'Right dose differentiates poison from remedy' Dr Narendra Deshmukh, Director, INTOX, answers key queries put across by Sachin Jagdale on toxicological studies for pre-clinical safety assessment of drugs Why do we need to test safety of drugs and that too using non-human test systems, particularly animals? One should never forget the age old postulate of toxicology. This states that all substances are poisonous; there is none which is not a poison; it is the right dose which differentiates a poison from the remedy. It has also been established beyond doubts that results obtained from experiments conducted in animals, when properly qualified, provide most valuable information on the safety of a drug substance. One should know that safety of the drugs is indeed tested in human volunteers before these are given to patients. However, the first human dose to be administered to these brave healthy human volunteers has to be very carefully selected to avoid any unacceptable consequences. Hence, this is often derived from the MTD (maximum tolerated dose) obtained from animal studies. What are the steps involved in the toxicology study of any drug? The paths to be taken for safety evaluation of drugs would depend on what we already know (i.e. have reliable data) about the safety (toxicity) of that drug. If it is a new drug entity (NDE/NCE/NBE) then you need to explore toxicity to greater depths and extent. If it is a drug ‘similar’ to the one already introduced in other regulated markets of the world (generic / similar biologic) then apart from demonstrating CMC (chemistry, manufacturing controls) and biosimilarity you need to demonstrate safety in an abbreviated testing programme. For a new drug discovery programme which spans over several years, different types of toxicity studies are conducted over such period depending on the stage of
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discovery and development. Tell us about various subtypes of toxicology? The science of toxicology is very diverse and encompasses areas such as clinical toxicology (poisoning / effects of accidental or intentional exposure on humans or animals), forensic toxicology (medico-legal), environmental toxicology, mechanistic toxicology (deals with mechanism of toxicity), descriptive toxicology (concerned directly with toxicity testing) and regulatory toxicology. A regulatory toxicologist usually works in governmental regulatory agencies, and has the responsibility to decide, on the basis of data provided by descriptive and mechanistic toxicologists, whether a drug or another chemical poses a sufficiently low risk to be marketed for a stated purpose. Please know that all toxicity studies are not animal studies. Safety assessment studies also heavily draw inferences from in-vitro tests (i.e. conducted outside body), in-silico tests (using computer programmes) and the science of chemistry. However, these in-vitro systems are fairly www.expresspharmaonline.com
over-simplified simulations of the extremely complex in-vivo environments (i.e. real insidebody conditions), which at least today, are still considered indispensible. Has introduction of new molecules by pharma companies made toxicology studies more challenging? Due to advances in knowledge of complex processes in cells, tissues / organs and the body as a whole, there has been a growing insistence on molecularly targeted drugs. It is a challenge to toxicologists to select an appropriate model for conducting safety studies. The model has to be relevant and the findings of the studies require a great deal of qualification before these can be interpreted meaningfully. How are protocols and guidelines different for toxicology studies of biopharmaceuticals and allopathic medicines? Biopharmaceuticals are made of large molecules. Their absorption, distribution, metabolism and excretion occur in a different manner than that of micro-molecules, i.e. of chemical pharma.
There are issues of stability, variation in host responses, neutralisation of pharmacological activity due to antibody response, deposition of immune complexes in tissues, toxicity to immune system including exaggerated hypersensitivity reactions which can turn fatal. Biopharmaceuticals are highly specific and potent in activity and their dosing regimen and response of the body have to be monitored more closely, including effects on endocrine functions. Use of monoclonal antibodies and development of targeted delivery systems using such MABs has opened a new chapter in the science of toxicology. Due to such differences, the regulatory guidelines for safety assessment of such biotechnology derived pharma have been written separately (e.g. ICH S6). WHO has issued a separate guidance on safety assessment of vaccines. In India, the Department of Biotechnology and its RCGM with CDSCO have been very vigilant and active in issuing and updating guidance documents over past decade. The CDSCO has created an altogether separate division for biological. Toxicology study parameters/requirements/regulations may vary depending on the country where the product is to be exported. Could you provide details regarding such different regulatory requirements? Regulated markets of USCanada, Europe and Japan have laid down requirements which are also continuously reviewed and updated. Their regulatory requirements have been made available on the websites of respective authorities (US-FDA, European Medicines Agency, MHLW of Japan). Similarly, emerging markets have been specifying their requirements. Though the world pharmaceutical regulations are in continuous process of harmonisation, and the format of data submission such as the CTD are getting similar, it is important that designs of toxicity studies are Continued on Pg 107 November 16-30, 2012