Therapeutic Innovation & Regulatory Science

This paper presents the background to the DIA Workshop “Clinical Trials and GCP in East Asia,” in which experts from China, Japan, Republic of Korea, Singapore, and Taiwan participated. Common features and differences among these five countries are discussed. A brief historical review of Good Clinical Practice (GCP) is provided, including some recent developments in the region. Some recent forums in Asia relating to clinical trials and GCP are introduced and ethical issues involved in clinical trials are addressed from the socio-cultural context, particularly the different ethical principles in the East Asian region and the West. Cross-national ethics in the use of foreign clinical trial data are also addressed.

One area of deliberation undertaken by the International Conference on Harmonization (ICH) Member States is the formulation of international and scientific quality standards for designing, conducting, recording, and reporting trials that involve the participation of human subjects or the standards for good clinical practice (GCP). This paper presents an overview of the ICH GCP and a background summary of the ICH which is the matriarch of this GCP topic.

This paper highlights the characteristic features of the Japanese good clinical practice and the Japanese clinical trial system. It also discusses the ongoing reform of the system, including the revision of the Pharmaceutical Affairs Law and substitute ordinances.

With increasing concern about the investigational use of drugs developed outside of Korea, the Korean drug regulatory authorities began discussing the concept of good clinical practice in the early 1980s. The first draft of the Korean Good Clinical Practice (KGCP) guideline was issued in July 1987 but it was not effective until October 1, 1995 when this guideline was finally legislated. Extensive revisions of the first draft, influenced by the current good clinical practice (GCP) guidelines of the United States Food and Drug Administration (FDA) and the World Health Organization (WHO) were made before its final legislation. The current KGCP incorporates most of the basic principles of the International Conference on Harmonization (ICH) GCP. Some differences still exist, however, particularly in quality assurance procedures. These differences are discussed in this paper.

It took a long time, however, for the government to smoothly implement the GCP principles in clinical research practice in Korea. Since the early 1990s, the government, in collaboration with academia and the industry, has initiated a number of activities to improve the quality of clinical trials in Korea. These activities include regulatory supervision, educational workshops, publication of a guideline for drug evaluation, and more.

The implementation of the KGCP has increased the burden on the drug industry and medical institutions, particularly the sponsors and clinical investigators. The implementation of the guideline has increased clinical trial costs as well as efforts to maintain high quality ethical standards and quality assurance of clinical trial data. Notwithstanding this burden and while there are still a number of areas to be improved, undoubtedly, the implementation of the KGCP has positively influenced the conduct of clinical research in Korea, particularly the need for peer group review of trial protocols and results thereof. The KGCP has elicited recognition among medical professionals on the importance of clinical trials in drug research as well as their strong interest in new drug trials.

Cultural and ethical differences between Western and East Asian standards must be considered in order to make the International Conference for Harmonization (ICH) work. This paper covers six broad ethical rules of East Asian society, implications for the ICH process, and concerns that still need to be addressed in the ICH guideline.

Taiwan has chosen to promote drug development as a strategic industry in the coming years. The development and implementation of good clinical practice (GCP) is an essential step for Taiwan to be part of the global pharmaceutical market. This paper covers the development and implementation of GCP in Taiwan, which has started a revolution in every aspect of clinical trials.

The Republic of Singapore and Hong Kong are discussed together because of the clear similarities in the population, per capita gross national product, disease patterns, medical practice, and regulatory requirements for clinical trials. A major difference is highlighted and that is the role of the Singaporian government, whose expressed aim is to establish Singapore as a viable coordinating hub for drug development in the region. The steps to realize this objective by building the necessary infrastructure are outlined. Finally, difficulties and issues encountered in running clinical drug trials to good clinical practice (GCP) guidelines are described with the aim that sharing such experiences will assist others in the implementation of GCP in East Asia.

Requiring high quality clinical trials in China is essential to the safe and effective use of drugs, yet it must be remembered that China is still a developing country. This paper describes the mechanism and procedures for new drug approval, as well as the development of good clinical practice (GCP) in China. Descriptions of each of the 13 chapters of the Chinese GCP are included. The current status of and problems with GCP implementation in China are covered.

Eight papers were presented at the DIA Workshop “Clinical Trials and GCP in East Asia.” Questions raised about these presentations were deliberated in this panel discussion.

In response to criticism a generation ago, the United States Food and Drug Administration (FDA) has made many changes to the regulatory approval process. This paper highlights those changes. Descriptions of relevant Federal Register notices are provided. Many of these changes, while claiming to foster faster and more efficient review, have actually increased FDA's influence over industry activities.

Multinational pharmaceutical companies are looking into expanding Phase III clinical trials to regions outside of the United States, Europe, and Japan. Inclusion of Asian sites during drug development could shorten drug development time, perhaps decrease drug development cost, address the issue of ethnic diversity, and accelerate local registrational approvals. Typically, trials are discouraged during the post-new drug application (NDA) submission preapproval stage (Phase III B). With increasing market pressures, however, more and more Phase III B studies are being performed for foreign registration or marketing purposes.

In order to successfully bid for Phase III participation, a region has to have investigators with proven track records, adequate centralized facilities, responsive regulatory authorities, and ready access. Through participation in multinational studies, a region can increase its visibility in the field of new drug development, facilitate technical transfer, build expertise in clinical trials, and enhance the international standing of opinion leaders. Being fully cognizant of the potential benefits of active involvement in new drug development, Taiwan has been gearing up for an expanded role.

During the development and approval process of a new drug, the concept of good statistics practice (GSP) is necessarily implemented. GSP is a set of principles which assures the validity of the design and analysis of the intended studies conducted at various stages of the process of drug development and regulatory approval. GSP provides a fair assessment of the drug product with the desired accuracy, precision, and reliability. In essence, GSP not only concerns the validity of statistical inference regarding drug efficacy and safety, but also provides assurance of the proper identity, strength, quality, purity, and stability of the drug product. This paper describes regulatory requirements for statistics and the role of statistics in the drug development and regulatory process. The concept and importance of GSP are illustrated through some practical and/or regulatory statistical issues that commonly occur during the drug development and regulatory approval process.

For approval of a drug product, the United States Food and Drug Administration (FDA) requires that substantial evidence of the effectiveness and safety of the drug product be provided through the conduct of two adequate, well-controlled clinical trials. To assist the sponsors in preparation of final clinical reports for regulatory submission and review, the FDA and other regulatory agencies and conferences such as the International Conference on Harmonization (ICH) have developed guidelines for the format and content of a clinical report. The FDA and ICH guidelines require that the following statistical issues be addressed in the final clinical report: 1. Baseline comparability, 2. Adjustments for covariates, 3. Dropouts or missing values, 4. Interim analyses and data monitoring, 5. Multicenter studies, 6. Multiplicity, 7. Intention-to-treat subset versus efficacy subset, 8. Active control trials, and 9. Subgroup analyses. This paper provides an overview of these statistical issues. In addition, statistical justification for these issues is also addressed.

Clinical trials demand that investigators pursue absolute truthfulness and objectivity and that they report only honest data. Medical ethics demand that the investigators be in a state of genuine uncertainty regarding the comparative merits of the test and control treatments.

Bias, misconduct, and mispresentation in clinical trials are prevalent worldwide. In addition to the universal problems of conducting clinical trials, in Taiwan clinical trials face a number of limitations, including: 1. Lack of qualified, competent clinical investigators, 2. Underpayment of health care providers resulting in poor quality medical service and clinical assessments, 3. Difficulty in recruiting cooperative, compliant patients, 4. Interference with traditional herbal medicines, 5. Criminal penalties for damage incurred during medical care, 6. A no-fault compensation law demanding safety assurance of medical service, 7. Inadequate financial support by local pharmaceutical companies with few assets and intolerance to negative results, 8. A traditional Confucianism doctrine deemed unethical to expose the flaws of the people, and 9. Patronage of traditional herbal medicine out of nationalism.

In conclusion, clinical trials in Taiwan are at risk of criminal penalties, are frequently poorly conducted and controlled, and are inadequately scrutinized. As a result, it is extremely difficult to generate high quality clinical trials in Taiwan.

After the implementation of good manufacturing practice in the early 1980s, Taiwan established a relatively effective regulatory process for pharmaceutical registration. The regulatory process for new drug applications (NDAs) in Taiwan, however, relied on foreign-derived documentation, especially the clinical data. The evolution of clinical trial requirements for product registration can be broken down into four phases over the past 15 years. It started with the initiation of postmarketing surveillance (PMS) in the early 1980s to restrict the entry of generic imitations and to provide adequate protection of pharmaceutical innovations. This was followed by a series of legislation or amendments on relevant legal requirements, such as the Patent Law, the Medical Care Act, the Bioavailability and Bioequivalence Guidelines, and the Pharmaceutical Affairs Law. The emerging pipeline protection in the early 1990s resulted in the 1993 Amendment of 1983 PMS that requires domestic clinical data for new drug applications.

Taiwan's experience with the evolution of clinical trial requirements for NDAs could serve as a good example for other developing countries to adopt. Its merits include the advancement of clinical research, the promotion of the generic-based pharmaceutical industry, and the improvement of pharmaceutical innovation protection to international standards.

This article reviews some basic principles of meta-analysis techniques for comparative clinical trials data and also discusses the use of logistic regression when comparative data are not easily available. In comparing a treatment drug and a control drug, a common problem in meta-analysis is that not many comparative clinical trials are available in the literature on the selected pair of drugs. There are, however, many clinical studies done separately on each of the drugs of interest. The situation is discussed where conventional meta-analysis results might not produce significant findings due to relatively few comparative studies involving the control drug of interest, while the logistic regression done by pooling all available individual and comparative trials could provide some insights on how the treatment and control drugs are different after controlling on covariates such as study design, patient age groups, disease groups, and so forth.

In drug development, pharmaceutical validation and process controls are important to assure that the drug product can meet standards for the identity, strength, quality, purity, and stability of the drug product. Pharmaceutical validation includes analytical method validation and (manufacturing) process validation. A validated analytical method is often employed for product testing at various critical stages of a manufacturing process to evaluate whether the manufacturing process does what it purports to do. For a validated manufacturing process, the current good manufacturing practice requires that a well-written procedure for process controls be established to monitor the performance of the manufacturing process. In this paper, statistical issues and regulatory requirements for pharmaceutical validation and process controls in drug development are discussed. The concept can be applied to new drugs, new dosage forms, and generic drug development.

According to the current bioavailability/bioequivalence regulations by the Food and Drug Administration (FDA), comparison of mean bioequivalence values between two formulations of the same drug in pharmacokinetic studies is sufficient for approval of the new formulation in a new drug application. Intrasubject variability of pharmacokinetic parameters may still statistically differ between two bioequivalent formulations which cannot be proven based on the typical 2 × 2 crossover design if no repeated measures for the same formulation can be evaluated. When repeated meaures are required in a study protocol, a parallel group study design may be preferred over a crossover study design due to a pharmacological and/or clinical reason. This paper evaluates two issues regarding intrasubject variability based on a parallel group design with repeated measures by two different approaches: 1. Conventional analysis of variance and 2. Individual subjects with respect to: an estimation procedure for variance and coefficient of variation (CV) with an emphasis on the different estimates for the CV, and different methods (parametric or nonparametric) for the comparison of variability with regard to variance and CV.

A guidance of the Food and Drug Administration (FDA) recommends that the pharmacodynamic (PD) equivalence of topical corticosteroid preparations be demonstrated by a two-step procedure. A pilot study would establish the ED50 of a PD relationship between dose duration and a vasoconstrictor response. The relevance of the assumed hyperbolic Michaelis-Menten response model is evaluated by both graphical exploratory and population PD analyses of the data presented in the guidance. It is shown that the observations are far removed from their asymptotic plateau, and that they can be characterized well by a simplified Hill equation with a Hill coefficient of 0.4. Consequently, it is suggested that pilot studies are not needed when the dose range for sensitive responses is known. Nonresponding subjects should be removed from the analyses of both stages of an investigation. PD equivalence should be assessed with dose durations distanced as far as possible from each other. Finally, the study demonstrates the usefulness of graphical, exploratory analyses without which modeling by regression, including population kinetic and PD computations, can be misinterpreted.

Single and multiple dose pharmacokinetics of a pharmaceutical compound (Compound A) have been assessed in blood, plasma, and urine from healthy elderly volunteers. Subjects were assigned to one of three treatment groups with 10 subjects/group. All three groups received a single dose of sesquifumarate salt (Compound Aa) of Compound A on Period 1; Groups I and II received a 5 mg dose and Group III received a 10 mg dose. In Period 2, Group I subjects received 5 mg b.i.d.; Group II subjects received 5 mg t.i.d., and Group III subjects received 10 mg b.i.d. Multiple dose treatment was given for seven days and Periods 1 and 2 were separated by at least seven days. Both blood (WB) and plasma (PL) concentrations were determined using LC-MS/MS. Both assays had a limit of quantitation of 0.1 ng/mL. Urine concentrations were determined with a LC-MS/MS assay having a limit of quantitation of 25 ng/mL. The AUC (0 → 24) and C_max of Compound A increased proportionally after single and multiple doses in both matrices. Steady state was reached before the first dose on Day 7. The accumulation was well predicted across three treatment groups in both matrices. For each b.i.d. group, the average exposure to Compound A after morning dose on Day 7 was increased by approximately two-fold from Day 1. These results demonstrate that C_max and AUC values for Compound A increased in a dose proportional fashion and that the accumulation of Compound A can be predicted based on single dose pharmacokinetics. No apparent effect of dose regimens upon the renal clearance was observed. There was also no significant difference demonstrated for the renal clearance of Compound A between single dose (Day 1) and multiple dose (Day 7). Approximately 4–7% of dose was recovered in urine as unchanged drug (Compound A).

This paper proposes a simple procedure for selecting sampling time points and sample allocation which reduce the mean square error or area under the curve (AUC) approximated by the trapezoidal approximation. It can generate desirable time points and allocation through an iterative scheme. The methodology is applicable to AUC estimation as well as other functional forms of serial plasma concentrations. The appropriate application of this procedure can lead to more efficient pharmacokinetic study designs.

During drug development, trough concentrations are usually monitored following repeated dosing to ensure that steady state has been achieved. Further utility of this information is explored in the estimation of intrasubject variability. Intrasubject variability is essential to the determination of sample sizes for planning within-subject (ie, crossover) studies of the effects of meals, concomitant drugs, or formulation changes (ie, bioequivalence). The utility of steady state trough concentration was evaluated as an indicator of intrasubject variability compared to a conventional approach of using a fraction of intersubject variability and to estimates obtained directly from crossover studies. Based on available data, estimates of intrasubject variability by the trough concentration approach were comparable to those from the other two approaches.

The concern of this work is the statistical evaluation of healing rate of gastric ulcers. To measure healing progress, the distance of linear advance of a specific ulcer margin toward center is recommended as an appropriate parameter. The sequence of linear advances is approximately linear over time; thus, the slope of this linear profile provides a good indication of the healing rate of the specific ulcer area. To estimate the mean slope in a treatment group, the mixed effects model technique is employed. A treatment effects comparison is made by both the F-test and the likelihood ratio test for a common slope across treatments. Also discussed are the advantages of using the linear advance as an endpoint and the mixed effects model technique as an analysis tool. A numerical example is presented as an illustration.

This paper addresses statistical issues of similarity factor f₂ as a criterion for assessment of similarity between two in vitro dissolution profiles as proposed in “Guidance on Immediate Release Solid Oral Dosage Forms; Scale-up and Postapproval Changes: Chemistry, Manufacturing, and Controls; In Vitro Dissolution Testing; In Vivo Bioequivalence Documentation” (SUPAC), issued by the United States Food and Drug Administration on November 30, 1995. These issues include the invariant property of f₂ with respect to the location change and the consequence of failure to take into account shape of the curve and unequal spacing between sampling time points. The similarity factor f₂ is a sample statistic which cannot be used to formulate a statistical hypothesis for assessment of dissolution similarity. It is, therefore, impossible to evaluate false positive and false negative rates of decisions for approval of drug products based on f₂. Implementation of f₂ to assess dissolution similarity is, in fact, a one-sided problem rather than an interval criterion suggested by the SUPAC. Complexity of the form in the distribution off even under a very strict assumption prevents one from finding its expected variance and hence, confidence interval for the mean. The large-sample distribution of f₂ by the usual delta method fails to provide an adequate approximation to the empirical distribution obtained by simulation. In addition, simulation results also indicate that the similarity factor is too liberal in concluding similarity between dissolution profiles.

In vitro dissolution has been recognized as an important element in drug development to assure the quality of drug products. It determines the rate and extent of the drug release and could be used as a surrogate for bioequivalence (BE) trials under certain conditions. Although methods for assessing the similarity of dissolution profiles between two drug products are available in the literature, most of them do not provide strong statistical and/or scientific justifications. This paper examines the properties of some commonly used methods and compares the results via a simulation study under the situations where the dissolution profile can be approximated by a linear or quadratic relationship over time. The similarity factor stated in the United States Food and Drug Administration (FDA) guideline (1) and the time series approach proposed by Chow (2) are also included. The results show that Chow's method is very sensitive to the variation in the amount dissolved. Both methods are more relaxed and have a lower probability of declaring dissimilarity than the others.

Traditionally, the bioequivalence of a generic drug with the innovator's product is assessed by comparing their pharmacokinetic profiles determined from the blood or plasma concentration-time curves. This method may only be applicable to formulations where blood drug or metabolite levels adequately characterize absorption and metabolism, not to the nonsystematic drugs categorized by the lack of systemic presence. When pharmacologic effects of the drugs can be easily measured, pharmacodynamic effect studies can be used to assess the therapeutic equivalence of nonsystemic drugs. When analytical methods or other tests cannot be developed to permit the use of the pharmacodynamic method, therapeutic equivalence clinical trials to compare one or several clinical endpoints may be the only suitable method of establishing therapeutic equivalence. This paper evaluates by Monte-Carlo simulations the fixed sample performances of some two one-sided tests procedures when the endpoints of the therapeutic equivalence trials are binary.

This paper provides an overview of the DIA workshop on immunotoxicity of pharmaceuticals held on October 2-4, 1996, in Montreux, Switzerland. The importance of immunotoxicity testing, and its current status, are discussed. The workshop's agenda: current animal tests and clinical efforts for which preclinical immunotoxicity assays need to be developed, are highlighted. Conclusions from the meeting are provided.

Autoimmunity and autoimmune disease are two different things. Autoimmunity can be physiologic (natural autoantibodies), is a normal consequence of aging, and is potentially reversible (as in drug-induced autoimmunity which disappears when the offending drug is eliminated). Autoimmune disease is a pathologic attack by a self-destructive hostile immune system for reasons unknown, although genetic, possibly viral, hormonal, and environmental factors are all involved. Autoimmune disease has been likened to a civil war in which “friendly fire” does much of the damage.

A new development in autoimmunity is its relationship to apoptosis or Programmed Cell Death (PCD). Abnormalities of PCD occur in autoimmune mice and in autoimmune patients. Autoantibodies may be produced in response to DNA and nucleoprotein fragments that arise during PCD.

Over 70 drugs are capable of inducing a lupus-like syndrome with antinuclear factors, arthritis, skin rashes, and pleurisy. Autoimmunity and autoimmune disease in these patients represents a form of immunotoxicity, perhaps an immune deviation related to cytokine imbalance and/or abnormal PCD in which the autoimmune potential that exists in all of us attains a level of serologic and clinical expression.

Drugs often cause adverse reactions, many of which involve the skin. Life-threatening skin reactions such as toxic epidermal necrolysis are rare, just like anaphylactic shock. Less severe but still worrisome eruptions are abundant but may develop into serious reactions.

Only a part (20%) of these eruptions are evoked by an allergic mechanism. Usually one does not know if the drug or a metabolite is the antigen. As a consequence, tests in vitro and in vivo will be rather unreliable. Negative tests are not helpful and not decisive as the test could be false negative. It might be necessary to carry out a provocation test, the gold standard. A provocation test is not without dangers and does not discriminate between allergic and nonallergic reactions. More clinically reliable skin and laboratory tests should be developed to identify allergic reactions and to detect the allergenicity of new drugs.

Tiered immunotoxicity testing strategies have been developed in both rats and mice. These tiered systems focus on the detection of compound-induced immunosuppression. Clinical relevance has clearly been demonstrated in the case of pharmaceuticals for which the primary aim is to induce immunosuppression in organ transplant recipients. Validation for pharmaceuticals is still ongoing.

In Japan, data on indirect immunotoxicity tests but not direct immunotoxicity tests are required for new drug applications. Antigenicity studies among indirect immunotoxicity tests are conducted on a case-by-case basis and empirically evaluated by acute systemic anaphylaxis and passive cutaneous anaphylaxis reactions in guinea pigs. The remaining skin sensitization and skin photosensitization studies are regulated by guidelines for dermatological preparations. Respecting direct immunotoxicity tests, a Japan Pharmaceutical Manufacturers Association (JPMA) questionnaire made it clear that some pharmaceutical companies have established the testing capabilities in their laboratories. In this paper, the practice of preclinical immunotoxicity testing in Japan is presented in comparison with those of the United States and the European Union.

Developing a battery of immune function assays to screen potential immunotoxic compounds has been a major issue these past years. Combining histopathology of lymphoid organs with several functional tests fosters the detection of an immunosuppressive drug and in addition provides information concerning the nonobservable adverse effect dose, thus fostering the performance of risk assessment. More work is urgently needed to carefully evaluate differences between results obtained in rodents and humans due to the origin of the cells used to perform the immune function assays, to develop more physiological tests, and to quantify the occupational risk linked to immunosuppressive molecules.

The sensitization potential of a drug depends on the activation of specific lymphocyte but the clinical outcome is related to Th1/Th2 differentiation and the “cytokine” background of the individual. Measuring cytokine production in “lymph node assays” will help to assess the potential of pharmaceuticals to produce contact and respiratory allergy.

This paper reviews the suitability of the popliteal lymph node (PLN) assay as a preclinical screening test to predict the potential of systemically administered pharmaceuticals to induce allergic or autoimmune responses. The basic assay provides a rapid, simple, and objective method to grade the immunostimulating capacity of compounds. Secondary PLN assays in sensitized animals can demonstrate specific immunological memory for the compound, whereas addition of defined reporter antigens allows identification of the type of response stimulated, and facilitates studies into the underlying mechanism.

Hypersensitivity reactions to drugs are a common clinical problem, for which it is difficult, however, to establish the causative mechanism. Some of the reactions are of the allergic nature. Animal models have been succesfully developed by using classical immune end-points. Animal models have been succesfully developed to detect human airway sensitizers by using classical immune endpoints. They are not, however, validated and standardized to a degree which would give them a predictive value.

Regarding contact allergy several animal assays are described which reliably identify substances which can cause allergic contact dermatitis. A number of guinea pig methods are available with their advantages and disadvantages. An overview of current methods is given. Predictive allergy test results cannot stand alone and should be interpreted with care. They are important tools, however, for safe development of new chemicals for topical use when the tests are executed and interpreted by trained people. Their value in the development of pharmaceuticals is less well documented.

During the past 20 years, significant progress has occurred in the fields of basic and clinical immunology which has provided newer, more sensitive methods to assess immune system effects following exposure to chemicals or drugs in humans and laboratory animals. Methods have been selected, optimized, and validated with reference compounds in rodents through several interlaboratory collaborative studies to evaluate the predictive value for detecting toxicity for the immune system of new chemicals and drug candidates. The approach at Sanofi with the evaluation and application of immunotoxicity methods to the preclinical development of new chemical entities (NCEs) (eg, 21 compounds examined) as well as with reference compounds (dexamethasone, cyclophosphamide, and cyclosporin A) is provided. The experience at Sanofi has led researchers there to believe that immunotoxicity endpoints represent another important aspect of safety assessment, can be integrated easily into the drug development process, do not yield a high rate of false positive results, and can be applied on an as needed basis. These evaluations can be driven by data suggestive of an immune effect, the drug's indication, and the class of the chemical being evaluated (eg, anti-AIDS NCE) or systematically performed.

Determination of the potential for an investigational drug to adversely affect the immune system is a standard component of nonclinical toxicology studies. Potential adverse immune effects include drug-induced hypersensitivity, immunosuppression, autoimmunity, immunostimulation, and drug antigenicity. Although immunotoxicology studies are rarely incorporated under a single heading in submissions, sponsors frequently conduct specialized assays to determine immunotoxic effects. Skin and respiratory sensitization studies are usually conducted if a drug is to be administered topically or by the inhalation route, respectively. These studies are designed to model clinical effects rather than to determine sensitization potential based on underlying immune mechanisms. Passive and active anaphylaxis assays are used to demonstrate biological effects indicative of drug antigenicity. Studies designed to determine immunosuppressive or immunostimulatory potential are often conducted when these effects are related to pharmacodynamic properties of the drug. Nonclinical studies designed to detect potential to induce autoimmune reactions are rarely conducted, primarily due to a lack of adequately characterized assays. In addition, newer assays designed to determine sensitization and autoimmunity-inducing potential are being evaluated.

Effects of a drug on the immune system can be assessed in humans but whether such effects result in decreased resistance to infections cannot easily be assessed in a direct sense. Extrapolation of data on immunotoxicity of agents resulting in decreased resistance to infections gathered from experiments with rodents to the human situation is, therefore, an important step for risk evaluation. This report describes the so-called parallellogram approach that can be used for this purpose. In this parallellogram there are four cornerstones, of which one is the health effect of exposure to a chemical, assessed as an endpoint (ie, infection model) in experimental animals, and another is the quantitative prediction of this endpoint in humans. The other cornerstones are assays that can be carried out both in experimental animals and humans or materials obtained from experimental animals and humans, and that are used for species comparison. For the immunotoxic agent ultaviolet light B radiation, and the environmental contaminant 2, 3, 7, 8-tetrachlorodibenzo-p-dioxin this approach was used. Such studies may direct risk evaluation for immunotoxicity of drugs.

A number of ex vivo assays have been developed and validated for the evaluation of immunotoxicity following exposure to drugs or environmental toxicants in animals. Although these assays have proven invaluable in researchers' understanding of the range and mechanisms of immunotoxicology, a number of them may prove to be impractical for use in human immunotoxicology, particularly for screening purposes in large-scale clinical trials. Due to their central role in the establishment and maintenance of the immune and inflammatory responses, cytokines would appear to be a reasonable choice to fill this role. There are a number of conceptual and technical considerations, however, which must be addressed before cytokine assessment can be used as a reliable measurement of immunotoxicity.

Drug-induced alterations in the immune system include immunosuppression, autoimmunity, and hypersensitivity. This paper focuses mainly on drug-induced autoimmunity. The main drug-induced organ-specific and nonorgan specific autoimmune diseases are described as are the clinical and laboratory features which are important in diagnosis. A number of factors which predispose people to the development of drug-induced autoimmune diseases have been identified, but the precise mechanisms underlying these diseases are unknown.

Environmental pollutants and other chemicals may have increasing impact on the immune system of human beings. Disregulation of the immune system by chemicals may be one of the reasons why the frequency of allergies and autoimmune diseases increases. Human hapten-specific memory lymphocytes can be detected in the blood of patients with drug-induced immunologic side effects but not in similarly exposed healthy individuals.

The immune reactivity of human lymphocytes in vitro to white coloring agent—titanium dioxide (TiO₂), and mercurial conservatives thimerosal and phenylmercury—has been studied. It was found that out of 650 patients tested, 3% reacted to titanium dioxide. The percentages for phenylmercury and thimerosal were 14% and 7%, respectively. Human memory cells can be used as markers of susceptibility in future choices of appropriate additives in pharmaceutic products.

This paper mainly deals with pharmaceutical products which are the responsibility of the Pharmaceuticals and Cosmetics Division of the Pharmaceutical Affairs Bureau in the Ministry of Health and Welfare (MHW) of Japan. These pharmaceutical products include drugs which are produced by utilizing biotechnology. An overview of the evaluation and registration procedures for these biological drug products is given here.

The Australian Guidelines for the Registration of Drugs recommend the contents and format of applications to register biologicals in Australia. This follows European guidelines and the European Union (EU) format is preferred. Registration does not require clinical trials in Australia. The Drug Safety and Evaluation Branch evaluates the application within defined time frames. The Compliance Branch handles Good Manufacturing Practices (GMP). Australia is a member of the APEC working party which is preparing draft guidelines on GMP for the region. Australia markets 17 recombinant products and two monoclonal antibodies. The problems encountered with biologicals are similar in Australia to those of other countries. Special conditions apply to blood products and gene therapy products. Australia has a policy of self-sufficiency in blood products but allows the supply and marketing of products from other countries when the equivalent product cannot be supplied in Australia. The Gene Therapy Committee of the Medical Research Council, as well as the Therapeutic Goods Administration, oversees the use of the gene therapy in humans. The costs of biologicals remains the greatest concern as many are government subsidized.

This paper gives an overall view of biotechnology products in China including drug legislation, classification of new drugs, and registration of biotechnology products. Special attention is given to the issues and concerns in the evaluation of new biotechnology products for approval in China.