BETHESDA, Md. -- Members of the RAC on Friday debated thequality of protocols, informed consent documents and whetherpatients should have to pay for treatment of problems that aresecondary to gene therapy.

It seemed that science was taking a back seat to social concernsat the Recombinant DNA Advisory Committee (RAC) of theNational Institutes of Health.

Some of the researchers "don't know diddley-squat aboutprotocol design," complained Brigid Leventhal of theDepartment of Pediatric Oncology at Johns Hopkins Hospital."We spend a lot of time redesigning protocols. We may need toreject a lot more of them."

The last hour was devoted to discussion of proposed reviewtracks, on which a subcommittee had failed to come toconsensus at the previous RAC meeting. This time, theBiotechnology Industry Organization wrote to RAC urgingadoption so that new treatments could reach patients morequickly, and BIO's director of technical affairs, AlanGoldhammer, expressed frustration to BioWorld over RAC'sslow deliberations.

Proposed areas for accelerated review include certaincategories of recombinant vaccines, lethally irradiated cells (noreplication competent virus); modifications of protocols notrelated to gene transfer; additional study sites; new principleinvestigators and new sites; and "umbrella" protocols, in whichthe principal investigator (PI) indicates intent to initiate a newstudy at multiple sites.

"If the RAC concentrates on what is new and novel, the FDAwith its large staff can track the less novel," said BruceMerchant, vice president of clinical regulatory and clinicalresearch at Viagene Inc. "The particular responsibility of theRAC is to look at emerging areas of gene therapy."

Regarding protocols before the RAC, French Anderson toldBioWorld, "The science is usually good. The concerns now aremuch more social implications. The time has clearly come formultiple tracks, some of which are major, some of which areminor, and soon, an exempt status."

The proposal will be published in the Federal Register and willbe considered at the next RAC meeting -- and maybe one afterthat, Anderson told BioWorld.

RAC OKS TWO IN VIVO GENE-THERAPY TRIALS

The RAC on Friday unanimously approved two protocols fordelivering genes directly into patients.

One of the two in vivo DNA transfers is aimed at cancerimmunotherapy; the other at correcting a hereditary disease,cystic fibrosis. Before the Phase I clinicals can begin, the FDAmust add its own green light to RAC's authorizations.

The cancer trial, sponsored by Vical Inc. of San Diego will takeplace at the Mayo Clinic's Comprehensive Cancer Center. VicalInc. will supply the antigen-encoding DNA, wrapped in itsproprietary "cytofectin" phospholipid vector, to oncologist JohnKovach, who directs Mayo's cancer center. The trial will enrolll5 patients whose colorectal tumors have spread to their liver.The study will test both single-dose and multidose escalationsto evaluate safety and immune stimulation.

Vical's vice president and chief financial officer, MarthaDemski, told BioWorld that the company's sponsorship of theimpending studies involves designing the protocol and payingfor the clinical work and the physicians' time.

The cystic fibrosis study at the University of Alabama, underclinician Eric Sorscher, will administer the gene fortransmembrane conductance factor, missing in cystic fibrosispatients, via intranasal inhalation. Sorscher's study issponsored by Genzyme Corp. of Cambridge, Mass., which has anoption to use Vical's cytofectins, and will supply its own geneconstruct to Sorscher, Demski said.

This marks the second time that RAC has permitted humantrials of gene therapy by direct injection of DNA into a patient,rather than via a conventional indirect vector, such as aretroviral vehicle. Its first authorization, in February 1992,allowed University of Michigan molecular biologist Gary Nabelto inject the tumors of end-stage melanoma patients withantigenic proteins (see BioWorld, Dec. 2).

Nabel reported success with this approach in the Dec. 1 issue ofPNAS, the Proceedings of the National Academy of Sciences..The University of Michigan licensed Vical to employ Nabel'spioneering methods in developing its own in vivo technology,and Nabel sits on the company's scientific advisory board.

Vical's CEO, Alain Schreiber, and its director of regulatoryaffairs, Steve Kradjian, both attended the RAC hearing. PP DavidN. Leff

RAC APPROVES GTI'S TRIAL FOR CNS TUMORS

Genetic Therapy Inc. (GTI) announced Friday that the RAC hasapproved its gene therapy protocol for treating a form ofmetastatic cancer known as leptomeningeal carcinomatosis.

In this type of cancer, tumor cells seed the coverings of thebrain and spinal cord (leptomeninges); mean survival time issix to seven months.

Edward Oldfield and Zvi Ram of the National Institute ofNeurological Disorders and Stroke will serve as the trial'sprincipal investigators (PIs).

The treatment approach used in this protocol, which still has tobe approved by the FDA, employs GTI's vector systems totransfer the gene for the enzyme thymidine kinase intodividing tumor cells. Cells producing the enzyme becomesusceptible to the anti-viral drug ganciclovir, which can then beadministered to destroy the tumor cells.

GTI of Gaithersburg, Md., is using a similar approach in itsongoing gene therapy trial in brain tumors (in which Oldfieldand Ram are the PIs, as well). In September, the companyreported the preliminary results of the brain tumor trial at the10th International Conference on Brain Tumor Research andTherapy in Stalheim, Norway. In that trial, five of the eighttreated patients had exhibited an anti-tumor response and allof them tolerated the treatment well.

Genetic Therapy's stock (NASDAQ:GTII) gained 25 cents onFriday, closing at $17.75. -- Jennifer Van Brunt

RAC also approved the following protocols:

-- Intrathecal gene therapy for the treatment ofleptomeningeal carcinomatosis. Malignant cells will berendered sensitive to the anti-viral drug ganciclovir byretroviral transfer of the herpes simplex thymidine kinasegene.

PI: Edward Oldfield, chief of the surgical neurology branch,National Institute of Neurological Diseases and Stroke.

-- Injection of colon carcinoma patients with autologousirradiated tumor cells and fibroblasts genetically modified tosecrete interleukin-2, Phase I.

PIs: Robert Sobol, Ivor Royston, San Diego Regional CancerCenter.

-- Retrovirus-Mediated Transfer of the cDNA for HumanGlucocerebrosidase into peripheral blood repopulating cells ofpatients with Gaucher's disease.

PIs: Friedrich Schuening, division of Clinical Research, FredHutchinson Cancer Research Center.

-- Induction of cell-mediated immunity against tumor-associated antigens presented by HLA-A2 or HLA-A1 using B-7-transfected lethally irradiated allogeneic melanoma cell linesin patients with stage IV melanoma.

PI: Mario Sznol, National Cancer Institute.

-- Evaluate the safety and biological activity of HIV-IT (v)(HIV-1 IIBenv/rev -- retroviral vector) in HIV-1-infectedsubjects.

PI: Richard Haubrich of the University of San Diego.

Sponsor: Viagene Inc.

-- Adoptive immunotherapy of melanoma with activatedlymph node cells primed in vivo with autologous tumor cellstransduced with the IL-4 gene.

PI: Alfred Chang, professor of surgery, University of MichiganMedical Center.

The RAC rejected a Phase I protocol to inject glioblastomapatients with tumor cells genetically modified to secreteinterleukin-2.

-- David C. Holzman Washington Editor

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