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We understand that the concept of follow-on biologics is of increasing interest, but we believe that there are important scientific and legal issues that need further exploration and must be appropriately addressed before moving forward. The term "follow-on biologic" generally refers to a biotechnology-derived protein drug (or biologic) that is comparable to a novel, previously approved biologic and that is approved with less supporting data than the innovator biologic. Our position is that:
Background Many small molecule drugs can be taken orally and tend to work in the body within the cells. Because of their significantly larger size, biologics are typically injected and interact within the body in the bloodstream or on the surfaces of cells, rather than within the cells. Small molecule drugs are typically composed of only 20 to 100 atoms. By contrast, small biologics, such as hormones, are typically composed of 200 to 3000 atoms, and large biologics, like antibodies, are typically composed of 5000 to 50,000 atoms. To give a sense of size, the following diagram presents same-scale computer models of three drugs — aspirin (a small molecule), somatropin (human growth hormone), and Herceptin® (Trastuzumab), an antibody — with an example of their relative complexity: 
The manufacturing process for biologics differs greatly from the manufacturing process for small molecule drugs. Small molecule drugs are generally synthesized using chemical reactions. Biologics, by comparison, are typically grown in specially engineered cells. Small molecules are well-characterized and can be easily purified and analyzed with routine laboratory tests. Biologics — especially larger biologics — tend to be produced as diverse mixtures of molecules that differ very slightly from one another, making them difficult to characterize. It follows that the properties of the drug often depend directly on the nature of the manufacturing process. Furthermore, biologics tend to have unique structural organization patterns (referred to as “folding”) that affect the way that they work in the body. Even biologics that are chemically the same may have differing biological effects due to differences in the structural folding. An example of this folding effect is the difference between a raw egg and a cooked one: chemically they are the same, but they are physically and biologically very different. Patient Safety We believe that because of these differences with biologics, there are extraordinarily challenging issues surrounding approval and marketing of follow-on biologic products. We further believe that the paramount consideration when evaluating these issues must be patient safety. Need for Clinical Trials and Indication-Specific Approval Because of the complexity of biologics and the distinctions introduced by differing manufacturing processes, Genentech believes that each follow-on biologic must be shown to be safe and effective based on its own adequate and well-controlled clinical studies. We also believe that follow-on biologic products should only be approved for the indication that is directly supported by the non-clinical and clinical safety and efficacy data package submitted by the sponsor. When an innovator product is approved for more than one indication, any follow-on product must be studied for each indication to establish similarity to support approval for the indication, except in cases where the mechanism of action is well-understood and applicable to other indications sought by the follow-on product. No Automatic Interchangeability In addition, we believe that because differing manufacturing processes mean that each follow-on biologic is likely to be inherently different from the corresponding innovator biologic, pharmacists and physicians should not be permitted to substitute the follow-on biologic freely for the innovator’s product. We believe that substitution may only be possible if adequate clinical trials are performed on the follow-on product to establish that it acts the same as — rather than similar to — the innovator product in the body. Product Identifiability and Traceability Biotechnology-derived products are complex proteins that are extremely difficult for even the innovator to manufacture. Minor changes in the manufacturing process can inadvertently result in significant and dangerous differences to the final product. Therefore, it is critical that products administered to patients be identifiable and traceable back to the manufacturer. Patient safety requires that adverse events be quickly and accurately correlated with the actual product administered. This correlation is essential for immediate action to recall products when manufacturing processes have resulted in a product that causes patients to experience serious adverse events. Post-Marketing Risk Management Plans Required Post-marketing risk management plans must be an essential element of any approval of a follow-on biologic product. Although we believe that follow-on products must contain their own adequate and well-controlled trials, we recognize that because follow-on products would be approved in part on the prior approval of the innovator product, follow-on manufacturers would be allowed to submit less data than that of the innovator to support approval of their products. As such, follow-on manufacturers would have less experience with their products upon approval. Protection of patients from products with less complete data packages requires continued assessment of the follow-on product after approval. Follow-on products must have risk management plans in place to compensate for this gap in data by collecting the additional necessary experiential information. Similarity and Comparability Are Distinct Concepts Along those lines, we believe that the concepts of similarity and comparability are distinct and must be properly applied to any approval process for a follow-on biologic product. Manufacturers of innovator products are correctly permitted to make post-approval manufacturing changes to their products based upon a showing of comparability of the two products. This approach is appropriate because innovator manufacturers possess a thorough and robust body of knowledge about the process used to manufacture the original product. That knowledge can be applied in support of subsequent modifications to the manufacturing process. In contrast, a follow-on product would be approved based on a determination that the product is similar enough to the innovator product. Because of important trade secret protections, the follow-on manufacturer does not have access to the critical manufacturing processes that are essential to production of the innovator product. This lack of knowledge necessarily requires a greater amount of data to support a determination that a follow-on product is similar to an innovator product than is necessary to support a determination that an innovator’s modification to its own manufacturing process results in a comparable product. No Reliance on Trade Secret or Confidential Commercial Information Finally, we believe that regulatory agencies should not refer to or rely on innovator trade secret and confidential commercial information to approve a follow-on biologic. |
