Clinical research regulation in India-history, development, initiatives, challenges and controversies: Still long way to go.

The Central Drugs Standard Control Organisation and its chairman Drug Controller general of India are bequeathed to protect the citizens from the marketing of unsafe medication. The startling findings, of the 59(th)report of the Parliamentary Standing Committee on Health and Family Welfare, have uncovered the lax standards followed by the regulatory authorities in India. The growing clinical research after the product patents rights for the pharmaceutical industries as per the trade related aspects of intellectual property rights agreement and adverse drug reaction monitoring of the marketed drugs have raised many ethical and regulatory issues regarding the promotion of new drugs in Indian markets. Many controversial group of medicines; unauthorised and irrational FDCs not relevant to India's medical needs, are available which are not sold in any of the countries with matured regulatory bodies. It becomes vital to understand the history, growth and evolution of the regulatory aspects of drugs which are handled by multiple Ministries and Departments of the Government of India. Although amendment to Schedule Y, registration of Contract Research Organisations, registration of Clinical Trials, Speeding up review process, Pharmacovigilance (PhV) programme for India and Inspection of clinical trial sites have been started by the various regulatory agencies. However due to casual approach in marketing approval for sale of the drugs, the unethical steps taken by some pharmaceutical companies and medical practitioners has reiterated the need to get appropriate understanding of present regulation of drugs and clinical research especially regarding the practical rules and regulations.

Fight with the disease is ever evolving frontier for human beings. Discovery of new drugs and devices through clinical research are the armamentarium to help fight with affliction of mankind.[1] Because of this sustained demand to develop a new therapeutic agent, biomedical research is conducted to enable discovery of more effective and safer medication and discovery of new therapeutic uses of already established drugs.[2] Thus clinical trials are important link between pre-clinical discovery of a new lead and their use.

Of late, there is growing interest towards Indian Pharmaceutical Industry in outsourcing pre-clinical and clinical bio-medical research from abroad.[3] And almost 70% of the total cost of a developing molecule as a drug is due to the clinical research.[4] Developing countries like India have become the preferred avenues for clinical trials related activities almost 20-30% of the activities of the global share.[5-7] It is forecasted to grow at a compound annual growth rate of 30%.[89] A recent report from the Indian Government's Planning Commission found that the country needs between 30,000 and 50,000 additional research personnel including investigators, auditors and staff qualified to serve on ethics committees and data safety management boards.[10]

There are many reasons for this inclination such as; nearly half of the operational cost, low per-patient trial cost; large no. of well trained, qualified, English speaking professionals; large pool of patients; diverse ethnic subjects; wide variation of disease and numerous government medical colleges, institutions and laboratories having state of the art facility, good communications with information technology and above all easy and fast recruitment of large no. of patients in clinical trials.[111-15] However this trend is leading to more cases of inadequate Informed Consent and unethical treatment of human subjects.[16] Pre-clinical and Clinical studies are thus monitored under strict government regulation in most of the countries in accordance with the International and local ethical and regulatory guidelines.[17-19]

History of Drug Regulation in India

Every government has the responsibility to provide access to the safe, effective and quality medication to its people. Therefore it enacts specific laws to regulate every aspect of the drugs i.e., manufacture, sale, distribution, import and clinical research in humans.[20] These regulatory measures are dynamic and ever evolving in consonance with the developing technologies. In India, there is broadening of regulation, Since independence, from mere manufacture and sale to newer aspects like import, clinical research and adverse drug reaction monitoring.[21] Indian drug regulatory system has been built on the basis of principles enshrined in documents of ministry of Chemicals and Fertilizers, Department of Chemicals and Petrochemicals [Table 1].[22]

Table 1

Basic principles of drug regulatory legislation

Quite evolved, though, history of drug Regulation dates back to the British Rule in India when majority of the drugs were imported from abroad. In early decade of 20th century, many unscrupulous foreign manufacturers flooded the Indian market with spurious and adulterated drugs. In response to widespread ‘Gigantic Quinine Fraud’; the Government, then, formed a Drug inquiry committee under Sir Ram Nath Chopra also known as ‘Chopra Committee’ whose recommendations later on tabled amidst growing protest in legislative assembly as ‘The Drug Bill’ later on amended to the Drugs and Cosmetic Act 1940 (D and C Act) and Drugs and Cosmetic rules of 1945.[23] This would be the central legislation that regulates India's drug and cosmetic import, manufacture, distribution and sale. This also established the Central Drugs Standard Control Organization (CDSCO), and the office of its controller, the Drugs Controller General (India) (DCG(I)).[24] The CDSCO in the Directorate General of Health services, is a division in Ministry of Health and Family welfare, Government of India, headed by Drug Controller General of India (DCGI). It has four zonal, three sub-zonal and seven port/airport offices and six laboratories to carry out its activities.[25]

The Drugs and Cosmetic Act, 1940 came into force from 1st April 1947. Later on, government, in 1962, extended the regulatory provisions to the cosmetics, and finally the Act came to known as Drugs and Cosmetic Act 1940. Drugs and Cosmetic Act has been divided in Chapters, Rules and Schedules and is amended from time to time to control the safety, efficacy and quality of the drugs. It is an act to regulate the import, manufacture, distribution and sale of the drugs and cosmetics. Manufacture and sale is under the respective states governments and union territories through their respective drug control organization, whereas setting standard, import, marketing authorization and monitoring of adverse drug reactions of a new drug is under Central Government.[24]

Under Chapter Two of this Act, one statutory board and a committee have been framed called Drugs Technical Advisory Board (DTAB) and Drug Consultative Committee (DCC) separately for Modern Scientific System of Medicine and Indian traditional system of Medicine and a provision of Central Drug Laboratory at Central Research Institute, Kasauli for testing drugs has been made in this act. DTAB comprises of technical experts who advises central and state governments on technical matters of Drug regulation. Amendment, if any, to Drug and Cosmetic are made after consulting this board. Drug Consultative Committee, which has central and state Drug Control officials as its members, ensures drug control measures in all over India. It is an advisory body for the Central Government, the State Government and DTAB.[26]

Later on, after the recommendations of Justice Rajagopala Ayyanger Committee report (1958)[2728] came the era of Process Patent when India followed the socialist-inspired policies. Most industry did not flourish except the generics industry. The Indian Patents Act of 1970 originally had provisions for ‘process’ patents only.[29] It included product patents for non-chemical substances and process patent for chemical substances including pharmaceuticals, agrochemicals and food products.[30] Here is how it was done: Indian companies were able to copy still-patented drugs by slightly altering a process of production resulting in booming India's generic market. Resultantly, western firms had apprehension in introducing their new innovative products in Indian markets.

In 1994, Government signed the agreement on Trade Related Aspects of Intellectual Properties (TRIPS) to provide minimum protection to the Intellectual Property by the member states of World Trade Organization (WTO).[31] India amended the Patent (Amendment) Bill before 2005 and extended its weak process patent to strong TRIPS competent ‘Product’ patent system for pharmaceutical products.[32-34]

The Indian government, realizing the potential of clinical research for new therapies, has modified and amended Schedule Y to the Drug and Cosmetics Rules of 1945. Schedule Y[35] establishes a set of guidelines and requirements for clinical trials. However, Schedule Y was written with the generics industry in mind but increase entry of foreign pharmaceutical companies after the introduction of strict patent rules in the area of clinical research led the government to introduce many changes. The government recognized the importance of their regulation and thus developed Ethical and Regulatory Guidelines. The Indian Council of Medical Research (ICMR) issued the Ethical Guidelines for Biomedical Research on Human Subjects in 2000[36] and CDSCO released Indian Good Clinical Practice (GCP) guidelines in 2001.[37]

Without a regulatory requirement for GCP compliance, however, most companies did not invest in clinical trials. Low quality data resulted in worsening India's reputation. Also, India's strict bureaucratic system made it hard to manage simple tasks like getting customs clearance for the equipment's. There were regulations which resulted in a phase lag, allowing companies to conduct a Phase II trial in India only if a Phase III study was going on somewhere else.[38] But in 2005, CDSCO made drastic revisions to Schedule Y to try to bring it on at par with internationally accepted definitions and procedures. The changes which took place were

Definitions for Phase I-IV trials, which eliminated the Phase lag.[39]

Clear responsibilities for investigators; and sponsors.

Requirements for notifying changes in protocol.

And then, application of Product patent in 2005, recognizing individual's innovations through the Trade Related Aspects of Intellectual Property Rights (TRIPS) agreement, which India had signed in 1995, became effective. Indian companies began to respect Intellectual Property rights, consistent with international standards.[40]

With the increasing faith in the system, companies flooded the market and more global trials came. Lately, to decrease the review time of application from 16 weeks to 10 weeks the CDSCO has introduced the fast tracking of clinical trials in 2006.[41] The DCG (I) created two categories of applications;[4243] Category: (A) Those also being conducted in countries with competent, mature regulatory systems, and Category: (B) Everything else.

Trials that fell into category A (received approval in the U.S., Britain, Canada, Germany, South Africa, Switzerland, Australia, Japan and countries in the European Medicines Agency (EMEA)) would be eligible for fast tracking in India, with approval taking no more than two to four weeks. Trials in category B would fall under more scrutiny; with approval taking 12 weeks once an application is considered under Category B, it, in any case, cannot be shifted to Category A. Nearly all global trials are in the Category A.

The Indian Government gave another boost to the drug-development industry by canceling the 12 percent service tax on clinical trials in 2007.[44] In February 2009, the industry applauded new regulations on exporting samples. Previously, an export license was needed to get samples out of India but it has been removed now saving the time.

Current Drug Regulatory Procedures

A comprehensive understanding of regulatory issues is paramount due to dynamic changes at national and international levels, especially with reference to ongoing changes in Good Manufacturing Practices (GMP),[45] Good Clinical Practices (GCP),[46] Good Laboratory Practice (GLP)[47] and Good Clinical Laboratory Practices (GCLP).[48] Sometimes a word ‘current’ is used as prefix to depict the dynamic nature of these guidelines. It is the responsibility of regulatory bodies in India to ensure a quality drug supply, their monitoring in the market and maintaining rights, safety and well-being of the clinical trials participants. Towards this end, there are multiple regulatory bodies entrusted with the responsibility of ensuring production, pre-clinical, clinical trials and marketing of the drugs including pricing.

The Central Drugs Standard Control Organization (CDSCO) under Ministry of Health and Family Welfare (MoH and FW) prescribes standards for ensuring safety, efficacy and quality of drugs, cosmetics, diagnostics and devices in India. It also regulates the market authorization of new drugs and clinical trials standards; supervises drug imports and approves license to manufacture.[49] The Department of Chemical and Petrochemicals of Ministry of Chemicals and Fertilizers through National Pharmaceutical Pricing Authority (NPPA)[50] sets or revise the prices of drugs; maintains data on production, exports and imports; and enforces and monitors the availability of medicines and also gives opinions to parliament on the related issues. It also ensures administration of Drug Policy, 1986 (updated in 2002);[51] Drug (Price Control) Order, 1995[52] and Pharmaceutical Policy, 2002.[53]

There are two main ministries which regulate the drugs in India; the Ministry of Health and Family Welfare[57] concerned with public health and the Ministry of Chemicals and Fertilizers[58] on Industrial policy. Other ministries, though indirect, also have a role in regulation process; Ministry of Environment and Forests,[59] Ministry of Finance,[60] Ministry of Commerce and Industry[61] and the Ministry of Science and Technology.[62] Regulation of Patents, drug exports is governed by Department of Industrial Policy and Promotion[61] and Directorate General of Foreign Trade under the aegis of Ministry of Commerce and Industry[63] and the Ministry of Chemical and Fertilizers[58] respectively. Licensing and quality control and distribution maintained by CDSCO, MoH and FW, Department of Biotechnology, Ministry of Science and Technology (DST) and Department of Environment and Forests especially after the decline of vulture population.

Apart from these there are other Statutes and ministries [Tables 2 and 3] that regulate the various aspects of drugs such as; the poison Act, 1919;[64] the Pharmacy Act, 1948;[65] the Drug and Magic Remedies (Objectionable Advertisement) Act, 1954;[66] the Narcotic Drugs and Psychotropic Substances Act, 1985;[67] the Insecticide Act, 1968;[68] The Medicinal and Toilet preparation (Excise duties) Act, 1956[69] and The Drug (Price Control) Order, 1995 (under the essential commodities Act).[70] Some more laws having a bearing on pharmaceutical manufacture, distribution and sale in India are The Industries (Development and Regulation) Act, 1951,[71] The Trade and Merchandise Marks Act, 1958,[72] The Indian Patent Act, 1970[73] and the Design Act, 2000[74] and the Factories Act, 1948.[75]

Table 2

Regulatory bodies in india involved in drug regulation

Table 3

Statutes related to drug regulation

Lack of co-ordination between various agencies has resulted in approvals of around 33 drugs without any Clinical trials between January 2008 and October 2010 as concluded by the 59th report of Parliamentary Standing Committee on Health and Family Welfare.[76] However, clinical trials in India are regulated by the following guidelines/rules such as Rule 122 A to E of Drugs and Cosmetic Act,[77] Schedules Y of Drugs and Cosmetic Act and Rules thereunder (Amended in 2005), GCP guidelines issued by CDSCO in 2001 and Ethical guidelines for Biomedical Research on Human Subjects by ICMR. Rule 122 DA of D and C[37] Act enshrines that Clinical Trials for a new drug/investigational new drug, whether for clinical investigations, or any clinical experiment by an institution shall be conducted except under, in accordance with, the permission, in writing of the Licensing Authority designated by Central Authority while Rule 122 E[78] of Schedule Y clearly defines ‘new drug’ as new molecules as well as drugs used abroad but to be introduced for the first time in the country. New indication or new dosage form of an already approved drug is also considered as a new drug. Even fixed dose combinations of drugs already in use are considered as new drugs. Clinical trials has been defined in Rule 122DAA[44] of the D and C Act in India as “Systemic study of new drugs in human subject(s) to generate data for discovery and/or verifying the clinical, pharmacological (including pharmacodynamics and pharmacokinetics) and/or adverse effects with the objective of determining safety and/or efficacy of the new drugs.

It has to be a responsibility of all stakeholders viz., Investigators, Ethics Committee, Sponsor, Regulatory authority to ensure the safety and wellbeing of subjects and obtaining the quality data. New revised schedule Y of D and C act is step of Indian Government towards harmonizing with the guidelines of International bodies such as World Health Organization (WHO) and ICH guidelines based on ‘Declaration of Helsinki’.[77] For conducting a Clinical trial in India it is necessary to apply in prescribed Form ‘44’ along with requisite fees.

Indian government has strengthened CDSCO and DCG (I) office by expanding and reorganizing it along the line of FDA. DCG (I) along with ICMR have adopted many international guidelines for framing the local regulatory version such as guidelines. Schedule Y defines the clinical trials as the requirements and guidelines for import and manufacture of new drugs for sale or for clinical trials. It describes the details of application process for conducting clinical trials; responsibilities of the sponsor, investigators and the Independent Ethics Committee.

A Clinical Trials can only be initiated after obtaining written permission from IEC and DCG (I). Application utilizes form 44 accompanied by the requirement [Table 4], as per schedule Y, such as documents pertaining chemical, pharmaceutical information, animal pharmacology, toxicology and clinical pharmacology data. Other documents submitted with application are investigator's brochure, trial protocol, case report form, informed consent form, patient information sheet and investigator's undertaking. Additional requirements for studies in special population, e.g., children, pregnant women, nursing women, elderly patients, patients with renal or other organ system failure, and those on specific concomitant medication(s). The protocol must be reviewed and approved by an IEC, at minimum, seven members, including a medical scientist, a clinician, a statistician, a legal expert, a social scientist and a common person from the community.

Table 4

Important forms and rules of drug and cosmetic act for clinical research

Once approved by DCG(I) and IEC, an applicant can start clinical trial as per Schedule Y. Product imported from other countries require a separate license called ‘T-license’ (Trial License), This license is valid for multiple shipments for one year and issued simultaneously with that of the clinical trial approval. A No Objection Certificate (NOC) through separate application is required for shipping biological samples collected from the trial subjects out of India. Both T-License and NOC are granted within two to four weeks after approval of the study.

The protocol of the study can be amended in between, if necessary, whether major or minor changes. But all amendments should be notified in writing to the DCGI along with the approval of ethics committee. No changes should be implemented, unless to eliminate hazards to the participating subjects, without prior written approval of Ethics Committee and the DCGI. However administrative and/or logistic changes in the protocol should be notified to the approving authorities within 30 days of implementation. All unexpected serious adverse events (SAEs) must be communicate to the DCG (I), Directorate General of Health Services, CDSCO, Pharmaceutical company, Sponsor, CRO and all participating study investigators within 14 calendar days.[79] SAE notification must be submitted along with the proof that the same information has been submitted to the regulatory agencies in other countries where study is being conducted.

In addition sponsor is required to submit progress report every 6 months[80] as per the schedule Y format. For studies which are prematurely discontinued for any reason, a summary report should be submitted within three months. This report should provide a brief study description, the number of patients exposed to the drugs, dose and duration of exposure, details of adverse drug reactions, if any, and the reason for discontinuing the study or not pursuing the new drug application.

Latest Regulatory Initiatives

With the increasing pressure to manage research and development (R and D) in pharmaceutical industry, the government is taking many more initiatives to regulate it.

Registration of Clinical Trials

Indian council of medical research (ICMR) has started an online registration system of clinical trials in 2007 known as ‘Clinical Trial Registration-India (CTRI).[81] Mainly western and southern cities in India are involved in clinical trials related activities such as Mumbai, Pune, Ahmedabad, Hyderabad, Bangalore and Chennai.

Pharmacovigilance Programme For India

Although every sponsor is mandated to submit developmental safety update report and periodic safety update report but many drugs when exposed to larger masses during the marketing cause newer and unpredictable adverse effects. The government of India has launched the Pharmacovigilance Programme for India (PVPI)[82] in July 2010 through CDSCO to monitor such developments. It is to be launched in five phases. The first phase was introduced in mid-2010 with an objective of inducting ADR Monitoring Center (AMC) in 40 Medical colleges in one year; 60 more AMC centers are to be added by early 2012 and 100 by 2013. Various hospitals, Medical Colleges and private nursing homes will be covered till 2014. CDSCO will provide the operational and logistic support such as Internet connection, computer, telephone line and WHO will provide free softwares for ADR monitoring such as VigiBase and PaniFlow for ADRs due to vaccines. The National Coordinating Center (NCC) of PVPI is located at ‘Indian Pharmacopoeia Commission (IPC), Ghaziabad’[83] and provides all the technical supports to the CDSCO office. ADR reports generated at AMCs are sent to coordinating center which collate, assess and incorporate them into Pharmacovigilance database. The reports finally conveyed to WHO-Uppsala Monitoring Center ADR database.

Registration of Clinical Research Organisation

Clinical Research activities by pharmaceutical firms are generally outsourced to Clinical Research Organizations (CROs). There are many issues associated with clinical trials like inadequate informed consent, weaknesses of IRB/IEC, inadequate compensation and lack of post-access treatment by these CROs. CDSCO has put up a registration criteria and has issued a draft rules for these mushrooming CROs registration. As per schedule Y-1,[84] a CRO can carry out clinical research activities for five years if it is duly registered.

Speeding Up Review Process

Review process of clinical trials related applications by CDSCO has been very slow earlier but it has been speeded up by dividing applications in two categories; Category A – is a category where applications are received from the countries where review processes are matured and follow international ethical norms. Category B contains applications from other countries. The median review process has reduced from 16 weeks to 10 weeks and is targeted to be 45 days only. The introduction of e-governance initiatives has made file tracking system and daily dispatch of reports more transparent and accountable.

Clinical Trial Inspection

In 2008 the CDSCO started inspection of clinical trials in India.[85] But Full fledge onsite inspection started quite recently in 2010 by US-FDA trained Indian Inspectors and regulatory experts to uphold the quality of the trials. CDSCO has also started a Clinical Trial Inspection Programme and released a guidance document for clinical trial inspection of the site of clinical trial, Sponsor and CROs facilities as well as providing information to the investigators, Sponsors and CROs about procedures of inspection and follow up action.

Despite good guidelines in the book, there implementation has been a problem for the government. Many cases including Anticancer drug study in Kerala,[38] recruitment of poor family's children at AIIMS resulting in death of around 49 kids[86] points to the finger at the weaknesses of Institutional Review board/Independent Ethics committee.

Furthermore, many startling lapses on the part of Indian drug regulatory bodies have surfaced after the observation of 59th report of the Parliamentary Standing Committee on Health and Family Welfare. It is now obvious that much more needs to be done to prevent the unnecessary approvals of drug under waiver clause of 122A, 122B, 122D, 122DA, 122DAA and 122E of the Schedule Y rules and blocking the approvals of FDCs which are already banned in other countries.

In our view the Indian regulatory agency still have much to learn and realize the need for availability of safe medication in the public domain. There is a need to introduce new updated dynamic monitoring tools such as Adverse Events Reporting system (AERS) inbuilt in its website and Risk Evaluation and Mitigation Strategies (REMS) by the pharmaceutical companies as needed by FDA. It needs to frame a more systematic review process of drugs before approval as well as framing a priority review setup for Indian specific drugs discovery and marketing.