This article highlights the recently published, revised regulatory pathway in India and focuses on the regulatory changes and their impact on industry and on clinical trials. The authors discuss product registration, changes to clinical trials rules, revisions to “new drug” definitions, postmarketing studies, orphan drug registration, ethics committees, fees and waivers and the importation and manufacture of unapproved new drugs.
India’s Ministry of Health and Family Welfare (MoHFW) has published the final version of New Drugs and Clinical Trials Rules, 2019
The new regulations cover provision for promoting clinical research as well as complex topics such as orphan drug, post-trial access, and pre and postsubmission meeting. The new rules appear comprehensive, well-balanced, and likely to improve the ethical and quality standards of clinical trials in India, which will further benefit patients and industry. The conditions of waiving local clinical trials under these rules will help provide patients with earlier access to drugs. The approval for clinical trials in 30 working days for indigenous drugs will also speed up the trial process and encourage local drug development. Provision for accelerated product approval under some conditions, especially pre and postsubmission meetings with authorities, may add increased predictability and confidence in the system. However, shortened review timelines will certainly require additional manpower at the Central Drugs Standard Control Organization (CDSCO) to ensure timely review of applications.
The newly published New Drugs and Clinical Trials Rules, 2019
will be referred as New Rules, 2019
in this article. The new rules are structured around 13 chapters (including 107 rules) and eight schedules. The new rules will apply to all new drugs, investigational new drugs for human use, clinical trials, bioequivalence and bioavailability studies and ethics committees. The new rules will supersede Part XA and Schedule Y of Drugs and Cosmetics Rules, 1945
, and go into effect immediately. Drugs for veterinary use, earlier regulations and schedule Y will continue to be applicable.
The new regulations also are aimed at promoting clinical research in the country by implementing time-bound review of applications, allowing increased predictability and transparency of regulatory pathway and providing clarity on many complex subjects, including post-trial access.
In 2013, after a series of media allegations of unethical practices, the CDSCO office made stricter regulations for conducting clinical trials. Many new regulations were introduced, many of which led to degrees of confusion and uncertainty among sponsors who conduct Global Clinical Trials (GCT) in India. Despite changes implemented to overcome challenges in those regulations, much work was still required, evidenced by the fact that the number of clinical trials approved by the Indian regulator has still not yet reached the levels existing prior to 2013.
To overcome the challenge of reduced clinical research in India, CDSCO revisited the rules on clinical trials and new drugs and introduced New Drugs and Clinical Trials Rules, 2019.
Figure 1. Regulatory Pathway for Product Registration..
Key Changes in the 2019 New Drugs and Clinical Trials Rules
Regulations on Biomedical and Health Research (BHR)
Previously, studies other than clinical and bioavailability and bioequivalence (BA/BE) studies were not regulated in the Drug and Cosmetic Rules
and, consequently, there was insufficient control on the conduct of these studies. These types of studies were covered by the Indian Council of Medical Research (ICMR) in the National Ethical Guidelines for Biomedical and Health Research Involving Human Participants
(released initially in 2000, amended in 2006 and 2017). Since these were covered only under Indian Council of Medical Research (ICMR) Guidelines
and not under the Drugs and Cosmetics Rules,
these studies were unregulated and there was no clarity on the approval mechanism and or compensation process.
In New Rules, 2019
, such research has been defined to include “
studies on basic, applied and operational research or clinical research designed primarily to increase scientific knowledge about diseases and conditions (physical or socio-behavioral), their detection and cause and evolving strategies for health promotion, prevention or amelioration of disease and rehabilitation but does not include CT.”
The study types include:
- In Vitro Diagnostics (IVDs) performance testing for research
- new surgical intervention
- Assisted Reproductive Technology (ART)
- public health survey
- epidemiological health survey
- observational and non-interventional study of old drug
These types of studies would be approved by ethics committees constituted under Rule 16 and registered under Rule 17 with CDSCO office as the “Ethics Committee for Biomedical and Health Research.” Apart from approving such studies, ethics committees also are responsible for medical management and compensation for injury or death in these types of studies. Rules applicable to biomedical and health research would be applicable from 15 September 2019.
The pressing need was to not only to regulate such studies, but also keep them under the ethics committee oversight. It was not feasible to directly oversee so many studies from CDSCO. These kinds of studies are less likely to cause harm to subjects/consumers and it is a good policy to put these under ethics committee responsibility. While it has been mentioned that compensation needs to be given as per ICMR National Ethical Guidelines for Biomedical and Health Research Involving human Particpants
no mechanism has been defined to determine compensation, as in the case of clinical trials.
Academic Clinical Trials
New Rules, 2019
describes academic clinical trials as “Clinical trial of a drug already approved for a certain claim and initiated by any investigator, academic or research institution for a new indication or new route of administration or new dose or new dosage form, where the results of such a trial are intended to be used only for academic or research purposes and not for seeking approval of the Central Licensing Authority or regulatory authority of any country for marketing or commercial purpose.”
Some important points for academic clinical trials include:
- only for approved drug
- CT initiated by investigator, academic or research institute
- can be conducted for new indication, new route, new dose or dosage form
- results only for academic or research purpose and not for commercial purpose. Data cannot be used for seeking approval in any country
- EC can seek clarity from Central Licensing Authority (CLA) and CLA must respond in 30 days (or deemed that no approval is needed)
- medical management and compensation is applicable as per ICMR Guidelines for Biomedical Research on Human Participants
- academic CTs are required to be conducted in accordance with the CT protocol approved by the EC and ethical principles specified in the ICMR Guidelines for Biomedical Research on Human Participants
Academic clinical studies, whether Investigator Initiated Clinical Trials (IICT) or research conducted during post-graduation program in colleges, are the mainstay for basic research. In case of injury in Academic CT and Biomedical and Health Research (BHR), the Ethics Committee (EC) is responsible for relatedness of the Serious Adverse Events (SAE) and recommendation of appropriate compensation while it is the responsibly of the host institution to provide compensation and/or cover for compensation. However, it would be challenging for ECs to determine quantum of compensation as ICMR Guidelines do not have provision to calculate compensation. There is, thus, a strong need to develop guidelines for determining quantum of compensation.
CDSCO decided in January 2015 to introduce a system of formal presubmission meetings between applicants, CDSCO officers and subject experts to discuss a regulatory pathway for a specific application. The resulting document was published, but never implemented as this was not part of the rules and, subsequently, there were no follow up actions.
However, New Rules, 2019
has included a provision for presubmission meetings with the CLA or any other officer authorized by the CLA for seeking guidance about the requirements of laws and procedures for obtaining license or permission of manufacturing processes, clinical trials and other requirements.
The application for a presubmission meeting should be accompanied by documents referred to in the Second Schedule, as available with the applicant to support their proposal along with a fee specified in the Sixth Schedule. CLA, within a period of 30 days, will relate the facts to the applicant in writing and direct them to provide further information or documents as necessary.
As with developed countries’ regulators, these new rules also provide an opportunity to discuss regulatory pathways for product registration. This opportunity attempts to provide clarity regarding the pathway before a company starts planning its regulatory submission. This change also may help in cases where companies invest in studies which are not warranted by the authority or, in other cases, where certain studies are necessary from regulatory point-of-view, but are not conducted.
Presubmission meetings would provide written advice to companies which, previously, was based on limited discussion with a few regulatory officials.
Revising New Drug Definition
The definition of ‘new drugs’ has been revised to include following:
- phytopharmaceutical drugs
- novel drug delivery system of any drug
- living modified organisms, monoclonal anti-body, stem cell-derived products and gene therapeutic products or xenografts, intended to be used as drug
New drugs are classified into two categories. The first category would convert to an old drug after four years of its approval; the second category has always been considered ‘new drugs,’ irrespective of the period since they were first approved by the CLA. Class (i) is part of first category and Class (ii) and (iii) are part of second category. Sustained release and modified release dosage forms have been moved from the first category to the second.
For products in the second category, CTs and marketing approvals undertaken with these products would legally come under the control of CLA. Even for generic products (after four years of innovator approval) companies first need to take approval from CLA, followed by State FDA, for local manufacturing.
For sustained and modified release dosage forms, there would be additional timelines for generic product approval, as this would be first approved by CLA.
Phase IV and Postmarketing Studies (PMS)
Previously, there was ambiguity in the definition and requirements for Phase IV and PMS. New Rules, 2019
have differentiated the requirements for conducting Phase 4 CT and postmarketing surveillance studies for new drugs.
In New Rules, 2019
, Phase IV Study would include studies related to:
- drug-drug interactions
- dose-response or safety studies
- trials designed to support use under the approved indications
In such trials, the ethical aspects for protection of rights, safety and well-being of the trial subjects will be followed as per the regulatory provisions, including that for compensation in case of clinical trial-related injury or death and good clinical practices guidelines. Study drugs should be provided to the trial subject free-of-cost in such studies, unless there is a specific concern or justification for not providing the drug free-of-cost after approval from CLA and the EC.
Postmarketing Surveillance Studies
Such studies are conducted with a new drug under approved conditions of its use and with a scientific objective approved by CLA. Inclusion or exclusion of subjects are decided as per recommended use in the prescribing information or approved package insert. In such studies, the study drugs included in the protocol are a part of the patient’s treatment according to prescriber’s directions. The regulatory provisions and guidelines applicable for clinical trial of a new drug are not applicable when a drug is already approved for marketing.
|Table 1. Difference Between Phase IV and Postmarketing Studies From Regulations Perspective
|Approval required from CLA
||Approval required in case of new drug and not in case of old drug*
|Drugs to be provided
||Study drug to be provided
||Discretion of applicant
||As per study protocol design
||As per prescribing information
||INR 200,000 ($2,900)
|* Advised to check with CDSCO if truly old drug
There is an expectation that number of Phase IV studies being conducted in India will increase. This expectation is based on the assumption that with local clinical trial waiver, a Phase IV study might need to be conducted, except in special situations.
Orphan Drug Registration
New Rules, 2019
define orphan drugs as a “drug intended to treat a condition which affects not more than five lakh (500,000) persons in India.” To promote research in orphan drugs, there has been favorable provisions in New Rules, 2019
- provision for fast-track approval process and special status for orphan drugs, including a complete fee waiver for CT filing
- provision for expeditious review process. In situations where the evidence for clinical safety and efficacy have been established. Even if the drug has not completed all clinical trial phases, the sponsor or applicant may apply to the CLA for expedited review process. After accelerated approval, applicants could be required to conduct postmarketing trials for validating anticipated clinical benefits
- provision for waiver of local clinical study and Phase IV on satisfaction of CLA
In the US, the Orphan Drug Designation program provides orphan status to drugs and biologics defined as those intended for the treatment of a disease that affects fewer than 200,000 persons. Also, it provides a list of rare diseases considered as per rules in country.3
Similarly based in Indian registry data, the CDSCO office should develop similar means to list rare diseases. Such a list may be subject to review on a periodic basis as deemed appropriate by the CLA.
New Rules, 2019
defines post-trial access as “making a new drug or investigational new drug available to a trial subject after completion of clinical trial through which the said drug has been found beneficial to a trial subject during clinical trial, for such period as considered necessary by the investigator and the ethics committee.” These drugs should be free-of-charge upon approval of the ethics committee.
If the clinical trial is being conducted for an indication for which no alternate therapy is available, and the investigational new drug or new drug has been found to be beneficial to the trial subject by the investigator, the sponsor has no liability for post-trial use of an investigational new drug or new drug to which the patient commits in writing.
There are still some gaps in understanding and questions raised about issues needed to be addressed by CDSCO. These include:
- How long should post-trial access of medicine be provided to patients? This is of special importance when there is chronic disease with long term treatment.
- How are safety signals monitored for this period? Would sponsor/investigators/ethics committee have responsibility to record and report safety issues after study completion?
- Should the sponsor continue to provide drugs under post-trial access after marketing authorization approval and drug availability in market?
Considering these areas currently open for interpretation, it is recommended there should be separate guidelines for post-trial access to drugs.
Ethics Committees (ECs)
As per new rules, ECs need to include at least one female member and 50% of membership must consist of those who are not affiliated with the institution or organization in which the committee is constituted. The new rules also mandate each EC member to undergo such training and development programs as may be specified from time-to-time by CLA. Further, any change in membership or constitution of registered E, is to be reported to CLA in writing within 30 working days. ECs will have to go through reconstitution (and subsequent re-registration) to comply with new rules before taking up any new CTs for review.
ECs reviewing biomedical and health research proposals should register by using Form CT-01 with the authority designated by the Department of Health Research (and not with the CLA), within the Ministry of Health (MoH). Initially, provisional registration would be granted, with a validity of two years. Subsequently, based on scrutiny of the documents furnished, the designated authority may grant final registration using Form CT-03.
Increased Fees for Various Applications
Fees for all types of applications have been increased. Some have increased substantially. For example, the application fees for a Phase III Clinical Trials have increased to INR 200,000 from INR 25,000. While previously there were no fees for a Phase IV study, the applicant must now pay INR 200,000 for a Phase IV study. There are also some new categories for which fees have been included. For example, applicants must now pay a fee for the CLA to reconsider their application when CLA has previously rejected the proposal. Government organizations are not required to pay fees to conduct clinical trials. Similarly, for Micro Small Medium Enterprises (MSME), a 50% concession in application fees is available for conducting clinical trials, approval of new drugs, presubmission meetings and postsubmission meetings. No application fee is charged for conducting clinical trials for orphan drugs.
Although the increase of application fee in some cases is very steep, it is also true that the fee amounts had not been revised for a very long time. The increased fees will be justified if they help the government in supplementing the costs associated with expected increase in manpower, assisting the regulator in faster review of an ever-increasing number of applications and efficient oversight of clinical trial sites.
Waivers of Local Clinical Trial Data
Rule 75 provides specific conditions under which local clinical trials requirements may be waived for import of new drugs. The waiver may be instituted if: the drug is approved and marketed in certain countries specified by the licensing authority (Rule 101), a global clinical trial is ongoing in India with the drug and in the meantime such new drug has been approved in certain countries specified by the licensing authority (Rule 101) and no major unexpected serious adverse events have been reported. Additionally, waiver implementation requires there is no probability or evidence on the basis of existing knowledge of differences in the Indian population, enzymes or genes involved in the metabolism of the new drug or any factor affecting pharmacokinetics (PK) and pharmacodynamics (PD), safety and efficacy of the new drug. In this case, the applicant will have to conduct a Phase IV study as per design approved by CLA. The requirement for conducting a Phase IV study may be relaxed in such cases where the drug is indicated for life threatening or serious diseases, diseases of special relevance to Indian health scenario, conditions with an unmet need in India, rare diseases for which drugs are not available or available at a high cost or if it is an orphan drug. Data submission from animal toxicology, reproduction, teratogenic, perinatal, mutagenicity and carcinogenicity studies may be modified or relaxed in case of new drugs that have been approved and marketed for more than two years in other countries.
Rule 80 provides specific conditions under which requirements of local clinical trials may be waived for permission to manufacture new drugs (local products). The conditions are almost same as those in the case of import of new drugs, except that relaxation of data submission from animal toxicology, reproduction, teratogenic, perinatal, mutagenicity and carcinogenicity studies may be modified or relaxed in case of new drugs approved and marketed for several years in other countries.
These provisions take into account the completed review and approval of the new drug by a regulatory authority in another country. This provision can help reduce the time between the launch of a drug globally and the availability of the drug in India for patients who need them.
Import and Manufacture of Unapproved new Drug
Under the Rule 36 of Drug and Cosmetic Rules, 1945
, provision was made for patients to apply for a license to import an unapproved new drug. The applicant is required to apply using Form 12A, along with the prescription of the Registered Medical Practitioner (RMP) indicating the quantity of drug required for treating the patient. So long as the application is submitted as per required documents and on satisfaction of Licensing Authority (LA), the permission Form 12B is issued on priority basis. Now, under New Rules, 2019
, a medical officer from a government hospital also may import unapproved drugs approved for marketing in a country of origin. This provision is for patients suffering from a life-threating disease or a disease causing serious permanent disability or for an unmet medical need. There is also provision to manufacture an unapproved new drug in India, in limited quantity, one currently in clinical trials and only used to treat a patient with a life-threatening disease.
Other Significant Updates
With New Rules, 2019
there is also a provision to accelerate the approval of a new drug intended for use for diseases of special relevance to India or for filling an unmet medical need in India, especially for a disaster or special defense use. In such a situation, marketing approval could be granted based on Phase II clinical data if remarkable efficacy had been observed. In such cases, however, a Phase IV clinical trial will be mandatory to validate anticipated clinical benefits.
Conditions for generating stability data have been revised for drug substances and formulations intended to be stored under general conditions for long-term from Zone IV(a) to Zone IV(b). Stability conditions have been revised as per Zone IV(b) for long-term from 30°C ± 2° C/65% RH ± 5% RH to 30°C ± 2° C/75% RH ± 5% RH.
New clinical trial approval timelines also have been included. For the clinical trial of drugs developed outside of India, there is a 90 working-day limit for the CLA to respond. However, this timeline for review may be further reduced to 30 working-days if the drug was discovered in India or research and development of the drug are being carried out in India, and the drug is proposed to be manufactured and marketed in India. In the event no communication is received from the CLA, permission to conduct a clinical trial shall be deemed to have been granted for BA/BE studies of new drugs or investigational new drugs within 90 working days of receipt of application.
After multiple consultations with stakeholders and review processes, the draft of these rules was published in early 2018. The new rules have been revised keeping various issues in mind. The most important among those issues are those aimed at reviving the clinical research industry in India, bringing more global clinical studies to India and promoting Indian indigenous drug development.
Overall, the new rules are comprehensive, well-balanced and will likely improve the ethical and quality standards of clinical trials in the country, which also will further benefit patients and industry. Waiving local clinical trial under these rules will help provide earlier access to drugs for patients in India. The deemed approval for clinical trials in 30 working days for indigenous drugs also will speed up the clinical trial process and encourage local drug development. Provision for accelerated product approval under some conditions, along with provision of pre and postsubmission with the CDSCO office, would add predictability and confidence in the system. The shortened review timelines would clearly require additional manpower at CDSCO to ensure timely disposal of applications. The government has already planned an expansion of CDSCO strength and it is expected that additional revenue generated through increased application fees will help ensure adequate human resources are available at CDSCO.
In future steps, the CDSCO office may start working on filling some of gaps in areas of Subject Expert Committee (SEC) and post-trial access guidance document. Finally, there could be difficulty in implementing these rules and it will be interesting to watch how the CDSCO office takes on the challenging task of meeting the objectives laid out by these rules.
The opinions expressed in this commentary are those of the authors. They do not purport to reflect the opinions or views of their employer organization.
The authors would like to thank Vikas Dhiman for his comments and suggestions during finalization of this article.
- G.S.R.227(E). New Drugs and Clinical Trials Rules, 2019. Ministry of Health and Family Welfare, India. March 2019. http://www.egazette.nic.in/WriteReadData/2019/200759.pdf. Accessed 19 July 2019.
- Indian Council of Medical Research. National Ethical Guidelines for Biomedical and Health Research Involving Human Participants. New Delhi; 2017. https://icmr.nic.in/guidelines/ICMR_Ethical_Guidelines_2017.pdf. Accessed 19 July 2019.
About the Authors
Parveen Jain, RPh,
- Developing Products for Rare Diseases and Conditions. 2018. FDA website. https://www.fda.gov/industry/developing-products-rare-diseases-conditions. Accessed 19 July 2019.
is regional regulatory manager, South Asia, Reckitt Benckiser (India) Pvt Ltd. He is a regulatory affairs professional with extensive knowledge, understanding and experience in pharmaceutical, biological, OTC and Ayurvedic formulation. Jain started his professional journey with Clinigene (Biocon Group), followed by Eli Lilly. He has a proven track record of completing complex regulatory projects and gaining regulatory approvals in India and other South Asia countries. He can be contacted at email@example.com
Rahul Chauhan, RPh,
is director, regulatory affairs at Reckitt Benckiser (India) Pvt Ltd. Chauhan is a regulatory affairs and pharmacovigilance professional with extensive knowledge and experience in pharmaceuticals, biologicals, OTC, medical devices, Ayurvedic preparations, cosmetics, pesticides and consumer goods. He has led important assignments in major pharmaceuticals and FMCG companies like MSD, Eli Lilly and Reckitt Benckiser. He has strong experience across markets in Asia, team management, regulatory agency liaison, technical dossier compilation, strategy development, portfolio management, regulatory intelligence and relationship management. He can be contacted at firstname.lastname@example.org
Jain P and Chauhan R. “India’s New Drugs and Clinical Trials Rules: An Industry Perspective.” Regulatory Focus.
July 2019. Regulatory Affairs Professionals Society.