FDA Withdraws Jan. 17 Rule Relaxing Phase I GMP Standards

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ePT--the Electronic Newsletter of Pharmaceutical Technology

In a May 2 Federal Register notice (1), the US Food and Drug Administration withdrew its Jan. 17 direct final rule, "Current Good Manufacturing Practice Regulation and Investigational New Drugs" (2), which would have exempted manufacturing of drugs for Phase I clinical trials from most provisions of 21 CFR 211.

In a May 2 Federal Registernotice (1), the US Food and Drug Administration (Rockville, MD, www.fda.gov) withdrewits Jan. 17 direct final rule, "Current Good Manufacturing PracticeRegulation and Investigational New Drugs" (2), which would haveexempted manufacturing of drugs for Phase I clinical trials from mostprovisions of 21 CFR 211.(See the Jan. 19 ePT report, "FDA Eases Phase I Manufacturing Requirements").

The withdrawal effectively re-instates the agency's fifteen-year-old Guidelineon the Preparation of Investigational New Drug Products (Human andAnimal), which required IND adherence to commercial-scaleCGMP standards.

Under the Agency's direct final rule procedure, "the receipt of anysignificant adverse comment will result in the withdrawal of the directfinal rule," according to the May 2 notice. Many of the commentssubmitted to FDA were, in fact, highly critical.

Some commentators, such as the Pharmaceutical Research and Manufactuers of America (PhRMA, Washington, DC, www.phrma.org) Vice-President Alice E. Till, Parenteral Drug Association (Bethesda, MD, www.pda.org) PresidentRobert B. Myers, and Biotechnology Industry Organization (BIO, Washington, DC, www.bio.org) Managing Director Sara Radcliffe,expressed broad support while suggesting changes (some of themextensive) in the details. (Most comments are available on FDA's Website, at http://www.fda.gov/ohrms/dockets/dockets/05n0285/05n0285.htm)

In her March 7 letter, Till said, "PhRMA strongly supports thedevelopment of this FDA guideline, as we believe there is currently ageneral consensus within Industry that there should be an incrementalapplication of CGMP expectations throughout clinical development as aproduct approaches commercialization."

Others, like Peter Lurie and Sidney M. Wolfe of Public Citizen's HealthResearch Group (Washington, DC, www.citizen.org) and  Barbara Immel of ImmelResources (Petaluma, CA, www.immel.com),voiced strong opposition, triggering the automatic withdrawal.

"We can see no reason," wrote Lurie and Wolfe, "why subjects in Phase Iclinical trials should be any less deserving of FDA protection thanthose in later phases of development (or, subsequently, marketing).From the perspective of any patient injured by a GMP-violating drug ina Phase I study, it will be cold comfort that the FDA deemed followingaccepted standards too cumbersome. If some company or academiclaboratory cannot follow GMPs, they should probably not be in thepractice of preparing drugs for administration to humans."

Immel had similar concerns. "I am opposed to this rule," she wrote,"and believe that a guidance document, which is not legally binding,should not be used to replace an existing regulation that provides theminimum requirements for the safe manufacture of drugs or biologics forhuman beings. I believe that this rule may place patients in phase 1 injeopardy."



1. US Food and Drug Administration, "Current Good ManufacturingPractice Regulation and Investigational New Drugs; Withdrawal,"" Federal Register 71 (84), 25747 (May 2, 2006, DOCID:fr02my06-6).
2. FDA, "Current Good Manufacturing Practice Regulation andInvestigational New Drugs," FederalRegister 71 (10),2458-2462 (Jan. 17, 2006, DOCID:fr17ja06-4. Docket No. 2005N-0285).