Industry Researchers Decry Tone Of NIH Gene Therapy Panel Report

In what some industry observers liken to biotechnology's early days of scientific hope mixed with public pessimism, gene therapy has come under the scope of scrutiny at the National Institutes of Health. A much-publicized December panel report commissioned by NIH director Harold Varmus lambastes companies' use of clinical trials to lure investors; urges stringent peer review of gene therapy protocols; calls for more basic research; and warns that "overselling of the industry" could cause a backlash from disappointed investors and the public. Caution: Panel cochairman Arno Motulsky says gene therapy "has great promise" but notes "many hurdles it needs to overcome." Just how funding of-and feelings toward-gene therapy will be affected by the "Report and Recommendations of the Panel to Assess the NIH Investment in Research on Gene Therapy" (accessible via the Internet at http://www.nih.gov/news/panelrep.html) remains to be seen. Researchers say the report-which also praised gene therapy's long-term potential-will not hurt the scientific community, and some even agree with its conclusions. However, few are happy with the document's knuckle-rapping tone. "Much of what they said was right in the sense that there is a lot of basic research to be done, and it doesn't help to be hyping the field," says Alan Smith, senior vice president of research at Genzyme Corp., a publicly held gene therapy company in Cambridge, Mass. "On the other hand, part of running a business is getting funded, and hype wouldn't be unheard of. The biotech industry was accused of that in the beginning." "Academic and commercial-based gene therapy programs will likely have different reactions to the report," predicts James Wilson, director of the Institute for Human Gene Therapy at the University of Pennsylvania Medical Center. Wilson, who is also a founder of and consultant to Genovo Inc., a gene therapy startup based in Philadelphia, says it is harder for clinically focused commercial programs to "reinvest from development back into discovery," while academic researchers concentrating on basic investigation may "foster a more patient approach" to getting gene therapy off the ground. The NIH panel-composed of 14 biomedical scientists from academia and government without direct ties to gene therapy-had a distinct mission: to assess the state of gene therapy and offer advice on how NIH should fund the research. A second panel evaluated NIH's role in reviewing gene therapy protocols (see accompanying story). NIH currently spends about $200 million a year, or 2 percent of its budget, on gene therapy. The panel report approves of current funding levels. However, it recommends some shift in funding from clinical research-currently three-quarters of NIH's gene therapy budget-to basic investigations. The report also rejects a potential separate NIH study section specifically devoted to gene therapy, saying the field must compete directly with more traditional therapies for funding. Last, the document calls for researchers in general to tone down exaggerated claims of gene therapy's short-term promise. Some gene therapy researchers bristle at the idea that NIH has the right to judge industry work in the specialty. "I think it's a bit impertinent for NIH to tell people in the industry how to develop drugs, given that no one on the panel has ever developed a drug," remarks Smith. Malcolm Brenner, director of the cell and gene therapy program at St. Jude's Children's Research Hospital in Memphis, agrees. "I think the report would have been strengthened if there were people on the panel who knew first-hand what the problems were and could offer constructive criticism for altering clinical protocols," he says. Competitive Protocols: Panelist David Botstein wants to discourage "copycat" experiments. But NIH panel member David Botstein, a geneticist at Stanford University, argues that the report is constructive because it urges NIH to fund only well-defined, competitive gene therapy protocols. Botstein and others complain that current gene therapy trials often are "copycat" experiments that don't advance the field. "I think the impact [of the report] will be very positive because it will keep gene therapy in the mainstream of competitive research," Botstein says. Varmus, a vocal critic of gene therapy's rapid entry into clinical trials, is expected to set up a panel of NIH institute directors who will implement the report's conclusions over the next several years. "That's one very practical outcome," says Arno Motulsky, a geneticist at the University of Washington in Seattle, who cochaired the panel with Harvard University hematologist Stuart Orkin. "The group will keep close track of what's going on at NIH." LITTLE IMPACT: Barrie Carter doubts the report will greatly affect companies. Industry leaders say that's important-but only within NIH-funded institutions. "If NIH is trying to coordinate how to best spend its $200 million, that's wonderful," comments Barrie Carter, director of research and development at Targeted Genetics Corp., a publicly held gene therapy company in Seattle. "But I don't think it will have much impact on companies." Carter notes that NIH dollars are merely a drop in the bucket of gene therapy funding. Indeed, the pharmaceutical industry's optimstic investment in gene therapy stands in contrast to what some see as NIH negativity toward the field. "The pharmaceutical industry invested $900 million in gene therapy last year," remarks Fred Ledley, vice president of medicine at GeneMedicine Inc., a public gene therapy company in Houston. "Obviously, people who really know about drug development are investing in the field." In 1995, the recent trend toward partnership between big pharmaceutical and gene therapy companies continued (K .S. Brown, The Scientist, Nov. 13, 1995, page 1). Bermuda-based Corange International Ltd., parent company of the German-based Boehringer Mannheim Group, agreed to pay up to $100 million in equity investments to GeneMedicine, which is working on gene-carrying plasmids to fight cancer. Bristol-Myers Squibb Co. of New York pledged up to $20 million to Somatix Therapy Inc., a public gene therapy company in Alameda, Calif., at work on treatments for various types of cancer. Given booming pharmaceutical investment, researchers wonder why the NIH-commissioned scientists seem somewhat negative toward gene therapy. "There is absolutely no reason for the pessimism that's been kicking around," says Ledley. While several gene therapy trials in academia did not pan out last year, Ledley notes, that's perfectly normal. "Remember, 80 percent of biologicals [drugs made from living organisms] fail in the clinic," he says. "Is it going to be different in gene therapy? I hope so-but I don't think so." Many academic and industrial scientists blame pessimism toward gene therapy on the media, which they say quickly build up a technology-and then tear it down when immediate results do not appear. Several recent articles have focused on the NIH report's negative side (E. Marshall, "Less hype, more biology needed for gene therapy," Science, 270:1751, 1995; M. Wadman, "Hyping results 'could damage' gene therapy," Nature, 378:655, 1995; D.S. Greenberg, "Gene therapy is the new snake-oil product," Philadelphia Inquirer, Jan. 7, 1996, page E5). "The way it's being reported, it's as though we think gene therapy is just a lot of hype and not so great," says Motulsky. "We certainly are not saying that. We feel strongly that gene therapy has great promise. But there are many hurdles it needs to overcome." 'Enthusiastic': Michael Knowles is optimistic, but notes that moving forward takes time. "What you read in the press does not always reflect a cross-section of perspective in the science community," comments Michael Knowles, a professor of medicine with the Cystic Fibrosis (CF) Research Center at the University of North Carolina, Chapel Hill. Knowles was involved in a recent trial that unsuccessfully attempted to treat CF patients with healthy genes carried in an adenovirus vector (M.R. Knowles et al., New England Journal of Medicine, 333:823-31, 1995). "I remain very enthusiastic about gene therapy as something that will become part of our medical care," Knowles says. "But I was never optimistic that we would actually move to treatment on the first try." The bad press may simply reflect the public's fickleness toward new technology, according to William T. Golden, cochairman of the Carnegie Commission on Science, Technology, and Government in New York. "The American public has a way of being manic-depressive about these things," Golden says. "And that will continue. Still, gene therapy is in an exciting time scientifically." Public and media mood swings vis-Æ-vis gene therapy are reminiscent of the 1980s, notes Robert Gottlieb, senior vice president of Feinstein Partners Inc., a Cambridge, Mass., biotechnology consulting firm. Back then, the wonder drug interferon-a natural protein prized for its antiviral activity-was in the news. "There were wild fluctuations in expectation about interferon," Gottlieb recalls. "Opinion swung up and down. But science moved along as it does, in fits and starts. By the time alpha-interferon was approved in 1986, the public had virtually written it off. And then it became a successful therapeutic." In gene therapy's time of challenge, biotechnology shines like a beacon of potential, say its proponents. According to reports by Hambrecht & Quist, an investment banking firm in San Francisco, the biotech industry ended a three-year slump last year, finishing 1995 up 68.4 percent. Gottlieb predicts a similar future for gene therapy-though he won't say when. While no one knows when-or where-gene therapy trials will finally meet success, researchers agree one thing seems clear: to get there, university and industry scientists must work together. Academic researchers need industry-produced vectors and funding. And industry specialists build off basic academic research. "In the final analysis, you have to have both for success," Knowles says. So while the NIH panel report freely complains that "uncritical gene therapy reports [from companies] are used by industry to promote investment and perceived research dominance," it stops far short of suggesting that academic researchers sever their ties to industry. Rather, the report says just the opposite, recommending that NIH "encourage collaborative arrangements between academic institutions and industry." In particular, small companies are expected to continue forging ties with academic or pharmaceutical partners, notes Gottlieb. "It's not a life-or-death decision for, say, Smith-Kline Beecham to spend an extra couple of years" refining the basic science behind a therapeutic approach, Gottlieb says. "But a small startup with just a few million dollars in the bank will ask: 'Will it pay for me to do more clinical research?' There is a balance between putting all the [basic science] bricks in place and taking a product to reasonable market trials." Achieving that balance often lies in partnerships with academia. "It is a fruitful collaboration," comments Motulsky. Yet it is sometimes a difficult one. "In industry, our job is to get a product through clinical trials and onto the market," states Ledley. "In academia, their job is to push back the forefront of science." The trick, says Knowles, is to make those differences work. "Tension is not a bad thing, if it makes both sides work harder," he maintains. "For example, it wouldn't have been possible to do early gene-transfer trials without industry being aggressive in producing human-quality vectors. We would still be wondering: How would these things work in a human body? We wouldn't even know we had to go back and get the basic science right." SIDEBAR : ZOOMING THROUGH REVIEW: RAC STEPS OUT OF THE WAY Another NIH panel moves out of routine clinical-protocol review Kathryn S. Brown is a freelance science writer based in Columbia, Mo.

Industry Researchers Decry Tone Of NIH Gene Therapy Panel Report

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