New Drug and Clinical Trial Rules 2019: Paradigm Shift in Indian Pharmaceutical Industries

The government notified the New Drugs and Clinical Trial Rules on 19th March 2019, to replace Part XA and Schedule Y of the Drugs and Cosmetics Rules 1945. Many new desirable changes have been made and these will help clinical research and trials in India. However, there are discrepancies which offset some of the advantages offered by the new rules. Including timelines for many regulatory functions, is among the main advantages offered, but incorrect use of terms, duplication of rule numbers is likely to complicate the regulatory procedures. The changed classification of Ethics Committees is a welcome feature, but it is unclear why the composition recommended by ICMR is accepted for the EC for Biomedical and Health Research, but not for the one for Clinical Trials, Bioavailability and Bioequivalence Studies. The government would do well to consider the suggestions made herein and amend the New Drugs and Clinical Trial Rules 2019.


INTRODUCTION
Clinical research in India is regulated both by ethical guidelines and research regulations and both of these overlap in a number of situations. Ethical guidelines have not seen many changes in the recent past, but clinical research regulations have been recently changed. Schedule Y was introduced in the Drugs and Cosmetic Rules of 1945, almost 30 years ago. It survived for this period, though it went through at least two major amendments and numerous revisions, to finally move out of the rule book on 19th March 2019. It was a historic document, since for the first time, it laid down the procedures to introduce new drugs in the country. Prior to its introduction, new drug introduction was haphazard and unpredictable, at the hands of the powers that be.
Reverse engineering was the main strength of the Indian Industry then and any new drug cleared by the FDA, would be synthesized in India at a fraction of its cost and launched in the market.
Schedule Y was brought in to regulate the launch of such molecules. The schedule brought in 1988, required Phase III clinical trials before a new drug could be launched in India, but this rule applied only for the first manufacturer who launched it, the followers were allowed to introduce the same molecule after demonstration bioequivalence of their formulation with that available abroad. 1 A major amendment to Schedule Y 2 was necessitated following the publication of the ICH Guidelines 3 and India's entry into the TRIPS agreement. 4 With this amendment, Schedule Y was brought on par with ICH GCP. Yet this was not sufficient, a series of new rules were brought in, in 2013 and these were followed by regular amendments. 5 Among these were two important rules, which made the audio-video recording of the consent process mandatory 6 and required accreditation of Ethics Committees. 7 Despite the fact that the government has asked the Drugs Controller to make accreditation by NABH mandatory, there is no clear-cut instruction to this effect from CDSCO. Now, the Schedule Y along with Part XA of the D and C Rules have been replaced by the New Drugs and Clinical Trial Rules 2019. The draft of these rules was published on February 1, 2018 and the government gave 45 days for comments and suggestions. 8 In September 2018 the Supreme Court at the behest of Swasthya Adhikar Manch asked the government to give more time for parties to comment on the rules. 9 In March 2019, the government finally notified the New Drugs and Clinical Trial Rules 2019. Careful study of the rules shows that changes are very few, but the arrangement and presentation of the rules has changed significantly. If one were to evaluate whether the new rules are better than the earlier ones and honest answer would be that, it is a mixed bag. Some changes are for the better, but some new problems have cropped up. To analyse the new rules, it might be better to deal with the positive and negative points separately and this could be used by the authorities to make further amendment and improvement to the rules.

Arrangement
The original rules were arranged in a rather odd manner, with little logic. Take Rule 122 as an example. There were numerous sections of the rule, devoted to different aspects of clinical trials, but no logic is discernible. The sections of the rule were as follows: 122: Substances specified in Schedule C (1) days. Additional improvements are that the validity of registration of the EC has been increased from 3 years to five years, thus the frequency of the re-registration exercise reduces. Every EC has to inform the DCGI of any approval granted to a research proposal within 15 days of granting the approval. Additionally, timelines are provided within which registration will be granted or refused by the authorities, so also a method for appeal and redress has been defined.

Timelines
For the first time, the drug rules define timelines for receiving response from the regulators. The given timelines may not please all stakeholders and they can be improved. Promising a timeline during which a particular job will be completed is a conceptual advance in government work. Some tightening of the timelines may be desired and the authorities may consider this recommendation that is up to them.

Post-Trial Access
The Declaration of Helsinki provided for access to the investigational drug even after he trial to those subjects who have found it beneficial. 10 Since this is a guideline, subjects in India could not demand or claim post trial access unless the sponsor agreed to it. The NDCTR has however made post trial access a requirement, if the investigator recommends it and this is approved by the ethics committee. The Rule 27 puts certain conditions, namely the drug is for a condition for which there is no alternate therapy and the subject or legal heir has consented to the condition that the sponsor shall not be liable for post-trial use. Meaning thereby, that should the subject suffer any AE or SAE, the sponsor shall not be required to pay for the medical treatment or compensation for the same.

New Problems
While provided adequate grounds to do so. The NDCTR has provided an additional mechanism of relief to such an aggrieved investigator. Rule 25 (iii) states as follows: "In case an ethics committee of a clinical trial site rejects the approval of the protocol, the details of the same shall be submitted to the Central Licensing Authority prior to seeking approval of another Ethics Committee for the protocol for conduct of the clinical trial at the same site;" An investigator could find another EC that would approve of the proposal and he/she could conduct the study at the institute whose EC had rejected the proposal. Further the investigator is required to submit the details of the EC decision to the CLA before approaching another EC. The rule does not say that the approval of the CLA is necessary. The problem with this rule is that it actually encourages EC shopping. One wonders why the new rules have brought in such a clause and how will this aid ethical research in the country?
This rule (Rule 25(iii)) gives an upper hand to an outside EC, which would now provide oversight to the study. Rule 25(ii) does allow an investigator to approach another EC, but only if his/her parent institute did not have a registered EC. With the sub rule (iii) the investigator can go another EC even when the EC of the parent institute has rejected the study proposal

Compensation
Compensation for clinical trial injuries is an important aspect of subject protection. As it is, due to different rules across the globe, there is lot of discrepancy among subjects of international studies. 12 There have been complaints that rules for compensation for clinical trial injuries are complicated, 13 there have been proposals for a simple compensation formula even in the US, where no compensation is provided by country's law. 14 Nominee and legal heir are two distinct parties.
The Legal Dictionary defines a nominee as "a person or entity who is requested or named to act for another, such as an agent or trustee." An heir is defined as "an individual appointed by law to succeed to the estate of an ancestor who died without a will. The term legal heir is commonly used to refer to a person who succeeds to property, either by will or law." According to law, a nominee is a trustee and not the owner of the assets. In other words, he is only a caretaker of the assets. The nominee will only hold the assets (in this case the compensation) as a trustee and will be legally bound to transfer it to the legal heirs. For most investments, a legal heir is entitled to the assets of the deceased. Thus, anyone may appoint a nominee, but an heir can be decided by a will or by law.
The two terms nominee and legal heir are not interchangeable, but the NDCTR has used them in this sense. On the death of a participant, the compensation is required to be paid by the sponsor to the legal heir (Chapter VI, Rule 39 (1)). The mechanism by which the sponsor or the investigator would identify the legal heir of the participant is not clear. In the ICF the participant has to declare www.ajphr.com 25 the name of the nominee and their relation (Table 3, Third Schedule, NDCTR). There appears little clarity on how the legal heirs are to be identified and whether it is the responsibility of the investigator to identify the legal heirs of deceased participants. In the past compensation was payable to the nominee, whose name was provided by the participant in the ICF. The legal heirs could lay their claim before the nominee and get their share without involving the sponsor or the investigator. The present rules put the onus on the sponsor for ensuring that the payment is made to the legal heirs. The confusion between heir and nominee is likely to get the site and the sponsor within 30 days, which would be non-refundable. In this paper we have highlighted the inconsistencies and sections which are likely to damage clinical research in the country. We bring the drawbacks in the NDCTR so that there is a nationwide understanding of the drawbacks of the rules. We also request the authorities to consider these problems