Guest Post by Prof. Christopher M. Holman, UMKC School of Law
Much of the current discussion surrounding the proposed follow-on biologics bills assumes that a "statutory path" is necessary before FDA can implement an abbreviated biologics license application (BLA) process for biotechnology-derived therapeutic proteins. In fact, FDA probably already has the authority to create such a process by regulation, but so far has declined to do so.
The argument that FDA requires a statutory path is based largely on the fact that the PHSA (the statute governing the regulation of most biotechnology-derived therapeutic proteins) does not explicitly provide an abbreviated BLA approval processes analogous to the FDCA's 505(b)(2) "paper NDA" and 505(j) abbreviated NDA (ANDA). But the FDCA explicitly requires clinical trials for the approval of an NDA, so FDA arguably needs explicit statutory authorization to implement an abbreviated process that dispenses with the requirement of clinical trials. As noted in the House Report published in connection with the passage of Hatch-Waxman, the only statutory difference between a NDA and an ANDA is the requirement of human clinical trials.
The PHSA, on the other hand, does not require clinical trials for approval of a BLA, and hence no explicit statutory path should be required for biologics. FDA's regulations require clinical trials to show safety and efficacy of biologics approved under the BLA process, but these are regulations dating back to the mid-1970s (well before the approval of any biotechnology-derived proteins), and could be updated by FDA to dispense with such a requirement in some instances, assuming the science would support such a revision, without requiring Congress to amend the PHSA.
In 1996, a district court specifically found that FDA has the statutory authority under the PHSA to approve a comparable biologic without requiring new clinical trials. Berlex Labs v. FDA, 942 F.Supp. 19 (D.D.C. 1996). Although that case dealt with a change in manufacturing process implemented by the original manufacturer, with respect to the question of statutory authority the court's rationale should apply equally to a comparable protein produced by a different manufacturer.
During recent Congressional testimony, FDA's representative Dr. Woodcock was questioned on the supposed need for a statutory path. She walked a close line, at one point indicating that a statutory path was required, but on closer questioning conceding that the PHSA does not require clinical trials, and that the only statutory requirement is that the FDA ensure the "purity, potency and safety" of biologics approved under the Act. Members of Congress also queried whether the rationale of Berlex Labs v. FDA should not also apply to biologics, but did not receive a direct answer. Earlier, in January 2007, Reps. Dingell and Stupak sent a letter to FDA questioning whether a statutory path was really necessary, and asking for a response from FDA no later than February. To my knowledge, FDA has not responded.
So why does FDA intimate that it needs a statutory path? It has been reported that some in FDA are of the opinion that no such path is required, but apparently the agency is reluctant to defend against the lawsuits that would inevitably be filed by brand biotechnology companies if FDA actually asserted its authority and implemented an abbreviated BLA process. FDA would presumably prefer to have Congress minimize any ambiguity in the law by providing the agency with specific statutory authorization.
The situation harkens back to circumstances surrounding the passage of Hatch-Waxman. At that time, FDA had implemented a regulatory ANDA approval process for pre-1962 drugs, and had since 1978 considered implementing such a process for post-1962 drugs. Not only FDA but some members of Congress apparently did not believe FDA needed explicit statutory authorization. As expressed in the House Report, "While the FDA has been considering since 1978 an extension of the pre-1962 ANDA policy to post-1962 drugs, it has not extended the regulation. Because of the agency's failure to act, Title I of H.R. 3601 is necessary to establish a post-1962 ANDA policy." Thus, in a sense the Hatch-Waxman ANDA process was implemented to spur FDA into action as much as to clear any statutory obstacles.
Ironically, the proposed follow-on biologics legislation purporting to clear the statutory obstacles to such regulations would actually restrict FDA's discretion relative to the current statute.
For example, Representative Inslee's H.R. 1956 (the Patient Protection and Innovative Biologic Medicines Act of 2007), would amend the PHSA to require clinical trials, which are not required under the current statute. Recent Congressional hearings have revealed a consensus opinion that clinical trials are often not the best way to compare the safety and efficacy of a follow-on biologic relative to a reference biologic. Instead, analysis of fine molecular structure and assaying for trace contaminants will often be a more sensible approach. For example, a low frequency adverse event (e.g., an event that occurs only in 1-10,000 people) would probably not be identified even in a huge clinical trial, although subtle changes that might result in such an event could potentially be determined by modern analytical technology. Requiring human clinical trials in instances where FDA determines such tests are unnecessary also raises ethical concerns.
H.R. 1956 would also bar the FDA from designating a similar biological product as therapeutically equivalent to a reference product, regardless of whether FDA believes the science would warrant such a designation. Therapeutic equivalence, also referred to as interchangeability, is necessary to allow pharmacists to switch a brand prescription for generic. If FDA cannot designate a follow-on product as therapeutically equivalent, much of the cost-savings associated with generic drugs will be unavailable for biologics.
Representative Waxman's competing bill, H.R. 1038 (the Access to Life-Saving Medicines Act), the more generic-friendly of the two house bills, would impose its own substantial statutory restraints on FDA discretion. For example, it would bar FDA from requiring post-marketing studies to compare a follow-on biologic with the reference product. This seems to be a step backwards, in view of the current push for FDA to require more post-marketing monitoring and studies. The importance of such comparative monitoring is particularly warranted in the case of protein drugs, where an apparently minor modification in manufacturing can lead to severe adverse reactions for some individuals. This was the case several years ago, for example, when it was discovered that a version of erythropoietin sold outside the U.S. (Eprex) was associated with far more autoimmune reactions than apparently identical products (Epogen and Procrit) sold in the U.S. In contrast, the Inslee bill would mandate comparative safety monitoring after approval of a comparable biologic.
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