THE REGULATORY REQUIREMENTS UNDER INDIAN LAW FOR NEW DRUG APPROVALS

The Drugs and Cosmetics Act, 1940 is the primary legislation covering the sphere of drug regulation in India. The legislation which was enacted in 1940, even before India declared independence from the British has remained in place with a few minor amendments. The DCA is quite a skeletal legislation which only lays down a legal framework for the institutions which are required to carry out regulatory functions along with definitional clauses on sub standard or spurious or misbranded drugs. The primary regulatory requirements, including the clinical trials protocols, are delegated by the DCA to the GOI which for its part has enacted the Drugs and Cosmetics Rules, 1945 . these rules can be amended by the GOI without prior approval from the Parliament and as these rules or any amendments to them are rarely ever debated in Parliament. Discussed below are the key provisions which lay down the requirements for clinical trials for new drugs in India.

(i). Rule 122 E- Definition of “New Drug”:

Contrary to the normal scheme of Indian legislations, the definition of New Drug is found in the DCR, 1945 and not the DCA, 1940. The relevant rule is Rule 122E. this provision classifies a new drug into the three following categories:

  • Any drug , “including bulk drug substances, which has not been used in the country to any significant extent under the conditions prescribed, recommended or suggested in the labeling thereof and has not been recognized as effective and safe by the licensing authority”:
  • A new drug already approved by the licensing authority for “certain claims, which is now proposed to be marketed with modified or new claims, namely indications, dosage, dosage form and route of administration. It should be noted at this stage, that new uses or incremental innovations not resulting in increasing therapeutic efficacy are not patentable under Section 3 of the Indian Patents Act, 1970.
  • “A fixed dose combination of two or more drugs, individually approved earlier for certain claims, which are now proposed to be combined for the first time in a fixed ratio, or if the ratio of ingredients in an already marketed combination is proposed to be changed, with certain claims, viz, indications, dosage form and route administration”. This component of Rule 122Epertaining to “fixed dose combination” will have to read along with Appendix VI to the DCR, 1945. The Appendix specifies in some detail the various clinical trial requirements for FDCs of different permutations and combinations. For instance, if one or more of the active ingredients are new, the resulting FDC will necessarily have to undergo clinical trials. If both active ingredients constituting the FDC have been individually approved, the resulting FDC may still be required to undergo clinical trials. Similarly if the ratio of active ingredients in an already approved FDC is sought to be changed, there may be a new to carry out clinical trials depending on certain parameters.

(ii) The clinical trials requirements –Rule 122A, Rule 122B AND Schedule Y to the Drugs and Cosmetics Rules, 1945: 

Rule 122A, Rule 122B lay down the regulatory requirements to either import into India or manufacture in India a new drug as defined in Rule 122E. Both Rules 122A and Rule 122B require that new drugs meet the regulatory requirements laid down in Schedule Y to the DCR, 1945.

“Schedule Y”, which is titled “Requirement and Guidelines on Clinical Trials for Import and Manufacture of New Drug”, lays down the requirements for the three phases of clinical trials. According to Schedule Y, the three phrases of a clinical trial are as follows(1):

Phase I :The main objective of Phase I of clinical trials is to determine the maximum tolerated dose in humans; pharmacodynamic effects; adverse reactions, if any, with their nature and intensity; and pharmacokinetic behavior of the drug as far as possible.

Phase II: The main objective of Phase II of clinical trials is to evaluate the effectiveness of a drug for a particular indication or indications in patients with the condition under study and to determine the common short term side effects and risks associated with the drug. While Phase I trials are carried out on a small group of healthy volunteers, Phase  II trials are required to be carried out on a small group of patients.

Phase III: Also known as “therapeutic confirmatory trials”, these are the most rigorous and extensive phase of trials and are designed to “ to confirm the preliminary evidence accumulated in Phase II that a drug is safe and effective for use in the intended indication and recipient population”. This phase tests the dosage related effected, usage in different population groups, in different stages of disease and the safety of the drug in combination with other drugs. Phase III trials are typically the most expensive and by implications most expensive.

(iii) Waiver of Clinical Trials: While the clinical trial requirements themselves seem to be rather rigorous, Schedule Y actually begins by providing an exemption from conducting Phase I, Phase II, Phase III clinical trials in those cases where the drug has already received foreign regulatory approval. Given that most new drugs are introduced in the market after they have received  foreign regulatory approval, the Indian drug regulator, routinely exempts manufacturer or importers, of the new drug from carrying out any clinical trials and approval is instead granted on the basis of bio equivalence tests. However even if all three phases of clinical trials are waived, Schedule Y still requires local clinical trials on 100Indian patients. The logic behind local clinical trials is to confirm the safety and efficacy of the drug on Indian patients since it is presumed that clinical trials carried out predominately in Western countries, on Western populations need to be re confirmed on Indian people who may be genetically different from Western population and also live in a different socio economic context.

Predictably, a proviso in Rule 122A or Rule 122B allows for the Indian drug regulator to waive even local clinical trials on Indian patients on the grounds of “ public interest”. The proviso read as follows: “ Provided that the requirement of submitting the results of local clinical trials may, in public interest decide to grant such permission on the basis of data available from other countries”. The grounds of “public interest” are not explained and as will be explained and as will be explained in a later section of this essay, this provision has come under withering criticism from a Parliamentary Standing Committee.

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