Drug development is a process that calls for utmost care. An error can cause
fatal result. Clinical trials are developed in such a way that it not only helps the
discovery of new drugs but also ensures safety profile of such drugs.
A clinical trial in simple terms can be defined as a set of practice that helps certify a new drug molecule as safe and efficacious before reaching the market.
To determine the safety and efficacy of drug research on humans is always warranted, but one needs to be cautious and vigilant as to how the players in this field undertake the process. Adherence to the principles of good clinical practices or GCPs, including adequate human subject protection universally recognized as a critical requirement to the conduct of research involving human subjects. Most countries have adopted good clinical practice principles as laws or regulations. In India, compliance with GCP guidelines 1 issued by the Central Drugs Standard Control Organization or the CDSCO is recommended.
APPLICABLE LAWS AND REGULATORY FRAMEWORK-
Clinical trials, in addition to national laws, are governed by –
- Guidelines and directives at international level like EU regulations and directives,
- ICH2– Good Clinical Practices (GCP) guidelines,
- Recommendations of World Medical Association Declaration of Helsinki,
- Guidelines for Good Pharmacoepidemiology3 Practices and ICMR (Indian Council of Medical Research) guidelines.
These guidelines, recommendations and opinions are considered as “soft law” and are not legally binding but play an important role in regulating these clinical trials. Most of the multi -national corporations carrying out clinical trials worldwide voluntarily and as a good practice follow these guidelines and recommendations.
These guidelines and directives primarily aim at-
- protecting the subject from taking undue risk in participating in a clinical trial;
- Enforce both voluntary consent to research and the continual assessment of risk and benefit.
In India, Central Drugs Standard Control Organization (CDSCO) (headed by Director Control General of India) is the primary authority and “Drugs and Cosmetics Act, 1940” (along with the rules framed there under) is the principal legislation for the regulation of clinical trials. Schedule Y of the Drugs and Cosmetics Rules, 1945 (“Rules”) provides for the detailed conditions, and compliances relating to clinical trials in India.
The legislative framework governing medical research in India are:
- Drugs and Cosmetics Act 1940 (Schedule Y)
- Drugs And Cosmetics (II Amendment) Rules, 2005
- ICMR guidelines, DBT guidelines
- 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 Constitution of India
- The Biomedical Research on Human Subjects (regulation, control and safeguards)
Acts, rules and codes of ethics of professional bodies regulating the practice of medicine in India, such as the Medical Council of India, Department of Ayurveda, Yoga and Naturopathy, Unani, Siddha and Homoeopathy (AYUSH). Bill – 2005
Apart from these legislation’s, The Indian Council of Medical Research or the ICMR, which was established with a view to foster a research culture, improve and develop infrastructure and foster community support, plays a significant role in controlling clinical trials in India.
The Drugs and Cosmetics Act and The Medical Council of India Act state that all clinical trials in India should follow the ICMR guidelines of 2000. The ICMR has a mechanism of review for its own institutions, and so do other government agencies.
The Drugs Controller General of India or the DCGI is responsible for regulatory approvals of clinical trials in India. The DCGI’s office depends on external experts and other government agencies for advice. The ICMR has a Central Ethics Committee on Human Research. This committee audits the functioning of this Institutional Ethics Committee or the IEC. The amended Schedule Y of Drugs and Cosmetic Rules order the composition of the IEC as per the ICMR guidelines. Compliance with GCP guidelines issued by the Central Drugs Standard Control Organization or the CDSCO is recommended.
DRUG AND COSMETIC RULES–
Schedule Y of the Drugs and Cosmetics Act -1940 was amended in the year 2005. Earlier, we required that all foreign drugs be retested at one phase below the highest phase of testing abroad. Now parallel global clinical trials have come. Schedule Y now permits concomitant phase 2 and phase 3 trials. India can become part of global trials. But even then phase 1 has to be repeated for safety.
New chemical entities cannot be administered to human subjects in a clinical trial without permission from the Drugs Controller General of India. Such permission may be obtained by submitting to the DCGI an application for a clinical trial. The application must include-
- a protocol for the study,
- a draft of the Informed Consent Document,
- a list of proposed investigators who have agreed to participate in the study, and
- background information about the drug in accordance with Schedule Y of the Drugs & Cosmetics Rules.
It takes almost 12 weeks to obtain permission for a clinical trial for most investigatory drugs. The duration may be longer for drugs with special significance to the healthcare concerns of the country or those that may be considered controversial since these are liable to be referred to the Indian Council of Medical Research for comments. If clinical supplies are to be imported, a “Test-Import License” must also be applied for. Import and manufacture of clinical trial supplies is governed by Rules 33 & 34 and provisions contained in Part X-A of the rules.
CHANGING REGULATION IN INDIA
A major threat India faces in this area is its low literacy levels, which has always kept regulators skeptical about the possibility of the volunteers being not adequately informed about the risks they are undertaking. However, compliance to International Conference on Harmonization-Good Clinical Practice or ICH-GCP norms, trained investigators, a growing population of experienced monitors and exposure to international protocols seem to provide some relief to such issues but at the same time a lot of issues needs to be addressed.
1. CLINICAL TRIALS REGISTRATION
The Clinical Research Organizations or the CROs use to operate using a voluntary process administered by the Indian Council of Medical Research along with World Health Organization. As this process has proved insufficient, the DGCI came up with plans for mandatory registration of CROs in a central registry.4 The Clinical Trials Registry- India (CTRI), hosted at the ICMRs National Institute of Medical Statistics (NIMS), is a free and online public record system for registration of clinical trials being conducted in India that was launched on 20th July 2007 5Initiated as a voluntary measure, since 15th June 2009, trial registration in the CTRI has been made mandatory by the Drugs Controller General (India) (DCGI)
2. SWASTHIYA ADHIKAR MANCH INDORE AND ORS. VS MINISTRY OF HEALTH OF HEALTH AND FAMILY WELFARE AND ORS.-
In February 2012, a non-governmental organization(Swasthiya Adhikar Manch )filed a public interest lawsuit complaining about unregulated clinical trials of new drugs conducted in India by multinational pharmaceutical companies. On January 3,2013 the Supreme Court heard the complaint and castigated the Union government “for being negligent in curbing illegal clinical trials despite the deaths of at least 2,374 persons who had undergone the dubious testing for unregistered drugs between 2007 and 2012. The apex court said that the government has gone into deep slumber on the issue and has failed to put in place proper mechanisms to stop rackets of multinational companies, which are conducting illegal clinical trials. A bench of justices R.M. Lodha and A.R. Dave said in its interim order that all clinical trials will be done under the supervision of the Health Secretary at the Center.
3. RECENT AMENDMENTS–
Recently on 30th January 2013, just after the interim order was passed by the apex court in the above-mentioned matter, the Government of India came out with certain amendments to Schedule Y of the Rules with a view to tighten the norms relating to the conduct of clinical trials especially in terms of taking informed consents from the trial subjects and providing them or their legal representatives (as the case may be) compensation in case of any trial related injury or death. The amendment has imposed complete and ultimate liability on the sponsor of the clinical trial to reimburse any cost incurred by the trial subjects for the medical treatment of “any injury” suffered by the trial subjects as well as financial compensation for such injury or death. Further in case the sponsor fails to provide the proper medical treatment and/ or the financial compensation as per the orders of the licensing authority to the trial subjects (or their representatives as the case may be), then the authority may cancel or suspend the license of the sponsor to carry out the clinical trials and may even debar it from carrying any clinical trial in future in India. The amendment also mandates GCP compliance and adverse event reporting. The amendment has certainly acted as a deterrent on the multi-national corporations and is a negative catalytic agent to the prospects of clinical trials in India.
- Insertion of Rule 122- DAB in the Drugs and Cosmetics Rule, 1945 (called as The Drugs and Cosmetics (First Amendment) Rules, 2013.6
Rule 122-DAB (1) lays down the requirement of providing free medical management as long as required, in the case of an injury occurring to a clinical trial subject. Further if the injury suffered by the trail subject is related to the clinical trial conducted on such subject, he or she shall also be entitled for financial compensation as per order of the Licensing Authority. In case the clinical trial results in the death of the subject, financial compensation, as per the order of the Licensing authority, has to be compensated to the nomiee (s) of the deceased subject. The preceding subsections of the Rule explain the circumstances which is considered as a “direct nexus” to an immediate cause to the injury/death, consequences of non-payment of compensation, etc.
2. Insertion of Rule 122 DAC in the Drugs and Cosmetics Rule, 1945 (called as The Drugs and Cosmetics (Second Amendment) Rules, 20137.
Rule 122 DAC specifies the prerequisites required for a clinical trial to be considered as adequate so as to grant permission by the Licensing Authority to be conducted on any human body. Further the rule lays down the power of the Licensing Authority to impose any additional conditions to be fulfilled in case of grant of permission in respect of any specific clinical trial, as it is deem fit.
3. Insertion of Rule 122 DD in the Drugs and Cosmetics Rule, 1945 (called as The Drugs and Cosmetics (Third Amendment) Rules, 2013.8
Rule 122 DD deals with mandatory registration of the Ethics Committee and specifies that no Ethics Committee shall review and accord its approval to a clinical trial protocol without prior registration with the Licensing Authority as defined in clause (b) of rule 21 and describes the procedure of such registration to be made by filling an application to be made to the Licensing Authority in accordance with the requirements as specified in the Appendix VIII of Schedule Y of the Rule and the procedure thereof.
The Supreme Court on July26, 2013 directed the Union government to come up with a new regulatory regime for clinical trials that reflects the concerns of all stakeholders, including those who volunteer to undergo the tests at the risk of adverse health effects and even death.
The Swasthiya Adhikar Manch’s petition filed as a public interest litigation, came on top of criticism faced by the government for poor regulation of clinical trials conducted by foreign companies.
The Supreme Court bench also instructed the government to take suggestions from the National Human Rights Commission and activists groups such as Swasthya Adhikar Manch (which translates roughly as Right to Health Forum), one of the petitioners.
The health ministry has been directed to file an affidavit detailing its compliance with Friday’s order within six weeks from july26 ,2013.
The government proposals included-
- registration of ethics committees.
- a provision to suspend or revoke their registration in case of misconduct.
- regular inspections during clinical trials, and medical treatment and compensation for those adversely affected, serious adverse impact caused by negligence will result in penalties.9
As India is approaching towards globalization in the recent developments in the Pharmaceutical sector occurring worldwide, India portrays to be a prospective hub for many big foreign Pharmaceutical Companies for drug innovation, based on its comparatively low cost and skill base, so as to exploit this opportunity for the betterment of the country. However, all these while India was failing to implement a rigid and stricter vigilance mechanism on the Pharmaceutical Companies who conduct such clinical trial at the cost of the lives of some vulnerable and poor individuals who are not even aware that in our Country there is existence of “right” to lead a safe and healthy life. To conclude, with the insertion of the rules and the active effort of government in hearing and examining the PIL filed by Swasthiya Adhikar Manch has brought ray of hope to many of those vulnerable ones and it is expected that the concept of Good Clinical Practices (GCP) will be a reality and not just on papers.
2 The International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) launched in 1990, ICH is a unique undertaking that brings together the drug regulatory authorities and the pharmaceutical industry of Europe, Japan and the United States. to discuss scientific and technical aspects of drug registration. Since its inception in 1990, ICH has evolved, through its ICH Global Cooperation Group, to respond to the increasingly global face of drug development, so that the benefits of international harmonisation for better global health can be realised worldwide. ICH’s mission is to achieve greater harmonisation to ensure that safe, effective, and high quality medicines are developed and registered in the most resource-efficient manner
3 Pharmacoepidemiology is the study of the use of and the effects of drugs in large numbers of people
4 Vide F.No. 12-01/09-DC-(Pt-32)Directorate General of Health Services, Office of Drugs Controller General (India)
(New Drug Division)
6 Vide Notification of the Government of India, Ministry of Health and Family Welfare (Department of Health) number G.S.R 53(E) dated 30th January 2013 in the Gazette of India
7 Vide Notification of the Government of India, Ministry of Health and Family Welfare (Department of Health) number G.S.R 63(E) dated 1st February 2013 in the Gazette of India
8 Vide Notification of the Government of India, Ministry of Health and Family Welfare (Department of Health) number G.S.R 72(E) dated 8th February 2013 in the Gazette of India
9 Supreme Court tells govt to seek range of views on clinical trials,july,26,2013. http://www.livemint.com/Politics/NqAGQucZSwrkc3dSuY2PAJ/Supreme-Court-tells-govt-to-seek-range-of-views-on-clinical.html