The participants discussed a variety of issues related to the preclinical stages in the development of traditional medicines and other natural products for the treatment of AIDS. The major points are summarized below.
3.1 Botanical verification
The performance of a clinical trial under controlled conditions requires a constant supply of a product whose botanical identification and characterization can be verified. Lack of assurance of plant species identity is arguably the most serious deficiency of commercial herbal products. If there is no reliable chemical basis for determining identity, and botanical morphology is destroyed during formulation by such processes as powdering and extraction, only independent botanical certification can provide the necessary assurance.
A botanical certification scheme, organized along the lines of the WHO certification scheme for pharmaceutical products, would be an invaluable international stimulus towards botanical quality assurance. Each professional grower/supplier of medicinal plant material would be required to submit to the designated national botanical authority an appropriate sample of the plant, in a state of sufficient integrity to allow physical identification for confirmation of species identity. If appropriate, a certificate would then be issued indicating the currently accepted Latin binominal, and synonyms, with associated authority, and its usual common names, as well as the site and date of harvest of the crop. Professional growers could be registered with the national authority and samples for testing could be collected by trained inspectors or qualified botanists. Plant products with established pharmacological activity would be standardized on the basis of correlation of activity with levels of their known active constituent(s) or with appropriate chemical profiles. The products would also be checked for the presence of “characterizing substances”, where applicable, for further confirmation of botanical origin. The part(s) of the plant used to make each preparation should be indicated, as well as detailed instructions for harvesting (e.g., stage of growth), storage and processing, prior to and following formulation.
3.2 Pharmacological activity
Before a new drug of known chemical structure is tested in a clinical trial, there must be adequate data from in vivo and/or in vitro studies to validate its claimed therapeutic efficacy. In the case of known herbal remedies, such evidence may be available from the current practices of traditional health practitioners or from reports in the literature.
Establishing a correlation of pharmacological activity with some component in the plant is an invaluable aid to assuring comparability between preparations of a medicinal plant product. In the case of HIV infection, a number of in vitro approaches are available for evaluating antiviral activity. The in vitro anti-HIV assay could also lead to a chemical assay for active constituent(s).
There are several aspects of safety that need to be considered for herbal products that are candidates for a clinical trial. The first requirement is to identify any potential toxicity by undertaking an extensive search of the literature and evaluating performance in preclinical toxicological tests. The range of preclinical tests available for the evaluation of a synthetic drug before beginning clinical trials is well known. What is not known, however, is whether such preclinical tests need to be so extensive for traditional medicines.
The use of traditional plant remedies over a long period of time may provide important information on the pharmacological effects in humans of a particular group of chemical compounds - information that is usually not available when testing begins on a new synthetic drug. Because herbal remedies have often been used for centuries, their preparation having been described in classical texts of traditional medicine, they cannot be considered “new drugs” in the same sense as new drug candidates from the pharmaceutical industry, which are usually pure and well characterized chemical entities, never before used in humans. Testing requirements formulated by regulatory authorities to ensure the safety of “new drugs” are therefore not necessarily applicable to traditional remedies. A more limited range of preclinical toxicological tests may be adequate for traditional remedies. Consideration must also be given to the cost of performing extensive animal toxicological tests in developing countries, particularly where laboratory infrastructure is limited. Further, such tests require time that cannot be justified when no other treatment is available. Thus, limited animal testing of a herbal medicine may be justified by the remedy’s previous use in human disease and the fatal character of AIDS.
Because of time-tested usage, national drug testing policies may permit some herbal remedies to be submitted directly to clinical evaluation without prior preclinical or toxicological tests. Other remedies may need at least some preclinical toxicological testing. The requirements for testing will be determined for each country, by its own authorities, in the context of its own regulations, and on the basis of pertinent scientific data on the herbal preparation and its history of use in humans.
When a traditional remedy results in promising activity, either in a bioassay or a human study, further investigation may yield a chemically defined active principle, which might then be considered a “new drug” that would have to be tested for safety and efficacy as prescribed by drug regulatory authorities. Such active agents, however, would probably be given special (“fast-track”) consideration because of the urgent need for new drugs effective against AIDS.
A second safety consideration is the prompt recognition of any toxic events that may occur during the course of a clinical trial. It may be particularly difficult to recognize toxic events during a clinical trial in persons with AIDS because of the large number of organ systems usually involved in the disease state and the presence of secondary disease/opportunistic infections. Thus, adverse side effects may be masked by the normal progression of AIDS and related diseases and it may be difficult to determine whether a new drug actually accelerates the progress of the disease. It is also possible that the incidence and extent of drug toxicity may be increased in organ systems that are compromised by AIDS or AIDS-related diseases, a problem that even extensive testing in animals may fail to predict.
All patients with AIDS, and particularly those entering clinical trials, must be carefully screened for underlying diseases that may not yet have become clinically important. Such diseases are particularly important when they may compromise either liver or renal function and thus prevent adequate drug elimination. Overall health status must therefore be well characterized at the time that a patient is evaluated for entrance to a study.
Because there is always the possibility of an adverse drug reaction during the testing of a new drug, the study design must include a plan for managing patients who experience some manifestation of drug toxicity. Such problems may be exacerbated in AIDS patients because of their susceptibility to secondary infections, which may require treatment with additional drugs. Additional diseases and the drugs used to treat them increase the likelihood of adverse drug interactions as well as adverse reactions to the drugs themselves. The preclinical plan must address these possibilities.