RAJIV GANDHI SCHOOL OF INTELLECTUAL PROPERTY LAW
INDIAN INSTITUTE OF TECHNOLOGY, KHARAGPUR
CLINICAL TRIAL-Evaluation of role of regulatory and administrative authorities in the backdrop of the concept of good governance.
Submitted by Sajal Dutta
RGSOIPL,IIT,KGP
Roll no. 06IP6040
Dated:11-04-2008
Contents:
1. Introduction
2. Country Background
3. Patients’ Rights and Safety
4. Opportunities and operational deficiencies for clinical trial in India
4.1 Role of Institutional Ethical Committee in Clinical ethics
4.2 Institutional ethical committees- Indian scenario
5. Phases of Clinical Trials
6. Strengthening ICMR control
7. Regulatory Framework
8. Conduct of Illegal/Unethical Trials
9. Infrastructure
9.1 Training
10. Pricing
11. Capacity building for clinical trial in India
12. Regulatory authority and rules
13. Testing drugs in human subjects
14. Formation of central drugs authority of India
15. Clinical Trials and Regulatory Tribunals
15.1 The principal investigator and participating investigators
15.2 Self-regulation required while India's clinical regulatory body matures
Conclusion
Bibliography
1. Introduction:
Clinical trial or research is an indispensable part of the drug discovery process to ensure the safety and efficacy of any new drug. In today’s global scientific era, clinical trials are the mainstay for bringing newer and better drugs to market. Although a set of robust guidelines is available to govern the conduct of clinical trials in any country, the conduct of clinical research is also looked upon as an area of humanitarian concern. Various articles published recently in the professional and popular press enumerate the opportunities and challenges of conducting global clinical trials in India. However, the majority have been from the perspective of authors who have never conducted clinical trials in India themselves. In contrast, this article conveys the perspective of someone who has worked as a principal investigator for various global clinical trials in medical oncology.
2. Country Background:
A nation with more than 1 billion people, India has the second largest population in the world. Having gained its independence from British rule in 1947, its prime minister is the head of government and its president is the head of state. Internationally, India became a member of the World Trade Organization (WTO) in 1995 and agreed to adhere to the product patent regime by 2005. As a result, the global pharmaceutical industry has the rights to patent products as well as processes throughout the world, including India. This has led to a significant growth of the pharmaceutical industry, both domestically in India and globally, including increased stakes of multinational companies in Indian operations. As a signatory to the WTO agreements, India is looked upon as a favorable destination for conducting global clinical trials. India clearly provides an opportunity in terms of availability of large patient populations, highly educated talent, a wide spectrum of disease, lower costs of operations, and a favorable economic and intellectual property environment. The overall time and cost advantage in bringing a drug to market by leveraging India’s resources could be as high as millions of dollars, hence the steadily increasing number of global studies in India over the past two years. Major pharmaceutical companies estimate the total market for conducting clinical trials either directly or through contract research organizations (CROs) in India through 2010.CROs themselves are fast gaining importance because of their global presence, specialized local expertise, and competition pricing strategies. And a significant number of new CROs have set up operations in India over the past two years. However, some key barriers stand in the way of opportunities, including patients’ rights and safety, regulatory framework, infrastructure, organization of ethics committees, data quality, lack of training curricula focusing on clinical research, and other factors. Most of these barriers are common to all developing countries and need to be addressed in a similar way. Because the clinical investigator plays a major role in the ethical conduct of any clinical trial, its successful outcome depends on how the investigator(s) has assumed overall responsibility. Most of the barriers mentioned above can be easily addressed if a clinical investigator is committed to the ethical conduct of trials. A segment of ideologues in India believe that clinical trials conduct poses a serious threat to society because of issues related to patient rights and safety, regulatory compliance, unethical trials, infrastructure and training issues, and exorbitant drug pricing. These threats are perceptions, not reality.
3. Patients’ Rights and Safety:
In today’s scientific era, research is taking major strides in multiple areas to develop new and better drugs to cure ailments that are difficult to treat. In a majority of cases, these drugs are aimed at providing answers to unmet medical needs. However, the drug development process requires 10 to 12 years on average to reach the marketing approval stage. Participation in clinical trials provides an opportunity to experience the benefits of these new drugs. So a critically ill patient who participates in a clinical trial, and who may not be alive after 8 to 10 years when the drug would be made available in the market, has access to what may provide either longer term health benefits or an improved quality of life. By carefully evaluating the eligibility criteria, a clinical investigator can offer new hope to patients across a wide range of therapeutic areas. Participation in clinical trials also provides research professionals opportunities to offer the best care to patients. A well-designed and executed study has built-in provisions to ensure patient rights and safety. In fact, a patient may be far safer in a clinical trial than in routine medical care because careful observations are made on safety (toxicity) and efficacy. In addition, clinical trials move in phases, that is, Phase II trials are initiated only if the Phase I results are promising. Similarly, Phase III trials are conducted only if the drug has shown required safety and efficacy in early phase trials. Hence, a patient is at minimized risk during later phases of clinical trials. In contrast, historical events like the sulfanilamide and thalidomide disasters could have been avoided with appropriate clinical trials. This phase process is particularly important in developing countries if carefully understood and explained to potential subjects.
4. Opportunities and operational deficiencies for clinical trial in India:
Clinical Research industry in India is set for a major growth in terms of revenue. The growth of clinical industry is directly linked to the growth of health industry in India as well as world over. In particular increase in research and development activities would lead to a higher demand for clinical trial services which meet global standards.
Opportunities-
Favorable environment: Increasing the expenditure on drug development, lengthening time lines for clinical trials, patent regime, changing regulations have become serious problems/bottlenecks in pharmaceutical research for the past decade. The emerging positive trends in India offer a potential solution to some of these problems. There are key broad areas to leverage the advantages that India offers to the established pharma and biotech industries. These include contract research, R & D alliances, and clinical trials.
Higher growth in Asia Pacific: As pharmaceutical and biotechnology companies continue to explore new geographic opportunities to expand their pipelines products and create business efficiencies of Asia-Pacific market growing. The quality of science and capabilities in drug discovery vary widely between India, China, Japan, Taiwan and Singapore. Pharmaceutical R & D expenditure in Asia is growing faster than in United States and Europe.
New patent Regime: The new patent regime will have a potential impact on domestic and foreign companies doing business in India. The protection of intellectual property rights I India which was one of the biggest concerns of global pharmaceutical companies seeking to enter India in the past has changed rapidly to post- Trade Related Aspect of Intellectual Property rights (TRIPs) and World trade Organization (WTO) scenario. A well established statutory, administrative and judicial framework, to safeguard intellectual property rights in India is slowly gaining momentum. It is focused on issues like infringement drug discovery, patents, royalties, damage exemptions for clinical trials and statutes blocking importation of products.
Alliances: India has already established its strength in developing, manufacturing and marketing generic products for global market. This success is attributed primarily to its strength in the prices chemistry, formulation development and manufacturing areas. Transition to innovate R & D is naturally the next step for India. There are a number of contract research organizations that offer quality and cost-effective services in medical chemistry, formulation development and toxicology areas. In order to leverage these resources, pharma companies from developed countries are already forging R & D alliances with Indian companies. These alliances are giving preclinical candidate or clinical candidates with proof of concept in humans.
Cost Advantage: The probability of success increases to about 50-75% once a molecule enters phase III clinical trials. By conducting R & D on new molecule up to Phase II of clinical trials in India, the cost of innovation and development can be drastically reduced. It is conceivable to reduce the cost of failure and eventually overall cost of bringing new medicines to patients. This is one of the unique opportunities in India. Low cost of innovation and development will allow bringing new molecules for the neglected diseases to market at a much reduced cost. Since the medicines for neglected disease must be affordable to patients in the poor countries, it is essential to develop these drugs in the most cost effective manner. Early estimates are that drugs could be tested in India at 60% of the price.
Established Pharma Companies: Indian companies are highly capable in research and development particularly in drug discovery. It has already proven its capability in discovering and developing drug candidate molecules. A number of development candidates are out licensed by Indian companies to the medium size as well as large pharmaceutical companies in the developed countries. The trend is expected to continue. In India alternative medicine system are well established. However the molecular mechanism of action and identify active ingredients may not be known for most of these traditional medicines. There are opportunities to apply modern science to elucidate molecular mechanism of action and to identify active ingredients of these medicines. The process of reverse pharmacology can be applied to discover new drug candidate molecules from these traditional medicines.
Operational Deficiencies-
The increase in clinical trials is fueled by the recent push for global commerce. Regulatory uncertainties about time to approval, involvement of multiple agencies for approval of biotech products and for processing import/export licenses, and several other factors are hurdles in planning clinical trials. A large majority of potential investigators lack knowledge of regulations, ethics and GCP and skills for clinical trial management. The quality of global trials and academic clinical research is not uniform. There are also issues of inadequate permanent research staff and lack of adequate infrastructure for communication, drug/sample storage, archival. The situation is worse in non-metro cities which have tremendous potential for participation in global trials. In addition the institutional policies are not geared up to support the investigator in managing clinical trials efficiently. Perhaps the most important challenge is that of designing elegant clinical trials that will test concepts rather than simply compare products. Some of the major operational deficiencies are as follows:
Government policies: Regulatory approvals in India can take three months or more, compared to 30 days in US. Even more serious is the lack of confidentiality. Unlike India, China does not yet grant protection for data gleaned from clinical trials, which makes it easy for generic drug makers to copy the drug under trial. Under the India’s existing laws, only those drugs that have already passed phase-I safety trials in the country of their origin can be tested on Indians.
Weak patent law: In India opportunities will become limited unless there is a very strong patent law and mechanism to enforce it. Drafting patent law with the help of industry experts and its implementations is highly essential.
4.1 Role of Institutional Ethical Committee in Clinical ethics:
The potential importance of the IEC’s consultative role has been recognized in numerous ways. Health care organization has an established mechanism to address conflicts, requirements of most often met by establishing a IEC. Law suggests that IEC deliberations may serve as evidence in court, proposals to establish an IEC as an alternative judicial review and requirement of the joint commission on accreditation of health care organizations.
4.2 Institutional ethical committees- Indian scenario:
In India, ethical guidelines drafted by Indian Council of Medical Research (ICMR) for conducting biomedical research in laboratory animals and clinical trials for new drugs on human population. The institute was given authority to monitor the implementation of ethical guidelines in clinical trials and biomedical research activities. Each institute has its own ethical committee for monitoring the guidelines. As per the guidelines, at any stage, any deviation in ethics, on the basis of religion, socioeconomic status, protecting the confidentiality of the volunteers will be awarded severe punishments. All the life science researchers, particularly biomedical researchers, working with laboratory animals, human patients, and volunteers in clinical trials have to follow the guidelines strictly.
The clinical trials usually are of 3 types as per ICMR guidelines-
I. studies where intervention is clearly “demarcated research” such as phase I trial of a new compound;
II. Studies with a mix of standard medical practices and specific research elements, e.g. trials of two competing ant nausea drugs following standard chemotherapy;
III. Studies involving research on therapeutic practices, such as the trial of two already approved anti-diabetic drugs.
5. Phases of Clinical Trials:
All phases require approval from EC. The first three of the following four phases of clinical trials of drug require Drug Controller General of India's clearance: -
Phase-I (Human Pharmacology) - This is a non-therapeutic trial and the objective is to determine the safety of a new drug and determine the maximum tolerated dose as also to determine the nature of adverse reactions that can be expected. In healthy adults of both sexes. Healthy female volunteers could be included provided they have completed their family or do not intend to have a child in the future. These studies include both single and multiple dose administration and should ideally be carried out at a site that is adequately equipped.
Combined Phase I and Phase II - Such trials are conducted on populations for whom the therapeutic options are exhausted, as in the case of HIV/AIDS and cancer. Toxic drugs like anti-retroviral or anti-cancer drug, cannot be tested in normal healthy volunteers as in Phase I studies as the risk far outweighs any benefit. Hence such studies are planned in patients suffering from the disease so that the risk benefit ratio is more favorable. Since here the patient population is a vulnerable group and trial on them has to be planned very carefully.
Phase II (Therapeutic Exploratory Trials) - These are controlled studies conducted in a limited number of patients of either sex to determine therapeutic effects, effective dose range and further evaluation of safety and pharmacokinetics in patients. Generally due to selection of patients with narrow inclusion criteria to find effective dose the study population is more or less homogenous. The dose used is lesser than the highest dose used in phase I. Another objective of this Phase II is evaluation of potential study endpoints, therapeutic regimens including concomitant medications and target populations, and mild versus severe disease, for further studies in Phase II or III. These objectives may be served by exploratory analyses of subsets of data and by including multiple endpoints in trials. Normally 20-25 patients should be studied for assessment of each dosage. These studies are usually limited to 3-4 centre. It is advisable to include a clinical pharmacologist as a co-investigator in such studies.
Phase III (Therapeutic Confirmatory Trials) – The purpose of these trials is to obtain adequate data about the efficacy and safety of drugs in a larger number of patients of either sex in multiple centre usually in comparison with a standard drug and / or a placebo if a standard drug does not exist for the disease under study. This is to validate efficacy and safety found in Phase II. On successful completion of phase III trials permission is granted for marketing of the drug.
Phase IV - The Phase IV studies should have valid scientific objectives. After approval of the drug for marketing, phase IV studies or post marketing surveillance is undertaken to obtain additional information about the risks and benefits resulting from long term usage of drug. It is an important aspect of drug trial on the long term effects of the drugs and the adverse reactions induced by drugs, if any, should be brought to the notice of the Ethics Committee. There is a need to correlate the adverse events reported during Phase IV trials with the toxicity data generated in animals, to draw markers for future warnings of potential adverse events likely to occur with other drugs. These trials may not be necessary for approval of new drug for marketing but may be required by the Licensing Authority for optimizing its use.
6. Strengthening ICMR control:
ICMR lacks the authority to take action against unethical IECs. There exists no mechanism for accreditation of IECs and quality control of ethics review is practically impossible. There is no comprehensive database on either IECs or Research participants. India has also given birth of unaffiliated Ethics Committees to review protocols for institutions with no IECs, supported by fees from the pharmaceutical industry. Institutional mechanisms for ethical reviewing of research involving human participants in India are weak and vulnerable. A concerned effort is required to strengthen them to fulfill their stated missions. The problem is likely to be worse in India. These are major threats to the international companies to conduct clinical trials in India.
7. Regulatory Framework:
Multinational pharmaceutical companies and CROs are able to conduct good quality clinical trials in India despite infrastructural challenges at the regulatory department level. They can do so because of required professional training and the professionals’ willingness to comply with regulations and applicable standards in a spirit that protects the rights and safety of trial subjects. In India, no less than in the rest of the world, it is the responsibility of individual stakeholders (sponsors, CROs, investigators) to observe self-discipline while conducting clinical trials, especially when there are more than 20,000 big and small companies and a mere handful of regulatory professionals. The belief that compliance with Good Clinical Practices (GCP) and applicable regulatory guidelines requires the presence of a robust regulatory inspection system is erroneous. Rather, what may be required is a change of mindset from one of “situational ethics” (that is, compliance with medical ethics in clinical trials only) to one of “holistic ethics” (that is, compliance with medical ethics in clinical trials as well as routine medical care).
No regulatory authority can ensure 100% GCP compliance unless the individual stakeholders are willing to comply with the applicable regulations.
8. Conduct of Illegal/Unethical Trials:
Scientific misconduct is a global phenomenon linked to human behavior rather than to an individual country. For instance, the U.S. Food and Drug Administration (FDA) website lists the details of clinical investigators who have been “disqualified” or “restricted” from doing research on grounds of scientific misconduct. Details of warning letters issued to various stakeholders (clinical investigator, ERB/IRB, sponsor, CRO, etc.) can also be obtained from the same website. However, FDA has not banned clinical trials based on these grounds, these individuals, or individual organizations. Rather, FDA has increased its surveillance over clinical research programs. In like manner, the Indian regulatory authority is also in the process of setting up surveillance teams for ensuring ethical conduct of clinical trials. Companies acting ethically set globally consistent standards and conduct trials only in the countries where GCP compliance is assured. Indian investigators have demonstrated their compliance by virtue of participation in more than 60 global trials so far. Moreover, a majority of those trials were FDA or European registration trials, requiring strict compliance with GCP and regulatory guidelines. The data have been accepted by foreign regulatory authorities and published in international scientific journals of repute.
9. Infrastructure:
Participation in global clinical trials requires an upgrade in existing infrastructure and facilities at a majority of Indian hospitals in terms of functioning of ERB/IRB, calibration and quality control of diagnostic equipments, maintenance of patient medical records, handling of investigational product, and other critical areas. There have been instances of sponsors providing highly expensive diagnostic instruments to trial sites in order to achieve consistency in trial data globally. All the trials include investigator grants and funding that is generally utilized to upgrade the infrastructure and education facilities at a site. The Institutional Ethics Committees at a majority of Indian hospitals are gaining competence in evaluating the trial proposals from scientific and ethical standpoints. This, in turn, is strengthening the healthcare system of the country while bolstering the ability of institutions to conduct research. In short, clinical research or trials offers value and value-added infrastructural incentives to the country.
9.1 Training:
Lack of technical know how on drug development and the habit of “copying” (mostly producing generic drugs) are the major hurdles for indigenous drug research. Participation in global trials provides learning opportunities to Indian doctors and scientists, which in turn can be utilized to find the answers for the diseases that are endemic to the country, such as kala-azar, leprosy, trachoma, and tuberculosis. The medical research intellectual base of the country has been sub optimally utilized so far due to the absence of basic research facilities and knows how. Participation of Indian investigators in global trials and subsequent publication/ presentation motivates them to develop research protocols for domestic healthcare issues. This, in turn, is nurturing a culture of medical research that can match international standards.
10. Pricing
Less than 10% by value of drugs used in India are of the premium category; the other 90% are established off-patent drugs (drugs for which multiple generic versions are available). Even for premium category drugs, the pricing is generally moderated by three important factors:-
A. the purchasing power of the customers;
B. the existence of unpatented drugs and cheaper substitutes; and
C. the Drug Price Control Order,
Which regulates the pricing of essential life-saving drugs in India? Even today, people who can afford the premium category drugs are getting them imported from the West or are traveling to other countries to get better medical care. The availability of such drugs in India is going to reduce the overall healthcare cost.
11. Capacity building for clinical trial in India:
Recent events worldwide have challenged the integrity of research on pharmaceutical products and have triggered calls by legislators, medical associations, the International Committee of Medical Journal Editors (ICMJE), the World Health Organization (WHO) and others, for increased accountability and transparency in health products research and development. India, which is projected to have accelerated growth in this sector with the entry of a number of major global and domestic players and a more research focused pharmaceutical industry, is poised to face formidable challenges.
Building the right kind of capacity to meet the anticipated demand for clinical trials in India is an important issue. Along with the optimism for growth in this industry is the concern that vulnerable populations may be exploited. Access to experimental drugs, exposure to latest therapies, improvement in equipment and infrastructure, and creation of new knowledge assets are among the many benefits of this growth. New, difficult to meet expectations and moving local resources away from basic healthcare are among costs and risks of this enterprise. The regulatory regime in India has to identify ways of creating a balance between these benefits and costs/risks.
There is a need at the present time for a strong centralized regulatory regime which can guide high quality development of ethical capacity with extra vigilance but an informed understanding of acceptable risk. Such a system while conforming to international standards needs to be uniquely Indian. It needs to include indigenous medicine, devices, drugs and therapies while incorporating the advent of biotechnology in general and genomics and proteomics in particular.
While Good Clinical Practices (GCPs) have been clearly spelt out and ethical guidelines have been articulated, our experience with implementation is relatively short. The regulatory system is already stretched in terms of its ability to monitor proper implementation. The expected fast growth in the industry is going to further stretch the capabilities of the system and highlight complexities and unintended consequences.
Clinical trials have different types of risks associated with them. Ability to safely perform a trial is a challenge and should be factored into the prioritization process. Thus, a placebo trial involving vulnerable population (including socio economically vulnerable) will have a higher risk and may be given a different priority. Higher risk trials need to have special monitoring and more intense review. Risk should include a "site's" ability to safely conduct the trials and the pool from which trial subjects are sought. A number of operational issues to implement such a system of priorities need to be discussed and procedures developed. A working group to measure risk associated with "site capabilities" needs to be constituted. This may be particularly relevant for approval of Phase 1 trials. Criteria for "disallowed" trials as well as guidelines for exceptions should be specified.
Ethics Committees, ethical guidelines and norms, and independent review boards are all different ways of ensuing compliance with established ethical guidelines and good practices. Ethics committees cannot conduct their task responsibly unless they get the data needed to evaluate ethical behavior. There has been an unprecedented growth in CROs in India with most Indian and major multinationals setting up operations in India either directly or as joint ventures.
There is no system of registration and/ or approval of such organizations. Quality control and potential for abuse remain a major concern for the nation, for which there is need for self regulation through accreditation as well as legislation, to ensure high standards through a system of monitoring by a regulatory agency.
There has been a global demand that all clinical trials be registered as also emphasized by the ICMJE. The ICMJE has made registration of trials mandatory without which they will not publish the results of trials. The WHO has suggested a structure of the registry with a minimum required data set to be followed by all countries. An Indian registry, with the minimum data set and requirements suggested by WHO, needs to be implemented. It is important to include stakeholders from industry, national laboratories and regulatory authority in the development of such a registry in order to get compliance. The help of IT could be used to ensure quality data management.
12. Regulatory authority and rules:
The Indian Clinical Research Outsourcing (CRO) industry is growing rapidly and brings with it attendant regulatory concerns. Of special concern is the matter of Phase- I trials which, in general terms, are first-time trials in the country on human subjects of new drugs especially of investigational new drugs. Since this involves testing on humans of new drugs that is to say drugs generally inadequately tested before on humans, and in the context of investigational new drugs, not tested at all on humans before, the subject is understandably sensitive in the public domain as well. The initial testing on humans of drugs recently invented or discovered in the laboratory and having been tested, if at all, only on animal subjects, is a subject potentially capable of abuse in the absence of proper legal regulation, as featured indeed in a number of books and films. It remains a matter of concern for all jurisdictions and particularly of weak, less developed and more vulnerable ones.
Clinical Trial is now, since January 20, 2005, defined in Rule 122 DAA of Drugs and Cosmetics Rules, 1945 is as follows:
Clinical trial means a systematic study of new drug(s) in human subject(s) to generate data for discovering and/or verifying the clinical, pharmacological (including pharmaco dynamic and pharmacokinetic) and /or adverse effects with the objective of determining safety and / or efficacy of the new drug.
The Rules themselves are framed under the Drugs and Cosmetics Act, 1940, the principal statute in the field. This is a law enacted by Parliament and applies along with the Rules, in all the states in the country. Drugs themselves to which the statute applies are defined in Section 3 (b) of the Act.
To take drug development to the market, clinical research is necessary at different stages to different ends. These are broadly categorized in phases, Phase I being the earliest and Phase IV being the last.
Rule 122 DA of Drugs and Cosmetics Rules, 1945 requires an application to be made to the statutory Licensing Authority for permission to conduct clinical trials for New Drug/Investigational New Drug and for prior permission to be granted before conducting the clinical trial. This Rule is extracted hereunder in relevant part for a Phase-I trial.
122DA. Application for permission to conduct clinical trials for New Drug/Investigational New Drug
(1) No clinical trial for a new drug, whether for clinical investigation or any clinical experiment by any Institution, shall be conducted except under, and in accordance with, the permission in writing of the Licensing Authority defined in clause (b) of rule 21.
(2) An application for grant of permission to conduct-
(a) human clinical trials (Phase-I) on a new drug shall be made to the Licensing Authority in Form 44 accompanied by a fee of fifty thousand rupees and such information and data as required under Schedule Y.
.
Provided that the Licensing Authority shall, where the data provided on the clinical trials is inadequate, intimate the applicant in writing…intimating the conditions which shall be satisfied before permission could be considered.
Under Schedule Y, Paragraph 2 (6), Phase- I trials are described. As per this-
The objective of studies in Phase I is the estimation of safety and tolerability with the initial administration of an investigational new drug into human(s). Studies in this Phase of development usually have non-therapeutic objectives and may be conducted in healthy volunteer’s subjects or certain types of patients. Drugs with significant potential toxicity e.g. cytotoxic drugs are usually studied in patients. Studies conducted in Phase I, usually intended to evaluate maximum tolerated dose, pharmacokinetics, pharmacodynamics and early measurement of drug activity.
It is only after completion of Phase I trial, the subsequent phases of trial can take place.
A conjoint reading of Rule 122DA (2) (a) and Schedule Y, paragraph 2 (6) indicates that an application and grant of permission is envisaged and is necessary for conducting Phase-I trials in India, which by definition are trials of ‘investigational new drugs’, that is to say new drugs not having previously been tested on humans anywhere. The statutory definition of ‘Investigational New Drug’ means a new chemical entity or product having therapeutic indication but which have never been tested on human being." The Rule by itself without reference to the Schedule seems to cover Phase I trials of ‘New Drug’ more generally defined in Section 122E of The Drug and Cosmetics Act as "a drug" which has not been used in the country to any significant extent under the conditions prescribed, recommended or suggested in the labeling thereof .. even if it is not an ‘Investigational New Drug.’ A reading of the Rule by itself leaves it open to the interpretation that for Phase-I trials, Schedule Y is relevant only for indicating the ‘information and data’ required to support the application. But the scope of the Rule gets restricted to only ‘Investigational New Drugs’ in light of the description of Phase-I in the Schedule as being limited to ‘Investigational New Drugs.’ The reference in the Rule to the Schedule is mandated by the express stipulation in this regard in the language of Clause 2 (a) of the Rule itself. It becomes clear from this that Phase-I trials concerns testing of drugs on human subjects in India of drugs that have never been tested before on human subjects and that applications are maintainable to carry out such tests and permissions will be granted in suitable cases by the Indian Licensing Authority. It is also notable that the statutory provisions cited above do not distinguish between indigenous and foreign ‘investigational new drugs.’ That is to say, that in considering applications for Phase-I trial in India permissions, the provisions noticed above do not disqualify drugs discovered or developed outside India but instead specifically envisaged as a category in which applications will be entertained and considered for grant of the necessary permission.
What cases of Phase-I trials of foreign drugs will be considered suitable by the Licensing Authority for grant for permission, is governed statutorily yet appears to leave some scope for non-statutory discretion to be exercised ad hoc or in terms of a policy decision. To understand the scope of this discretion, one needs to appreciate the legal position prevailing until 20th January of 2005 when the law was amended, as well as the change in the law.
Earlier, an ‘investigational new drug’ was not a statutory expression. Previously Rule 122-A governed licenses to import new drugs including for the purposes of trials which were required to comply with the guidelines for the same as set out in Schedule Y (unamended). The earlier Rule did not deal specifically with ‘investigational new drugs’ nor specifically with any particular Phase of trial such as Phase-I. Earlier the description of Phase-I trials in Schedule Y did not specifically make it applicable to ‘investigational new drugs,’ in the sense of the expression as only now defined. And the earlier Schedule Y expressly made a distinction between foreign drugs and indigenously discovered or developed drugs. In relevant part, the earlier Schedule Y read as under-
Nature of clinical trials.- The clinical trials required to be carried out in the country before a new drug is approved for marketing depend on the status of the drug in other countries. If the drug is not approved/marketed trials are generally allowed to be initiated at one phase earlier to the phase of trials in other countries.
For new drug substances discovered in other countries phase I trials are not usually allowed to be initiated in India unless phase I data as required under Item 5 of the said Appendix from other countries are available. However, such trials may be permitted even in the absence of phase I data from other countries if the drug is of special relevance to the health problem of India. For new drug substances discovered in India, clinical trials are required to be carried out in India from Phase I as required under through Phase III,...permission to carry out these trials are generally given in stages, considering the data emerging from earlier phase.:
The earlier position was thus clearly that Phase-I trial of an ‘investigational new drug’, as now defined, was not permitted in the usual course if the concerned drug was discovered outside India subject only to the exception that the drug was of special relevance to the health problem of India.
This position changed significantly with the coming into force of the amendment in January of 2005.
The amended Schedule Y now provides Application for permission-
(1) Application for permission to import or manufacture new drugs for sale or to undertake clinical trials shall be made in Form 44 accompanied with following data in accordance with the appendices, namely-
(iv) "Human Clinical Pharmacology Data as prescribed in items 5, 6 and 7 of Appendix I are as stated below-
(a) for new drug substances discovered in India, clinical trials are required to be carried out in India right from Phase I and data should be submitted as required under items 1, 2, 3, 4, 5 (data, if any, from other countries) , and 9 of Appendix I;
(b) for new drug substances discovered in countries other than India, Phase I data as required under items 1, 2, 3, 4, 5 (data from other countries) and 9 of Appendix I should be submitted along with the application. After submission of Phase I data generated outside India to the Licensing Authority, permission may be granted to repeat Phase I trials and/or to conduct Phase II trials and subsequently Phase III trials concurrently with other global trials for that drug. Phase III trials are required to be conducted in India before permission to market the drug in India is granted..."
Post amendment, therefore, the position that emerges from the above reproduced portion of Schedule Y is that in India, Phase- I trials of foreign drugs is possible but only as a ‘repeat’ of an earlier Phase-I trial already conducted outside India and the application for this requires submission of the earlier Phase-I data generated outside India. But if the concerned foreign drug has already been tested on humans outside India in Phase-I trials already held outside India, it will no longer fall within the definition of an ‘investigational new drug’ and therefore not within the description of a ‘Phase-I trial.’ This is anomalous as ‘repeat’ Phase-I trials would have to be envisaged as Phase-I trials to be covered under the scheme of Rule 122DA. Still, the harmonious interpretation of the conflicting statutory provisions would be that Phase-I trials in India of foreign drugs are possible and properly the subject of applications and grant of necessary permissions, only if there is some pre-existing Phase-I data from outside India. The interpretation that the earlier ban on Phase-I trials of foreign drugs has not been abolished by the amendment would be extreme in rendering altogether otiose certain portions of the amended Schedule Y. The key issue, though, remains as to how much such initial foreign Phase-I data would be adequate before permission to ‘repeat’ the Phase-I trial in India can or should be granted.
The second Proviso to Rule 122DA, noticed earlier, enables the Licensing Authority to go into the matter of adequacy/inadequacy of the data provided on a drug in support of the application for grant of the necessary permission. Beyond that it is in the discretion of the Licensing Authority to accord appropriate weight and worth to whatever data is submitted and on the basis thereof, on impose such pre-conditions as considered exigent before considering the application further for grant of permission. Evidently, if the Licensing Authority expects or requires data from a full fledged foreign Phase-I trial, there will be few if any applications for a ‘repeat’ Phase-I trial in India as that would be unnecessary and a waste of time, expense and effort. Evidently also, if the data is so token or nominal that the ‘repeat’ Phase-I trial would actually amount to almost a first-time Phase-I trial, and especially if the drug is potentially particularly novel and hazardous, then the Licensing Authority would be expected to treat it as inadequate
13. Testing drugs in human subjects:
Most of us understand that, drugs intended to treat people have to be tested in people. These tests, called clinical trials, determine if a drug is safe and effective at what doses it works best, and what side effects it causes information that guides health professionals and for non prescription drugs, consumers in the proper use of medicines. Clinical testing is not the only way to discover what effect drugs have on people. Unplanned but alert observation and careful scrutiny of experience can often suggest drug effects and lead to more formal study. But such observations are usually not reliable enough to serve as the basis for important, scientifically valid conclusions. Controlled clinical trials, in which results observed in patients getting the drug are compared to the results in similar patients receiving a different treatment, are the best way science has come up with to determine what a new drug really does. That’s why controlled clinical trials are the only legal basis for the Regulatory Authority to conclude that a new drug has shown “substantial evidence of effectiveness as well as confirmation of relative safety in terms of the risk to benefit ratio for the disease that is to be treated”. It is important to test drugs in the kind of people they are meant to help. It is also important to design clinical studies that ask and answer the right questions about investigational products.
14. Formation of central drugs authority of India:
The Union Cabinet gave its approval to the following proposals -
(I) a) Setting up of Central Drugs Authority of India as an autonomous organization under the Ministry of Health & Family, Welfare to be located at the Food and Drug Bhawan, New Delhi
b) Up gradation of the post of Drug Controller (India) from the present level of the grade of Joint Secretary to the Addl. Secretary to the Govt. of India.
c) Revival of one post of Additional Drugs Controller (India) (AYUSH) in the grade of Joint Secretary to Government of India.
d) Creation of one post of Additional Drugs Controller (India) in the grade of Joint Secretary to the Government of India.
(II) A phased five year transition from the present system of grant of manufacturing licenses to a complete central licensing of drug manufacturing units from State to Union Government.
(III) Amending the Drugs & Cosmetics Act, 1940 by introducing, the Drugs & Cosmetics Amendment Bill, 2006 in Winter Session of the Parliament with such changes, as required.
15. Clinical Trials and Regulatory Tribunals:
Unless the regulatory system of India rises to the occasion by being transparent and efficient, the country shall fail to seize the opportunities in clinical trials. In recent years, India’s potential as a major hub of international clinical has been recognized. The advantages of large patient pool of treatment-naive patients, well-trained investigators and reduced trial costs have made international pharmaceutical companies and contract research organizations (CROs) look at India favorably. In a regulatory situation where it takes 10-15 years and millions of dollars to develop one new drug, each day’s delay in obtaining an approval can result in a loss of over $1.5 million for the sponsor. Hence, their major requirement is rapid initiation and timely completion of clinical trial. One of the biggest hurdles in the clinical trial plans is uncertainty and time to obtain regulatory permissions. If the regulatory system of a country is not transparent and efficient, the international trials will go to other countries. Is our regulatory system responsive to this need?
No official Indian survey of time for Health Authority approval is available. Informal discussions with sponsors and CROs suggest a range from 4-6 months. Some claim to obtain approval in two months time. However, such short timelines are exceptions. Sometimes an international MNC turns to India, when the global trial is close to completion and it has not been able to recruit adequate number of patients. The challenge for the local subsidiary is to recruit patients within a short time of 4-6 months. As the Health Authority (HA) timelines in our country are longer and unpredictable, the local subsidiary is unable to accept such a project. This means a loss of opportunity for India to participate in international trial!
The companies embarking on new drug research have complained about delays in getting approval for phase I. The timelines for approval have been 5-8 months or longer. In a world where international competition can get a phase I approval from USFDA in just 30 days, such delays are costly for these Indian companies! Most of the sponsors are concerned about uncertainty of the timelines, as it could take much longer than six months. There are hardly any technical queries from HA on the protocol.
Most often the applicant receives some administrative queries or is asked to fulfill new requirements that are not part of Schedule Y or any other regulatory guidelines. If the HA authorities seek opinion of external experts or ICMR on the protocol, the timelines become much longer and unpredictable. Applications submitted to the DCGI for permission for clinical trials in respect of new drug applications (NDA) and abbreviated new drug applications (ANDA) are often referred to outside agencies like the Indian Council of Medical research (ICMR) and the Department of Biotechnology, Government of India (DBT) for review. This arrangement often leaves very little control with regard to the time runs.
The Regulatory Authority for clinical trial in India is the- The Drugs Controller General of India or an office nominated by him is the regulatory authority for the purpose of carrying out Clinical Trials in India. The Regulatory Authority approves the study Protocol, reviews the submitted data and conducts inspections.
15.1 The principal investigator and participating investigators:
This section details the responsibilities of those involved in the running of the trial on a day-to-day basis. The practices detailed here should be followed by all those involved in the recruitment and follow up of trial participants. With respect to multicentred trial, a principal investigator has overall responsibility for the conduct of trial and this role is specified accordingly. The principal investigator has overall responsibility fore design of the proposed trial and co-ordination and the day-to-day management of the trial. The principal investigator ensures that: 1) The trials is run in accordance with these guidelines (ICMR Guidelines); and 2) All the investigators involved are aware and adhere to these guide
15.2 Self-regulation required while India's clinical regulatory body matures:
As India's clinical regulatory authorities find their feet, the clinical trials industry must practice self-regulation to maintain global standards. The clinical trials industry in India has exploded over the last few years as drug companies have realized the potential for outsourcing trials to this region for fast subject recruitment and major cost savings. Meanwhile, Indian regulatory authorities are not yet experienced enough and do not have the infrastructure set up to adequately cope with this clinical trial explosion and monitor the situation as tightly as possible.
During this time they need to build up more staff, become more electronically savvy, and work together with other global regulatory authorities such as the US Food and Drug Administration (FDA) to put the best procedures in place. In the meantime, those in the industry need to apply a lot of self-regulation as the cost of making a mistake or having to repeat a trial is very high. Pharma firms and CROs operating in India can do their best to ensure that clinical trials in the region are carried out ethically and according to global regulatory standards.
First of all it is crucial that all investigators and clinical research associates (CRAs) are well trained in informed consent, including how to accurately document this informed consent, as well as any questions and answers asked, in the hospital records.
Secondly, because we know that realistically principal investigators don't have enough time to spend with each patient explaining the clinical trial process to them and gaining satisfactory informed consent, another physician should be nominated as a co-investigator to do this
Conclusion:
Although it typically takes 10 to 12 years and millions of dollars to bring one new drug to market after a long process of clinical trial. The success rate is small in the developing world, no company or institute wants to, or can, invest such time and resources for a marginal improvement in responses over existing therapies. Fortunately, in a majority of cases, clinical trials can provide answers regarding the use or not of a therapeutic agent that can benefit millions of patients worldwide. Being the second most populated country in the world, India can contribute significantly to global drug development programs. The foundation of knowledge-based industries in India was laid down by the information technology industry, and there is no reason why clinical research cannot follow in those footsteps. Indian investigators and clinical research professionals have already demonstrated their medical and scientific skills by participating in multiple global clinical trials. It is time now to move forward to capitalize on the opportunity. So good administrative and regulatory bodies are required to keep maintain all these clinical trials properly and ethically, where there is no chances of give permission for the illegal or unauthenticated clinical research.
Bibliography:
1. Drug and Cosmetics Act, 1940 (Ministry of Health and Family Welfare, Government of India).
2. Drug and Cosmetic Rules, 1945 (Ministry of Health and Family Welfare, Government of India).
3. Indian Council for Medical Research, Ethical guidelines for Biomedical Research on Human Participants (New Delhi, 2006).
4. Jim Worrell, Practical Issues for Conducting Clinical Trials in India, 2007.
5. P. K. Julka, Clinical trials in India, Dilemmas for Developing Countries, 2007.
6. Nisha Shah, Ethical Guidelines for Biomedical Research on Human Subjects (Trends Biomater. Artif. Organs, Vol 18 (2), January 2005)
7. Kirsty Barnes, Clinical trials in India: ‘The wind is blowing’ (iGate, India, September, 2007)
INDIAN INSTITUTE OF TECHNOLOGY, KHARAGPUR
CLINICAL TRIAL-Evaluation of role of regulatory and administrative authorities in the backdrop of the concept of good governance.
Submitted by Sajal Dutta
RGSOIPL,IIT,KGP
Roll no. 06IP6040
Dated:11-04-2008
Contents:
1. Introduction
2. Country Background
3. Patients’ Rights and Safety
4. Opportunities and operational deficiencies for clinical trial in India
4.1 Role of Institutional Ethical Committee in Clinical ethics
4.2 Institutional ethical committees- Indian scenario
5. Phases of Clinical Trials
6. Strengthening ICMR control
7. Regulatory Framework
8. Conduct of Illegal/Unethical Trials
9. Infrastructure
9.1 Training
10. Pricing
11. Capacity building for clinical trial in India
12. Regulatory authority and rules
13. Testing drugs in human subjects
14. Formation of central drugs authority of India
15. Clinical Trials and Regulatory Tribunals
15.1 The principal investigator and participating investigators
15.2 Self-regulation required while India's clinical regulatory body matures
Conclusion
Bibliography
1. Introduction:
Clinical trial or research is an indispensable part of the drug discovery process to ensure the safety and efficacy of any new drug. In today’s global scientific era, clinical trials are the mainstay for bringing newer and better drugs to market. Although a set of robust guidelines is available to govern the conduct of clinical trials in any country, the conduct of clinical research is also looked upon as an area of humanitarian concern. Various articles published recently in the professional and popular press enumerate the opportunities and challenges of conducting global clinical trials in India. However, the majority have been from the perspective of authors who have never conducted clinical trials in India themselves. In contrast, this article conveys the perspective of someone who has worked as a principal investigator for various global clinical trials in medical oncology.
2. Country Background:
A nation with more than 1 billion people, India has the second largest population in the world. Having gained its independence from British rule in 1947, its prime minister is the head of government and its president is the head of state. Internationally, India became a member of the World Trade Organization (WTO) in 1995 and agreed to adhere to the product patent regime by 2005. As a result, the global pharmaceutical industry has the rights to patent products as well as processes throughout the world, including India. This has led to a significant growth of the pharmaceutical industry, both domestically in India and globally, including increased stakes of multinational companies in Indian operations. As a signatory to the WTO agreements, India is looked upon as a favorable destination for conducting global clinical trials. India clearly provides an opportunity in terms of availability of large patient populations, highly educated talent, a wide spectrum of disease, lower costs of operations, and a favorable economic and intellectual property environment. The overall time and cost advantage in bringing a drug to market by leveraging India’s resources could be as high as millions of dollars, hence the steadily increasing number of global studies in India over the past two years. Major pharmaceutical companies estimate the total market for conducting clinical trials either directly or through contract research organizations (CROs) in India through 2010.CROs themselves are fast gaining importance because of their global presence, specialized local expertise, and competition pricing strategies. And a significant number of new CROs have set up operations in India over the past two years. However, some key barriers stand in the way of opportunities, including patients’ rights and safety, regulatory framework, infrastructure, organization of ethics committees, data quality, lack of training curricula focusing on clinical research, and other factors. Most of these barriers are common to all developing countries and need to be addressed in a similar way. Because the clinical investigator plays a major role in the ethical conduct of any clinical trial, its successful outcome depends on how the investigator(s) has assumed overall responsibility. Most of the barriers mentioned above can be easily addressed if a clinical investigator is committed to the ethical conduct of trials. A segment of ideologues in India believe that clinical trials conduct poses a serious threat to society because of issues related to patient rights and safety, regulatory compliance, unethical trials, infrastructure and training issues, and exorbitant drug pricing. These threats are perceptions, not reality.
3. Patients’ Rights and Safety:
In today’s scientific era, research is taking major strides in multiple areas to develop new and better drugs to cure ailments that are difficult to treat. In a majority of cases, these drugs are aimed at providing answers to unmet medical needs. However, the drug development process requires 10 to 12 years on average to reach the marketing approval stage. Participation in clinical trials provides an opportunity to experience the benefits of these new drugs. So a critically ill patient who participates in a clinical trial, and who may not be alive after 8 to 10 years when the drug would be made available in the market, has access to what may provide either longer term health benefits or an improved quality of life. By carefully evaluating the eligibility criteria, a clinical investigator can offer new hope to patients across a wide range of therapeutic areas. Participation in clinical trials also provides research professionals opportunities to offer the best care to patients. A well-designed and executed study has built-in provisions to ensure patient rights and safety. In fact, a patient may be far safer in a clinical trial than in routine medical care because careful observations are made on safety (toxicity) and efficacy. In addition, clinical trials move in phases, that is, Phase II trials are initiated only if the Phase I results are promising. Similarly, Phase III trials are conducted only if the drug has shown required safety and efficacy in early phase trials. Hence, a patient is at minimized risk during later phases of clinical trials. In contrast, historical events like the sulfanilamide and thalidomide disasters could have been avoided with appropriate clinical trials. This phase process is particularly important in developing countries if carefully understood and explained to potential subjects.
4. Opportunities and operational deficiencies for clinical trial in India:
Clinical Research industry in India is set for a major growth in terms of revenue. The growth of clinical industry is directly linked to the growth of health industry in India as well as world over. In particular increase in research and development activities would lead to a higher demand for clinical trial services which meet global standards.
Opportunities-
Favorable environment: Increasing the expenditure on drug development, lengthening time lines for clinical trials, patent regime, changing regulations have become serious problems/bottlenecks in pharmaceutical research for the past decade. The emerging positive trends in India offer a potential solution to some of these problems. There are key broad areas to leverage the advantages that India offers to the established pharma and biotech industries. These include contract research, R & D alliances, and clinical trials.
Higher growth in Asia Pacific: As pharmaceutical and biotechnology companies continue to explore new geographic opportunities to expand their pipelines products and create business efficiencies of Asia-Pacific market growing. The quality of science and capabilities in drug discovery vary widely between India, China, Japan, Taiwan and Singapore. Pharmaceutical R & D expenditure in Asia is growing faster than in United States and Europe.
New patent Regime: The new patent regime will have a potential impact on domestic and foreign companies doing business in India. The protection of intellectual property rights I India which was one of the biggest concerns of global pharmaceutical companies seeking to enter India in the past has changed rapidly to post- Trade Related Aspect of Intellectual Property rights (TRIPs) and World trade Organization (WTO) scenario. A well established statutory, administrative and judicial framework, to safeguard intellectual property rights in India is slowly gaining momentum. It is focused on issues like infringement drug discovery, patents, royalties, damage exemptions for clinical trials and statutes blocking importation of products.
Alliances: India has already established its strength in developing, manufacturing and marketing generic products for global market. This success is attributed primarily to its strength in the prices chemistry, formulation development and manufacturing areas. Transition to innovate R & D is naturally the next step for India. There are a number of contract research organizations that offer quality and cost-effective services in medical chemistry, formulation development and toxicology areas. In order to leverage these resources, pharma companies from developed countries are already forging R & D alliances with Indian companies. These alliances are giving preclinical candidate or clinical candidates with proof of concept in humans.
Cost Advantage: The probability of success increases to about 50-75% once a molecule enters phase III clinical trials. By conducting R & D on new molecule up to Phase II of clinical trials in India, the cost of innovation and development can be drastically reduced. It is conceivable to reduce the cost of failure and eventually overall cost of bringing new medicines to patients. This is one of the unique opportunities in India. Low cost of innovation and development will allow bringing new molecules for the neglected diseases to market at a much reduced cost. Since the medicines for neglected disease must be affordable to patients in the poor countries, it is essential to develop these drugs in the most cost effective manner. Early estimates are that drugs could be tested in India at 60% of the price.
Established Pharma Companies: Indian companies are highly capable in research and development particularly in drug discovery. It has already proven its capability in discovering and developing drug candidate molecules. A number of development candidates are out licensed by Indian companies to the medium size as well as large pharmaceutical companies in the developed countries. The trend is expected to continue. In India alternative medicine system are well established. However the molecular mechanism of action and identify active ingredients may not be known for most of these traditional medicines. There are opportunities to apply modern science to elucidate molecular mechanism of action and to identify active ingredients of these medicines. The process of reverse pharmacology can be applied to discover new drug candidate molecules from these traditional medicines.
Operational Deficiencies-
The increase in clinical trials is fueled by the recent push for global commerce. Regulatory uncertainties about time to approval, involvement of multiple agencies for approval of biotech products and for processing import/export licenses, and several other factors are hurdles in planning clinical trials. A large majority of potential investigators lack knowledge of regulations, ethics and GCP and skills for clinical trial management. The quality of global trials and academic clinical research is not uniform. There are also issues of inadequate permanent research staff and lack of adequate infrastructure for communication, drug/sample storage, archival. The situation is worse in non-metro cities which have tremendous potential for participation in global trials. In addition the institutional policies are not geared up to support the investigator in managing clinical trials efficiently. Perhaps the most important challenge is that of designing elegant clinical trials that will test concepts rather than simply compare products. Some of the major operational deficiencies are as follows:
Government policies: Regulatory approvals in India can take three months or more, compared to 30 days in US. Even more serious is the lack of confidentiality. Unlike India, China does not yet grant protection for data gleaned from clinical trials, which makes it easy for generic drug makers to copy the drug under trial. Under the India’s existing laws, only those drugs that have already passed phase-I safety trials in the country of their origin can be tested on Indians.
Weak patent law: In India opportunities will become limited unless there is a very strong patent law and mechanism to enforce it. Drafting patent law with the help of industry experts and its implementations is highly essential.
4.1 Role of Institutional Ethical Committee in Clinical ethics:
The potential importance of the IEC’s consultative role has been recognized in numerous ways. Health care organization has an established mechanism to address conflicts, requirements of most often met by establishing a IEC. Law suggests that IEC deliberations may serve as evidence in court, proposals to establish an IEC as an alternative judicial review and requirement of the joint commission on accreditation of health care organizations.
4.2 Institutional ethical committees- Indian scenario:
In India, ethical guidelines drafted by Indian Council of Medical Research (ICMR) for conducting biomedical research in laboratory animals and clinical trials for new drugs on human population. The institute was given authority to monitor the implementation of ethical guidelines in clinical trials and biomedical research activities. Each institute has its own ethical committee for monitoring the guidelines. As per the guidelines, at any stage, any deviation in ethics, on the basis of religion, socioeconomic status, protecting the confidentiality of the volunteers will be awarded severe punishments. All the life science researchers, particularly biomedical researchers, working with laboratory animals, human patients, and volunteers in clinical trials have to follow the guidelines strictly.
The clinical trials usually are of 3 types as per ICMR guidelines-
I. studies where intervention is clearly “demarcated research” such as phase I trial of a new compound;
II. Studies with a mix of standard medical practices and specific research elements, e.g. trials of two competing ant nausea drugs following standard chemotherapy;
III. Studies involving research on therapeutic practices, such as the trial of two already approved anti-diabetic drugs.
5. Phases of Clinical Trials:
All phases require approval from EC. The first three of the following four phases of clinical trials of drug require Drug Controller General of India's clearance: -
Phase-I (Human Pharmacology) - This is a non-therapeutic trial and the objective is to determine the safety of a new drug and determine the maximum tolerated dose as also to determine the nature of adverse reactions that can be expected. In healthy adults of both sexes. Healthy female volunteers could be included provided they have completed their family or do not intend to have a child in the future. These studies include both single and multiple dose administration and should ideally be carried out at a site that is adequately equipped.
Combined Phase I and Phase II - Such trials are conducted on populations for whom the therapeutic options are exhausted, as in the case of HIV/AIDS and cancer. Toxic drugs like anti-retroviral or anti-cancer drug, cannot be tested in normal healthy volunteers as in Phase I studies as the risk far outweighs any benefit. Hence such studies are planned in patients suffering from the disease so that the risk benefit ratio is more favorable. Since here the patient population is a vulnerable group and trial on them has to be planned very carefully.
Phase II (Therapeutic Exploratory Trials) - These are controlled studies conducted in a limited number of patients of either sex to determine therapeutic effects, effective dose range and further evaluation of safety and pharmacokinetics in patients. Generally due to selection of patients with narrow inclusion criteria to find effective dose the study population is more or less homogenous. The dose used is lesser than the highest dose used in phase I. Another objective of this Phase II is evaluation of potential study endpoints, therapeutic regimens including concomitant medications and target populations, and mild versus severe disease, for further studies in Phase II or III. These objectives may be served by exploratory analyses of subsets of data and by including multiple endpoints in trials. Normally 20-25 patients should be studied for assessment of each dosage. These studies are usually limited to 3-4 centre. It is advisable to include a clinical pharmacologist as a co-investigator in such studies.
Phase III (Therapeutic Confirmatory Trials) – The purpose of these trials is to obtain adequate data about the efficacy and safety of drugs in a larger number of patients of either sex in multiple centre usually in comparison with a standard drug and / or a placebo if a standard drug does not exist for the disease under study. This is to validate efficacy and safety found in Phase II. On successful completion of phase III trials permission is granted for marketing of the drug.
Phase IV - The Phase IV studies should have valid scientific objectives. After approval of the drug for marketing, phase IV studies or post marketing surveillance is undertaken to obtain additional information about the risks and benefits resulting from long term usage of drug. It is an important aspect of drug trial on the long term effects of the drugs and the adverse reactions induced by drugs, if any, should be brought to the notice of the Ethics Committee. There is a need to correlate the adverse events reported during Phase IV trials with the toxicity data generated in animals, to draw markers for future warnings of potential adverse events likely to occur with other drugs. These trials may not be necessary for approval of new drug for marketing but may be required by the Licensing Authority for optimizing its use.
6. Strengthening ICMR control:
ICMR lacks the authority to take action against unethical IECs. There exists no mechanism for accreditation of IECs and quality control of ethics review is practically impossible. There is no comprehensive database on either IECs or Research participants. India has also given birth of unaffiliated Ethics Committees to review protocols for institutions with no IECs, supported by fees from the pharmaceutical industry. Institutional mechanisms for ethical reviewing of research involving human participants in India are weak and vulnerable. A concerned effort is required to strengthen them to fulfill their stated missions. The problem is likely to be worse in India. These are major threats to the international companies to conduct clinical trials in India.
7. Regulatory Framework:
Multinational pharmaceutical companies and CROs are able to conduct good quality clinical trials in India despite infrastructural challenges at the regulatory department level. They can do so because of required professional training and the professionals’ willingness to comply with regulations and applicable standards in a spirit that protects the rights and safety of trial subjects. In India, no less than in the rest of the world, it is the responsibility of individual stakeholders (sponsors, CROs, investigators) to observe self-discipline while conducting clinical trials, especially when there are more than 20,000 big and small companies and a mere handful of regulatory professionals. The belief that compliance with Good Clinical Practices (GCP) and applicable regulatory guidelines requires the presence of a robust regulatory inspection system is erroneous. Rather, what may be required is a change of mindset from one of “situational ethics” (that is, compliance with medical ethics in clinical trials only) to one of “holistic ethics” (that is, compliance with medical ethics in clinical trials as well as routine medical care).
No regulatory authority can ensure 100% GCP compliance unless the individual stakeholders are willing to comply with the applicable regulations.
8. Conduct of Illegal/Unethical Trials:
Scientific misconduct is a global phenomenon linked to human behavior rather than to an individual country. For instance, the U.S. Food and Drug Administration (FDA) website lists the details of clinical investigators who have been “disqualified” or “restricted” from doing research on grounds of scientific misconduct. Details of warning letters issued to various stakeholders (clinical investigator, ERB/IRB, sponsor, CRO, etc.) can also be obtained from the same website. However, FDA has not banned clinical trials based on these grounds, these individuals, or individual organizations. Rather, FDA has increased its surveillance over clinical research programs. In like manner, the Indian regulatory authority is also in the process of setting up surveillance teams for ensuring ethical conduct of clinical trials. Companies acting ethically set globally consistent standards and conduct trials only in the countries where GCP compliance is assured. Indian investigators have demonstrated their compliance by virtue of participation in more than 60 global trials so far. Moreover, a majority of those trials were FDA or European registration trials, requiring strict compliance with GCP and regulatory guidelines. The data have been accepted by foreign regulatory authorities and published in international scientific journals of repute.
9. Infrastructure:
Participation in global clinical trials requires an upgrade in existing infrastructure and facilities at a majority of Indian hospitals in terms of functioning of ERB/IRB, calibration and quality control of diagnostic equipments, maintenance of patient medical records, handling of investigational product, and other critical areas. There have been instances of sponsors providing highly expensive diagnostic instruments to trial sites in order to achieve consistency in trial data globally. All the trials include investigator grants and funding that is generally utilized to upgrade the infrastructure and education facilities at a site. The Institutional Ethics Committees at a majority of Indian hospitals are gaining competence in evaluating the trial proposals from scientific and ethical standpoints. This, in turn, is strengthening the healthcare system of the country while bolstering the ability of institutions to conduct research. In short, clinical research or trials offers value and value-added infrastructural incentives to the country.
9.1 Training:
Lack of technical know how on drug development and the habit of “copying” (mostly producing generic drugs) are the major hurdles for indigenous drug research. Participation in global trials provides learning opportunities to Indian doctors and scientists, which in turn can be utilized to find the answers for the diseases that are endemic to the country, such as kala-azar, leprosy, trachoma, and tuberculosis. The medical research intellectual base of the country has been sub optimally utilized so far due to the absence of basic research facilities and knows how. Participation of Indian investigators in global trials and subsequent publication/ presentation motivates them to develop research protocols for domestic healthcare issues. This, in turn, is nurturing a culture of medical research that can match international standards.
10. Pricing
Less than 10% by value of drugs used in India are of the premium category; the other 90% are established off-patent drugs (drugs for which multiple generic versions are available). Even for premium category drugs, the pricing is generally moderated by three important factors:-
A. the purchasing power of the customers;
B. the existence of unpatented drugs and cheaper substitutes; and
C. the Drug Price Control Order,
Which regulates the pricing of essential life-saving drugs in India? Even today, people who can afford the premium category drugs are getting them imported from the West or are traveling to other countries to get better medical care. The availability of such drugs in India is going to reduce the overall healthcare cost.
11. Capacity building for clinical trial in India:
Recent events worldwide have challenged the integrity of research on pharmaceutical products and have triggered calls by legislators, medical associations, the International Committee of Medical Journal Editors (ICMJE), the World Health Organization (WHO) and others, for increased accountability and transparency in health products research and development. India, which is projected to have accelerated growth in this sector with the entry of a number of major global and domestic players and a more research focused pharmaceutical industry, is poised to face formidable challenges.
Building the right kind of capacity to meet the anticipated demand for clinical trials in India is an important issue. Along with the optimism for growth in this industry is the concern that vulnerable populations may be exploited. Access to experimental drugs, exposure to latest therapies, improvement in equipment and infrastructure, and creation of new knowledge assets are among the many benefits of this growth. New, difficult to meet expectations and moving local resources away from basic healthcare are among costs and risks of this enterprise. The regulatory regime in India has to identify ways of creating a balance between these benefits and costs/risks.
There is a need at the present time for a strong centralized regulatory regime which can guide high quality development of ethical capacity with extra vigilance but an informed understanding of acceptable risk. Such a system while conforming to international standards needs to be uniquely Indian. It needs to include indigenous medicine, devices, drugs and therapies while incorporating the advent of biotechnology in general and genomics and proteomics in particular.
While Good Clinical Practices (GCPs) have been clearly spelt out and ethical guidelines have been articulated, our experience with implementation is relatively short. The regulatory system is already stretched in terms of its ability to monitor proper implementation. The expected fast growth in the industry is going to further stretch the capabilities of the system and highlight complexities and unintended consequences.
Clinical trials have different types of risks associated with them. Ability to safely perform a trial is a challenge and should be factored into the prioritization process. Thus, a placebo trial involving vulnerable population (including socio economically vulnerable) will have a higher risk and may be given a different priority. Higher risk trials need to have special monitoring and more intense review. Risk should include a "site's" ability to safely conduct the trials and the pool from which trial subjects are sought. A number of operational issues to implement such a system of priorities need to be discussed and procedures developed. A working group to measure risk associated with "site capabilities" needs to be constituted. This may be particularly relevant for approval of Phase 1 trials. Criteria for "disallowed" trials as well as guidelines for exceptions should be specified.
Ethics Committees, ethical guidelines and norms, and independent review boards are all different ways of ensuing compliance with established ethical guidelines and good practices. Ethics committees cannot conduct their task responsibly unless they get the data needed to evaluate ethical behavior. There has been an unprecedented growth in CROs in India with most Indian and major multinationals setting up operations in India either directly or as joint ventures.
There is no system of registration and/ or approval of such organizations. Quality control and potential for abuse remain a major concern for the nation, for which there is need for self regulation through accreditation as well as legislation, to ensure high standards through a system of monitoring by a regulatory agency.
There has been a global demand that all clinical trials be registered as also emphasized by the ICMJE. The ICMJE has made registration of trials mandatory without which they will not publish the results of trials. The WHO has suggested a structure of the registry with a minimum required data set to be followed by all countries. An Indian registry, with the minimum data set and requirements suggested by WHO, needs to be implemented. It is important to include stakeholders from industry, national laboratories and regulatory authority in the development of such a registry in order to get compliance. The help of IT could be used to ensure quality data management.
12. Regulatory authority and rules:
The Indian Clinical Research Outsourcing (CRO) industry is growing rapidly and brings with it attendant regulatory concerns. Of special concern is the matter of Phase- I trials which, in general terms, are first-time trials in the country on human subjects of new drugs especially of investigational new drugs. Since this involves testing on humans of new drugs that is to say drugs generally inadequately tested before on humans, and in the context of investigational new drugs, not tested at all on humans before, the subject is understandably sensitive in the public domain as well. The initial testing on humans of drugs recently invented or discovered in the laboratory and having been tested, if at all, only on animal subjects, is a subject potentially capable of abuse in the absence of proper legal regulation, as featured indeed in a number of books and films. It remains a matter of concern for all jurisdictions and particularly of weak, less developed and more vulnerable ones.
Clinical Trial is now, since January 20, 2005, defined in Rule 122 DAA of Drugs and Cosmetics Rules, 1945 is as follows:
Clinical trial means a systematic study of new drug(s) in human subject(s) to generate data for discovering and/or verifying the clinical, pharmacological (including pharmaco dynamic and pharmacokinetic) and /or adverse effects with the objective of determining safety and / or efficacy of the new drug.
The Rules themselves are framed under the Drugs and Cosmetics Act, 1940, the principal statute in the field. This is a law enacted by Parliament and applies along with the Rules, in all the states in the country. Drugs themselves to which the statute applies are defined in Section 3 (b) of the Act.
To take drug development to the market, clinical research is necessary at different stages to different ends. These are broadly categorized in phases, Phase I being the earliest and Phase IV being the last.
Rule 122 DA of Drugs and Cosmetics Rules, 1945 requires an application to be made to the statutory Licensing Authority for permission to conduct clinical trials for New Drug/Investigational New Drug and for prior permission to be granted before conducting the clinical trial. This Rule is extracted hereunder in relevant part for a Phase-I trial.
122DA. Application for permission to conduct clinical trials for New Drug/Investigational New Drug
(1) No clinical trial for a new drug, whether for clinical investigation or any clinical experiment by any Institution, shall be conducted except under, and in accordance with, the permission in writing of the Licensing Authority defined in clause (b) of rule 21.
(2) An application for grant of permission to conduct-
(a) human clinical trials (Phase-I) on a new drug shall be made to the Licensing Authority in Form 44 accompanied by a fee of fifty thousand rupees and such information and data as required under Schedule Y.
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Provided that the Licensing Authority shall, where the data provided on the clinical trials is inadequate, intimate the applicant in writing…intimating the conditions which shall be satisfied before permission could be considered.
Under Schedule Y, Paragraph 2 (6), Phase- I trials are described. As per this-
The objective of studies in Phase I is the estimation of safety and tolerability with the initial administration of an investigational new drug into human(s). Studies in this Phase of development usually have non-therapeutic objectives and may be conducted in healthy volunteer’s subjects or certain types of patients. Drugs with significant potential toxicity e.g. cytotoxic drugs are usually studied in patients. Studies conducted in Phase I, usually intended to evaluate maximum tolerated dose, pharmacokinetics, pharmacodynamics and early measurement of drug activity.
It is only after completion of Phase I trial, the subsequent phases of trial can take place.
A conjoint reading of Rule 122DA (2) (a) and Schedule Y, paragraph 2 (6) indicates that an application and grant of permission is envisaged and is necessary for conducting Phase-I trials in India, which by definition are trials of ‘investigational new drugs’, that is to say new drugs not having previously been tested on humans anywhere. The statutory definition of ‘Investigational New Drug’ means a new chemical entity or product having therapeutic indication but which have never been tested on human being." The Rule by itself without reference to the Schedule seems to cover Phase I trials of ‘New Drug’ more generally defined in Section 122E of The Drug and Cosmetics Act as "a drug" which has not been used in the country to any significant extent under the conditions prescribed, recommended or suggested in the labeling thereof .. even if it is not an ‘Investigational New Drug.’ A reading of the Rule by itself leaves it open to the interpretation that for Phase-I trials, Schedule Y is relevant only for indicating the ‘information and data’ required to support the application. But the scope of the Rule gets restricted to only ‘Investigational New Drugs’ in light of the description of Phase-I in the Schedule as being limited to ‘Investigational New Drugs.’ The reference in the Rule to the Schedule is mandated by the express stipulation in this regard in the language of Clause 2 (a) of the Rule itself. It becomes clear from this that Phase-I trials concerns testing of drugs on human subjects in India of drugs that have never been tested before on human subjects and that applications are maintainable to carry out such tests and permissions will be granted in suitable cases by the Indian Licensing Authority. It is also notable that the statutory provisions cited above do not distinguish between indigenous and foreign ‘investigational new drugs.’ That is to say, that in considering applications for Phase-I trial in India permissions, the provisions noticed above do not disqualify drugs discovered or developed outside India but instead specifically envisaged as a category in which applications will be entertained and considered for grant of the necessary permission.
What cases of Phase-I trials of foreign drugs will be considered suitable by the Licensing Authority for grant for permission, is governed statutorily yet appears to leave some scope for non-statutory discretion to be exercised ad hoc or in terms of a policy decision. To understand the scope of this discretion, one needs to appreciate the legal position prevailing until 20th January of 2005 when the law was amended, as well as the change in the law.
Earlier, an ‘investigational new drug’ was not a statutory expression. Previously Rule 122-A governed licenses to import new drugs including for the purposes of trials which were required to comply with the guidelines for the same as set out in Schedule Y (unamended). The earlier Rule did not deal specifically with ‘investigational new drugs’ nor specifically with any particular Phase of trial such as Phase-I. Earlier the description of Phase-I trials in Schedule Y did not specifically make it applicable to ‘investigational new drugs,’ in the sense of the expression as only now defined. And the earlier Schedule Y expressly made a distinction between foreign drugs and indigenously discovered or developed drugs. In relevant part, the earlier Schedule Y read as under-
Nature of clinical trials.- The clinical trials required to be carried out in the country before a new drug is approved for marketing depend on the status of the drug in other countries. If the drug is not approved/marketed trials are generally allowed to be initiated at one phase earlier to the phase of trials in other countries.
For new drug substances discovered in other countries phase I trials are not usually allowed to be initiated in India unless phase I data as required under Item 5 of the said Appendix from other countries are available. However, such trials may be permitted even in the absence of phase I data from other countries if the drug is of special relevance to the health problem of India. For new drug substances discovered in India, clinical trials are required to be carried out in India from Phase I as required under through Phase III,...permission to carry out these trials are generally given in stages, considering the data emerging from earlier phase.:
The earlier position was thus clearly that Phase-I trial of an ‘investigational new drug’, as now defined, was not permitted in the usual course if the concerned drug was discovered outside India subject only to the exception that the drug was of special relevance to the health problem of India.
This position changed significantly with the coming into force of the amendment in January of 2005.
The amended Schedule Y now provides Application for permission-
(1) Application for permission to import or manufacture new drugs for sale or to undertake clinical trials shall be made in Form 44 accompanied with following data in accordance with the appendices, namely-
(iv) "Human Clinical Pharmacology Data as prescribed in items 5, 6 and 7 of Appendix I are as stated below-
(a) for new drug substances discovered in India, clinical trials are required to be carried out in India right from Phase I and data should be submitted as required under items 1, 2, 3, 4, 5 (data, if any, from other countries) , and 9 of Appendix I;
(b) for new drug substances discovered in countries other than India, Phase I data as required under items 1, 2, 3, 4, 5 (data from other countries) and 9 of Appendix I should be submitted along with the application. After submission of Phase I data generated outside India to the Licensing Authority, permission may be granted to repeat Phase I trials and/or to conduct Phase II trials and subsequently Phase III trials concurrently with other global trials for that drug. Phase III trials are required to be conducted in India before permission to market the drug in India is granted..."
Post amendment, therefore, the position that emerges from the above reproduced portion of Schedule Y is that in India, Phase- I trials of foreign drugs is possible but only as a ‘repeat’ of an earlier Phase-I trial already conducted outside India and the application for this requires submission of the earlier Phase-I data generated outside India. But if the concerned foreign drug has already been tested on humans outside India in Phase-I trials already held outside India, it will no longer fall within the definition of an ‘investigational new drug’ and therefore not within the description of a ‘Phase-I trial.’ This is anomalous as ‘repeat’ Phase-I trials would have to be envisaged as Phase-I trials to be covered under the scheme of Rule 122DA. Still, the harmonious interpretation of the conflicting statutory provisions would be that Phase-I trials in India of foreign drugs are possible and properly the subject of applications and grant of necessary permissions, only if there is some pre-existing Phase-I data from outside India. The interpretation that the earlier ban on Phase-I trials of foreign drugs has not been abolished by the amendment would be extreme in rendering altogether otiose certain portions of the amended Schedule Y. The key issue, though, remains as to how much such initial foreign Phase-I data would be adequate before permission to ‘repeat’ the Phase-I trial in India can or should be granted.
The second Proviso to Rule 122DA, noticed earlier, enables the Licensing Authority to go into the matter of adequacy/inadequacy of the data provided on a drug in support of the application for grant of the necessary permission. Beyond that it is in the discretion of the Licensing Authority to accord appropriate weight and worth to whatever data is submitted and on the basis thereof, on impose such pre-conditions as considered exigent before considering the application further for grant of permission. Evidently, if the Licensing Authority expects or requires data from a full fledged foreign Phase-I trial, there will be few if any applications for a ‘repeat’ Phase-I trial in India as that would be unnecessary and a waste of time, expense and effort. Evidently also, if the data is so token or nominal that the ‘repeat’ Phase-I trial would actually amount to almost a first-time Phase-I trial, and especially if the drug is potentially particularly novel and hazardous, then the Licensing Authority would be expected to treat it as inadequate
13. Testing drugs in human subjects:
Most of us understand that, drugs intended to treat people have to be tested in people. These tests, called clinical trials, determine if a drug is safe and effective at what doses it works best, and what side effects it causes information that guides health professionals and for non prescription drugs, consumers in the proper use of medicines. Clinical testing is not the only way to discover what effect drugs have on people. Unplanned but alert observation and careful scrutiny of experience can often suggest drug effects and lead to more formal study. But such observations are usually not reliable enough to serve as the basis for important, scientifically valid conclusions. Controlled clinical trials, in which results observed in patients getting the drug are compared to the results in similar patients receiving a different treatment, are the best way science has come up with to determine what a new drug really does. That’s why controlled clinical trials are the only legal basis for the Regulatory Authority to conclude that a new drug has shown “substantial evidence of effectiveness as well as confirmation of relative safety in terms of the risk to benefit ratio for the disease that is to be treated”. It is important to test drugs in the kind of people they are meant to help. It is also important to design clinical studies that ask and answer the right questions about investigational products.
14. Formation of central drugs authority of India:
The Union Cabinet gave its approval to the following proposals -
(I) a) Setting up of Central Drugs Authority of India as an autonomous organization under the Ministry of Health & Family, Welfare to be located at the Food and Drug Bhawan, New Delhi
b) Up gradation of the post of Drug Controller (India) from the present level of the grade of Joint Secretary to the Addl. Secretary to the Govt. of India.
c) Revival of one post of Additional Drugs Controller (India) (AYUSH) in the grade of Joint Secretary to Government of India.
d) Creation of one post of Additional Drugs Controller (India) in the grade of Joint Secretary to the Government of India.
(II) A phased five year transition from the present system of grant of manufacturing licenses to a complete central licensing of drug manufacturing units from State to Union Government.
(III) Amending the Drugs & Cosmetics Act, 1940 by introducing, the Drugs & Cosmetics Amendment Bill, 2006 in Winter Session of the Parliament with such changes, as required.
15. Clinical Trials and Regulatory Tribunals:
Unless the regulatory system of India rises to the occasion by being transparent and efficient, the country shall fail to seize the opportunities in clinical trials. In recent years, India’s potential as a major hub of international clinical has been recognized. The advantages of large patient pool of treatment-naive patients, well-trained investigators and reduced trial costs have made international pharmaceutical companies and contract research organizations (CROs) look at India favorably. In a regulatory situation where it takes 10-15 years and millions of dollars to develop one new drug, each day’s delay in obtaining an approval can result in a loss of over $1.5 million for the sponsor. Hence, their major requirement is rapid initiation and timely completion of clinical trial. One of the biggest hurdles in the clinical trial plans is uncertainty and time to obtain regulatory permissions. If the regulatory system of a country is not transparent and efficient, the international trials will go to other countries. Is our regulatory system responsive to this need?
No official Indian survey of time for Health Authority approval is available. Informal discussions with sponsors and CROs suggest a range from 4-6 months. Some claim to obtain approval in two months time. However, such short timelines are exceptions. Sometimes an international MNC turns to India, when the global trial is close to completion and it has not been able to recruit adequate number of patients. The challenge for the local subsidiary is to recruit patients within a short time of 4-6 months. As the Health Authority (HA) timelines in our country are longer and unpredictable, the local subsidiary is unable to accept such a project. This means a loss of opportunity for India to participate in international trial!
The companies embarking on new drug research have complained about delays in getting approval for phase I. The timelines for approval have been 5-8 months or longer. In a world where international competition can get a phase I approval from USFDA in just 30 days, such delays are costly for these Indian companies! Most of the sponsors are concerned about uncertainty of the timelines, as it could take much longer than six months. There are hardly any technical queries from HA on the protocol.
Most often the applicant receives some administrative queries or is asked to fulfill new requirements that are not part of Schedule Y or any other regulatory guidelines. If the HA authorities seek opinion of external experts or ICMR on the protocol, the timelines become much longer and unpredictable. Applications submitted to the DCGI for permission for clinical trials in respect of new drug applications (NDA) and abbreviated new drug applications (ANDA) are often referred to outside agencies like the Indian Council of Medical research (ICMR) and the Department of Biotechnology, Government of India (DBT) for review. This arrangement often leaves very little control with regard to the time runs.
The Regulatory Authority for clinical trial in India is the- The Drugs Controller General of India or an office nominated by him is the regulatory authority for the purpose of carrying out Clinical Trials in India. The Regulatory Authority approves the study Protocol, reviews the submitted data and conducts inspections.
15.1 The principal investigator and participating investigators:
This section details the responsibilities of those involved in the running of the trial on a day-to-day basis. The practices detailed here should be followed by all those involved in the recruitment and follow up of trial participants. With respect to multicentred trial, a principal investigator has overall responsibility for the conduct of trial and this role is specified accordingly. The principal investigator has overall responsibility fore design of the proposed trial and co-ordination and the day-to-day management of the trial. The principal investigator ensures that: 1) The trials is run in accordance with these guidelines (ICMR Guidelines); and 2) All the investigators involved are aware and adhere to these guide
15.2 Self-regulation required while India's clinical regulatory body matures:
As India's clinical regulatory authorities find their feet, the clinical trials industry must practice self-regulation to maintain global standards. The clinical trials industry in India has exploded over the last few years as drug companies have realized the potential for outsourcing trials to this region for fast subject recruitment and major cost savings. Meanwhile, Indian regulatory authorities are not yet experienced enough and do not have the infrastructure set up to adequately cope with this clinical trial explosion and monitor the situation as tightly as possible.
During this time they need to build up more staff, become more electronically savvy, and work together with other global regulatory authorities such as the US Food and Drug Administration (FDA) to put the best procedures in place. In the meantime, those in the industry need to apply a lot of self-regulation as the cost of making a mistake or having to repeat a trial is very high. Pharma firms and CROs operating in India can do their best to ensure that clinical trials in the region are carried out ethically and according to global regulatory standards.
First of all it is crucial that all investigators and clinical research associates (CRAs) are well trained in informed consent, including how to accurately document this informed consent, as well as any questions and answers asked, in the hospital records.
Secondly, because we know that realistically principal investigators don't have enough time to spend with each patient explaining the clinical trial process to them and gaining satisfactory informed consent, another physician should be nominated as a co-investigator to do this
Conclusion:
Although it typically takes 10 to 12 years and millions of dollars to bring one new drug to market after a long process of clinical trial. The success rate is small in the developing world, no company or institute wants to, or can, invest such time and resources for a marginal improvement in responses over existing therapies. Fortunately, in a majority of cases, clinical trials can provide answers regarding the use or not of a therapeutic agent that can benefit millions of patients worldwide. Being the second most populated country in the world, India can contribute significantly to global drug development programs. The foundation of knowledge-based industries in India was laid down by the information technology industry, and there is no reason why clinical research cannot follow in those footsteps. Indian investigators and clinical research professionals have already demonstrated their medical and scientific skills by participating in multiple global clinical trials. It is time now to move forward to capitalize on the opportunity. So good administrative and regulatory bodies are required to keep maintain all these clinical trials properly and ethically, where there is no chances of give permission for the illegal or unauthenticated clinical research.
Bibliography:
1. Drug and Cosmetics Act, 1940 (Ministry of Health and Family Welfare, Government of India).
2. Drug and Cosmetic Rules, 1945 (Ministry of Health and Family Welfare, Government of India).
3. Indian Council for Medical Research, Ethical guidelines for Biomedical Research on Human Participants (New Delhi, 2006).
4. Jim Worrell, Practical Issues for Conducting Clinical Trials in India, 2007.
5. P. K. Julka, Clinical trials in India, Dilemmas for Developing Countries, 2007.
6. Nisha Shah, Ethical Guidelines for Biomedical Research on Human Subjects (Trends Biomater. Artif. Organs, Vol 18 (2), January 2005)
7. Kirsty Barnes, Clinical trials in India: ‘The wind is blowing’ (iGate, India, September, 2007)
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