'1996' Starting the modern era of biologics regulation: FDA's elimination of establishment licensure and other changes

Biotechnology and Applied Biochemistry

Volumn 25, Issue 3, 1997, Pages 189-195

  Gamerman, Gary E ^a   Mackler, Bruce F ^a   Landa, Michael M ^a  

^a Fenwick and West LLP   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

BIOTECHNOLOGY; DRUG INDUSTRY; DRUG LEGISLATION; HEALTH CARE POLICY; HUMAN; LICENSING; MEDICAL RESEARCH; REGULATORY MECHANISM; REVIEW;

BIOPHARMACEUTICS; BIOTECHNOLOGY; DRUG AND NARCOTIC CONTROL; GUIDELINES; HUMANS; LICENSURE, PHARMACY; ORGANIZATIONAL POLICY; UNITED STATES; UNITED STATES FOOD AND DRUG ADMINISTRATION;

EID: 0030917843     PISSN: 08854513     EISSN: None     Source Type: Journal    
DOI: None     Document Type: Review

References (31)

1. Gary E. Gamerman is an attorney with Fenwick & West LLP and a former product reviewer with the FDA Center for Biologies Evaluation and Research. His 1994 article [Gamerman, G.E. (1994) Regulation of Biologics Manufacturing: Questioning the Premise, 49 Food Drug L.J. 213], written under a Vincent A. Kleinfeld Memorial scholarship from the Food and Drug Law Institute, first anticipated FDA's elimination of establishment licensure and direct manufacturing requirements for biologic products discussed in the present article.
2. Bruce F. Mackler, an Immunologist, is a partner and Chair of the FDA Legal/Regulatory Group Chair, Fenwick & West, LLP. He has practiced in the biologies area for 18 years and contributed to the biotech industry initiative to change biologics regulations as General Counsel to one of the two original biotech industry trade associations. Comments on the present article can be sent to him by mail to the Fenwick & West LLP address, by telephone to (+1)-1202-463-6300, by fox to (+1)-202-463-6520, or by e-mail to bfm@fwpa.com
3. Michael M. Landa, a partner at Fenwick & West LLP, was formerly an Associate Chief Counsel of FDA for 16 years and has hands-on knowledge of the internal FDA process relative to significant policy changes.
4. Abbreviations used: NIH, National Institutes of Health; FDA, Food and Drug Administration; ELA, establishment license; WCBs, well-characterized biologies; Fed. Reg., Federal Register; C.F.R., Code of Federal Regulations; cGMP, current Good Manufacturing Practice; NDA, new drug approval; PMA, premarket approval; 510(k), premarket notification; PLA, product license; CBER, Center for Biologies Evaluation and Research; CDER, Center for Drug Evaluation and Research; REGO, 'Reinventing the Regulation of Drugs made from Biotechnology': BLA, Biologics License Application; IND, investigational new drug.
5. 37 Fed. Reg. 26,913 (1972)
6. Pub. L. No-57-244, 32 Stat. 728, chpt. 1378 (1902); revised 58 Stat. 682, 702 03 (1944) [codified at 42 U.S.C. § 262 (1988)] (hereinafter the Biologics Act).
7. 61 Fed. Reg. 24,227 (1996)
8. 21 C.F.R. § 601.2(c)(1) (1996) ("To obtain marketing approval for a therapeutic DNA plasmid product, therapeutic: synthetic peptide product of 40 or fewer ammo acids, monoclonal antibody product for in vivo use, or therapeutic recombinant DNA-derived product, an applicant shall submit to the Director, Center for Biologies Evaluation and Research, a biologies license application on a form prescribed by the Director. Center for Biologies Evaluation and Research. For such products, a separate establishment license application shall not be required ...") (emphasis added).
9. 21 C.F.R. § 600.3(t)(1996) ("Manufacturer means any legal person or entity engaged in the manufacture of a product subject to licensure under the act; Manufacturer also includes any legal person or entity who is an applicant for a license where the applicant assumes responsibility for compliance with the applicable product and establishment standards.") (emphasis added).
10. That is, by requiring the marketer of a biologic to hold both an ELA and PLA. 21 C.F.R. pt. 601.
11. 61 Eed. Reg. at 24,227 and 61 Fed. Reg. at 2723 (1996): [See also, 60 Fed. Reg. 63, 048 (1995) (Notice: Interim Definition and Elimination of Lot-by-Lot Release For Well-Characterized Therapeutic Recombinant DNA-Derived and Monoclonal Antibody Biotechnology Product); 58 Fed. Reg. 38,771 (1993) (Guidance on Alternatives to Lot Release for Licensed Biological Products)].
12. Supra note 1.
13. Id.; see also the documents cited in Table I.
14. It should be noted that the production of many traditional biologies continues to this day using essentially the same techniques as used at the turn of the century.
15. The article referred to in note 1, at 218, These events presaged the subsequent and similar origins of the Food, Drug and Cosmetic Act, which was passed as a direct result of tragic deaths of over 100 people who consumed the toxic elixir of sulfanilamide.
16. Prior to 1972, biologics were regulated by other agencies (NIH at the time). There does not appear to have been any complaint about the requirements for establishment licensure and direct ownership of the manufacturing establishment during this period.
17. This is especially true, as a number of complex biological products are regulated as drugs (e.g. recombinantly produced hormones and anti-sense nucleic acid products).
18. 48 Fed. Reg. 50,795 (1983)
19. It should be noted, however, that even with drugs, 21 C.F.R. § 201,1 prevents drug developers from being identified as the drug manufacturer, absent direct ownership or operation of the manufacturing establishment.
20. 57 Fed. Reg. 55,544 (1992)
21. At the time, CBER would typically require conducting new clinical studies in order to approve any significant process changes, such as a change in location or scale.
22. Bruce F. Mackler participated in pre-1992 meetings of the joint task force before the merger of the two industry trade associations into BIO which continued the negotiations.
23. See the FDA Policy Report. 'Reinventing the Regulation of Drugs Made from Biotechnology' (REGO) (November 1995)
24. 60 Fed. Reg. 54,695 (1995)
25. 60 Fed. Reg. 63,048 (1995) (Interim Definition and Elimination of Lot-by-Lot Release for Well-Characterized Therapeutic Recombinant DNA-Derived and Monoclonal Antibody Biotechnology Products)
26. 61 Fed. Reg. 2733 (1996) (Proposed Rule: Well-Characterized Biotechnology Products; Elimination of Establishment License Application)
27. Therapeutic monoclonal antibodies, proteins and peptide vaccines, such as those being developed to treat autoimmune diseases, allergies and cancers, appear to be eligible for ELA exemption, as they are regulated by the CBER Office of Therapeutics and not the Office of Vaccines. Informal discussions by the authors with both CBER and BIO indicate that CBER is willing to consider expanding the definition of 'specified products,' but the onus is on the industry to champion such changes by presenting the agency with sufficient data to justify such change.
28. 61 Fed. Reg. 2,739 (1996) (Proposed Rule: Changes to an Approved PLA Application of a Well-Characterized Biotechnology Derived Product): FDA Guidance Concerning Changes to an Approved Application of a Well-Characterized Biotechnology Derived Product (January 1996 draft)
29. 60 Fed. Reg. 63,048 (1995) (Notice: Interim Definition and Elimination of Lot-by-Lot Release For Well-Characterized Therapeutic Recombinant DNA-Derived and Monoclonal Antibody Biotechnology Product): 58 Fed. Reg, 38,771 (1993) (Guidance on Alternatives to Lot Release for Licensed Biological Products). It should be noted that waivers of the lot-by-lot release were available to companies individually if they sought it after demonstrating a good track record in the previous 2-3 years (source: Bruce F. Mackler).
30. 61 Fed. Reg. at 24,229 (cmt. 9) and 24,231 (Implementation)
31. The authority of FDA to grant 'generic' approvals for biologies through comparability testing was recently suggested by the opinion in Berlex Laboratories, Inc. versus Food & Drug Administration, civil action 96-0971, 12-18 (October 7, 1996) (memorandum opinion).