Thursday, May 30, 2024

Covid-19 Vaccine: Rules of Clinical Trials

With the world in desperate wait for a vaccine or miracle drug as a cure for Covid-19, the burning question is not where, but when and what does it take to formulate an approved new drug and whether we have the right parameters to conduct such clinical tests. It has also raised numerous legal issues pertaining to the fundamental rights of individuals

By Saju Jakob with Nancy Shah and Ekta Barathi

Amidst the Covid-19 pandemic and its stigma, hundreds of thousands of people are dying globally, leaving the rest to hope that an angel will appear soon in the sky with a miraculous drug or vaccine to deport the virus.

We come across news regarding one or the other drug, which is ready for the Phase 1, Phase 2 or Phase 3 testing or completion of clinical test.

Countries are in a race to invent a new drug. Some countries have made tall claims about their results, but so far, no magic has worked in reality, despite huge efforts on the part of various multinational companies.

The crucial question is not where, but when and what does it take to form an approved new drug and whether we have the right parameters to conduct such clinical tests. 

Whenever a new combination of chemicals is formed to create a new drug, it is necessary to conduct clinical testing of the drug before inflicting it on actual patients. The clinical testing means the testing of the drug on human subjects. In case of vaccines, the lighter version of the disease germ is injected in healthy individuals to train their immune systems to prepare antibodies in case of exposure to the disease germ. This type of testing on humans has to be conducted considering different variables and thus, the testing occurs in four phases, wherein the number of subjects is increased in each phase.

While the clinical testing is deemed necessary and beneficial for obvious reasons, it has raised numerous legal issues pertaining to the fundamental rights of individuals.

Though it can be argued in a utilitarian way that the pain can be laid upon a few persons for the larger interest of the populace, it seems highly absurd to put the constitutionally protected fundamental rights on the backseat.

In 1767, John Hunter, a Scottish surgeon, renowned for advocating research and experimentation and a propagator of scientific methods in medicine, performed a human experiment, where he injected pus from one patient who was suffering from gonorrhea into the penis of another man who was perfectly normal. But later on, it was discovered that the man developed gonorrhea and syphilis simultaneously. The results of the trial suggested that syphilis and gonorrhea had the same origin.

In 1892, Albert Neisser injected the serum of syphilis patients in numerous females between the age of adolescence and maturity i.e. 10-24 years of age, in order to develop the vaccine for syphilis. As a result, no patient developed the condition for syphilis; however, they developed gonorrhea and condyloma. Simultaneously, he injected 30 ml of serum from syphilis patients in a group consisting of prostitutes aged between 17-21 years, and in a time-frame of a few months, they developed syphilis. With this study, he concluded that females are prone to syphilis due to their sexual interactions and not due to the injection of infected serum.

This led to a huge legal issue as the courts observed that whereas the clinical trial was not objected to, the infliction of disease germ on the trial subjects disregarding their consent could not be tolerated. This led to the first Ethical Code in this aspect, called the Prussian Code, that mandated the unequivocal consent of the subjects.

Later at the end of World War II, clinical testing was defined as an atrocity by war criminals in Russia.

Famously known as the Nuremberg Doctors’ Trial, 16 doctors were held guilty and seven were sentenced to death. This led to the formation of the Nuremberg Code which came up with the concept of informed consent and the right of the subject to withdraw consent at any time till the conclusion of the test.

Further, the Helsinki Declaration put forth the binding aspect of ethical guidelines on countries in case of clinical testing as well as resistance to conducting testing among vulnerable groups.

Subsequently, in 1976, the United Nations International Covenant of Civil and Political Rights (ICCPR) recognised “the inherent dignity of the equal and inalienable rights of all members of the human family as the foundation of freedom, justice and peace in the world”, and while dealing with the clinical testing involving human participants, provides for three non-derogable rights to individuals—right to life, freedom from non-consensual medical experimentation on humans, and non-discrimination.

Furthermore, ICCPR defined the responsibility of the State for ensuring these mentioned rights as the “core  obligations” of the State, and hence introduced the accountability of the State in regulating domestic and foreign clinical trials.

The Council for International Organisations of Medical Sciences (CIOMS), established by the World Health Organisation (WHO) and the United Nations Educational, Scientific and Cultural Organisation (UNESCO) for the representation of the biomedical scientific community, put forward ethical guidelines on testing involving human participants.

The WHO even provides a Handbook for Good Clinical Research Practice (GCP) covering a range of issues to do with trial protocols; Standard Operating Procedures, support systems and tools; documents concerning generation and approval of trial; selection of trial sites and properly qualified, trained, and experienced investigators and study personnel. It also mandated an Ethics Committee Review and other factors to do with monitoring the trial and trial data.

Not only does the handbook specifically disseminate the information that is required to be given to the trial subject to form an informed consent, but it also specifies the eligibility criteria for the administrator for taking the consent. Additionally, WHO has also published the “International Standards for Clinical Trial Registries”, which mandates the registration of clinical trials. The aim is to have a global clinical trial registration at one stop and to publish the results of those clinical trials as well.

The International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH), an international body generally known as International Conference on Harmonisation of Good Clinical Practice or ICH-GCP puts emphasis on the necessity of globally approved standards for the protection of human beings from exploitation by various stakeholders while conducting the trials and has also come up with ethical guidelines, to be adhered to during the process of conducting clinical testing. It requires strict documentation of every step of clinical protocol and ensures quality control, protection of basic human rights, and regular inspection for strict adherence to clinical guidelines.

In the United States, ICH-GCP is not statutorily mandated, though it is approved by the Food and Drug Administration (FDA) as the National Institute of Health demands all clinical investigators and staff be qualified as trainers of Good Clinical Practice. The principles of GCP are even accepted by the European Union, which has adopted special guidelines in the form of directives in this respect. While the Ethical Guidelines were made to demonstrate an ideal situation, the actual challenge has always been the administration of clinical trials.

India has always been a favoured country for conducting trials on human subjects as the subjects are avilable for testing at very cheap rates  due to illiteracy and poverty. Earlier, the conduct of clinical testing was regulated by the Guidelines of the Indian Council of Medical Research (ICMR), Drugs and Cosmetics Act and Rules, 1945, and the Indian Medical Council Act, 1956, the Central Council for Indian Medicine Act, 1970, and the Drugs and Clinical Trial Rules, 2019. The Central Drugs Standard Control Organisation (CDSCO) is the national regulatory authority of India and the department of Drug Controller General of India (DCGI) is the prime licence granting authority to sponsors.

For several years, numerous resolutions demanding stringent applications of the ethical guidelines in India as well as regarding the concern of low or nil compensation in case of death or injury to the trial subject, were put forward.

As a result, in 2013, a Draft Amendment Bill to the Drugs and Cosmetics Act was released, proposing changes in the regulation of the import, export, manufacture, distribution and sale of drugs, cosmetics and medical devices as well as to ensure safety, efficacy, quality and conduct of the clinical trials.

For the first time ever, the Bill provided penal provisions in case of violations of the rules and guidelines. However, it was not converted into an Act by the then government. The period of 2015-2018 in India witnessed a high number of deaths, around 1400, in clinical trials, out of which only the legal heirs of 88 participants were compensated.

According to the Ethical Guidelines of the ICMR, the sponsor is only liable for medical management of the subject and subsequent compensation in case of injury or death of the subject till the extent the Ethics Committee opines the injury was directly related to the test.

This was protested widely, and a rectification was introduced in the Draft Bill of New Drugs and Cosmetics Rules in 2018, which had a provision of No Fault Compensation wherein the sponsor had to mandatorily grant interim compensation, amounting to 60 percent of the total amount incurred in the injury, within 15 days of the opinion of the Ethics Committee.

However, the current government, realising the reasons for reluctance of sponsors for new clinical trials, relaxed the regulatory pathways to conduct clinical trials in India. It relaxed the rules for marketing foreign drugs in India by introducing the New Drugs and Clinical Trials Rules, 2019.

The review timeline for approval of the licence from DCGI was accordingly reduced from six months in the previous provisions to 30 days if the drug is manufactured or marketed in India. Moreover, no response from the DCGI within 30 days shall be considered as deemed approval. The need for local clinical trials were also waived in the new rules, if the drug has already been approved by the DCGI approved country, which the DCGI can decide on a case-to-case basis.

The doctors and the officers of government hospitals have the authority to seek permission from DCGI to import unapproved drugs from other countries, which are approved for marketing in the country of origin, in case of life-threatening diseases.

Section 92 of the Patents Act provides the power to the Government of India to grant compulsory licences to non-patent holders to manufacture patented drugs without any legal implications in case of national emergency, extreme urgency or public non-commercial use.

The 2019 Rules limited the responsibility of the sponsors in case of post-trial patients, from whom the receiving of the declaration has been mandated to waive any claim of compensation, in lieu of the free administration of the drug. The discretion to grant and the extent of grant of compensation and medical management is kept with the investigator, with no appellate right with the trial subject. 

Most interestingly, the 2019 Rules added a provision of accelerated approval of drugs in case of serious conditions based on severity, high prevalence, lack of alternative treatment and also if the new drug is more beneficial than the already existing one or to fulfil an unmet medical need.

Under the accelerated approval, the medical benefits of the drug are anticipated based on the first two phases of the testing and the approval of the Central Licencing Authority, with regard to new drugs, can be had following Phase 2 and further post-marketing strategies are used in order to ascertain the medical benefit.

On June 5, 2020, the Government of India again released Draft Rules, 2020, considering the growth of Covid-19, where they proposed an amendment to Rule 96 of the Original Rules, 2019. Under this, the procedure of accelerated approval to manufacture or import a new drug has been added for “compassionate use”.

The compassionate use suggests that the dying patient can make a declaration through a medical officer to the Central Licensing Authority to import or to manufacture the unapproved drug in a limited quantity for that patient’s use only, prohibiting sale in the domestic open market. This suggests administering of those drugs which haven’t completed four phases of trials, to patients who are not considered trial subjects or even post-trial subjects.

With the rapid increase in the numbers of Covid-infected people, this makes the entire population subject to a trial and error method with zero responsibility of the sponsors or the doctors, and ensuring the administration of “on request drugs” are certainly not free. 

—Saju Jacob is a Supreme Court lawyer. His co-authors Nancy Shah and Ekta Barathi are advocates

Lead picture: UNI


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