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The Indian Clinical Research Outsourcing (CRO) industry is growing rapidly and brings with it attendant regulatory concerns. Of special concern is the matter of Phase- I trials which, in general terms, are first-time trials in the country on human subjects of new drugs especially of investigational new drugs. Since this involves testing on humans of new drugs that is to say drugs generally inadequately tested before on humans, and in the context of investigational new drugs, not tested at all on humans before, the subject is understandably sensitive in the public domain as well. The initial testing on humans of drugs recently invented or discovered in the laboratory and having been tested, if at all, only on animal subjects, is a subject potentially capable of abuse in the absence of proper legal regulation, as featured indeed in a number of books and films. It remains a matter of concern for all jurisdictions and particularly of weak, less developed and more vulnerable ones, that the subject remains in the realm of science fiction. How adequately does Indian law deal with the growing challenge?
Clinical Trial is now, since January 20, 2005, defined in Rule 122 DAA of Drugs and Cosmetics Rules, 1945 is as follows:Clinical trial means a systematic study of new drug(s) in human subject(s) to generate data for discovering and / or verifying the clinical, pharmacological (including pharmacodynamic and pharmacokinetic) and /or adverse effects with the objective of determining safety and / or efficacy of the new drug."
The Rules themselves are framed under the Drugs and Cosmetics Act, 1940, the principal statute in the field. This is a law enacted by Parliament and applies, alongwith the Rules, in all the states in the country. Drugs themselves to which the statute applies are defined in Section 3 (b) of the Act.
To take drug development to the market, clinical research is necessary at different stages to different ends. These are broadly categorized in phases, Phase I being the earliest and Phase IV being the last.
Rule 122 DA of Drugs and Cosmetics Rules, 1945 requires an application to be made to the statutory Licensing Authority for permission to conduct clinical trials for New Drug/Investigational New Drug and for prior permission to be granted before conducting the clinical trial. This Rule is extracted hereunder in relevant part for a Phase-I trial.
122DA. Application for permission to conduct clinical trials for New Drug/Investigational New Drug
(1) No clinical trial for a new drug, whether for clinical investigation or any clinical experiment by any Institution, shall be conducted except under, and in accordance with, the permission in writing of the Licensing Authority defined in clause (b) of rule 21.
(2) An application for grant of permission to conduct:-
(a) human clinical trials (Phase-I) on a new drug shall be made to the Licensing Authority in Form 44 accompanied by a fee of fifty thousand rupees and such information and data as required under Schedule Y... ..."
Under Schedule Y, Paragraph 2 (6), Phase- I trials are described. As per this-
The objective of studies in Phase I is the estimation of safety and tolerability with the initial administration of an investigational new drug into human(s). Studies in this Phase of development usually have non-therapeutic objectives and may be conducted in healthy volunteers subjects or certain types of patients. Drugs with significant potential toxicity e.g. cytotoxic drugs are usually studied in patients.... Studies conducted in Phase I, usually intended to evaluate maximum tolerated dose, pharmacokinetics, pharmacodynamics and early measurement of drug activity.
It is only after completion of Phase I trial, the subsequent phases of trial can
A conjoint reading of Rule 122DA (2) (a) and Schedule Y, paragraph 2 (6) indicates that an application and grant of permission is envisaged and is necessary for conducting Phase-I trials in India, which by definition are trials of ‘investigational new drugs’, that is to say new drugs not having previously been tested on humans anywhere. The statutory definition of ‘Investigational New Drug’ is "...means a new chemical entity or product having therapeutic indication but which have never been tested on human being." The Rule by itself without reference to the Schedule seems to cover Phase I trials of ‘New Drug’ more generally defined in Section 122E of The Drug and Cosmetics Act as "a drug" which has not been used in the country to any significant extent under the conditions prescribed, recommended or suggested in the labeling thereof .. even if it is not an ‘Investigational New Drug.’ A reading of the Rule by itself leaves it open to the interpretation that for Phase-I trials, Schedule Y is relevant only for indicating the ‘information and data’ required to support the application. But the scope of the Rule gets restricted to only ‘Investigational New Drugs’ in light of the description of Phase-I in the Schedule as being limited to ‘Investigational New Drugs.’ The reference in the Rule to the Schedule is mandated by the express stipulation in this regard in the language of Clause 2 (a) of the Rule itself. It becomes clear from this that Phase-I trials concerns testing of drugs on human subjects in India of drugs that have never been tested before on human subjects and that applications are maintainable to carry out such tests and permissions will be granted in suitable cases by the Indian Licensing Authority. It is also notable that the statutory provisions cited above do not distinguish between indigenous and foreign ‘investigational new drugs.’ That is to say, that in considering applications for for Phase-I trial in India permissions, the provisions noticed above do not disqualify drugs discovered or developed outside India but instead specifically envisaged as a category in which applications will be entertained and considered for grant of the necessary permission.
What cases of Phase-I trials of foreign drugs will be considered suitable by the Licensing Authority for grant for permission, is governed statutorily yet appears to leave some scope for non-statutory discretion to be exercised ad hoc or in terms of a policy decision. To understand the scope of this discretion, one needs to appreciate the legal position prevailing until 20th January of 2005 when the law was amended, as well as the change in the law.
Earlier, an ‘investigational new drug’ was not a statutory expression. Previously Rule 122-A governed licenses to import new drugs including for the purposes of trials which were required to comply with the guidelines for the same as set out in Schedule Y (unamended). The earlier Rule did not deal specifically with ‘investigational new drugs’ nor specifically with any particular Phase of trial such as Phase-I. Earlier the description of Phase-I trials in Schedule Y did not specifically make it applicable to ‘investigational new drugs,’ in the sense of the expression as only now defined. And the earlier Schedule Y expressly made a distinction between foreign drugs and indigenously discovered or developed drugs. In relevant part, the earlier Schedule Y read as under-
1. Clinical Trials.1.1 Nature of trials.- The clinical trials required to be carried out in the country before a new drug is approved for marketing depend on the status of the drug in other countries....If the drug is not approved/marketed trials are generally allowed to be initiated at one phase earlier to the phase of trials in other countries.
For new drug substances
discovered in other countries phase I trials are not usually allowed to be
initiated in India unless phase I data as required under Item 5 of the said
Appendix from other countries are available. However, such trials may be
permitted even in the absence of phase I data from other countries if the drug
is of special relevance to the health problem of India
The earlier position was thus clearly that Phase-I trial of an ‘investigational new drug’, as now defined, was not permitted in the usual course if the concerned drug was discovered outside India subject only to the exception that the drug was of special relevance to the health problem of India.
This position changed significantly with the coming into force of the amendment
in January of 2005.
The amended Schedule Y now provides-
(iv) "Human Clinical Pharmacology Data as prescribed in items 5, 6 and 7 of Appendix I are as stated below:-
(a) for new drug substances discovered in India, clinical trials are required to be carried out in India right from Phase I and data should be submitted as required under items 1, 2, 3, 4, 5 (data, if any, from other countries) , and 9 of Appendix I;
(b) for new drug substances discovered in countries other than India, Phase I data as required under items 1, 2, 3, 4, 5 (data from other countries) and 9 of Appendix I should be submitted along with the application. After submission of Phase I data generated outside India to the Licensing Authority, permission may be granted to repeat Phase I trials and/or to conduct Phase II trials and subsequently Phase III trials concurrently with other global trials for that drug. Phase III trials are required to be conducted in India before permission to market the drug in India is granted..."
Post amendment, therefore, the position that emerges from the above reproduced portion of Schedule Y is that in India, Phase- I trials of foreign drugs is possible but only as a ‘repeat’ of an earlier Phase-I trial already conducted outside India and the application for this requires submission of the earlier Phase-I data generated outside India. But if the concerned foreign drug has already been tested on humans outside India in Phase-I trials already held outside India, it will no longer fall within the definition of an ‘investigational new drug’ and therefore not within the description of a ‘Phase-I trial.’ This is anomalous as ‘repeat’ Phase-I trials would have to be envisaged as Phase-I trials to be covered under the scheme of Rule 122DA. Still, the harmonious interpretation of the conflicting statutory provisions would be that Phase-I trials in India of foreign drugs are possible and properly the subject of applications and grant of necessary permissions, only if there is some pre-existing Phase-I data from outside India. The interpretation that the earlier ban on Phase-I trials of foreign drugs has not been abolished by the amendment would be extreme in rendering altogether otiose certain portions of the amended Schedule Y. The key issue, though, remains as to how much such initial foreign Phase-I data would be adequate before permission to ‘repeat’ the Phase-I trial in India can or should be granted.
The second Proviso to Rule 122DA, noticed earlier, enables the Licensing Authority to go into the matter of adequacy/inadequacy of the data provided on a drug in support of the application for grant of the necessary permission. Beyond that it is in the discretion of the Licensing Authority to accord appropriate weight and worth to whatever data is submitted and on the basis thereof, on impose such pre-conditions as considered exigent before considering the application further for grant of permission. Evidently, if the Licensing Authority expects or requires data from a full fledged foreign Phase-I trial, there will be few if any applications for a ‘repeat’ Phase-I trial in India as that would be unnecessary and a waste of time, expense and effort. Evidently also, if the data is so token or nominal that the ‘repeat’ Phase-I trial would actually amount to almost a first-time Phase-I trial, and especially if the drug is potentially particularly novel and hazardous , then the Licensing Authority would be expected to treat it as inadequate.
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