There are sufficient legal and scientific precedents to support positions ranging from arguments against the approval of any ‘generic’ biologic to arguments that support the position that existing Food and Drug Administration (FDA) precedents permit the approval of a generic biologic. While it seems highly likely that at some point there will be a legally and scientifically acceptable construct for the approval of generic biologics, given the diverse opinions and varied interests of the US Congress, the FDA, the pharmaceutical and biotechnology industries, health service providers, insurers, consumers and the scientific community with regard to generic biologics, it is difficult to determine what such a construct will entail, or when it might be implemented. The only certainty is that there are presently no absolutes regarding this issue, either legally or scientifically. This paper seeks to trace past and current events that are quickly culminating to set the stage for a war over generic biologics, and which may offer some insight into the agency's thinking on their uncertain future.
FDA's ‘historical bias’ to generic biologics is the result of the position taken by the Center for Biologics Evaluation and Research (CBER), that a biological product is defined in major part by the process by which it is created. Thus, according to the CBER, two biological products created by different manufacturing processes cannot be the same.
2.
PHS Act §351 (i).
3.
See PHS Act §351 (a)(1).
4.
See, for example, FDA, ‘Guidance on Providing Clinical Evidence of Effectiveness for Human Drugs and Biological Products’, p. 4 (May 1998); 21 CFR §600.3 (s).
5.
PHS Act §351 (g) & (j).
6.
Pub. L. No. 98–417, 98 Stat. 1585 (1984).
7.
See FDC Act §201(p).
8.
See FDC Act §505 (b)(1).
9.
See 46 Fed. Reg. 27,396 (19th May, 1981) (‘NDAs for Duplicate Drug Products of Post-1962 Drugs’).
10.
Ibid. at 27,397.
11.
FDC Act §505 (b)(2).
12.
FDA, SBA for Oculinum Botulinum Toxin Type A, ELA Ref. No. 85-0226, PLA Ref. No. 85-0227 (1990).
13.
See FDA (1996) ‘Guidance Concerning Demonstration of Comparability of Human Biological Products, Including Therapeutic Biotechnology-Derived Products’.
14.
For example, in the mid-1980s, while its application for the tissue plasminogen activator (t-PA) product, Activase®, was in the final stages of FDA review, Genentech, Inc. made a change to the manufacturing process. Initially, Genentech conducted its dose-finding studies and pilot studies with t-PA manufactured by a ‘roller bottle’ fermentation method that produced a two-chain t-PA molecule. In 1985, based on the need for commercial quantities of t-PA, Genentech changed the t-PA production method to a more efficient system using a suspension culture. See Transcript of the Proceedings of the Cardio-Renal Drugs Advisory Committee 374, 376–77, 29th May, 1987. While certain in vitro and in vivo studies revealed no significant differences between the ‘roller bottle’ and suspension culture t-PA, other studies in primates and rabbits demonstrated that the suspension culture t-PA was less potent than the ‘roller bottle’ t-PA. See ibid. The CBER's experience with Activase® validated the agency's position at that time, that changes in manufacturing processes could affect the finished biological product, and that the product subject to regulation was therefore more correctly defined as the manufacturing process. The FDA's position that a biological product is defined by its manufacturing process (that is, the process is the product) softened somewhat in the first half of the 1990s. The most prominent example of this was the FDA's 1994 approval of Boehringer Ingelheim's (BI's) Verluma® (nofetumomab), a monoclonal antibody used for diagnosing small cell lung cancer. The FDA approved Verluma® notwithstanding the fact that production of the antibody switched from one manufacturer and manufacturing site to another. See FDA, SBA, Clinical Review of NR-LU-10 PLA Submission, PLA Ref. No. 94–308, p. 5, 7th September, 1994. Indeed, the FDA explicitly noted that BI had submitted ‘bioequivalence data’ to compare the monoclonal antibody that had been produced at the original site with the monoclonal antibody that was submitted as Verluma®. The FDA's use of bioequivalence data to establish comparability between two manufacturing sites represented a substantial departure from its historical view that ‘the process is the product’.
15.
FDA (1996) ‘Guidance Concerning Demonstration of Comparability of Human Biological Products, Including Therapeutic Biotechnology-Derived Products’, p. 4.
16.
See Memorandum from the Director of the CDER to the Director of the Office of Generic Drugs re: Approvability of a Synthetic Generic Version of Premarin, p. 36, 5th May, 1997.
17.
See FDA Response to Serono Laboratories’ Citizen Petition, Docket No. 92P-0487, 17th June, 1997.
18.
See Citizen Petition filed by the Biotechnology Industry Organization, ‘Follow-on Therapeutic Proteins’, 23rd April, 2003, Docket No. 03P–0176.
19.
See FDC Reports (‘The Pink Sheet’) (2003) ‘Generic Biologics On FDA Fast Track?: “Follow-On” Process Under Debate’, 26th May.
20.
FDA Talk Paper, 16th July, 1999.
21.
1991Intercenter Agreement between the CDER and CBER, p. 3.
22.
FDC Reports (‘The Pink Sheet’) (2002) ‘Abbott Abbokinase Relaunches with Limited Indication, Without Bold Warning’, 14th October.
23.
See FDA, SBA, Clinical Review of drotrecogin alfa [activated], BLA No. 125029/0, pp. 79, 98, 140.
24.
SiegelJ. P. (2002) ‘Assessing the use of activated protein C in the treatment of severe sepsis’, New England Journal of Medicine, Vol. 347, No. 13, pp. 10321033; see also FDA, SBA, Clinical Review of drotrecogin alfa [activated], BLA No. 125029/0, p. 98.
25.
See FDA, SBA, Memorandum – BLA Review re Pharmacology and Toxicology Assessment, BLA No. 125036, p. 1, 7th February, 2002.
26.
See ibid at Clinical Pharmacology Review of Alefacept, p. 1.
27.
See ibid. at Final Clinical Review, pp. 84, 86 (‘By pharmacodynamic and clinical criteria alefacept manufactured by Creative Biomolecules appears to be comparable to alefacept manufactured by Biogen’); Memorandum from Ezio Bonvini, MD to Division Director, Division of Monoclonal Antibodies, FDA, pp. 3–4, 21, 24–25, 28th January, 2003.
28.
See FDC Reports (‘The Pink Sheet’) (2000) ‘Generic Biologics: Xigris Approval Suggests Precedent for FDA, GPhA Says’, 16th December; FDC Reports (‘The Pink Sheet’) (2001) ‘Generic Biologics Process May Be Molecule-Dependent — GPhA's Bende’, 12th November.
