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May 2002
Vol. 5, No. 5, pp 23–24.
clinical trials track

Clinician-initiated trials

Research studies are not proposed solely by the pharmaceutical industry.
opening art

Whenone thinks about clinical research, what comes to mind is the process by which new chemical compounds, developed by pharmaceutical companies, are tested to prove their safety and efficacy. In truth, this is what drug research usually entails.However, numerous studies are designed by physicians, often in university settings, that receive little direction from the pharmaceutical industry. The purpose of these trials is to develop new therapeutic products, expand the approval of products to include the treatment of other diseases, and rigorously investigate the safety and efficacy of products for which FDA approval otherwise is not required.

The sources of funding for clinician-initiated and designed trials span the range of industrial, governmental, and private granting institutions. Specifically, pharmaceutical companies often are happy to fund small-scale projects that could identify new areas of effective treatment for their already approved products. The National Institutes of Health provides a significant amount of money for physicians to conduct their own research programs, and venture capital groups help support the development of products created by private and university research labs.

New directions
When the FDA allows a drug to be marketed and sold in the United States, the approval is disease- and treatment-specific. Put another way, the FDA does not give blanket approvals to drugs. What is really being agreed to by the FDA isthat a pharmaceutical company has successfully demonstrated that its new product is safe and effective for the treatment of a specific disease when taken in a prescribed manner. The reasoning for this qualification is understandable: Clinical trials are not, and cannot be, designed to determine all the potential uses for a medication, nor are they meant to blindly ascertain the safety of dosing all possible patients.

In the normal course of treating patients, however, physicians often use approved medications in unapproved ways (these are known as “off-label” prescriptions).For many drugs, in fact, this is quite common. The FDA, however, does not sanction this use; and drug companies cannot advertise, market, or in any way try to sell their products for off-label purposes. Thus, if a manufacturer comes to realize that its blockbuster cure for male pattern baldness is also effective for treating teenage acne, then it must conduct human trials before marketing its drug as an acne therapy.

This kind of study is known as postmarketing; although it resembles a Phase III project in every respect, for clarity it is referred to as a Phase IV clinical trial. It is also worth noting that pharmaceutical companies conduct Phase IV trials for two reasons: to extend their abilities to market certain drugs, and to obtain legal extensions for the patent lives of those drugs.

Although it is true that pharmaceutical companies routinely conduct Phase IV studies, quite often research physicians independently propose these projects. Typically, a physician will come to believe that off-label uses of a particular product are significant and will approach the manufacturer with a proposal for a clinical trial. It is certainly possible for a physician to conduct a research program without a pharmaceutical company’s involvement, but if such work infringes an existing patent, the physician is ill-advised to do so.

Frequently, the pharmaceutical company will review and approve the proposal and provide the researcher with a modest grant, free drug supplies, and assistance with the filing of necessary FDA applications. Depending on the arrangement, that may be the extent of the manufacturer’s participation in the trial. But many companies also offer assistance with drug packaging (particularly if a placebo is required), protocol and casebook development, statistical analyses, and report writing for FDA submissions. Furthermore, most companies provide monitoring services to assist investigators in their efforts in assuring that the research process meets all FDA requirements.

Achieving credibility
Herbal remedies and other homeopathic treatments are commonplace, and while many practitioners decry their unproven, unscientific use, just as many patients rely on them. For most of these treatments, the FDA does not require human testing, and thus no scientific evidence exists to prove their safety or justify their manufacturers’ therapeutic claims.

Not all medical researchers, however, dismiss herbal treatments. In fact, the reality is quite the opposite: Researchers are aggressively and rigorously testing “natural” treatments to determine their scientific worth. For example, a tremendous amount of media and research interest in the past few years is related to the use of St. John’s wort for the treatment of mild depression.

Pharmaceutical companies rarely have an interest in conducting or funding research for herbal therapeutics. Thus, most researchers gain money to investigate these materials through governmental and private sources. Often, the herbal distributors help fund various projects. For them, of course, the advantage is clear: Sales are likely to increase if a product can cite scientific justification for its claims. Furthermore, a supplier who can boast that its product was successfully tested has an immediate leg up against competitors in a market where patent protections rarely exist.

When physicians decide to test a legally marketed but otherwise unapproved therapeutic product, they have less support than when teaming with a major pharmaceutical company. In general, this means that they must develop the protocols and casebooks independently, analyze the data personally, and produce a final report with little staff assistance. The FDA, of course, requires clinical trial monitoring, and the funding supplier often provides this oversight function. But the onus for developing, conducting, and concluding each trial rests more heavily on the investigators than in many other research situations.

Wholly independent
Another level of investigator-initiated research involves the human testing of chemical compounds developed entirely in a researcher’s own laboratory. As might be expected, this kind of work encompasses the smallest fraction of investigators and is usually limited to individuals who have earned both M.D. and Ph.D. degrees and work in academic institutions. For these researchers, the challenges, risks, and benefits are greatest.

Generally speaking, once a new chemical entity is developed in a laboratory, the principal researcher seeks outside, venture capital funding before attempting human trials. This requires forming a new business entity and separating the project from the originating university. (Of course, universities profit from the entrepreneurial ventures spun off from research developed under their roofs.) In addition, the researchers who first realized their chemical compound’s potential therapeutic value are moved to the sidelines in the human testing process so as to avoid the possibility of bias.

Two examples of such product developments are the cases of Myloral and Colloral, which were developed by Howard Weiner of Harvard University.Weiner, who specializes in autoimmune diseases (such as multiple sclerosis [MS] and rheumatoid arthritis), was one of the first to realize the possibility of treating these disorders with “oral tolerance”. Autoimmune diseases cause a patient’s immune system to destroy otherwise normal, healthy tissue; oral tolerance describes the beliefthat feeding those suffering from these types of diseases the very proteins their systems attack will allow them to build up a tolerance that eventually will cure them of their disorders.

After proving the effectiveness of his oral tolerance idea in a laboratory-based, animal testing program, Weiner formed a company called AutoImmune to raise the venture capital necessary to begin human trials. Specifically, AutoImmune went on to develop and test an oral formulation of myelin, called Myloral, meant to cure humans of MS, and Colloral, a collagen formulation intended to treat patients suffering from rheumatoid arthritis. Ultimately, this process required Weiner to hire corporate managers, battle academic egos, placate nervous investors, plan clinical projects, and convince a skeptical medical community of the value and validity of his ideas.

Unfortunately, AutoImmune eventually failed because its products, while effective, were not sufficiently more effective than placebos. (In fairness, the determined placebo rate was one of the largest ever encountered, and AutoImmune may have blundered with the design of its early trials so that its later efforts were unavoidably handicapped.)

Benefiting patients
The effect of individual research projects on the availability of therapeutic treatments is substantial. Physician researchers are often the oneswho first identify new ways of using existing treatments, thus improving the health of numerous other patients. Furthermore, without the work of private researchers, the true safety and efficacy of many herbal therapies might not be known: For example, clinician-initiated trials first demonstrated the positive effects on fetal brain development that occur when pregnant women ingest regular doses of omega-3 fatty acids.

In today’s world of drug discovery, major pharmaceutical companies, who use exhaustive combinatorial chemistry and high-throughput screening techniques, obviously identify most new products. However, because of various unavoidable financial realities, these companies are often more interested in discovering potentially profitable therapies that can be applied to a given disease than starting with a disease and attempting to find its treatment. As a result, investigators who single-mindedly pursue the cure to a specific disease, independent of the pharmaceutical industry, play a critical role in the improvement of health care for all.

Cullen T. Vogelson is a former assistant editor of Modern Drug Discovery. Send your comments or questions regarding this article to mdd@acs.org or the Editorial Office by fax at 202-776-8166 or by post at 1155 16th Street, NW; Washington, DC 20036

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