FDA’s Gottlieb Wants to Make It Easier to Obtain and Study Biologic Samples

Over the next couple of weeks, I’ll be further analyzing some details of the Food and Drug Administration’s (FDA’s) new Biosimilars Action Plan.

 

biosimilar developmentMuch has been made of the difficulties biosimilar manufacturers have been having in obtaining reference product samples. These are used for the most basic biosimilar development tasks: (1) the reverse engineering of the molecule, (2) physiochemical comparison of the originator and the new biosimilar, and (3) clinical testing in humans to compare the effects of the new product with the originator.

Manufacturers of the originator biologics have not made it easy. A couple of strategies used to protect access to the samples include exorbitant pricing and withholding products based on Risk Evaluation and Mitigation Strategies (REMS) mandates. These and other creative methods can delay the supply of samples to biosimilar manufacturers, and thus access to competitive products.

Legislative attempts to bypass these tactics include the CREATES Act, which is making its way through the Senate. However, at the rollout webinar of the Biosimilars Action Plan on July 18, FDA Commissioner Scott Gottlieb suggested a sensible solution: allowing the prospective biosimilar developer to purchase samples of the originator product outside the US.

He noted, “The FDA is seeking to strengthen its partnerships with regulatory authorities in Europe, Japan and Canada. Such partnerships can enable greater efficiency in developing safe and effective biosimilars.” Dr. Gottlieb continued, “For example, we’re actively exploring whether data sharing agreements could give us better insights into biosimilars’ real-world safety and efficacy and, in some circumstances, facilitate the increased use of non-US-licensed comparator products in certain studies to support an application under Section 351(k).”

Within the framework of the biosimilar approval pathway, biosimilar manufacturers had been permitted to use “bridging studies.” These allow drug trials using the EU-licensed version of a biologic after comparator studies have demonstrated the similarity of the EU- and US-licensed samples. The idea, in simplest terms, is that an EU-approved version of Remicade® is not exactly the same as the US-approved version. In biologic manufacturing, lot-to-lot differences in some structural elements are common, but they do not seem to affect the clinical outcomes of the product. Dr. Gottlieb has allowed that the differences between the two versions may be insignificant, and this could spur biosimilar development.

“We know that when those developing biosimilars use biologics sourced ex-US as their comparator product, it can lower the cost of clinical studies since many of these products can be procured more easily, and cheaply, in European and Asian markets,” Dr. Gottlieb said.

Furthermore, the Biosimilars Action Plan states that FDA will also explore “ways to reduce the number of lots of the reference product required for testing.” Overall, this can make the initial steps in biosimilar development less expensive.

Would Biosimilar Approvals With Limited Indications Alter the IP Discussion?

Over the next couple of weeks, I’ll be issuing a series of posts to further analyze some of the Food and Drug Administration’s (FDA’s) new Biosimilars Action Plan.

The Biosimilars Action Plan contains several important components. One of the more interesting items FDA Commissioner Scott Gottlieb mentioned in his remarks at the Brookings Institution webinar on Wednesday, July 18, involved modifying the intellectual property (IP) discussion with biosimilar approval for limited indications.

Originator drug makers have erected a so-called patent maze or patent wall over time to protect their IP and thus their marketing exclusivity as far into the future as possible. Patents can be filed for product composition, manufacturing techniques, new formulations, delivery systems, and indications. Often, the biologic products facing potential biosimilar competition have several indications. Adalimumab, for instance, is approved for use in nine unique conditions (I’ve included Crohn’s disease and pediatric Crohn’s as one disease state).

Dr. Gottlieb said that the FDA will be “updating guidance to provide additional clarity on how biosimilar manufacturers can carve out indications from their labels where a branded drug maker might still maintain some IP.” He continued, “And we’re going to describe how these indications can be efficiently added into a biosimilar label once that IP on the branded alternative has lapsed.”

This component was not spelled out in the Biosimilars Action Plan. Limited indications may indeed be an avenue to work with originator manufacturers to help reduce patent litigation that is barring patient access to biosimilars. One would assume that it would take some level of negotiation with the manufacturer of the originator. However, biosimilars with limited indications may be a hornets’ nest for reference manufacturers like AbbVie.

This gets back to the entire issue of extrapolation. From the outset, patients and providers recoiled at the notion of approving a biosimilar product for use in a disease state in which no clinical studies were done. The FDA has been pretty liberal in granting extrapolation to several or all indications for the 11 approved biosimilars. If FDA explored this option as a mechanism for getting biosimilars to the market sooner, it would be sending a new message. That is, the biosimilar drug may be expected to yield similar outcomes compared with the reference drug based on the totality of the evidence, but we’re unwilling for other reasons to give it our approval for those other indications.

Biosimilar Indications Laws or regulations do not exit to prevent doctors from prescribing a biosimilar for a nonapproved indication. Furthermore, health plans and insurers have consistently reported in our own market research that they would not discourage use of a biosimilar for other indications for which only the originator biologic was approved. This assumes the biosimilar is sufficiently less expensive than the originator. As a result, drug makers like AbbVie may be very wary of the limited-indication approach to improve biosimilar access.

Still, some way must be found to break the logjam of litigation on IP. This is a specific target of Commissioner Gottlieb’s. He may take even more creative approaches.