The trends of new drug development in the 21st century were described. First, the history of drug development including that of the drug delivery system (DDS) was shown. Then, the recent drugs and therapeutic technology were discussed in detail. These topics are biomedicine, gene related technology, vaccine, hybrid artificial organ, chemical and phage library, fetal growth hormone, cell therapy, humanized anti-body and Viagra. In addition, some natural products were introduced, emphasizing the relationship between food and human health. Finally, I stated my opinion about the new drug development in the 21st century in Japan.
In recent years, drugs developed in Japan are used internationally in other countries. The pharmaceutical pre-clinical phase is critical in the drug developing cycle. Pharmacologists contribute to finding the leading compounds and evaluate the right compound for clinical trial. The selection of the right compound for development will save both time and money. In the pharmacological evaluation of a development candidate, in vivo animal studies that can assure the clinician that the drug is both effective and safe are usually required. Studies on the mechanism of action of the drug and how the drug works in the diseased state becomes important since a known target molecule usually serves as the basis for the development of a new drug.
Preclinical studies are defined as experiments other than clinical trials that are conducted in test systems under laboratory conditions for determining the safety of test materials for anticipated human use. It is known that preclinical studies are an indispensable requisite for but constitute time resource-consuming processes in research and development of new pharmaceuticals. Therefore, they must be designed and conducted in a manner to satisfy the criteria that the obtained data are mutually acceptable among various countries to avoid unnecessary duplication of testing. The purpose of the International Conference on Harmonisation (ICH) has been directed towards the resolution of this issue. Major scientific issues in preclinical studies comprise the interpretation of test data with respect to prediction of potential adverse effects of a test material in humans. Mechanistic consideration of the toxic effects occurring in animals given a test material can usually provide a scientific basis for evaluating the potential hazard of the material in humans. For example, when a test material was found to exhibit a carcinogenic effect in a long-term animal test, one will attempt to determine, on the basis of data from genotoxicity studies, repeated dose toxicity tests, toxicokinetic studies or pharmacology studies on the substance, whether the carcinogenic effect is due to its genotoxicity (genotoxic carcinogen) or a sequela of some secondary mechanisms (non-genotoxic carcinogen). In the cases where a test meterial was shown to exert toxic effects with either functional manifestation or non-neoplastic morphological manifestation, elucidation of the mechanism will also be useful for extrapolation of animal data to the human situation. It is known that pharmaceuticals induce their toxic effects through various mechanisms such as covalent binding of active intermediates with macrolecules of target cells, oxidative stress-mediated effects, hormone-mediated effects or cytokinemediated effects. As shown in hepatocarcinogenesis or elevation of plasma transaminase activities in rodents attributable to activation of PPAR-α, nuclear receptors or ligand-dependent transcription factors are, now, regarded as important targets for toxicity evaluation of pharmaceuticals.
The working group for reevaluation of the Guideline for General Pharmacology Studies has completed a draft guideline for Safety Pharmacology studies and plan to recommend replacing the existing guideline with the revised one. This proposed guideline is now subject to domestic and international consultation. The basic principle of the revision is to harmonize the guideline with the international concepts. The working group decided to change the title of “General pharmacology” to “Safety pharmacology”, because the objective of this guideline is to assess the safety of a test substance in humans by examining the pharmacodynamic properties of the substance. The proposed guideline includes studies on vital functions as essential studies that should be performed prior to human exposure. Studies are also required to be conducted when predictable or unexpected observed effects are concerned. The working group recommends a case-by-case approach to select the necessary test items in consideration of the variable information available.
Pharmacokinetics studies are performed to clarify the absorption, distribution, metabolism, and excretion of drug candidates. The data are not only useful for the planning of animal toxicity studies and pharmacological studies but also required for establishing the efficacy and safety in humans by indicating the pharmacokinetically appropriate drug formulation and drug usage. Identification of the major metabolic enzymes related to the major metabolism of a drug is also essential for predicting pharmacokinetic drug interactions. Use of human tissues in drug metabolism studies becomes more and more important for rational and efficient drug development. It is necessary to establish an organization in Japan for supplying human tissues originating from the Japanese population.
The development of a new chemical entity for human use is a stepwise process based on an assessment of both animal and human data on efficacy and safety of the drug. Clinical pharmacologists always refer to animal data through an Investigator's Brochure (IB) when planning and performing a clinical trial(s). The IB should provide the investigator (s) with useful information to select doses, dosing intervals, and safety monitoring procedures and also to support the clinical management of subjects during the trial(s). Non-clinical animal studies contained in the IB, however, lack a relationship to the pharmacological and toxicological findings of the investigated product(s). Most of the non-clinical animal studies address the methodology and the results obtained, but are lacking in a discussion of the relevance of the findings. The IB shoud include not only a summary of the findings in each field of animal study but also relationships of the findings through some indicator (s) such as blood and tissue concentrations of the parent drug and/or metabolites. I do hope Pharmaceutical Companies will provide much useful information about their product (s) through the improvement of their system of research and development.