Dr. Andrew von Eschenbach, the head of the Food and Drug Administration, addressed the issue of biogenerics at the annual meeting of the annual meeting of the Pharmaceutical Research and Manufacturers of America (PhRMA).  Eschenbach basically outlined that biogenerics would be considered only “similar” to brand-name drugs, not interchangeable or able to be substituted.

This is similar to the approach of the EU as used by the European Medicines Agency. “We recognize that the end point would be what could be best described as similarity,” von Eschenbach said. “Similarity in the sense that when a doctor gives you the product — delivered it to a patient — it will achieve an effect that is similar to the effect that we expected from” the brand-name drug.

The Generic Pharmaceutical Association maintains the FDA already has the scientific knowledge to approve knockoffs, just as it now can sign off on changes made by brand-name biotech companies in how they produce their drugs.

Recent approvals of follow-on biologics by the FDA have been limited to those few biotechnologically derived products such as human growth hormone and certain insulin products approved under the New Drug Approval provisions of the Food, Drug, and Cosmetic Act, such as Novartis’ Sandoz approval of a 505(b)(2) NDA for its Omnitrope® version of Pfizer’s Genotropin® human growth hormone. While not a true generic application, a 505(b)(2) NDA allowed Sandoz to submit less than a full NDA.

The problems currently faced stem from the fact that biologics are approved under the Public Health Service Act (PHSA) not under the FD&C Act like small molecule drugs. While the FD&C Act provides an abbreviated new drug application (ANDA) provision that allows for generic versions of chemical drugs, the PHSA lacks any statutory mechanism that allow filing an abbreviated license for a biologic. The agency itself has taken the position that it lacks the authority to approve generic biologics under the PHSA.

Using the existing mechanisms for approving generic versions of biogeneric drugs involves two problems: (a) proving that the generic drug is identical to the brand name active ingredient, dosage form, route of administration, conditions of use (i.e., labeling) and dosage strength; and (b) proving that it is bioequivalent to the brand-name drug. If these are proven for small molecule generic versions, the generic product can be substituted for the brand-name product.

With biogenerics, you would have to show that the two biologics, made using different processes, contain the same ingredient. Then, you would have to prove that the two products are bioequivalent, especially when analytical methodology often does not exist or is proprietary to the brand name product. This would be quite difficult absent clinical studies.

In the Omnitrope case, the European Medicines Agency (EMEA) concluded that, while Omnitrope was not identical to Genotropin, it was similar enough to warrant approval with labeling comparable to that of Genotropin. EMEA determined that the two products were comparable as to their effectiveness, it did not declare them as bioequivalent. Having reached those conclusions, EMEA was able to regard Omnitrope as a biosimilar to Genotropin.

Concurrently with endorsing Omnitrope, EMEA issued a number of guidelines on how biosimilar medicines should be regulated:

Comparability studies are required between the biosimilar and the reference brand medicine. The extent to which comparability can be proven impacts how many nonclinical and clinical studies the biosimilar applicant will be required to perform.

Nonclinical studies, usually less extensive that those for innovator applications, will be required for the biosimilar.

Clinical studies (rather than the classic bioequivalence studies used for chemical drugs) will be needed to support the biosimilar drug’s safety and effectiveness. In particular, the studies must address immunogenicity concerns.

Postmarket pharmacovigilance plans will be expected as part of approval commitments.

EMEA also issues drug-specific guidelines for developing biosimilars. EMEA has issued these annex guidelines on human growth hormone, recombinant erythropoietins, recombinant granulocyte-colony stimulating factor and recombinant human insulin.

After lots of pressure from the courts and lawmakers, the FDA approved Sandoz’s 505(b)(2) NDA for Omnitrope. In so doing, the agency made clear that the Omnitrope approval did not establish any distinct precedent for other follow-on biologics, stating:

Is this FDA’s first approval of a follow-on protein product?

No. FDA has approved other follow-on protein products under section 505 of the Food, Drug, and Cosmetic Act. These include GlucaGen (glucagon recombinant for injection), Hylenex (hyaluronidase recombinant human), Hydase and Amphadase (hyaluronidase), and Fortical (calcitonin salmon recombinant) Nasal Spray.

Does today’s approval of Omnitrope create a new pathway for follow-on versions of all protein products?

No. The approval of Omnitrope in a 505(b)(2) application does not establish a pathway for approval of follow-on products for biological products licensed under section 351 of the Public Heath Service Act, nor does it mean that more complex and/or less well-understood proteins approved as drugs under the Food, Drug, and Cosmetic Act could be approved as follow-on products.

The FDA has classified Omnitrope as “BX” (insufficient data to determine therapeutic equivalence) in FDA’s Approved Drug Products with Therapeutic Equivalence Evaluations (Orange Book).

Reps. Waxman, Clinton and Schumer have now introduced H.R. 6257, the Access to Life-Saving Medicine Act (ALMA).  The Act would establish the a path for follow-on biologic applications including:

An abbreviated process for biological licenses for products that is comparable to approved biologics by amending the PHSA

Comparability requirements based upon the follow-on product having no clinically meaningful differences from the approved reference product in terms of safety, purity or potency, based upon nonclinical or clinical studies, as needed

An approval process that includes a focus on correlating comparability to the reference product’s mechanism of action (If the mechanism of action is known, the follow-on applicant need only demonstrate comparability in one proposed condition of use. In contrast, if the mechanism is unknown, the applicant must show comparability for each proposed condition of use.)

Comparability requirements for the follow-on and reference products’ principal molecular structure features

Option for a comparable biologic product applicant to establish interchangeability with the reference product (if so established, the applicant may earn tax credits and an exclusive marketing period that would block other subsequent interchangeable versions of the reference product); to be interchangeable, a product must produce the same clinical results as the reference

Requirement that FDA approve or disapprove a follow-on biologic application at the earlier of eight months after submission or 180 days after the application is accepted for filing; this deadline would only be extendable by joint agreement of FDA and the applicant

The FDA says it will continue to develop guidelines required to consider applications on biogenerics.


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One Comment

  1. […] That’s going to be a much higher entry barrier than the standard ANDA process for small-molecule generics, which isn’t going to help bring down costs. There are a number of tricky regulatory issues as well, and in the end we’re probably going to have to settle for “biosimilar” instead of “bioequivalent”. For more details, I can recommend this recent post at PatentBaristas. […]