recent changes in regulatory aspect of clinical trials in india - wjpps

WORLD JOURNAL OF PHARMACY AND PHARMACEUTICAL SCIENCES Suvarna et al.

World Journal of Pharmacy and Pharmaceutical Sciences

SJIF Impact Factor 5.210

Volume 4, Issue 07, 1948-1959.

Review Article

ISSN 2278 – 4357

RECENT CHANGES IN REGULATORY ASPECT OF CLINICAL TRIALS IN INDIA Dr.Yashasvi Suvarna* and Dr.Rathai Rajagopalan Department of Pharmacology, M S Ramaiah Medical College, Bangalore-560054.

Article Received on 15 May 2015, Revised on 08 June 2015, Accepted on 01 July 2015

ABSTRACT India has been a hub for conducting various multi centre trials. The Central Drugs Standard Control Organisation (CDSCO), headed by the Drug Controller General of India(DCGI), lays down the regulations for the conduct of clinical trials in India. This trend has but changed from

*Correspondence for Author

2011 when most of the trials are being outsourced to other countries like China and Philippines. The conduct of trials, regulations in India

Dr.Yashasvi Suvarna Department of

and quality of data generated may be the cause for this development.

Pharmacology, M S

There is a paucity of reviews which sum up the changes in the

Ramaiah Medical College,

regulations of clinical trials introduced from then on. Updating our

Bangalore-560054.

knowledge about these is of utmost importance in today‗s turbulent scenario that prevails in the pharmaceutical industry. Thus, this review

provides an insight into the recent changes with respect to the regulations of clinical trials and its impact on the clinical research industry in India. KEYWORDS: randomised controlled trials, drug regulatory, ethics committee, serious adverse event. INTRODUCTION Randomised controlled trial (RCT) is defined as ―a study in which people are allocated at random to receive one of several clinical interventions. One of these interventions is the standard of comparison or control. The control may be a standard practice, a placebo ("sugar pill"), or no intervention at all. RCTs seek to measure and compare the outcomes after the participants receive the interventions. Because the outcomes are measured, RCTs are quantitative studies.[1]

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Following implementation of the product patent in India, almost all multinational companies started large RCTs here. The main attractions were a 50% drop in operational cost, low perpatient trial cost, large number of qualified English speaking professionals, large patient pool with diverse ethnicity, extensive network of hospitals and laboratories, good communications with information technology and above all, easy and fast recruitment of patients.[2] The path was smooth until 2011 when a dramatic drop in conducting and delivering the international RCTs outsourced to India was noticed. According to certain calculations, this drop is up to 50%.[3] At the same time international outsourcing of RCTs to China, Russia and Philippines has increased. In a pursuit to find an answer to this drastic decline-the conduct of trials, ethics, regulatory environment and the quality of data – all are challenged. This review focuses on the changes in regulatory aspects introduced subsequently and their impact on clinical trials in India. Regulatory bodies involved with clinical trials in India The role of regulatory bodies in clinical trials is to ensure quality drug supply and maintaining health and well being of trial participants. In India, the central government‘s Central Drugs Standard Control Organisation under the Ministry of Health and Family Welfare( headed by the Drug Controller General of India) develops standards and regulatory measures for drugs, diagnostics and devices; lays down regulatory measures; and regulates the market authorisation of new drugs as per the Drugs and Cosmetics Act .[4] The Department of Chemical and Petrochemicals of Ministry of Chemicals and Fertilisers, through National Pharmaceutical Pricing Authority (NPPA),[5] sets the prices of drugs; maintains data on production, exports and imports; and enforces and monitors the supply of medicines and also gives opinions to parliament on the related issues. Other ministries that play an indirect role in regulation include the Ministry of Finance, Ministry of Environment and Forests, Ministry of Science and Technology and the Ministry of Commerce and Industry. Regulation of Patents, drug exports is governed by Department of Industrial Policy and Promotion and Directorate General of Foreign Trade, under the aegis of Ministry of Commerce and Industry and the Ministry of Chemical and Fertilisers respectively. Licencing, quality control and distribution is maintained by the CDSCO, Ministry of Health and Family Welfare, Department of Biotechnology, Ministry of Science and Technology (DST) and Department of Environment .[6] Drug Controller General of India

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(DCGI) handles the approval of licences of specified categories of drugs such as I. V. Fluids, vaccines, sera, blood and blood products.[7] The CDSCO office regulates the clinical trials via its central office at New Delhi and four zonal offices situated at Mumbai, Chennai, Kolkata and Ghaziabad.[7] These zonal offices work in close collaboration with the state offices to bring about uniform enforcement of the regulations imposed by the central government. Some of the important rules that regulate clinical trials in India include a) Schedule Y of Drugs and Cosmetic Act and Rules (Amended in 2005)

[8]

: These are the

requirements and guidelines for permissions to import and manufacture new drugs for sale or to undertake clinical trials. b) GCP guidelines issued by CDSCO in 2001[9]:These guidelines specify ―the design, conduct, termination, audit, analysis, reporting and documentation of the studies involving human subjects.‖ They ensure safety and well being of subjects and verify the authenticity of the data being generated. They must be followed at all stages of drug development. c) Ethical guidelines for Biomedical Research on Human Subjects by ICMR (amended in 2006)

[10]

: They lay down the principles of essentiality, voluntariness, non exploitation,

privacy and confidentiality of subjects. Despite having many principles and bodies to regulate clinical trials, nothing much is seen in practice. The 59th report of Parliamentary Standing Committee on Health and Family Welfare stated gross lack of qualified staff, lack of co-ordination between various agencies, improperly conducted trials for 39 drugs and 33 new drugs approved without conducting clinical trials on Indian patients in the period of January, 2008 to October, 2010.[11] This report opened the eyes of the regulatory bodies and various amendments are applied to make conduct of clinical trials more stringent, reliable and transparent in India. This might have not have helped with the number of clinical trials but protecting the rights of the subjects has gained supremacy. Recent amendments in Schedule Y a) Introduction of Rule 122DAB (also called as the Drug and Cosmetics Act (First Amendment) and Appendix XII: This rule provides directives about compensation for

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injury and death


during the clinical trials. It states that a subject is entitled to

compensation if injury or death is due to: 

Adverse effect of investigational product (s) (IP);



Violation of the approved protocol, scientific misconduct or negligence by the sponsor or his representative or the investigator;



Failure of IP to provide intended therapeutic effect;



Use of placebo in a placebo-controlled trial;



Adverse effects due to concomitant medication excluding standard care, caused as part of approved protocol;



For injury to a child in-utero because of the participation of parent in a clinical trial;



Any clinical trial procedures involved in the study.[12]

This was more like a sweeping application where all patients who died during the trial period, whether related to the trial or not, were liable to receive compensation. Also, if a Serious Adverse Event (SAE) takes place, the Schedule Y states that it should be reported within 24 hours to the sponsor. Most of the trials being outpatient in nature, this is difficult to achieve and would lead to no compensation for worthy subjects. The procedure to be followed while reporting such an SAE to CDSCO is enlisted in Appendix XII of the Schedule Y.[13] Receiving a lot of scrutiny from professionals nationwide, certain words are added later to the sub-rules to better certify subjects worthy of compensation. for e.g. in case of placebo controlled trial and failure of I.P. to provide intended therapeutic effect, the words ―in case the standard care, though available, was not to be provided to the subject as per the clinical trial protocol ‖ is proposed to be added.[14] Though these changes make up for deficiencies on the part of the Sponsor and investigator, the rules are very generous toward subjects. Compensation is likely to become an alternative to insurance in terminally ill subjects. Implementing these rules makes conduct of clinical trials in India more expensive and has hurt the industry that is already struggling to keep its stance. There is an urgent need to make the environment more industry friendly to attract clinical research. (b) Introduction of Rule 122DAC

(Second Amendment): This rule specifies various

conditions for conduct and inspection of clinical trials. It specifies the prerequisites required for a clinical trial to be considered as adequate ,in order for the Licencing

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Authority to grant permission for conduct of the trial on humans. Further, the rule lays down the power of the Licencing Authority to impose any other conditions to be fulfilled in case of grant of permission to a clinical trial, as considered fit. b) Insertion of Rule 122 DD (Third Amendment): It 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 Licencing Authority as defined in clause ( b) of rule 21 and describes the procedure of such registration to be made by filling an application directed to the Licencing Authority as per the requirements specified in the Appendix VIII of Schedule Y of the Rule and the procedure thereof.[15] Audio-Visual Recording of Consent The central government together with Drugs Technical Advisory Board (DTAB) vide the Gazette of India notification dated 7thJune 2013 proposed to make draft rule that audio-video (AV) recording of the informed consent process of individual participant by an investigator including procedure of providing information to the subject and his understanding on such consent shall be maintained by the investigator for record while conducting clinical trials in India. [16] This step has now become mandatory. The AV recording will safeguard the rights of the subjects and stakeholders involved in the trial. A lot of time and effort is saved in the absence of laborious mechanical documentation of consent .Voluntary participation of patients who understand their role in the study and adhere to the study protocol is assured resulting in quality data generation.[17] The AV recording increases the transparency and the conduct of the consent process. [18] But, there are many practical downsides to this step. First, the customs and traditions still prevalent in many parts of India could make convincing people to appear on camera, especially women, a tough job for the site management staff. This also impacts recruitment severely. A single recording of such a long duration is difficult to achieve. In case of sexually transmitted disorders and immunodeficiency syndromes, discussing the ailment over the camera is uncomfortable for the patients and they refuse to do so. Also, a lot more costs are incurred for the equipment required. In the current scenario, the highest priority is to reassure the government and community at large about standards adopted by the industry and AV recording is a positive step ahead to build trust and confidence in the clinical research industry in India. Education of the trial

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participants about the need of AV recording and reassuring them about its confidentiality may help curb the limitations. Report of the Prof. Ranjit Roy Chaudhury expert committee This report put forward in July 2013 by the Expert Committee constituted by the Ministry of Health and Family Welfare enlists practices that would be conducive for the growth of clinical trial industry in India while meeting the regulatory standards.[19] It formulated policy and guidelines for approval of new drugs, clinical trials and banning of drugs. The actions taken by the Ministry based on the recommendations hereon included 

Clinical trials should be conducted in accredited sites by an accredited Investigator with the oversight of accredited Ethics Committees (ECs). The Accreditation would be provided by a Quality Council of India.



As discussed above with Rule 122 DD, Registration of Ethics Committee is made mandatory but the proposed accreditation required a special procedure which calls for amendments in Drugs and Cosmetics Act.



Regarding the procedure for review and application of new drugs, New Drug Advisory Committees are renamed as Subject Expert Committees. Applications for new drugs will initially be evaluated by these followed by review from the Technical Review Committee (TRC). CDSCO will take the final decision based on recommendations from the TRC.



A computerized database of experts in each area will be generated which will be updated every year based on specific selection criteria.



If India takes part in a global clinical trial for a new drug, approval should be sought from the CDSCO before marketing the drug.



The CDSCO will review applications for approval of clinical trials within six months and ultimately bring down the timeline to one month.



If at all, a placebo controlled trial needs to be done, it should be efficient; ethical and appropriate.



Audio-visual recording of the consent process will be undertaken. Violation of the informed consent process can cause debarment of the investigators.



An investigator cannot take part in over three trials at a time. All details about payment of the investigator by the Sponsor should be made available to the DCGI.



Use of information technology shall be used at all points in the clinical trial to ensure total transparency.

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


If an investigator fails to report an SAE within 24 hours, he should give the reason for delay to the satisfaction of the DCGI along with the SAE report.



Amendments in Rules 122 DAB and Schedule XII are called upon regarding compensation in injury or death discerned at a later stage.



Academic clinical trials may be approved by the Institutional Ethics Committee. If a new drug is being tested or a new use for an existing drug is being evaluated, then approval of the CDSCO is required.



There is no restriction as to the number of clinical trials carried out in the country and no deletion of existing drugs needs to be done in case a new drug is approved for a particular disease.



A waiver of clinical trial in Indian population for approval of new drugs, which have already been approved outside India, can be considered only in cases of national emergency, extreme urgency, epidemic and for orphan drugs for rare diseases and drugs indicated for conditions/diseases for which there is no therapy.



Post marketing surveillance is to be conducted for 4 years as per Schedule Y which needs to be extended for 6 years. [20]

These guidelines definitely improvised the shortcomings of the clinical trial industry in India by clearly specifying how and when new drugs would be approved. But much of this need to be put in practice and change is still a long way to go. SAE Reporting and Compensation a) System of Pre-screening for submission of reports of SAE s to CDSCO The initial scrutiny of the SAE report will be done by a CDSCO officer based on the checklist. Once the report is accepted, the SAE will be reviewed by the CDSCO as per the specified procedure. b) Panel of experts for reviewing of SAE of death The expert committee consists of a chairman, a subject expert and another non expert member. They will analyse the SAE to find the cause of death and to assess whether the death is justified for compensation or not within a period of 30 days. It will also decide the quantum of compensation to be paid by the sponsor to DCGI. c) Formula to determine the quantum of compensation In 2013, The Independent Expert Committee had already devised a formula for compensation in case of clinical trial related death as: Compensation= (B * F* R)/99.37 www.wjpps.com

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Where B= Base amount i.e. 8 lacs F=Factor depending upon the age of the subject as per Annexure 1 R= Risk factor depending upon the seriousness and severity of the disease, presence of comorbidity and duration of disease of the subject at the time of enrolment in the clinical trial between a scale of 0.5 to 4 as : 0.5- terminally ill patient (expected survival not more than (NMT) 6 months) 1.0 - Patient with high risk (expected survival between 6 to 24 months) 2.0 Patient with moderate risk 3.0 Patient with mild risk 4.0 Healthy Volunteers or subject of no risk In case of patients whose expected mortality is 90 % or more within 30 days, a fixed amount of Rs. 2 lacs should be given. On 4 April 2014, the committee met and deliberated the matter about the various criteria that need to be met for compensation in trial related injury. These included (i) A permanent disability (ii) Congenital anomaly or birth defect (iii) Chronic life-threatening disease and (iv) Reversible SAE in case it is resolved. The individual formulas are illustrated in the report of the committee to determine the quantum of compensation in clinical trial related injury(other than death).[22] i) SAE resulting in a permanent disability: The committee arrived at the following formula for this scenario Compensation = (Dx80 x C)/ (100x100) D= Percentage disability the subject has suffered. C= Quantum of Compensation which would have been due for payment to the subject‘s nominee(s) in case of death of the subject ii) SAE causing congenital anomaly or birth defect The Committee decided that quantum of compensation in such cases of SAE should be half of the base amount i.e.8 lacs as per formula for determining the compensation for SAE resulting into death. In case of permanent disability but no death, the Sponsor would give medical management as long as required over and above the financial compensation. iii) SAE causing life-threatening disease The Committee decided that the compensation in this case should be linked to number of days the patient required medical care and the compensation per day should be equal to the minimum wage for an unskilled labourer in Delhi. Thus, the following formula was arrived at Compensation = N x W www.wjpps.com

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Where, N= Number of days for which the trial subject remained under life-threatening situation requiring medical care, irrespective of number of days of hospitalisation. W=Minimum wage per day of the unskilled worker (in Delhi) iv)Reversible SAE in case resolved The formula arrived at was Compensation = 2 x W x N Where, W=Minimum wage per day of the unskilled worker (in Delhi) N= Number of days of hospitalization India became the first country in the world to give out compensations to victims of clinical trials on the basis of a formula that computes the sum after considering the age and health risk of the deceased.[23] To take this further, we now have formulas for clinical trial injuries too. This step has ensured fair quantum of compensation to deserving subjects and their families. This novel step will in the long run boost recruitment to clinical trials. Ethics Committee Registration As per rule 122 DD discussed above, no Ethics Committee shall review and accord its approval to a clinical trial protocol without prior registration with DCGI. To streamline the applications, a preliminary scrutiny will first be performed by a CDSCO officer as per a checklist. Despite the requirement of registration with DCGI,the Independent Ethics Committee registered for bioavailability/bioequivalence studies can conduct periodic review of ongoing clinical trials,though,no new clinical trial can be approved by them.[25] CONCLUSION On 30th September 2013,the Supreme Court‘s hearing on the petition filed by Indore based group, Health Forum, brought 162 ongoing clinical trials in India to a halt as it asked the government to give details about its trial approval process.[26] This was a major setback but a dim ray of hope still exists as 76 new trials ;64 of which were ongoing and 12 of which are yet to begin are approved last year as on August 2014 based on the three parameters — ―assessment of risk versus benefit to the patients, innovation vis-a-vis existing therapeutic choice and unmet medical need in the country‖ as directed by the Supreme Court.[27]

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The road has been bumpy and there are lots of hurdles. The recent regulatory amendments call for a fresh breath of air in the clinical research industry gripped by ethical issues and non transparency. Both the stringent procedure for clinical trial approval and patient recruitment has had a severe impact on the industry in the past few years. All that can be expected in the coming few years are more refinements to cover the loopholes in the regulations to make India a trial and patient friendly global destination. REFERENCES 1. MedicineNet.com,

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