No Trials Without Money, No Money Without Trials

Susan Slovin develops vaccines at the Memorial Sloan-Kettering Cancer Center in New York City using tumor- associated antigens for prostrate cancer. She has completed multiple Phase I and Phase II clinical trials, which test safety and dosing. She has designed a Phase III trial for efficacy--the last stage required for approval by the Food and Drug Administration (FDA). Nevertheless, she can't proceed. Scientists are required to use the FDA's Good Manufacturing Practices (GMPs), which makes the cost of preparing the vaccine prohibitive for Slovin. Through each of her early cancer vaccine trials, which typically enrolled only 15 to 30 patients, Memorial Sloan-Kettering's own bioorganic chemistry laboratory, a nonGMP facility, synthesized the precursor of the vaccine and then a small GMP facility conjugated it. But for a larger Phase III trial with more than 200 patients, the FDA requires scientists to test the same compound that would be marketed if approved. And only GMP-manufactured vaccines fit the requirement. "You have to have the money," Slovin says. "You have already invested heavily, by a variety of grants or individual funding agencies, let's say about a million dollars, and you've synthesized the vaccine--you have the patient population. [But] you realize that [the money] is insufficient, and you really can't afford to do it." Many researchers intent on getting a potential vaccine from the bench into clinical trials have trouble overcoming the GMP obstacle if they lack the support of a government clinical-trials network or industrial partner. "It is just getting more and more complicated," says Stuart Shapiro, extramural officer of the Vaccine and Prevention Research Program, division of AIDS, National Institute of Allergy and Infectious Diseases (NIAID). "On top of that, we have people who are trained as clinicians, as doctors, who have some scientific knowledge to come up with new ideas, but they have never been trained in the complexity of what they are about to undertake. And it is driving the FDA crazy." Despite such obstacles, cancer vaccine research soared in the 1990s. The National Institutes of Health Web site lists 157 clinical trials that involve vaccines; of those, 120 are for cancers. The commercial vaccine market has grown at 15% a year, with vaccines accounting for $7 billion (US) of $300 billion in annual pharmaceutical sales, according to Pamela Bassett, president of BioTrend, and a biotech industry analyst. Bassett projects that in 10 years, the demand for vaccines will approach $20 billion annually. Gross profit margins for newer vaccines are projected to be from 70% to 80%. Despite these high stakes, many researchers have trouble brining the product to market. Training to Translate Slovin, who initially ran her own immunology laboratory, enrolled in medical school at 33 and obtained her MD--while running the lab--to help her overcome challenges in translational research. As an assistant professor at Memorial Sloan-Kettering, Slovin investigates conjugated multivalent vaccines composed of glycoproteins, several carbohydrates, and mucin-related molecules. Preclinical work and some early clinical trials may use small batches of very good laboratory-grade product. Even though laboratory vaccines may be of better quality, according to Shapiro, GMP product can be made in much larger quantities and will be more reproducible. Some researchers resort to contract manufacturers for GMP-quality vaccines. These specialized firms allow academic researchers and pharmaceutical companies to develop new products without building GMP plants, which cost $300-$500 million. If the product doesn't work, the pharmaceutical company loses only the cost of materials produced and the contract-manufacturing fee. "Increasingly this is the way it is being done," says Shapiro, "Which is good actually, because it means that small and academic investigators, if they get the grant resources or their universities want to foot the resources, can take a vaccine all the way through Phase III. Slovin estimates the minimum cost of contracting enough vaccine for a Phase III trial to be $500,000. Nevertheless, her group is conducting further studies and documenting the progress of more than 200 volunteers from the previous trials. If enough data show that the vaccine delays progression of the disease or improves the quality of life, Slovin may be better able to convince a pharmaceutical company that her vaccine would be worth the risk of an investment. Pharmaceutical companies set high standards, however, for evidence of drug efficacy. "When academic investigators want to test to see if their product is better than standard of care [in a Phase III trial], they have to have enough compelling data so that people who have enough money will be willing to invest in it," says H. Kim Lyerly, a professor in Duke University's division of surgery, and a cancer-vaccine researcher. The need for compelling data creates a catch-22: Researchers must prove efficacy to attract industry, but efficacy is often only determined after a Phase III trial, which many researchers can not finance without the help of industry. Slovin says the only way to validate efficacy is with "a very large Phase II [trial] that could be randomized, or ... a Phase III trial that is either placebo-based or [uses] something else that may be equally effective. The problem again here is that no company is willing to sponsor or manufacture a drug under GMP." Dear Entrance Fee A pioneer in AIDS vaccines, Harriet Robinson, a researcher at Emory University, says it takes $1 million just to prepare a new vaccine for an investigational new drug (IND) application. The IND must be approved before it can undergo Phase I trials. She is involved in a DNA vaccine for AIDS that will begin a Phase I trial in June. Emory University has created a private company called GeoVax, which will establish process engineering and manufacturing operations. But, until GMP facilities are available, GeoVax will hire contract-GMP companies. "For a university scientist to be able to take something into a Phase I trial without a company supporting the GMP manufacturing would be difficult," says Robinson, chairman of microbiology and immunology at Emory's Yerkes Primate Research Center. Some academic centers design and staff GMP facilities, such as Dana Farber's Connell and O'Reilly Cell Manipulation Laboratory in Boston, and Center for Biomedicine & Genetics at the City of Hope National Medical Center in Los Angeles. "Any university that plans on doing translation research will need to have a GMP facility to at least create enough material for a Phase I trial," Robinson adds. "By the time you get to Phase III, you will need an industrial partner or an outside contractor." NIAID's Shapiro, who advises researchers about HIV vaccine development, recommends that they consider hiring research or regulatory affairs consultants, or both, early in the process. "There are some companies that are organized to be research project managers [and can] go through all the research stages," he says. "I really recommend that people find a good company to work with." Both the NIAID and the National Cancer Institute (NCI) have experience with contract manufacturing companies. NCI's Rapid Access to Interventional Development program provides GMP materials to academic cancer researchers, but only for preclinical and early clinical trials. At NIAID's Vaccine Research Center, a planned GMP pilot plant will produce HIV vaccine for Phase I/II human trials. BioTrend's Bassett advises bench researchers embarking on studies of similar vaccines to talk with other R&D scientists about what worked and what failed for them. "I don't want to scare these people off because, even though [the vaccine development] is not going to be perfect, even if it never makes it to the market, you just don't know where it is going to go," Bassett says. "It can always lead to the next step." Katherine Uraneck (Kuraneck@nyc.rr.com) is a physician and freelance writer in New York. Resources for researchers: Regulatory Affairs Professionals Society www.raps.org National Biotech Register www.biotech-register.com World Health Organization www.who.int/vaccines-access/CMProject/index.htm

No Trials Without Money, No Money Without Trials

Interested in reading more?

Become a Member of