WellButrin XL. A potential problem that might exist among generic versions of extended release products.

This year marks the 30-year anniversary of the Hatch-Waxman Act – the Act strikes a balance that encourages innovation on the one hand while, at the same time, allowing an easier path to market for generic drugs on the other. The Act allows a generic to rely on the innovator’s clinical trial data and in exchange, the generic must notify the innovator of its filing if the innovator has patents that cover its product. Therein lays the rub. The FDA allows generics to modify various non-active excipients in the formulation of the product. This presents a problem because those modifications may alter the performance of the product, particularly if it is an extended release product.

Extended release or controlled release products are designed to release the active drug over a specified time or in a specified place in the body. The end result is that, because of the extended release mechanism, the product may only need to be taken once a day. The extended release profile of the product is achieved through various non-active excipients used in the drug product’s formulation. That formulation though is often the subject of patent protection that extends well beyond the exclusivity the Hatch-Waxman Act provides. To avoid these patents, generics may modify the excipients and/or the amounts of those excipients. Modification of those excipients may alter the products behavior. In the case of Budeprion XL, the generic version acted more like an immediate release, dumping the active out of the formulation too quickly. The end result was that the product failed to maintain adequate blood levels of the drug.

For most drugs, the FDA only requires single dose testing for bioequivalence studies – bioequivalence studies are required to be done so that a generic can rely on an innovator’s clinical trial data. However, those studies are far less robust than the trials that were originally performed. More thorough testing is often not required. Often it falls on the innovator to petition the FDA to require further testing but that process is not always successful. Recent events may signal a departure at the FDA from the status quo, and more testing may be required in the future, particularly of extended release products.