By Kevin E. Noonan —
Under the biologics pathway provisions of the Patient Protection and Affordable Care Act (P.L. 111-148), § 351(k) of the Public Health Service Act, codified at 42 U.S.C. § 262(k)), the FDA is given the authority to develop procedures for approving biosimilar applications. Recognizing the complexities of the issues involved, Congress granted the agency broad authority to impose, or dispense with, explicit requirements under the broad umbrella that a biosimilar have comparable safety and efficacy of the reference biologic drug product:
§ 351(k)(2)(A):
(i) REQUIRED INFORMATION.—An application submitted under this subsection shall include information demonstrating that—
(I) the biological product is biosimilar to a reference product based upon data derived from—
(aa) analytical studies that demonstrate that the biological product is highly similar to the reference product notwithstanding minor differences in clinically in- active components;
(bb) animal studies (including the assessment of toxicity); and
(cc) a clinical study or studies (including the assessment of immunogenicity and pharmacokinetics or pharmacodynamics) that are sufficient to demonstrate safety, purity, and potency in 1 or more appropriate conditions of use for which the reference product is licensed and intended to be used and for which licensure is sought for the biological product;
(II) the biological product and reference product utilize the same mechanism or mechanisms of action for the condition or conditions of use prescribed, recommended, or suggested in the proposed labeling, but only to the extent the mechanism or mechanisms of action are known for the reference product;
(III) the condition or conditions of use prescribed, recommended, or suggested in the labeling proposed for the biological product have been previously approved for the reference product;
(IV) the route of administration, the dosage form, and the strength of the biological product are the same as those of the reference product; and
(V) the facility in which the biological product is manufactured, proessed, packed, or held meets standards designed to assure that the biological product continues to be safe, pure, and potent.
(ii) DETERMINATION BY SECRETARY.—The Secretary may determine, in the Secretary's discretion, that an element described in clause (i)(I) is unnecessary in an application submitted under this subsection.
The devil being particularly resident in the details of how FDA will make these decisions, there is great interest in the standards the agency will set on for fulfilling these requirements, from both innovator biologic drug companies and potential biosimilar drug applicants (who some, like the FTC, believe will be the same companies in many instances).
This month there were hints from FDA officials on the general contours of these requirements. The most significant of these came from Janet Woodcock, Head of the FDA's Center for Drug Evaluation and Research, who was quoted by Reuters on May 9th as saying that human clinical trials may not be required in every case to obtain biosimilar approval. She described there being a "spectrum," where "some [biologic drugs] will get much closer than others in your ability to characterize them," for example on analytical grounds. Dr. Woodcock also said that if a company were to develop a longer-lasting version of a drug (for example, a PEGylated version), or increased its safety or efficacy, such a drug would be considered a "new molecule" that would be entitled to 12 years of data exclusivity, thus raising the possibility of "evergreening" biologic drugs in ways that many in the debate over the pathway thought (or intended) would be precluded. Dr. Woodcock further indicated that the experience of biosimilar drug applicants in Europe would be considered by the agency.
Similar statements were made by Dr. Rachel Behrman, Associate Director of Medical Policy at CDER in an interview broadcast on the May 1st edition of BioCentury This Week. In her responses, Dr. Behrman stated that the standard generally was whether the agency "has confidence" that the biosimilar will have the same safety and efficacy as the innovator biologic drug. Conceding that biologic drugs could not have the same degree of "sameness" as conventional generics, she said that the agency had made an "extraordinary amount of progress" since the Act was passed, including gathering resources for implementation and meeting with manufacturers, including a "significant outreach to the [biosimilar] community." She also affirmed that the "biosimilar industry" will be broader than small molecule generics and will include traditional innovator companies.
What all these companies want to know is the standards that will be required for biosimilar applicants, and she echoed remarks by Dr. Woodcock that the agency expects to issue guidances — "not just one" — by the end of 2011. She said that analytical comparisons would be "fundamental" in establishing that approved biosimilar drugs will have "the same [biological] effect without any clinically meaningful differences" with regard to safety and efficacy. The focus will be on analytics regarding, for example, chemical structure of molecule prior to any clinical data, and her remarks suggested that the quality of the analytical data will be relevant to the extent of the biological/clinical testing required. In this regard, she said that a basic tenet of the agencies thinking is that "duplicative testing is unethical," and that data and other information from biosimilar drugs licensed in Europe will be considered. She noted however that the law requires a single reference drug product approved by the FDA (i.e., a licensed "American" biologic reference product), which precludes wholesale reliance on European products. With regard to interchangeability, Dr. Behrman called that a "high hurdle" where the "safety of patients is paramount." While not enunciating a formal standard, Dr. Behrman said that a patient would have to be able to go "back and forth and back and forth . . . without any compromise in safety or efficacy" for a biosimilar drug to be declared interchangeable. She also emphasized that each biosimilar drug would be evaluated on a "case-by-case" basis with regard to extrapolation of different indications based, inter alia, on common mechanisms of action.
These considerations will be important, particularly in view of the many biologic drugs that will be "eligible" for biosimilar competition in the next five years, where the market is estimated to increase from $243 million to $3.7 billion, according to a report by Datamonitor.
