WASHINGTON _ A recent proposal to streamline regulatoryreview of experimental gene therapies has emerged, torn and tattered,after legal and bureaucratic skirmishes at the FDA and the NationalInstitutes of Health (NIH). According to industry observers, what'sleft is not a pretty picture.

Biotechnology companies had hoped that a new plan for"consolidated review" of gene therapy protocols would offer theconvenience of one-stop shopping at a single government agency _the FDA. Currently, sponsors must deal separately with the FDA andthe NIH's Recombinant DNA Advisory Committee (RAC), each ofwhich has different forms, submission requirements and approvalmechanisms.

However, legal complexities at the FDA and RAC's own reluctanceto relinquish its high-profile role in reviewing gene therapy protocolshave conspired to reduce the consolidated review concept to a mereshadow of its former self, according to industry critics.

Originally, consolidated review meant a system whereby aninvestigational new drug application (IND) to the FDA would serveas the sole entry point for gene therapy researchers' proposals to thegovernment. RAC was to become, essentially, an FDA advisory bodythat reviewed protocols on an "as-needed" basis and grappledprimarily with the broader societal and ethical issues raised bygenetic research.

In contrast, "consolidated" review in its present incarnation willinvolve simultaneous submission of gene therapy protocols to theNIH's Office of Recombinant DNA Activities (ORDA) and to theFDA. The two agencies will then make a joint decision about whichprotocols merit RAC review. The only real change from currentprocedures is a slight reduction in the months-long lead time nowrequired for submission of data to RAC in order to make it on thecommittee's quarterly public meeting agenda.

RAC voted to approve the new version of consolidated review onMarch 6. According to ORDA director Nelson Wivel, the details willbe published in the Federal Register once NIH Director HaroldVarmus has signed off on the plan. After that, it will be open topublic comment.

"There is no obvious advantage of a simultaneous submission to twobodies," said Daniel Hoth, a senior vice president at Cell GenesysInc., a Foster City, Calif.-based company that has developed severalpotential gene therapy products. "The issue is, are we going to havetwo independent review processes, each potentially exercising itsveto authority, or are we going to find a way to truly streamline theprocess while at the same time ensuring the scientific excellence ofthe proposals?"

Philip Noguchi, director of the division of cellular and gene therapiesat the FDA's Center for Biologics Evaluation and Research, toldBioWorld that under the current proposal, the FDA "will have moreinfluence over what topics and which protocols the RAC reviews."But he conceded that the plan falls short of a true consolidation of theprocess.

What went wrong? FDA commissioner David Kessler and Varmusboth hopped cheerfully on board the consolidated review bandwagonat a meeting of National Task Force of AIDS Drug Development(NTFADD) last August. NTFADD has been charged with identifyingand removing barriers to AIDS drug development.

A Wall Of Resistance

But Varmus hit a wall of resistance when he presented theconsolidated review scheme to RAC members last September. (SeeBioWorld Today, Sept. 14, 1994, p. 1.) Many worried that a keyelement of RAC's value _ open and public debate of geneticexperiments _ would be lost forever once gene therapy protocolswere sucked into the black hole of FDA confidentiality. Undercurrent law, INDs are considered as proprietary as new drugapplications (NDA), documents which the FDA is unequivocallybarred from discussing in public.

In sharp contrast, RAC meetings often involve open, freewheelingdiscussions of a company's product and its research plans, includingscrutiny of the quality of preclinical work, study designs, safetyissues and the adequacy of informed consent documents. Themeetings are attended by members of the public and the press.

Apparently, once Varmus realized that RAC might be unable toobtain information about gene therapy protocols that it wanted orneeded from the FDA, he changed his stance on consolidated review.He rejected a proposal earlier this year that involved companiessubmitting all data solely to the FDA, but signed a waiver allowingthe FDA to release the submissions to RAC. His concern: voluntarywaivers were an insufficient guarantee.

As a result, "the [consolidated review] proposal at this point does notreflect the spirit of what the task force [NTFADD] originallyrequested," said Hoth, who is a member of NTFADD.

Although some critics argue privately that RAC members are loath togive up the "intoxicating" power of approving and disapprovingresearch protocols, the truth is that the FDA is the sole governmentagency with the power to allow or disallow experimental drug trialsin humans. RAC has no statutory authority over private companiesconducting gene therapy research.

Companies Must Seek RAC's Blessing

However, because the NIH funds most of the premier universities andresearch institutions that conduct gene therapy research, they canrequire protocols carried out at those institutions to be reviewed andapproved by RAC. As a result, companies must "voluntarily" seekRAC's blessing in order to work with top researchers around thenation.

Responding to complaints about the system, RAC itself recently setup an accelerated review program that defined seven types ofprotocols or protocol amendments that need not undergo review bythe full committee. But that program doesn't go far enough,according to industry.

"While RAC has made some progress in speeding up review of `me-too' protocols, no significant progress has been made towardspeeding review of the vast majority of protocols," said GerardMcGarrity, vice president and director of development at GeneticTherapy Institute, based in Gaithersburg, Md., and a former chairmanof RAC (1988-1992). "The time has come for RAC to give upprotocol-by-protocol review of gene therapy activities and to focustheir energy on new concepts and new technologies."

The FDA's Noguchi agrees. "RAC is actually trivializing its effect bydoing case-by-case protocol reviews," Noguchi told BioWorld. "Wewant them to focus on relatively broader issues, like in utero genetherapy and germ-line manipulations." n

-- Lisa Piercey Washington Editor

(c) 1997 American Health Consultants. All rights reserved.