Biosimilars: The Way Forward In the United States

March 29, 2012 6:04 AM

Here is an important article about the biosimilars in the U.S. which was written by Dr. Lorna Speid,  the President of Speid & Associates, Inc., a regulatory affairs and drug development expert consulting firm based in San Diego, California.

Biosimilars: The Way Forward In the United States

1. Background: The European Medicines Agency has been approving biosimilars since 2006. The situation is different in the United States. Although “copies” of originator biological medicines have been approved in the US since 2006, these have not been approved as biosimilars.

Biological medicines have been registered by two main pathways in the US. Some biological medicines were approved under the Food Drug and Cosmetics Act (low molecular weight heparins, growth factor, insulins), while others were approved under the Public Health Services Act (e.g., erythropoietin). These different mechanisms of approval in the US, provide unique opportunities for registration of biological medicines that do not exist in Europe. For instance, Enoxaparin, a low molecular weight heparin was registered as a generic under 505(j), the generic pathway. Consequently, this medicine is fully substitutable for the originator product. The 505(b)(2) route has also been used to register Omnitrope, a recombinant growth hormone.

The challenge in the US was how would “copies” of originator biological medicines registered under the Public Health Service Act via 351(a) be registered. There has been much discussion on this over the years. After years of arguing strongly that such “copies” could not be made due to safety concerns, the prohibitive costs to global healthcare systems made it imperative that these arguments be cast aside. What was previously perceived to be impossible has suddenly become do-able.

The Biologics Price Competition and Innovation Act of 2009 (BPCI) amended the Public Health Service Act, creating an abbreviated pathway for the registration of medicines that are demonstrated to be highly similar to originator biological medicines. A new pathway for highly similar biological medicines was created, known as 351(k).

The 351(k) pathway stated what would be needed to enable registration of these highly similar medicines. The following would need to be conducted:

  1. Analytical studies
  2. Animal studies (including toxicity studies)
  3. A clinical study or clinical studies

– Including assessment of immunogenicity, PK, PD
– One or more indications licensed for the Reference Product

Meetings held with the pharmaceutical industry and other stakeholders in recent months had made clear that more meat would need to be put on the bone of the 351(k) language. The long awaited FDA guidelines were issued by FDA on the February 9th, 2012.

The initial three guidelines are the first in a set of guidelines that the FDA will undoubtedly issue over the coming months and years. The purpose of these guidelines is to clarify what is required to secure registration for biosimilars. The three guidelines issued on February 9 th, 2012 are as follows:

1. Guidance for Industry: Scientific Considerations in Demonstrating Biosimilarity to a Reference Product, February 2012, CDER, CBER.
2. Guidance for Industry: Quality Considerations in Demonstrating Biosimilarity to a Reference Protein Product, February 2012, CDER, CBER.
3. Questions and Answers Regarding Implementation of the Biologics Price Competition and Innovation Act of 2009.

In this article, the key concepts underlying the three draft guidelines and 351(k) will be explored.

2. Basic Tenet of the Guidelines: The basic tenet of the guidelines is that a biological medicine must be demonstrated to be highly similar to a biological medicine already registered under 351(a) (Public Health Service Act). A biological medicine registered under 351(a) that is no longer under patent is a medicine with which the FDA has quality, safety and efficacy experience. There is a tremendous amount of post-marketing experience with these medicines. A medicine that has been demonstrated to be highly similar to this medicine can benefit from the experience already in existence. On this basis the manufacturer will be able to conduct an abridged development program for the biosimilar medicine.

The extent to which the program can be abridged will be dependent upon the extent to which the medicine is demonstrated to be highly similar to the originator biological medicine. If the medicine is demonstrated to have differences, this is going to raise questions about its quality, safety and efficacy in relation to the originator biological medicine. Additional studies will need to be conducted to attempt to allay any concerns that have arisen.

3. Biobetters: The three new guidelines do not address biobetter medicines, except to indicate that biobetter medicines will not fall under 351(k), but under 351(a) of the Public Health Services Act. Consequently, the extent to which a biobetter development program can be abridged will need to be carefully explored with the company’s experts, and consultants before meeting with the FDA to propose an approach.

4. How Should Companies Approach the Development of Biosimilars? Any company that will be developing biosimilars should plan to meet with the FDA on a regular basis during development. The frequency of meetings will depend on the type of data that have come to light in the process of developing the biosimilar. These meetings should be seen as opportunities to discuss the data and provide justifications for the approach to be taken moving forward. Far too many (mainly small and emerging companies) seek to use the FDA like a consulting organization. This is ill-advised with any development program, and should certainly be avoided with biosimilar developments. Meetings should take place with the FDA after the data have been thoroughly reviewed. Data that clearly show that the proposed biosimilar medicine is not highly similar to the reference product should lead to soul searching in terms of next steps, rather than to another meeting with the FDA to discuss them. A proposed schedule of meetings is shown below.


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