For many years, the pharmaceutical business has been abuzz with a discussion of clinical trials in India. When the Agreement on Trade-Related Aspects of Intellectual Property (TRIPS) went into effect in 2005, it was certain that India would become a centre for pharmaceuticals on a worldwide scale. Clinical trials have a bright future because of elements including a sizable medical community, IT specialists, skilled labour, and a broad patient pool, the incidence of health issues, cost-effectiveness, and loose legal restrictions. The clinical trial environment in India was completely changed with the enactment of the New Drugs and Clinical Trial Rules, 2019 (CT Rules). All parties benefit from the exact and dependable system of clinical trial rules it offers. Only 1.4% of all clinical trials worldwide are conducted in India, which has 18% of the world’s population. However, from 2022 to 2030, the Indian clinical trial market is projected to expand at an unprecedented pace of 8.2%. The pandemic has boosted the number of vaccine and drug clinical studies. Clinical trials now have a massive and growing reliance on technology, which will be crucial for the sector in the future. In this article, the author has covered the legal framework for clinical trial registration in India.
What Are Clinical Trials?
A clinical trial is a research project to create new diagnostics and therapies to evaluate how they affect people’s health. An experimental product or medicine (New drug) is used to treat human volunteers, and its effects are assessed. A medicine, vaccine, medical device, surgical or radiological technique, behavioural treatment, preventative care, cells, or biological product that has been produced with the intention of receiving marketing permission in the nation might be the subject of the study. For each new treatment, a clinical trial is specially and carefully crafted depending on the requirements of the stakeholders, patients, and physicians. The trial protocol is examined, and the trial can only start when it has been authorised.
The several phases of a clinical trial are described below:
- Phase-1: Safety
Analysing the safety of a drug’s interactions with the human body
- Dosage and Safety
- Keep an eye on the effects
- To assess the safety even more
- Assess the dose’s efficacy in a smaller population.
- Safety and Efficacy
- Phase to gauge efficiency
- Keeping an eye on safety in a greater population
- Post-marketing effectiveness and safety
- To identify more medication side effects
- Gathering data about a drug’s impact outside of restricted surroundings and on a bigger population.
Brief History of Clinical Trial Regulation in India – Clinical Trial Registry
Due to its diversified population and favourable regulatory environment, India has long been a desirable market for clinical trials. The Drugs and Cosmetics Act of 1940 (DCA), overseen by the Central Drugs Standard Control Organization (CDSCO), is the principal piece of drug control law in India and has a long history of regulating clinical research. Clinical research was initially not regulated, and only the import, production, distribution, and sale of drugs in India were covered by the DCA and the Drugs and Cosmetics Rules, 1945 (DCR). Clinical trials themselves were infrequent and did not fall within the CDSCO’s purview. The Indian Patents Act of 1970 superseded the colonial patent laws in 1970 to establish a ‘process patenting framework’ and increase local output. As a result, generic medicine manufacturing moved to India, and international pharmaceutical companies were discouraged from entering the Indian market. Then, in 1988, Schedule Y was added to the DCR to control clinical trials in India in order to encourage the expansion of a mostly generic pharmaceutical business in country. Manufacturers were obliged under Schedule Y to carry out Phase III clinical studies before registering a new medicine and applying for marketing authorisations.
In order to guarantee some level of intellectual property protection, India ratified TRIPS in 1994, creating the ‘product patent system.’ As a result, there was an inflow of pharmaceutical firms into India, and in 2005, the government modified Schedule Y after realising the promise of clinical research for novel treatments. This modification legalised the Guidelines on Good Clinical Practice in India, 2001 (CDSCO-GCP) and introduced a four-phase clinical trial design, creating a robust regulatory framework for clinical trials. The Guidelines for Biomedical and Health Research Involving Human Participants, 2000, were developed concurrently by India’s top regulatory organisation for biomedical research, the Indian Council for Medical Research (ICMR), and were later revised in 2006. These formed the basis of India’s clinical trial regulatory system, together with Schedule Y of the DCR.
Clinical trials now operate in an environment that is supportive of business. The participants in clinical trials received only a minimum amount of protection due to the inadequate ethical review processes and the absence of a compensation mechanism. The Supreme Court of India8 was then confronted with complaints about insufficient patient safety and compensation measures. Clinical trials were thereby temporarily prohibited in India.
Following that, CDSCO issued a number of instructions incorporating safety and payment procedures to be adhered to throughout the clinical study process. An onerous three-tiered clinical trial approval process was implemented, which reduced the number of new entrants into the market. The Parliamentary Standing Committee on Health and Family Welfare then noted shortcomings in the oversight of clinical trials in its report. There was also agreement that all administrative, procedural, and reporting requirements needed to be combined into a single rule for simplicity of compliance. In order to overcome these issues and simplify the regulation of clinical trials in India, the CT Rules were passed.
The clinical trials framework established by the DCR and the following instructions given by the CDSCO were superseded and consolidated by the CT Rules. It regulates all facets of clinical trials in India, such as protocols, authorisations, payments, and waivers. The CT Rules provide explicit guidelines for the organisation, registration, and operation of ethical committees, as well as for the conduct of clinical trials, the payment of compensation, and the medical management process.
The CT Rules, CDSCO-GCP now frame the clinical trial and clinical research laws in India, and ICMR Guidelines for Biomedical and Health Research Involving Human Participants, 2017 (ICMR Guidelines).
The National Regulatory Authority in India is the Central Drugs Standard Control Organization (CDSCO). It is the division of the Indian government’s Ministry of Health and Family Welfare. Its goal is to protect and improve public health by guaranteeing the efficacy, safety, and quality of medications, cosmetics, and medical equipment. The European Medicines Agency, Health Canada, and the US Food and Drug Administration (US FDA) are some of its international equivalents.
The final regulatory body for the nation’s clearance of clinical trials is the Drugs Controller General of India (DCGI), a representative of the CDSCO. The scope also includes overseeing the Central Drugs Testing Laboratory (Mumbai) and the Regional Drugs Testing Laboratory, as well as leading the Indian Pharmacopeia Commission, among other roles, responsibilities, and duties. He also inspects trial sites, sponsors of clinical research, and manufacturing facilities in the nation.
What Is The Regulatory Path Way?
- New Drug: Application must be made in accordance with CT-06.
- Old Drug: CDSCO’s permission is not necessary. Only EC consent is needed. It has to be approved.
- Phyto Pharmaceuticals: Should be done in accordance with the regulations & standards established with new medications.
- Academic Clinical Study: CDSCO’s permission is not necessary. Only EC consent is needed. It has to be approved.
Additional authorizations and permits are available under CT Rules, and they are as follows:
|License for or Registration Certificate||Form for Application||Form for Grant||Relevant Rule||Validity of License (from date of application)|
|Ethics Committee for Clinical Trial||Form CT-01||Form CT-02||CT Rule 8||5 years|
|Permission to conduct clinical trial of a new drug or investigational new drug||Form CT-04||Form CT-06||CT Rule 21, CT Rule 22||2 years|
|Permission to conduct clinical trial of a new drug or investigational new drug as part of discovery, research and manufacture in India (Deemed approval)||Form CT 4A||Form CT 4A||CT Rule 23||2 years|
|Permission for conducting BA/BE studies||Form CT 05||Form CT 07||CT Rule 33, CT Rule 34||1 year (subject to extension)|
|Permission to manufacture new drug or investigational new drug for clinical trial or BA/BE study or for examination, test and analysis||Form CT 10||Form CT 11||CT Rule 52, CT Rule 53||3 years|
|Permission to manufacture unapproved active pharmaceutical ingredient for development of formulation for test or analysis or clinical trial or BA/BE study||By Manufacturer of formulation in Form CT 12 & By manufacturer of API in Form CT 13||To Manufacturer of formulation in Form CT 14 & To Manufacturer of formulation in Form CT 15||CT Rule 59, CT Rule 60||3 years|
|Import of new drug or IND for clinical trial or BA/BE study||Form CT 16||Form CT 17||CT Rule 67, CT Rule 68||3 years|
|Import of new drug for sale or distribution||Form CT 18||Permission to import API in Form CT 19 Permission to import pharmaceutical formulation in Form CT 20||CT Rule 75, CT Rule 76|
|Manufacture of new drug for sale or distribution||Form CT 21||Manufacture of API in Form CT 22 Manufacture of pharmaceutical formulation in Form CT 23||CT Rule 80, CT Rule 81|
|Import of unapproved new drug by Government hospital and medical institution||Form CT 24||Form CT 25||CT Rule 86, CT Rule 87|
|Manufacture of unapproved new drug under clinical trial, for treatment of patient with life threatening disease||Form CT 26||Form CT 27||CT Rule 91, CT Rule 92||1 year|
Data Safety Monitoring Board
While a clinical study is in progress, this impartial team of specialists keeps an eye on the participant safety and treatment efficacy data. Top priority of the board is the safety of the patient. The DSMB would advise stopping the trial if significant adverse events were to occur more often in the experimental arm than in the control arm. The risk against benefit ratio must be taken into account while making this assessment. In many instances, the experimental therapy might result in negative side effects while undergoing treatment, such as chemotherapy for some terminal cancers.
2019 New Drugs and Clinical Trials Rules: Major Changes
Following are some of the major changes made by the New Drugs and Clinical Trials Rules of 2019:
Academic Clinical Trials
Academic clinical trials are defined by the New Rules, 2019 as clinical trials of a drug already approved for a certain claim initiated by any investigator, academic or research institution for a new indication, new route of administration, 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.
The following are some key considerations for academic clinical trials:
- Only for authorised medications
- CT started by a researcher, academic institution, or research centre
- Can be done for a novel indication, a novel route, a novel dose, or a novel dosage form.
- Results should only be used for academic or research purposes; not for profit. In no nation may data be used to request approval.
- The Central Licensing Authority (CLA) must answer to EC’s request for clarification within 30 days (or deemed that no approval is needed)
- In accordance with the ICMR Guidelines for Biomedical Research on Human Participants, medical management and compensation are appropriate.
- The EC-approved CT protocol and the ethical standards outlined in the ICMR Guidelines for Biomedical Research on Human Participants must be followed while conducting academic CTs.
The mainstay of basic research is academic clinical investigations, including Investigator Initiated Clinical Trials (IICT) and research done during post-graduate programmes in colleges. While it is the responsibility of the host institution to provide compensation and/or cover for compensation in cases of injury in Academic CT and Biomedical and Health Research (BHR), the Ethics Committee (EC) is responsible for the relatedness of Serious Adverse Events (SAE) and recommendation of appropriate compensation. However, as the ICMR Guidelines do not include a provision for compensation calculation, it would be difficult for ECs to establish the amount of compensation. Therefore, there is a critical necessity to create standards for calculating the amount of compensation.
In order to explore a regulatory pathway for a particular application, CDSCO decided in January 2015 to implement a system of formal pre-submission meetings with applicants, CDSCO officers, and subject experts. The final paper was published, but it was never put into practise because this was against the regulations, and there were no following actions.
The New Rules, 2019 do, however, include a clause allowing for pre-submission meetings with the CLA or any other officer designated by the CLA to get advice on the legal requirements and processes for obtaining licences or permissions for manufacturing processes, clinical trials, and other requirements. The Second Schedule papers, if any are available with the applicant to support their proposal, should be submitted with the application for a pre-submission meeting, together with the fee listed in the Sixth Schedule. Within 30 days, CLA will communicate the facts to the applicant in writing and instruct them to supply any further information or documentation that may be required.
These new regulations offer a chance to talk about regulatory channels for product registration, much like with authorities in industrialised nations. Before a company begins to prepare its regulatory filing, this opportunity aims to clarify the roadmap. This modification may also be beneficial in situations when enterprises spend funds on studies that are not supported by the relevant authorities or in situations where certain studies are required from a regulatory standpoint but are not carried out.
Pre-submission meetings would give corporations with written guidance that, up until then, was based solely on conversations with a small number of regulatory officials.
Revising New Drug Definition
The following has been added to the definition of ‘new drugs’:
- Plant-based pharmaceuticals
- Novel medication delivery method for any substance
- Xenografts, monoclonal antibodies, stem cell-derived products, gene therapeutics, and living modified organisms are all intended for use as drugs.
Phase IV and Post-marketing Studies (PMS)
The definition and specifications for Phase IV and PMS were unclear in the past. The conditions for completing Phase 4 CT and post-marketing monitoring studies for new drugs have been differentiated under the New Rules of 2019.
The 2019 New Rules Phase IV Study will cover research on:
- Medication interactions
- Research on safety or dose-response
- Experiments made to support usage for the permitted indications
Post-marketing surveillance studies
These research projects employ a novel drug under authorised usage guidelines and with a CLA-approved scientific goal. The prescription information or authorised package insert’s recommended usage determines whether subjects are included or excluded. In these trials, the patient receives the study medicines as prescribed by the doctor as part of their treatment. The regulatory requirements and criteria that apply to a clinical study of a new medicine do not apply to drugs that have already received marketing approval.
Ethics Committees (ECs)
According to the new regulations, ECs must include at least one female member and 50% of its membership must be made up of people who are not connected to the institution or group that formed the committee. Furthermore, each EC member must complete any training and development programmes that CLA may occasionally specify under the new guidelines. Additionally, any modification to the membership or organisational structure of a registered E must be disclosed in writing to CLA within 30 working days. Before accepting any new CTs for review, ECs must undergo reconstitution (and subsequently re-registration) to conform to the new regulations.
Waivers of Local Clinical Trial Data
For the import of novel pharmaceuticals, Rule 75 specifies the circumstances under which the obligation for local clinical trials may be waived. The waiver may be implemented if the following conditions are met: the drug is approved and marketed in certain countries specified by the licencing authority (Rule 101), a global clinical trial is currently being conducted in India with the drug, and in the interim, and such new drug has been approved in certain countries specified by the licencing authority (Rule 101). Additionally, the waiver’s implementation mandates that there be no likelihood or evidence based on current knowledge of variations in the Indian population, enzymes or genes involved in the new drug’s metabolism, or any other factor affecting the pharmacokinetics (PK) and pharmacodynamics (PD), safety, and efficacy of the new drug. In this situation, the applicant will have to carry out Phase IV research in accordance with the plan certified by CLA. In situations where the drug is indicated for life-threatening or serious illnesses, illnesses with particular relevance to the Indian healthcare system, illnesses with unmet needs in India, rare illnesses for which there are no or very expensive treatments, orphan drug designations, the requirement for conducting a Phase IV study may be waived. In the case of novel pharmaceuticals that have been licenced and marketed for more than two years in other countries, data submission from animal toxicity, reproductive, teratogenic, perinatal, mutagenicity, and carcinogenicity studies may be adjusted or eased.
In accordance with the circumstances outlined in Rule 80, authorisation to manufacture novel medications may be granted without conducting local clinical trials (local products). The requirements are nearly identical to those for new drug imports, with the exception that data submission from animal toxicology, reproduction, teratogenic, perinatal, mutagenic, and carcinogenicity studies may be modified or relaxed in cases where new drugs have been approved and have been on the market for a number of years in other countries.
These clauses take into consideration the fact that a regulatory body in another nation has already reviewed and approved the new medicine. This clause may shorten the period of time between a drug’s global introduction and its eventual availability to patients in India.
Other significant updates
A clause in the New Rules of 2019 allows for the expedited licencing of new drugs that are designed to treat conditions of particular significance to India or to address a medical need there, particularly in the event of a disaster or for specific defence purposes. If exceptional effectiveness had been noted in this case, marketing authorisation may be given based on Phase II clinical evidence. However, under these circumstances, a Phase IV clinical study will be required to confirm any predicted therapeutic advantages.
For drug compounds and formulations intended to be held under general circumstances for a long time, conditions for obtaining stability data have been updated from Zone IV (a) to Zone IV (b). The long-term stability conditions have been changed from 30°C 2° C/65% RH 5% RH to 30°C 2° C/75% RH 5% RH as per Zone IV(b).
Timelines for new clinical study approvals have also been included. The CLA has 90 working days to react about clinical trials for medications created outside of India. However, if the medicine was discovered in India, is currently undergoing research and development there, and is planned to be produced and marketed there, the review period may be further shortened to 30 working days. For BA/BE studies of new medications or investigational new pharmaceuticals within 90 working days of application receipt, authorization to conduct a clinical trial should be presumed to have been granted if no notification is received from the CLA.
For improved functionality and monitoring, this timeline has been altered in accordance with the new CT regulations. In the absence of a revised notification from CLA, authorization to conduct a clinical study for a novel or investigational medicine within 90 days of the application’s receipt shall be presumed to have been granted.
What Is Clinical Trial Registry
Clinical trials have a great deal of potential to help patients, enhance therapy regimens, and guarantee the development of evidence-based medical practise. To restore public confidence in clinical trial data, all clinical studies must be registered in a single, centralised clinical trials registry. This will guarantee openness, accountability, and accessibility.
Presently, any researcher who is planning to conduct a clinical trial involving human of any intervention for example, drugs, surgical procedures, preventive measures, lifestyle modifications or the trials being conducted under the Department of AYUSH are required to register the clinical trial in the CTRI (Clinical trial registry – India) before enrolment of the first participant. Before the first patient is enrolled for the clinical trial, the trial’s investigators, sponsors, interventions, patient population, etc. must be publicly declared and identified.
CTRI- A Brief History
The Central Licensing Authority also called as CLA made clinical trial registration in the CTRI mandatory as of June 15, 2009. The CTRI was first introduced on July 20, 2007, initially as a voluntary measure. The CTRI’s goal is to make it possible for all clinical trials carried out in India to be prospectively registered before the first participant is enrolled. Bioavailability/bioequivalence studies and post-marketing monitoring studies must also be reported in the CTRI. The Department of Science and Technology (DST), ICMR, and WHO all come together to fund CTRI.
What Is The Process Of Registering A Clinical Trial?
If you wish to register a clinical trial, you must follow the steps mentioned below:
- Register yourself on the CTRI website and create your profile. Once this is done then you can move forward with the registration of the trial.
- New clinical trial is then added using the CTRI registration data set (information regarding the data set has been discussed below.)
- The above data set is then submitted to CTRI.
- After receiving all the information CTRI will give a reference number of the clinical trial.
- CTRI will verify the data set and trial form PI
- Once the CTRI is satisfied from the information, it will provide a unique registration number. This number has to be used while submitting your study in any journal.
Information Required For Clinical Trial Registration
The CTRI data set which needs to be submitted during the process of registering is mentioned below:
- Study title in simple language
- Scientific title of the study (Acronym, if any)
- Secondary ID which includes any Protocol Number or any other Trial Registry Number, registered in a registry other than the CTRI.
- Details of the Principal Investigator which includes heir name, official address, affiliation and designation, contact details and email ID.
- Details of the person for scientific query and person for public query
- List of sources for the monetary support as well as material support
- Details of primary and secondary sponsor(s)
- Details of site(s) of study
- Name of Ethics Committee and approval status
- Regulatory clearance obtained from CLA
- Details regarding the inclusion and exclusion criteria for participant selection, including age and sex
- Target sample size
- Details regarding the Phases of trial
- Date of first enrolment
- Estimated duration of trial
- Recruitment status of trial
Benefits of Clinical Trials Registration
- Enhance openness and accountability: The public’s trust in clinical trials is likely to be increased by revealing all necessary information on the protocol of studies.
- Increasing the trials’ internal validity: During the restoration of the experiment, it will be necessary to disclose the mechanism used to generate the random sequences, hide participant allocation to treatments adequately, blind participants, investigators, and outcome assessors adequately, and include the outcomes of all participants. These trial procedures are especially crucial for producing accurate results by reducing biases, confounders, and the impact of chance or coincidence. Such inclusions at the protocol stage are likely to improve the trial’s internal validity and raise the likelihood that it will be published in a high impact journal.
- Adhere to moral norms that are widely accepted:
- It will assist in providing ethical review boards with a glimpse of comparable work and data pertinent to the study they are evaluating when deciding whether to approve new trials.
- All clinical studies must have approval from their local ethics committees in order to be registered.
- Accurate reporting of all pertinent findings from registered trials: All results from registered trials shall be properly documented and made available to the public.
- Registration of clinical trials will stop selective publishing and selective reporting of results.
- It will stop pointless study effort duplication.
- It may be simpler to spot gaps in clinical studies by describing ongoing clinical trials and research
- Recruitment may be facilitated by informing researchers and potential participants about recruitment trials.
- Collaboration between researchers might be improved by giving practitioners and researchers the ability to discover studies in which they might be interested. Future meta-analysis may be a part of the partnership. Patients and the general public will benefit from knowing which studies are upcoming or currently underway and could be of interest to them.
- For publishing consideration: Editors of 11 prominent biomedical journals in India and publications that are members of the International Committee for Medical Journal Editors (ICMJE) now need registration in a public trials register as a condition for publication. Trials must register at the start of patient enrolment or earlier.
Why There Is Controversy Regarding Clinical Trial In India?
The current quarrel about carrying out clinical studies in India has escalated into a significant problem. The whole clinical trials industry has been damaged by a number of newspaper exposes and public debates on television. Public interest litigations filed in court by several NGOs have generated a lot of controversy and discussion. Unfortunately, a lot of these people and organisations are inciting strong feelings by emphasising only the negative aspects, such as how several terminally ill patients perished during a research study. People who take part in clinical studies are already unwell, some of them in extremely terrible conditions, according to the Indian Society for Clinical Research (ISCR). Thus, the medicine may not have been the cause of their demise. Even if they were terminally sick, the medicine might not have worked as it was anticipated.
It is significant to emphasise that many trials in India are Phase-III trials, which are international studies with a strict uniform methodology for medicines that have previously undergone extensive testing. Patient risks are therefore negligible. In any event, it is difficult to know if and how a medicine works without conducting a study. The results of trials can also be influenced by ethnic features, genetic makeup, and biochemical differences.
Trials are often carried out with the utmost transparency and with the full agreement of participants and their families, disclosing both possible benefits and hazards. There could be a few clinical trialists who act unethically, like in any sector, and they need to be dealt with harshly. However, this does not imply that the clinical trial business as a whole is questionable. Patients are frequently described as being handled like “guinea pigs.” It is evident that these accusations are unfounded in the vast majority of instances after reading the previous description of the informed consent procedure and the safety of trial participants. Not all clinical trialists are evil only because a few dishonest individuals use patients for their own selfish purposes and fraudulent techniques.
It is a fact that inaccurate media coverage might impede clinical advancement in India. We need to take a sensible approach to clinical trials; we need to recognise their importance to patients, understand how they are conducted, and handle problems logically rather than calling for their complete halt.
To guarantee that clinical trials are carried out with the highest openness and care, we need to close any gaps in the legislation and apply it strictly rather than rejecting all clinical studies as evil. Clinical trials will move to other poor nations if India restricts them. The only outcome would be that we would have no reliable data on our Indian patients. India declined to join in the Human Genome Project, and as a result, Indian data are tragically lacking from the project today.
India has become a key location for clinical trials worldwide, and there are enough regulatory safeguards in place to guarantee participant safety. India will continue to gain from clinical trials if regulatory requirements are followed properly, and relevant people are given enough GCP training. Clinical trials are the most reliable method of evaluating a new drug, which is why they must be conducted. When there are so many current medications accessible, we might wonder why clinical trials are necessary. The answer is to provide patients access to better medications in the future. The participants in clinical trials gain a variety of benefits in addition to helping science advance.