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... ..."
.
Provided that the Licensing Authority shall, where the data provided on the clinical trials is inadequate, intimate the applicant in writing…intimating the conditions which shall be satisfied before permission could be considered.
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 take place.
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
For new drug substances discovered in India, clinical trials are required to be carried out in India from Phase I as required under through Phase III,...permission to carry out these trials are generally given in stages, considering the data emerging from earlier phase.:
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-
1. Application for permission.
(1) Application for permission to import or manufacture new drugs for sale or to undertake clinical trials shall be made in Form 44 accompanied with following data in accordance with the appendices, namely:-
(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.
Showing posts with label CRO. Show all posts
Showing posts with label CRO. Show all posts
Saturday, October 4, 2008
Schedule Y and CROs
Schedule Y and CROs
Schedule Y deals with regulations relating to clinical trial requirements for import, manufacture and obtaining marketing approval for a new drug in India. The procedure for applying for marketing approval depends on the status of the new drug, which can be broadly classified into three categories viz. new drug substances discovered which are already approved/ marketed in other countries, new drug substances discovered which are not approved/ marketed in other countries and new drug substances discovered in India.
In case of the new drug substances discovered which are already approved/ marketed in other countries, it is sufficient if confirmatory trials (phase III) are conducted to obtain sufficient data about the efficacy and safety of the drug in a larger number of patients (minimum 100 in 3-4 centres) generally in comparison with a standard drug or a placebo to confirm efficacy and safety claims made in the product monograph.
For new drug substances discovered which are not approved/ marketed in other countries, permission for clinical trials are given with a phase lag in case new drug substances are not approved/ marketed in other countries.
For eg: phase I of a new drug substance is allowed only if the drug has completed phase I and moved to phase II in other countries; similarly phase II is allowed in India only after completion of phase II in other countries and phase III has commenced.
It is very clear that phase I trials cannot be initiated in India for new drug substances discovered in other countries unless phase I data from other countries is available.
In case of new drug substances discovered in India, clinical trials have to be carried out as human / clinical pharmacology trials (phase I). The phase I trials are carried out on healthy human volunteers (minimum 2 at each dose level) to determine maximum tolerated dose in humans, pharmacodynamic effects, adverse reactions, pharmacokinetic behaviours etc.
Under the exploratory trials or phase II trials are carried out on limited number of patients (normally 10 -12 at each dose level) to determine therapeutic uses, effective dose range and further evaluation of safety and pharmacokinetics.
Confirmatory trials or phase III trials are conducted to obtain sufficient data about the efficacy and safety of the drug in a larger number of patients (minimum 100 in 3-4 centres) generally in comparison with a standard drug or a placebo to confirm efficacy and safety claims made in the product monograph. If the new drug substance is not marketed in any other country Phase III trials should be conducted on a minimum of 500 patients spread across 10 - 15 centres.
It is to be noted that permission for the next phase will be given only after satisfactory completion of the previous phase. For e.g. permission for phase II trials will be given only after phase I trial is completed satisfactorily and data is submitted and reviewed by the regulatory authorities.
Implications of the revised Schedule Y
From a plain reading of the revised Schedule Y of the Drugs and Cosmetics Rules, it is clear that in cases of new drug substances discovered which are already approved and marketed in other countries where confirmatory trials are required and new drug substances discovered in India where all the stages of clinical trials are to be conducted, the regulations look clear and unambiguous.
However, in case of new drug substances discovered which are not approved or marketed in other countries where new drug substances are not approved or marketed in other countries, it puts back India by a step as compared to other countries due to Phase lag that need to be adhered to.
It is heartening to note that the revised Schedule Y will address the issue of phase lag in case of phase II and concurrent trials will be allowed. This is a welcome move since it is a well established fact that patient enrollment rates are high in India as compared to countries like USA and EU which will reduce the time to market. Acceptance of data from phase II trials conducted in India by other countries will pave way for all the drug companies to look at India for all their phase II requirements.
From a broader perspective, drugs will be available for patients in India earlier than what it is today. clinical research organizations (CROs) will be in a position to increase its offerings which is now confined to phase III trials and bioequivalence/ bioavailability studies. Phase II trials will be a great value addition and a major boost to the future of CROs. Needless to say that it will create more jobs, more foreign exchange and increased health for the society in general.
Status quo in case of phase I trials should be viewed from the regulators point. The clinical trial segment is yet to mature to desired levels and abundant caution needs to be exercised on the implications of allowing first in man studies. On the other hand it may still offer indirect advantages like multinational pharmaceutical companies trying to set up R & D units in India or looking at tie-ups for various new drugs being developed by Indian companies.
The relaxation on restrictions to export biological samples and revisiting regulatory procedures are steps in the right direction. This will boost confidence of overseas companies and more investments will follow. India will be the destination for pharmaceutical R & D with its huge knowledge base, alignment of regulatory provisions to global standards etc.
- (The author is MD, Lotus Labs Pvt. Ltd.)
Schedule Y deals with regulations relating to clinical trial requirements for import, manufacture and obtaining marketing approval for a new drug in India. The procedure for applying for marketing approval depends on the status of the new drug, which can be broadly classified into three categories viz. new drug substances discovered which are already approved/ marketed in other countries, new drug substances discovered which are not approved/ marketed in other countries and new drug substances discovered in India.
In case of the new drug substances discovered which are already approved/ marketed in other countries, it is sufficient if confirmatory trials (phase III) are conducted to obtain sufficient data about the efficacy and safety of the drug in a larger number of patients (minimum 100 in 3-4 centres) generally in comparison with a standard drug or a placebo to confirm efficacy and safety claims made in the product monograph.
For new drug substances discovered which are not approved/ marketed in other countries, permission for clinical trials are given with a phase lag in case new drug substances are not approved/ marketed in other countries.
For eg: phase I of a new drug substance is allowed only if the drug has completed phase I and moved to phase II in other countries; similarly phase II is allowed in India only after completion of phase II in other countries and phase III has commenced.
It is very clear that phase I trials cannot be initiated in India for new drug substances discovered in other countries unless phase I data from other countries is available.
In case of new drug substances discovered in India, clinical trials have to be carried out as human / clinical pharmacology trials (phase I). The phase I trials are carried out on healthy human volunteers (minimum 2 at each dose level) to determine maximum tolerated dose in humans, pharmacodynamic effects, adverse reactions, pharmacokinetic behaviours etc.
Under the exploratory trials or phase II trials are carried out on limited number of patients (normally 10 -12 at each dose level) to determine therapeutic uses, effective dose range and further evaluation of safety and pharmacokinetics.
Confirmatory trials or phase III trials are conducted to obtain sufficient data about the efficacy and safety of the drug in a larger number of patients (minimum 100 in 3-4 centres) generally in comparison with a standard drug or a placebo to confirm efficacy and safety claims made in the product monograph. If the new drug substance is not marketed in any other country Phase III trials should be conducted on a minimum of 500 patients spread across 10 - 15 centres.
It is to be noted that permission for the next phase will be given only after satisfactory completion of the previous phase. For e.g. permission for phase II trials will be given only after phase I trial is completed satisfactorily and data is submitted and reviewed by the regulatory authorities.
Implications of the revised Schedule Y
From a plain reading of the revised Schedule Y of the Drugs and Cosmetics Rules, it is clear that in cases of new drug substances discovered which are already approved and marketed in other countries where confirmatory trials are required and new drug substances discovered in India where all the stages of clinical trials are to be conducted, the regulations look clear and unambiguous.
However, in case of new drug substances discovered which are not approved or marketed in other countries where new drug substances are not approved or marketed in other countries, it puts back India by a step as compared to other countries due to Phase lag that need to be adhered to.
It is heartening to note that the revised Schedule Y will address the issue of phase lag in case of phase II and concurrent trials will be allowed. This is a welcome move since it is a well established fact that patient enrollment rates are high in India as compared to countries like USA and EU which will reduce the time to market. Acceptance of data from phase II trials conducted in India by other countries will pave way for all the drug companies to look at India for all their phase II requirements.
From a broader perspective, drugs will be available for patients in India earlier than what it is today. clinical research organizations (CROs) will be in a position to increase its offerings which is now confined to phase III trials and bioequivalence/ bioavailability studies. Phase II trials will be a great value addition and a major boost to the future of CROs. Needless to say that it will create more jobs, more foreign exchange and increased health for the society in general.
Status quo in case of phase I trials should be viewed from the regulators point. The clinical trial segment is yet to mature to desired levels and abundant caution needs to be exercised on the implications of allowing first in man studies. On the other hand it may still offer indirect advantages like multinational pharmaceutical companies trying to set up R & D units in India or looking at tie-ups for various new drugs being developed by Indian companies.
The relaxation on restrictions to export biological samples and revisiting regulatory procedures are steps in the right direction. This will boost confidence of overseas companies and more investments will follow. India will be the destination for pharmaceutical R & D with its huge knowledge base, alignment of regulatory provisions to global standards etc.
- (The author is MD, Lotus Labs Pvt. Ltd.)
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