Clinical trials are an important element of the medication development process all over the world. Clinical trials are a series of procedures that must be followed in order to certify a new medication molecule as safe and effective for use on the market. Medical research is a positive thing in general, and it is extremely important to cure a variety of chronic conditions.

In India, there are 40 million asthmatic patients, 34 million diabetic patients, 8-10 million HIV patients, 8 million epileptic patients, 3 million cancer patients, more than 2 million cardiac-related deaths, 1.5 million Alzheimer's patients; 15% of the population is hypertensive, and 1% has schizophrenia. 1 Human research is both required and desired in order to provide the best therapy for the diseases listed above.

"Any research study that prospectively assigns human participants or groups of individuals to one or more health-related treatments to evaluate the impact on health outcomes2," according to the definition of a clinical trial. Drugs, as well as cells and other biological products, surgical operations, radiologic procedures, gadgets, behavioural therapies, process-of-care improvements, and preventative care, are all examples of interventions.

In India, a set of guidelines3 for the ethical conduct of research has already been established to protect the interests of patients or volunteers participating in the study. The globalisation of international clinical trials raises new ethical concerns about the conduct of human clinical trials and research on marginalised or oppressed communities. Even after decades of discussion, experience, and regulation, research subjects have remained problematic.

This study intends to cover international and national laws on clinical trials, clinical research ethics, and current clinical trial problems, before concluding with a discussion on the need for higher standards and legislation for future medical research on human subjects.

India is being investigated in clinical studies throughout the world. Clinical research is not, however, being introduced to India by the West. Charaka Samhita (a textbook of medicine) and Sushruta Samhita (a textbook of surgery), both compiled as early as 200 B.C. and 200 A.D., respectively, demonstrate India's long-standing expertise in medical study. Since then, however, a lot has changed in the clinical research landscape4.

Clinical trials are now done in a controlled manner, following rules established by the International Conference on Harmonization (ICH), which is led by the United States of America, Europe, and Japan. Clinical research in India is governed by a variety of laws.

Indian Acts/Orders related to Clinical Trials is:

• Drugs and Cosmetics Act - 1940
• Medical Council of India Act - 1956,
• Central Council for Indian Medicine Act - 1970
• Guidelines for Exchange of Biological Material
• Right to Information Act - 2005,
• The Biomedical Research on Human Subjects (regulation, control and safeguards) Bill - 2005

Despite the fact that there are several laws governing clinical trials, the most significant is The Indian Council of Medical Research (ICMR) - 1947 (as revised in 2002), which was established to build a research culture in India, enhance and grow infrastructure, and foster community support. All clinical trials in India must follow the ICMR standards of 2000, according to the Drugs and Cosmetics Act, The Medical Council of India (MCI) Act.

The ICMR, like other government organisations, has a review system for its own institutions. The MCI Act applies to all doctors. Any doctor who makes a mistake in court or in practise can be punished, and the hospital can be shut down.

The MCI Act is quite powerful, and the MCI has the authority to take disciplinary action. The Drugs Controller General of India (DCGI) is in charge of clinical trial regulatory clearances in India. External specialists and other government entities provide recommendations to the DCGI's office. For the shipment of blood samples to foreign central labs, additional clearances are necessary. 5 A Central Ethics Committee on Human Research is part of the ICMR (CECHR).

This committee oversees the Institutional Ethics Committee's operations (IEC). The IEC must be composed according to the ICMR principles, according to the recently updated Schedule Y of the Drugs and Cosmetic Rules. The DCGI's office has been providing training sessions for members of Ethics Committees around the country in partnership with WHO ICMR and many dedicated research experts.

Clinical Trial Registration in India

To guarantee that clinical data and reports are accessible to all, the Indian Council of Medical Research (ICMR) has established an online clinical registry for the registration of any interventional study to meet the following goals:

• Transparency and accountability of clinical research
• Internal validity of clinical trials
• To oversee the ethical conduct of clinical trials
• Reporting of results of clinical trials

The Clinical Trial Registry of India (CTRI) is the country's online database for prospective clinical studies. The Indian Council of Medical Research's National Institute of Medical Statistics (NIMS) spearheaded this programme, which is backed by the Department of Science and Technology (DST) and the World Health Organization (WHO).

Following their registration, CTRI will establish a database of prospective clinical studies in India. After formal registration on their website, the public and professionals will have access to the data and reports of these clinical studies, as well as their current state. 9 Clinical trial registration is now optional rather than mandated. With greater knowledge of this programme and widespread acceptance of the objective of CT registration, it's possible that it may become necessary for clinical trial commencement in India in the future.

It has been agreed that CT registration should take place prior to the trial's actual recruitment of study participants. CT registration should be shared between the lead investigator and the sponsor. The primary investigator or sponsor should guarantee that the CT is recorded in multi-centric trials. The International Clinical Trial Registration Platform (ICTRP) of the World Health Organization requires that a CT be registered by declaring 20 things related to the CT (ICRTP-WHO).

Additional things relevant to the EC or IRB's clearance, as well as the consent of the Director Controller General of India (DCGI), are required for registration with the CTRI. Each CT is given a unique WHO identifying number called the Unique Trial Reference Number at the conclusion of a successful registration (UTRN).

Research In Emergency Situations

Santa Biotech, a pharmaceutical business, conducted a bioequivalence research in 2003-2004, pitting their version of the "clot-buster" streptokinase against the standard. Streptokinase is administered to stroke victims as an emergency life-saving medication. While there have been some debates over whether the firm had the proper authorization to conduct the study, the main concern is whether the patients would have given their consent to participate in the experiment.

Following that, Dharmesh Vasava was one of a group of daily wage employees who received a psychiatric medicine as part of a Sun Pharmaceuticals-sponsored bioequivalence trial in 2002. He died as a result of pneumonia. The death was investigated by the People's Union of Civil Liberties in Vadodara.

The subjects were unlikely to have given their voluntarily informed agreement to participate, according to PUCL. Second, was their health assessed before they started the experiment and was it constantly followed during it? Drug exporters, incidentally, do bioequivalence tests to demonstrate that their product is as effective as the licenced branded version. The Indian regulatory authorities do not require them.

Companies undertake clinical trials based on informed consent in certain circumstances. All of this is taking place in these days of advanced media and communication. Consider the conditions in rural regions, where people go to great lengths to obtain adequate food and shelter. A number of international corporations are taking advantage of these circumstances to further their commercial objectives. The ICMR is now in charge of policing unlawful clinical studies in India.

Background
Medical experimentation using humans as subjects is as old as the science of medicine itself. However, until the post World War II Nuremberg trials of Nazi physicians accused of conducting unethical research, there was no widespread public awareness of legal problems posed by medical research with human subjects. The Nuremberg Code, articulated in the court opinion that resulted from those trials, was subsequently adopted by the United Nations General Assembly. The code placed primary importance on the concept of individual consent.

In the United States during the 1960's, well publicized reports of research projects involving abuses of the rights of human subjects generated great concern. One of the most infamous examples of disregard for human subjects was the Tuskegee syphilis experiment, conducted from 1932 to 1972 by the United States Public Health Service. In Macon County, Alabama, 400 black men suffering from syphilis were deliberately deprived of treatment in order to enable researchers to study the effects of allowing the disease to take its natural course. Even though penicillin, discovered in 1929, had been found to be an effective treatment for syphilis, the drug was purposely withheld and at least 28 and perhaps as many as 107 men died as a direct result of the disease.

Another notorious case of human experimentation was the Willowbrook study in which live hepatitis virus was injected into institutionalized retarded children in an effort to develop a vaccine. The researchers justified their study by noting that hepatitis was rampant throughout the institution and that a new resident would probably contract the disease shortly after admission. Despite extensive publicity in medical literature, the study continued until the early 1970's, even after a treatment for hepatitis was discovered.

In the Jewish Chronic Disease Hospital experiment, researchers injected twenty-two elderly debilitated patients with live cancer cells without obtaining their voluntary informed consents. The Attorney General of New York brought an action before the state's Board of Regent's Discipline Committee, which found the principal investigators guilty of fraud, deceit, and unprofessional conduct. The doctors were punished not for performing experiments that resulted in harm to the patients, but for failing to obtain informed consent before proceeding.

Two ancient scripts, Charaka Samhita (a textbook of medicine) and Sushruta Samhita (a textbook of surgery), compiled as early as 200 B.C. and 200 A. D. respectively, show India's age-old proficiency in medical research. However, a lot has changed in the clinical research scenario since then4. Today, clinical trials are conducted through a regulated approach following certain guidelines laid down by the International Conference on Harmonization (ICH), which is spearheaded by U.S.A., Europe and Japan. There are number of laws governing clinical research in India.[3]

Charaka Samhita (a textbook of medicine) and Sushruta Samhita (a textbook of surgery), both compiled as early as 200 B.C. and 200 A.D., respectively, demonstrate India's long-standing expertise in medical study. In India, the most common environment for clinical trials is poverty and the absence of substantial social insurance. For more than a decade, the government has worked to reduce open assistance to human services administrations, which are already under-resourced.

Wellbeing industry specialists have pointed out that the government accounts for 15% of the Rs 1,500 billion spent on wellness in India. Four out of every penny comes from social security, and one out of every penny comes from private insurance companies. People who use private administrations and do not have protection spend the remaining 80 cents for each penny. Sixty-six percent of social insurance beneficiaries are responsible for every penny of their medical expenses.

Seventy percent of the people who need human services are impoverished. The majority of the poorest 20 per cent of Indians sold or borrowed money to pay for medical treatment. Patients in both government and commercial medical facilities are on the lookout for higher-quality, more moderate care. Patients choose open healing facilities because they cannot afford private clinic therapy; yet, even here, they must pay for a few drugs, tests, and procedures, which is a burden that many cannot endure. The vast majority of Indians must pay for medical treatment with their own money.

Patients at private healing facilities are more willing to pay for therapy, but catastrophic medical expenditures might force them to cut corners, go into debt, or halt fundamental care. According to many studies, the expense of medical care is a major factor that keeps many Indians on the verge of starvation. In this context, the government's support for clinical trials in India must be viewed with caution.

The legislation has been changed to allow trials to take place anywhere in the globe. Staff and foundation advancements, as well as administrative modifications, are all aimed at speeding up the processing of usage. Clinical trial sites are being promoted as open healing facilities. Checking frameworks are being developed to ensure good data quality and to fulfil the requirements of medicine administration experts across the world.

Clinical trial preparation groups are being asked to devote human energy to the process. The administration has not explained how the clinical research business in India is progressing. Clinical trials are led by contract research organisations (CROs), who are laying the groundwork for trials by expanding into residential neighbourhoods, identifying trial locations in small private doctor's offices, and compiling databases of possible trial participants. Restorative professionals are offered considerable incentives to choose their own patients for research studies.

This condition creates a significant irreconcilable issue that jeopardises patient well-being. India is regarded as a preferred location for universal clinical testing of pharmaceuticals throughout the world. According to the Drugs Controller General of India (DCGI), India will be a preferred site for clinical trials because it has a "substantial, diverse, and treatment-guileless [untreated] populace with six out of the seven hereditary assortments of mankind"; a pool of patients with both severe and endless illnesses, an increase in the number of patients with lifestyle issues, and a "substantial, diverse, and treatment-guileless [untreated] populace with six out of the seven The Indian government has embraced this opportunity and is working to improve the administrative climate in the country to accommodate the needs of international clinical trials.[4]

The Doctrine of Informed Consent

Informed consent means the "knowing" consent of a person or his legally authorized representative. An individual cannot consent to participate as an experimental subject unless he first understands for what he is volunteering. Informed consent has been found not to exist where the individual did not understand the words' or the language used.

Therefore, where language, educational or cultural differences exist between the researcher and the subject, the researcher should exercise precautions to ensure that the subject understands the proposed procedure. A subject's signature on a consent form does not necessarily constitute informed consent.

Informed consent consists of a dialogue between the prospective experimental subject, or his representative, and the researcher. The prospective subject gives the researcher information about himself which may be crucial to the experiment, and the researcher informs the prospective subject of basic details concerning the treatment so that the subject may decide whether or not to participate." This exchange of information serves as a check against unnecessary or inappropriate procedures from the perspectives of both the subject and the researcher.

The subject is better able to discern whether the proposed procedure is in his best interests and the researcher, by providing substantiated information about known and unknown risks of the experiment, may benefit by reevaluating his own notions of the procedure's efficacy. " Additionally, a well-informed patient knows more about his own condition and may feel freer to communicate such information.

The doctrine of informed consent was developed to protect the right of every individual to participate in decisions about his own medical care. To deprive an individual of the power to accept or refuse medical treatment that may affect his physical or psychological well being is to treat that individual as an object and not as a person. The concepts of autonomy and individuality are longstanding central values in Anglo-American society and law.

In addition, there is evidence that a patient benefits both physically and psychologically by receiving information about a proposed treatment. Although the medical profession traditionally has not recognized patient autonomy, even physicians are beginning to acquiese to patient demands for control and information.

Experimental cancer drug tested without people's consent

In November 1999, 25 people with oral cancer who went to the government-run Regional Cancer Centre in Thiruvananthapuram were given an experimental drug, the chemical tetra-O-methyl nor-dihydro-guaiaretic acid (M4N) or tetraglycinyl nor-dihydro-guaiaretic acid (G4N), though there was an established treatment for their condition.

They were not told that they were taking part in an experiment or that they were being denied an established treatment26. Only later did it become known that the trial had not been approved by the Drugs Controller of India (approval was obtained retroactively). Further, the sponsor institution, the Johns Hopkins University in the United States, had not given ethical clearance to the study, but managed to release the money for research anyway.

Diabetes drug tested on humans before toxicology studies completed.

In 2002, the multinational company Novo Nordisk conducted multi-centre phase III clinical trials of a diabetes drug before receiving the results of animal studies. The study report found that the drug, ragaglitazar, caused urinary bladder tumors in rats -- and this should have been known before the drug went for phase I trials, let alone phase II and phase III. Ragaglitazar was developed by Dr Reddy's Laboratories, Hyderabad, and licensed to Novo Nordisk which conducted the trials.

The trials were conducted on 650 people from North America, 200 from Latin America, 100 from Australia / New Zealand, 800 from the European Union, and 200 from non EU Europe- -and 550 from Asia -- including 130 people from eight centers in India. Half of these people received the experimental drug.

The adequacy of consent to a pure experiment or to experimental treatment raises more issues than consent to an established therapy simply because less is known about the risks involved in an experimental procedure. Although there exists no absolute guarantee that even an established treatment will be effective and will not cause harm, the risks are significantly increased when the proposed therapy is experimental. Therefore, a prospective subject must be made aware that little is known about the possible risks and consequences of participation in any aspect of human experimentation.

Clinical Trial Registration in India

In order to make clinical data and reports available to all, an online clinical registry has been initiated by the Indian Council of Medical Research (ICMR) for the registration of any interventional trial to ensure the following goals:

• Transparency and accountability of clinical research
• Internal validity of clinical trials
• To oversee the ethical conduct of clinical trials
• Reporting of results of clinical trials

The clinical trial registry of India (CTRI) is the online registry of prospective clinical trials in India. This is the initiative started by the National Institute of Medical Statistics (NIMS) of the Indian Council of Medical Research and is supported by the Department of Science and Technology (DST) and the World Health Organization (WHO).

CTRI will create a database of prospective clinical trials in India after their registration. The data and reports of these clinical trials and their status will be available to the public and professionals free of cost after formal registration on their website.9Currently, the registration of clinical trials is only voluntary and not mandatory. With increased awareness about this initiative and wide acceptance of the purpose of CT registration, it is likely that it may become mandatory in the future for initiation of clinical trials in India.

It has been affirmed that CT registration should be done before the actual enrollment of study subjects in the trial. The principal investigator or sponsor should share the responsibility of CT registration. In the case of multi-centric studies, the lead investigator or sponsor should ensure that the CT is registered. For the registration of a CT, it is essential to declare 20 items relevant to the CT as determined by the International Clinical Trial Registration Platform (ICTRP) of the World Health Organization (ICRTP-WHO).

For registration with the CTRI, additional items related to the EC or IRB's permission and that of Director Controller General of India (DCGI) are included. At the end of a successful registration, each CT is assigned a unique WHO identification number called the Unique Trial Reference Number (UTRN).

Regulations Pertaining To Clinical Trial

There are number of laws governing clinical research in India. Indian Acts/Orders related to Clinical Trials is:

• Drugs and Cosmetics Act - 1940
• Medical Council of India Act - 1956, (amended in the year 2002)
• Central Council for Indian Medicine Act - 1970
• Guidelines for Exchange of Biological Material (MOH order, 1997)
• Right to Information Act - 2005
• The Biomedical Research on Human Subjects (regulation, control and safeguards) Bill - 2005

The Biomedical Research on Human Subjects (regulation, control and safeguards) Bill - 2005

Whatever the case may be, a lot has happened in the clinical research landscape since then. Clinical trials are now conducted in a regulated manner, according to regulations established by the International Conference on Harmonization (ICH), which is led by the United States of America, Europe, and Japan. Clinical research is governed by a number of regulations in India.

Despite the fact that we have a number of statutes, the most important one for clinical trials is The Indian Council of Medical Research (ICMR) - 1947 (as amended in 2002), which was established with the goal of encouraging an exploration culture in India, improving and creating foundation, and cultivating group support. The Drugs and Cosmetics Act, also known as the Medical Council of India (MCI) Act, stipulates that any clinical study conducted in India must follow the ICMR standards of 2000.

The ICMR, like other government institutions, has an auditing tool for its own operations. The MCI Act appoints a representative for each expert. Any specialist who makes a mistake in a trial or in practise can be charged, and the doctor's practise can be closed. The MCI Act is quite strong, and the MCI has the authority to take corrective action.

Administrative approvals of clinical trials in India are handled by the Drugs Controller General of India (DCGI). For advice, the DCGI office turns to outside experts and other government agencies. The cost of blood testing to distant focus research sites necessitates additional consents. A Central Ethics Committee on Human Research is part of the ICMR (CECHR). This Institutional Ethics Committee's activity is reviewed by this board of trustees (IEC).

The IEC is created in accordance with the ICMR standards, pursuant to the recently updated Schedule Y of Drugs and Cosmetic Rules. The DCGI's office has been directing preparation programmes for persons from Ethics Committees around the country in collaboration with WHO ICMR and many submitted look into specialists.

Schedule Y of the Drugs and Cosmetics Rules governs clinical trials in India. The Rules are approved by the DCGI's office, which is also in responsibility of overseeing every single clinical research submitted to the office for approval. Clinical studies for novel pharmaceuticals made in India must begin in India from the beginning.

A stage 3 clinical study on roughly 100 patients in at least three centres is necessary for advertising endorsement of pharmaceuticals that have been successfully approved in other countries, with the specific purpose of determining the medication's effect on the Indian ethnic community.

An application for a new sign of an already-approved drug is treated the same way as an application for a new medication's approval. Bioequivalence studies may be conducted on new definitions of approved drugs.

Clinical trials of novel pharmaceuticals developed outside of India were permitted until January 2005, but only with a "stage slack":

A stage 2 trial may be conducted in India only after stage 3 trials had been completed elsewhere. Except for drugs with extraordinary relevance to India, stage 1 trials of overseas pharmaceuticals were not approved. This caveat, for example, allowed India to conduct stage 1 HIV vaccine trials. Truth be told, India has been conducting universal multi-center studies since the mid-1990s.

A change to Schedule Y of the Drugs and Cosmetics Rules in January 2005 eliminated stage slack in global clinical trials managed by remote patrons. In India, there will never be any more restrictions on "simultaneous stage" clinical studies. Stage 2 and stage 3 trials of drugs identified elsewhere can now be conducted in India at the same time and in the same manner as they are in other areas of the world.

Before starting a study, the trial support must acquire approval from the DCGI. For this approval, the support must present data from pharmacokinetic and creature studies, as well as previous stage trials; data on the medication's administrative status in various countries, the trial convention, specialist's leaflets, and educated assent reports.

Without permission from the local morality audit board of trustees (EC) at each location, trials cannot begin. Prior to 2005, the Drugs and Cosmetics Rules advised, but did not require, a morality survey board of trustees to audit clinical trial archives. The clinical investigation report must state that the study was conducted in accordance with the Declaration of Helsinki, Indian Good Clinical Practice guidelines, and the Indian Council of Medical Research's moral guidelines for human biomedical research, as amended in January 2005.

Furthermore, the DCGI lacks the necessary resources to monitor ongoing clinical studies in India. The DCGI's office now employs four or five professionals and does not currently audit clinical trial sites, despite the government's announcement that it is hiring more personnel for this reason. At the moment, only contract research firms and sponsors undertake audits of clinical trial data. The US Food and Drug Administration (USFDA) has began evaluating clinical trial sites.

Conclusion
As the field of medical research grows more worldwide, there is a growing demand for research that is both methodologically and culturally acceptable. Conducting research on human beings pushes the boundaries of medical ethics as well as international law's present capabilities. For doing human research, relying solely on non-binding and ambiguous medical ethics instruments is both naive and culturally insensitive.

Human lives are fundamentally complicated, and no one ethical framework, including ours, can claim to encompass the complexities of research or comprehend the ethical difficulties that occur in these many circumstances. The "effective" participation of oppressed communities in decision-making, in line with universal principles of justice, will be a critical step in resisting the social, economic, and political pressures of globalisation that limit human capacities. Look at how the rules on transplants and sex selection are breached to see how a law can't guarantee anything.

However, having a legislation will benefit people who are concerned about being scrutinised. The gang that is abusing the law will continue to do so. A law, on the other hand, allows you to ask inquiries, conduct investigations, and take action. Greater focus must be made to encouraging clinical research if India is to become a leader in good clinical research.

In order to achieve global justice, the gap between the developed and developing worlds must be bridged, particularly in terms of the broad availability of proven treatments in poor nations. The goal is to make research ethics an intrinsic aspect of all biomedical research. As a result, every stakeholder should regard study participants as essential players who must be safeguarded from any damage, for which suitable regulations must be in place.

End-Notes:

1. Medical Council of India Act - 1956 (amended in the year 2002)
2. Guidelines for Exchange of Biological Material (MOH order, 1997)
3. Aayushi Swaroop & Saif Ahmed, Medical Crimes in India, iPleaders (July 31, 2019), https://blog.ipleaders.in/white-collar-crimes/.
4. Sneha Gupta, Human Experimentation and Crimes: A Detailed Study of its Types and its Detrimental Effects, I National Social And Legal Research Journal III, 6 (2021).