TIGblogs - sruman bandaru

INTRODUCTION
Clinical 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.

What is a clinical trial?
Clinical trials are experiments to determine the value of treatments. There are two key components to the experimental approach. First, results rather than plausible reasoning are required to support conclusions. Second, experiments should be prospectively planned and conducted under controlled conditions in order to provide definitive answers to well defined questions.

Development of new drug involves two phases, namely drug discovery and drug development. The stage of drug discovery involves the identification of the target, drug designing and synthesis followed by its preliminary invitro screening.

The next step is preclinical evaluation, which involves rigorous testing of efficacy and safety of the new molecule by various in vivo assays using animals. The necessary data for evaluation in humans is generated here and the test drug is now ready for its last and most crucial stage of evaluation i.e., clinical evaluation.
The clinicians in coordination with the pharmacists evaluates the efficacy and the safety of the sample over four stages starting from healthy volunteers and moving onto small group of patients and then larger number of patients and special groups. Phase - I or clinical pharmacology forms the basis for clinical trial for any new drug and provides the link between pre clinical and clinical research (Kuhlmann, 1997). Finally, the application for regulatory review and approval may be applied and the approval sought.

Defination:
According to ICH-GCP
Clinical trial/study:
Any investigation in human subjects intended to discover or verify the clinical, pharmacological and/or other pharmacodynamic effects of an investigational product(s), and/or to study absorption, distribution, metabolism, and excretion of an investigational product(s) with the object of ascertaining its safety and/or efficacy. The terms clinical trial and clinical study are synonymous.

According to Indian-GCP
Clinical trial: A systematic study of pharmaceutical products on human subjects – (whether patients or non-patient volunteers) – in order to discover or verify the clinical, pharmacological (including / pharmacokinetics), and adverse effects, with the object of determining their safety and efficacy.

Scope of Clinical Research
Every new drug evidence from clinical research to support its launch. Thus, whether it is a new chemical entity or an existing drug that is being marketed for new indication, clinical studies have to be conducted. Similarly, launch of new formulations, drug delivery systems or even new fixed dose combination, requires clinical data before it can be marketed. Hence it is obvious that the area of clinical research holds immense scope and promise for without the supporting data, drug launch is not feasible. The conduct of clinical research is based on the GCP and ICH guidelines.

HISTORY OF CLINICAL TRIAL:
Sure, science involves trial and error. Scientists refine theories each day. But as they do, they help us grasp more clearly the wonders of the world and the universe.
Tony Snow

The history of Drug discovery is often fascinating. Many of the drugs that are used today have been discovered by chance or often by mere serendipity. India’s history of drug discovery and proficiency in Medical Research can be traced back to two ancient scripts, Charaka Samhita (a textbook of medicine) and Sushruta Samhita (a textbook of surgery), compiled as early as 200 B. C. and 200 A. D. respectively.

Clinical Trials Timeline (605 BC – 2000AD)
Clinical trial progress is depending on the progress of Science and Technology and Pharmacokinetics have all contributed to refining and redefining the whole process. The International Conference on Harmonization (ICH) meets from time to time to form and revise guidelines as per Good Clinical Practice.
A current 21st century drug discovery method has used some advanced technology. The biological revolution has given rise to many new and promising disciplines such as Nanotechnology, Pharmacometabonomic, Genomics, Proteomics, Metabolomines and Bioinformatics. Randomized controlled trial and Multicentric trial study is new design of clinical trial.
India Background:
Until recently, there were few clinical trials conducted in India by western pharmaceutical and biotech companies, primarily because of regulatory hurdles. In January 2005, recognizing the significant advantages that India offers to multinational companies and the potential and benefits of conducting clinical trials in India, the government of India upgraded schedule Y of the Drugs and Cosmetics Act of India, the equivalent of the sections of the code of Federal regulations applicable to the FDA, to harmonize it with U.S. and International Conference on Harmonization (ICH) standards. These changes removed a number of regulatory barriers to perform clinical trials in India. The changes formalized the definition and conduct of clinical trials; specified the responsibilities of the sponsor, the investigators and the Ethics Committees; developed guidelines and procedures for importing drugs for

Clinical trials; instituted required compliance with GCP; specified the requirements for informed consent; and defined the structure, content and formats of clinical study reports. In addition, the Indian Government provided increased protection for intellectual property (IP).

Indian Guideline for Clinical Trial:
After the achievement of Independence in 1947 from the British Empire, it has developed a drug regulation system that refused to allow clinical testing for therapies of foreign origin. After Independence Indian government was adopting and revised Drug and Cosmetic Act 1948. Indian regulatory systems have gradually opened up the country to foreign drug development, with the first Good Clinical Practices (GCP) trial being initiated in 1995. This guideline is called as Indian-GCP. The clinical trials legislative requirements are guided by specifications of schedule Y of Drugs and Cosmetics Act in India. Recently the Ministry of Health, along with DCGI and ICMR has come out with draft guidelines for research in human subjects. These are essentially based on Declaration of Helsinki, WHO guidelines and ICH requirements for GCP.
All clinical trials are conducted in India according to Indian-GCP and Schedule Y. Indian Clinical Research focus is shifting from cost advantages to quality and rapid response.

India Projections:
The cost per patient for trials in India is approximately 40 to 60% of the cost in western nations. More importantly, patient recruitment can be greatly accelerated, and this provides a major advantage in terms of shortening the time to market for a new drug. Based on these advantages, the number of clinical trials in India is expected to grow exponentially over the next five to ten years. It has been estimated that in 2005 only 1% of global clinical trials were conducted in India, this percentage is projected to grow to 15% of global trials by 2011. The charts below illustrate the effects of such rapid growth, projecting that by the year 2011 over 300,000 patients will be enrolled in clinical trials in India. Mckinsey projects that within five years 1,500 to 2,000 GCP studies will be conducted in India per

Year, requiring 10,000 to 15,000 GCP- trained investigators, and supported by 50,000 clinical research professionals.

Various Types of Clinical Trials being conducted in India:
Trials are on for drug which is indicated for reduction of mortality in adult patients and can be used for sepsis. Clinical Trials have already been held on more than 600 patients for human insulin and insulin. Clinical Trials are being conducted on oncology and developing a new molecule for lung cancer.

Clinical trials are on 300 patients on a new malaria 'cocktail' drug that combines chloroquine (to which Indian malarial strains have developed resistance) and azithromycin, an antibiotic. Clinical Trials are also being conducted for drugs to treat osteoporosis, breast cancer and schizophrenia.

Global trials are on in India for treatment of a particular variant of lung cancer. One of the reasons for considering India is that it has a vast patient population infected by this type of lung cancer, which is primarily triggered by use of tobacco products. India is also being considered a prospective site for future clinical trials involving new drugs and therapies for treatment of different variants of blood cancer and colorectal diseases.

The trials in India are mostly in different areas like oncology, endocrinology, traumatology, sports medicine, pulmonary diseases, pediatric diseases, and infectious diseases.

The largest Clinical Trial outside US for a drug delivery device has been conducted in India.

Status of clinical trial in India:

The Indian pharmaceutical industry is one of the fastest growing sectors of the Indian economy and has made rapid strides over the years. From being an import dependent industry in the 1950’s, the industry has achieved self-sufficiency and gained global recognition as a producer of low cost high quality bulk drugs and formulations. Having proved its mettle in the international market, India is now on the helm of taking up the challenge of proving its efficiency as the capital for global clinical trails. A number of factors favour the recognition of India as a hub for clinical research, due to which the multinational companies have identified it as their ideal destination, but In 1988, the government made it mandatory for all new drug introductions as a regulatory requirement for getting NCE’s approved. Schedule Y stipulated that the fist applicant for any new drug should generate data in local clinical trials conducted in approximately 100 patients at 4 to 5 centers. This schedule also indicates that permission for such clinical trials would be given for one phase behind the development status in the rest of the world. However, for a second and subsequent applicant for the same compound, no clinical trial would be required, since they could show bio-equivalence to the first product approved and introduces their brand of the generic in the market. Due to this lack of protection, innovator companies have been losing money by virtue of not being able to introduce their new and cutting edge research in the Indian market due to the presence of generic brands of innovator compounds.
Moreover, it also discouraged the pharmaceutical companies from carrying out global clinical studies by their local subsidiaries in India and preferred to wait for their innovator brands to be approved in source countries and then carry out limited bridging studies for local approvals. Consequently, there has been a gap between their introductions in India with the rest of the markets worldwide.

Table 1: Transition in regulatory authority capabilities in India

Before 2005 After 2005
Process patent law Product patent for drugs, food and agro chemicals
Phase II and III trials were only permitted after those phases were completed elsewhere (Phase lag)

Schedule Y amended for multi-centric concurrent clinical trials as per GCP upgraded schedule M.
Clinical trial registry - India (CTRI), funded jointly by DST, WHO and ICMR initiated.
GLP monitoring authority setup for pre-clinical (toxicological) studies.
New Drugs, imports, clinical trials, drug standards approved by central government enforcement by states.
CDSCO-WHO National pharmacovigilance program launched.

Product patent regime:
The draft National Pharmaceuticals Policy 2006 is committed to making Indian laws and policies relating to IPR, including data protection, fully complaint with TRIPS provisions. India has signed the Trade Related Intellectual Property Rights (TRIPS) agreement as a part of the WTO regulations, which will guarantee Intellectual Property Rights and patent protection to companies holding the patent from 2005. In the present Intellectual Property Right (IPR) regime, it has become extremely important for conducting timely clinical research. Increasingly, permission for phase-I trials is being granted after thorough appraisal of the protocols, products and claims. Favorably, the government has also relaxed the duties that are levied on clinical trials samples. These steps indicate the commitment of the government in strengthening India’s position and propelling it as world leader in clinical research.

Bioethics:
While conducting the clinical trials, the CRO’s need to bear the following principle’s in mind-essentiality, voluntariness, informed consent, non-exploitation, privacy, risk minimization, professional competence, accountability, maximization of public interest and totality of responsibility and compliance (ICMR,2000). The proposed clinical trial has to be reviewed and approved by Institutional Ethics Committee (IEC), or Institutional Review Board (IRB). Following ethical approval, the proposal has to be submitted for approval to Drugs Controller General of India (DCGI), as is necessary under the schedule Y of Drugs and Cosmetics Act, 1940.
In January 2005, India adopted a new rule that will allow pharmaceutical companies to begin phase II and III trials concurrently with trials of the same phase conducted abroad, there by reducing clinical development time. Under the old rule, phase II and III trials were only permitted after those phases were completed elsewhere. The rules were intended to create a “phase lag” between India and the rest of the world to prevent foreign pharmaceutical companies from using Indians to test their unproven therapies. With the latest amendment (20th January 2005) to the schedule Y of Drugs and Cosmetic Act

1945, the reporting of adverse events from clinical trials has become clearer and unambiguous. There is of course a quantum leap between the old and the new version and the serious intentions of the DCGI regarding stricter compliance are clearly palpable.

ICH-GCP compliance:
Good clinical practices (GCP) is an ethical and scientific quality standard for designing, conducting and recording trials that involve the participation of human subjects. Compliance with this standard provides assurance to public that the rights, safety and well being of trial subjects are protected. High level of International Conference on Harmonization (ICH) of technical requirements for registration of pharmaceuticals for human use, Good Clinical Practice (GCP) and US Food and Drug Administration (FDA) standards compliance-since 2001, the DCGI has implemented conformity to ICH GCP/Good Laboratory Practice (GLP) guidelines. Generally, most competent authorities (CA s), including the FDA, will find the standards of Indian clinical trials acceptable.

Clinical trial registry:
Two independent incidents underscored the need to have a serious re-look at the way clinical trials are conducted and reported. An early stage trial of TGN1412, a monoclonal antibody to treat leukemia, went seriously wrong in Britain with a dozen patients hospitalized due to multiple organ failure necessitating hospitalization. Coming as it did close on the heels of the intense controversy that Merck with held critical data from trials of vioxx, these incidents put the Pharma industry firmly in the dock. In fact, there have been several reports that all is not well with clinical trials, that aim to develop new therapeutic or preventive measures, assess or evaluate an existing medical treatments and techniques vis-à-vis a new one.
As a series of incidences of unfortunate events associated with clinical trials came to light, there has been a growing call for transparency, accountability and accessibility of clinical trials and their results in order to re-establish public trust in clinical trial data. All these appear to be possible only by

Mandatory registration of all clinical trials, with the ultimate goal of ensuring that all trial results, positive or negative will be released to the public. Several trial registries are already in place the world over, such as the ACTR, ClinicalTrials.gov, ISCRTN, etc. Furthermore the WHO is promoting an international initiative to develop a Meta register of controlled trials that would offer a one step search portal fed from existing registers and provide a unique identification number for clinical trials from certified registers that needs standard criteria for the exchange of essential trial data. Keeping with the times and its demands, a registry, Clinical Trial Registry-India (CTRI), funded jointly by DST, WHO and ICMR has been initiated. The CTRI has been set up at NIMS (ICMR), New Delhi to provide a platform for registration of all clinical trials in India. Primary objectives are to establish public record system by registering all prospective clinical trials conducted in India on health products including drugs, devices, vaccines and herbal drugs which will made publicly available on the internet at no cost.

National pharmacovigilance programme:
The government of India, with the World Bank, has initiated the National Pharmacovigilance Programme. The Central Drugs Standard Control Organization (CDSCO) is coordinating the country wide pharmacovigilance programme under the aegis of DGHS, Ministry of Health and Family Welfare, New Delhi. With the number of new drugs being regularly approved for marketing in India, there is a need for a vibrant pharmacovigilance system in the country to protect our population from the potential harms that may be caused by some of these new drugs. Besides, with the patent regime coming in force from 2005, it is widely believed that India would become the global hub for new drug trials. These situations make it pertinent for the Indian central drugs regulatory authority to have a vibrant pharmacovigilance system in the country.

The Regulatory Approval process:
Clinical trials are now regulated by the Drugs Controller General of India (DCGI), whos is responsible for assuring that all clinical trials comply with the requirements of the International Conference on Harmonisation (ICH) of Technical Requirements for Registration of Pharmaceuticals for Human Use, as well as Good Clinical Practices. The DCGI approval process categorizes clinical trials into two types. If the study protocol has already been approved by a recognized regulatory authority in more or more developed countries (such as the U.S., Canada, U.K., Switzerland, Germany, Australia, Japan, and South Africa), the study is classified as a Type A trial and can be approved using a fast track process within two to six weeks after the required documentation has been submitted. All other studies are classified as Type B, for these, the approval process is generally 8 to 12 weeks. The Institutional Review Board (IRB) approval process can be conducted in parallel with the DCGI review and, if import licenses are needed, the applications for these can also proceed in parallel. These provisions facilitate the process of getting study protocols in place and quickly initiating the trials.

Bridging the Needs:
Western Pharma companies need to increase productivity, decrease costs, and shorten the time to market for new drugs. One solution is conducting clinical trials that provide lower cost and faster recruitment without compromising the quality of the research. India clearly offers this solution. In the past, several constraints have limited the number of clinical trials conducted in India:
• Communication can be an issue because of cultural differences between Western countries and India.
• The difference in time zones creates further difficulties in communication and monitoring of work.
• There are some significant differences between Western and Indian business cultures.
• Indian researchers need to clearly understand the requirements of Western pharmaceutical companies and their regulatory requirements.
• Western companies need to overcome their perception of India as a non-traditional “developing” nation that is the “land of the generics” with limited capacity and uncertain quality of work.
These issues are not unique to clinical trails. Similar issues have been faces and successfully addressed in fields such as information technology (IT) and business process outsourcing (BPO), where India is now a leading provider of services to western clients.

Barriers:
The overall time and cost advantage in bringing a drug to market by leveraging India’s resources could be as high as US $200 million, 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 at US $ 2billion. CROs themselves are fast gaining importance because of their global presence, specialized local expertise, and competitive 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.

Patients’ Rights and safety:
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 eight 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 then 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. This phase process is particularly important in developing countries if carefully understood and explained to potential subjects.

Regulatory Framework:
Multinational pharmaceutical companies and CROs are able to conduct good quality clinical trials in India despite infrastructural challenges at the regulatory departmental level. They can do so because of required professional training and the professional’s 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.

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.

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 offers value-added infrastructural incentives to the country.

Functioning of ethics committees:
According to a survey conducted by ICMR, ECs are functioning in over 200 institutions. However, there is no accreditation of ECs. Besides, some ECs have an irregular schedule of meetings, lack standard operating procedures, and do not have a composition in line with GCP guidelines. The ICMR has planned to review and audit the functioning of ECs and to introduce a national accreditation system for them. Additionally, the ICMR has also established an Independent Forum for Ethics Review Committees, which will organize training programs for the members of ECs. The revised schedule Y of Drugs and Cosmetic Rules devotes significant attention to the roles and responsibilities of ECs, prescribes the composition of ECs as per the ICMR guidelines and provides formats for the approval letter of ECs. These government initiatives are likely to improve the current situation.

Responsibilities of investigators:
In 2002, there were 200-250 GCP trained investigators and 40-50 GCP clinical studies were conducted. These small numbers imply that many potential clinical investigators do not have the experience of conducting GCP trials. Though this is not considered negative, it does require a major investment in training during study start-up. For the investigators struggling to balance patient care and research activities, compliance to GCP is an additional new responsibility. In addition, low literacy levels and poverty amongst the patients and the pressure of quick patient recruitment from the sponsors pose significant challenges to an investigator making efforts to obtain proper informed consent from the patients. The stress on documentation of the informed consent process in the GCP training programs, and the adverse media publicity to several recent clinical trial mishaps and subsequent government enquires have increased the awareness amongst the investigators about ethical and regulatory issues and the need for adequate patient protection.

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 motivate them to develop research protocols for domestic health care issues. This, in turn, is nurturing a culture of medical research that can match international standards.

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:
 The purchasing power of the customers;
 The existence of unpatented drugs and cheaper substitutes; and
 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.

CASE STUDY:

Indian Guinea Pigs for Sale: Outsourcing Clinical Trials
This article was shown different perspective what type of unethical clinical trial business occurred in India
1) Two Indian pharmaceutical companies conducted trials of genetically engineered drugs without proper approvals, have renewed fears about unethical drug research in India. This case involved Bangalore-based Biocon and Hyderabad-based Shantha. Biotech conducted Phase III trials of genetically engineered drugs (insulin for diabetes by Biocon and streptokinase for heart attacks by Shantha) without appropriate prior approval of both the Drug Controller General of India (DGCI) and the Genetic Engineering Approval Committee. Press report was said that approval letter DCGI got or not. Also both companies applied to the GEAC only after the trials started.
Result of this study: Some people died in the Shantha trial, conducted on seriously ill patients. This study was conducted in 2003.Company does not followed Indian GCP regulation and ICH-guideline when recruiting patients in trial. In emergency situation company does not obtained proper informed consent process. Also company did not provide compensation to trial related injury.
2) Mumbai-based Sun Pharmaceutical Industries Limited bypassed the DCGI altogether and got private doctors to prescribe the anti-cancer drug Letrozole to more than 400 women for ovulation induction. They used the results to promote this drug through medical representatives for this unapproved usage. While there are debates about doctors' legal and ethical right to prescribe a drug off-label, off-label research done without following proper procedure is outright illegal. Letrozole is patented by Novartis. There is nothing to indicate that Novartis was involved in the illegal trial.

Conclusion:
Although it typically takes 10 to 12 years and millions of dollars to bring one new drug to market, 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 development programs.
The evolution of GCP in the west- from the Nuremberg Trials till the development of ICH-GCP guidelines-took almost five decades. India’s involvement in global GCP trials is only about a decade old. ICMR’s Ethical Guidelines for Biomedical Research on Human Subjects were launched in 2000 and Indian GCP guidelines became available in Dec 2001. The experience of conducting global GCP trials limited. GCP is a shared responsibility amongst sponsors, investigators, regulators and ethics committees. As all stakeholders are still learning, the journey towards achieving global quality is unlikely to be smooth. The efforts of the government and industry to create awareness through GCP workshops and to provide training to the investigators and ECs will go a long way in creating a culture of global GCP quality trials.
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.

BIBILOGRAPHY:-
1. “Outsourcing clinical studies advantage of India” by S K Gupta Chronicle Pharmabiz Page no 51 September 28.2006.
2. “Clinical Research in India” by Dr Swapneel Anaokar in Pharambiz.The author is Head - Clinical Research and Regulatory Affairs, GlaxoSmithKline Pharmaceutical Limited, India Tuesday, February 12, 2002 11:16 IST
3. Outsourcing in Clinical Research - The Indian Perspective” by Kapil Parab
4. Research Analyst-Healthcare Practice Frost & Sullivan, India published in med India.
5. History of clinical research published in med India.
6. “Clinical trials and regulatory tribulations” by Bhatt AD. Express Pharma Pulse 2002-Nov 21:32-3
7. “Outsourcing clinical trials to India rash and risky, critics warn” by Jayaraman KS. Nat Med 2004; 10:440.
8. “DCGI guidelines a booster shot for clinical drug trials” by Raghu Balakrishnan published in DNA new paper Wednesday, November 29, 2006 22:11 IST
9. Global Clinical Trials in India – Challenges and Opportunities” a report by Dr Dhananjay Bakhle in Business briefing Pharmatech 2003
10. Indian Guinea Pigs for Sale: Outsourcing Clinical Trials by Sandhya Srinivasan
11. India Resource Center September 8, 2004
12. Fenn CG, Wong E, and Zambrano D.2001. The contemporary situation for the conduct of clinical trials in Asia. International Journal of pharmaceutical Medicine 15: 169-73.
13. Wax PM. 1995. Elixirs, diluents, and the passage of the 1938 Federal Food, Drug and Cosmetic Act. Annals of Internal Medicine 122: 456-61.

14. Diggle GE.2001. Thalidomide: 40 years on. International Journal of pharmaceutical Medicine 55: 627-31.
15. U.S. Food and Drug Administration. Disqualified/ Restricted / Assurance List for ClinicalInvestigatorsAvailablefrom, www.fda.gov/ora/compliance_ref/bimo/dis_res_assur.htm.
16. Lamberti MJ, Space S, Gammbrill S. Going global. Appl Clin Trials 2004; 13:84-92.
17. Borfitz D. Lifting India’s Barriers to clinical trials. Center Watch 2003; 10(8): 1-9.
18. Jayaraman KS. Outsourcing clinical trials to India rash and risky, critics warn Nat Med 2004; 10:440.
19. Bhatt AD. Clinical trials and regulatory tribulations. Express Pharma Pulse 2002; Nov 21:32-3.
20. Mudur G. Johns Hopkins admits scientist used Indian patients as Guinea pigs. Br Med J 2001; 323: 1204.

هند كموقعة ل يوصل محاكمات سريريّة
Automatically translated into Arabic thanks to WorldLingo
تقديم
بحث سريريّة يلزم جزء من العقار إكتشاف عملية أن يضمن الأمان وفاعليّة من أيّ عقار جديدة. في عصر هذه الأيّام شاملة علميّة, محاكمات سريريّة الدعامة ل يحضر جديدة وعقارات جيّدة أن يتسوّق.

ماذا يكون محاكمة سريريّة?
محاكمات سريريّة تجارب أن يحدّ القيمة المعالجة. هناك اثنان [كي كمبوننت] إلى المقاربة تجريبيّة. أولى, تطلّبت نتيجات [رثر ثن] تفكير محتملة أن يساند استنتاجات. ثانية, تجارب سوفت كنت [بروسبكتيفلي] خطّطت وأوصلت تحت شروط مراقبة [إين وردر تو] زوّدت جوابات محدّدة إلى أسئلة [ولّ دفيند].

يتضمّن تطوير من عقار جديدة اثنان أطوار, أيّ عقار إكتشاف وعقار تطوير. يتضمّن المرحلة من عقار إكتشاف التحقق من الهدف, عقار يصمّم وتأليف يتبع ب ه تمهيديّة [إينفيترو] غربلة.

الخطوة تالية تقييم [بركلينيكل], أيّ يتضمّن شديدة يختبر من فاعليّة وأمان من الجزيء جديدة بفحوصات مختلفة [إين-فيفو] يستعمل حيوانات. ولدت المعطيات ضروريّة لتقييم في أناس هنا والإختبار عقار الآن يتأهّب لأخرىه وكثير مرحلة حاسمة من تقييم [إي.], تقييم سريريّة.
يقيّم الطبيب سريريّ في تنسيق مع الصيدليات الفاعليّة والأمان من العينة على أربعة مراحل [سترتينغ فروم] يصحّ متطوعات ويتحرّك على مجموعة صغيرة مريضات وبعد ذلك رقم كبيرة من مريضات ومجموعة خاصّة. طور - يشكّل أنا أو علم العقاقير سريريّة الأساس لمحاكمة سريريّة ل أيّ عقار جديدة ويزوّد الخطوة بين [بر] سريريّة وبحر سريريّة ([كوهلمنّ], 1997). أخيرا, التطبيق لمراجعات تنظيميّة وموافقة يمكن كنت طبّقت والموافقة بحثت.

[دفينأيشن]:
وفقا ل [إيش-غكب]
محاكمة سريريّة/دراسة:
نوى أيّ تحقيق في [هومن سوبجكت] أن يكتشف أو دقّقت السريريّة, [فرمكلوجكل] [أند/ور] أخرى تأثيرات مؤثّر بالأدوية من منتوج [إينفستيغأيشنل], [أند/ور] أن يدرس امتصاص, توزيع, أيض, وإفراز من منتوج [إينفستيغأيشنل] مع الشيء من يوقن ه أمان [أند/ور] فاعليّة. العبارات سريريّة محاكمة ودراسة سريريّة مرادفة.

وفقا ل محاكمة [إيندين-غكب]
سريريّة: دراسة نظاميّة [فرمسوتيكل برودوكت] على [هومن سوبجكت] - (ما إذا مريضات أو [نون-بتينت] متطوعات) - [إين وردر تو] اكتشفت أو دقّقت السريريّة, [فرمكلوجكل] (بما في ذلك/[فرمككينتيكس]), و [أدفرس فّكت], مع الشيء من يحدّد هم أمان وفاعليّة.

مجال من بحث
سريريّة كلّ جديدة عقار بيّنة من بحث سريريّة أن يساند إطلاقه. لذلك, ما إذا هو ذاتية جديدة كيميائيّ أو عقار موجودة أنّ يكون يكون تسوّقت لدلالة جديدة, دراسات سريريّة يضطرّ كنت أوصلت. بالمثل, يتطلّب إطلاق من صياغة جديدة, عقار تسليم نظامات [أر فن] جديدة ثابتة جرعة إدماج, معطيات سريريّة قبل أن هو يستطيع كنت تسوّقت. بالتّالي هو واضحة أنّ يمسك المنطقة من بحر سريريّة ضخمة مجال ووعد ل دون ال [سوبّورت دتا], عقار إطلاق ليس يمكن. أسّست التصرّف إداريّ من بحث سريريّة على ال [غكب] و [إيش] [غيدلينس].

تاريخ من محاكمة سريريّة:
يوقن, يتضمّن علم محاكمة وخطأ. عالمات يكرّسون نظريات كلّ يوم. غير أنّ بما أنّ هم يتمّون, يساعدنا هم أمسكت أكثر بوضوح الأعجاب من العالم والكوك.
ثلج

[توني] التاريخ من عقار إكتشاف غالبا رائعة. اكتشفت كثير من العقارات أنّ يكون استعملت اليوم يتلقّى يكون [بي شنس] أو غالبا ب [سرنديبيتي] مجرّدة. هند تاريخ من عقار إكتشاف ومهارة في [مديكل رسرش] يستطيع كنت تتبّعت [بك تو] اثنان قديمة نصوص, [شركا] [سمهيتا] (كتاب مدرسيّ الالطبّ) و [سوشروتا] [سمهيتا] (كتاب مدرسيّ الجراحة), ينسّق [أس رلي س] 200 [ب.]. [ك.]. و200 [أ.]. [د.]. على التّوالي.

سريريّة محاكمات [تيملين] (605 قبل المسيح - [2000د])
تقدم سريريّة تجريبيّة [دبندينغ ون] التقدم العلم ويسهم تكنولوجيا و [فرمككينتيكس] يتلقّى كلّ إلى تكرير ويعيد العملية كاملة. يلتقي ال [إينترنأيشنل كنفرنس] على حالة توافق ([إيش]) [فروم تيم تو تيم] أن يشكّل ونقّحت [غيدلينس] طبقا ممارسة جيّدة سريريّة.
حاليّة [21ست سنتثري] عقار قد استعمل [ديسكفري مثود] بعض [أدفنسد تشنولوج]. قد أوجد الثورة أحيائيّة كثير جديدة ويعد إنضباطات مثل [ننوتشنولوج], [فرمكمتبونوميك], [جنوميكس], [بروتيوميكس], [متبولومينس] و [بيوينفورمتيكس]. يوزّع محاكمة مراقبة و [مولتيسنتريك] دراسة تجريبيّة تصميم جديدة من محاكمة سريريّة.
هند خلفيّة:
[أونتيل رسنتلي], كان هناك قليل من محاكمات سريريّة يوصل في هند بغربيّة صيدلانيّة و [بيوتش] شركات, أوّلا بسبب حواجز تنظيميّة. في يناير - كانون الثّاني 2005, يميّز الميزات هامّة أنّ هند يقدّم إلى شركات متعدّد أجناس والإحتمال وفوائد من يوصل محاكمات سريريّة في هند, حسن الحكومة هند جدول [ي] من العقارات ومستحضر تجميل عمل هند, المعادلة من الأقسام من الرمز ال [فدرل رغلأيشن] مناسبة إلى ال [فدا], أن يتوافق هو مع الولايات المتّحدة الأمريكيّة و [إينترنأيشنل كنفرنس] على حالة توافق ([إيش]) معايير. أزال هذا تغيرات [ا نومبر وف] عوائق تنظيميّة أن ينجز محاكمات سريريّة في هند. شكّل التغيرات التعريف وتصرّف إداريّ من محاكمات سريريّة; عيّن المسؤوليات من الكفيلة, المحققات والعلم خلق لجن; يطوّر [غيدلينس] وإجراءات ل يستورد عقارات

لمحاكمات سريريّة; يعيّن يتطلّب إستجابة مع [غكب]; عيّن المتطلبات ل يعلم رضاء; يفيد ويعيّن البنية, محتوى وأشكال من دراسة سريريّة. [إين دّيأيشن], زاد الحكومة هنديّة يزوّد حماية ل [إينتلّكتثل بروبرتي] ([إيب]).

دليل هنديّة لمحاكمة سريريّة:
بعد الإنجاز الاستقلال في 1947 من ال [بريتيش مبير], قد طوّر هو عقار نظامة نظاميّة أنّ رفض أن يسمح سريريّة يختبر لمعالجة من أصل أجنبيّة. عقب استقلال تبنّى حكومة هنديّة كان وينقّح عقار وتجميليّة يتصرّف 1948. [أبن وب] جهاز تنظيمي هنديّة يتلقّى تدريجيّا البلد إلى أجنبيّة عقار تطوير, مع الأولى جيّدة سريريّة ممارسات ([غكب]) محاكمة يكون يبدأ في 1995. دعات هذا دليل بما أنّ [إيندين-غكب]. السريريّة محاكمات أرشدت متطلبات تشريعيّة بمواصفات الجدول [ي] من عقارات ومستحضر تجميل يتصرّفون في هند. مؤخّرا قد أتى ال [مينيستري وف هلث], مع [دكج] و [إيكمر] خارجا مع مسوّدة [غيدلينس] لبحث في [هومن سوبجكت]. أسّست هذا أساسا على إعلان من هلسينكي, [وهو] [غيدلينس] و [إيش] متطلبات ل [غكب].
أوصلت كلّ محاكمات سريريّة في هند وفقا ل [إيندين-غكب] وجدول [ي.]. هنديّة سريريّة بحث يغيّر بؤرة من تكلفة ميزات إلى نوعية وإستجابة سريعة.

هند أعراض:
التكلفة لكلّ مريضة لمحاكمات في هند تقريبا 40 [تو] 60% من التكلفة في أمم غربيّة. أكثر بأهمّيّة, تجنيد صبور يستطيع كنت للغاية أسرعت, ويزوّد هذا ميزة كبريات بخصوص يوجز ال [تيم تو مركت] لعقار جديدة. يؤسّس على هذا ميزات, توقّعت الرقم من محاكمات سريريّة في هند أن ينمو أسّيّا على التالية خمسة [تو] عشرة سنون. قدّمت هو يتلقّى يكون أنّ في 2005 فقط 1% من محاكمات شاملة سريريّة كان أوصلت في هند, هذا نسبة مئويّة سلّطت أن [غروو تو] 15% من محاكمات شاملة ب 2011. يوضّح المخططات [بلوو] التأثيرات من هذا حالة نموّ سريعة, يسلّط أنّ بالسنة 2011 على 300,000 مريضات كنت سيسجّل في محاكمات سريريّة في هند. سيوصل [مكينسي] يسلّط أنّ ضمن خمسة سنون 1,500 [تو] 2,000 [غكب] دراسات كنت في هند لكلّ

سنة, يتطلّب 10,000 [تو] 15,000 [غكب-] يدرّب محققات, وسيساند ب 50,000 سريريّة بحث محترفات.

أنواع مختلفة من محاكمات سريريّة يكون يوصل في هند:
محاكمات فوق لعقار أيّ يكون أشرت لتخفيض الوفاة في بالغ مريضات ويستطيع كنت استعملت لتعفن. أمسكت محاكمات سريريّة يتلقّى سابقا يكون على أكثر من 600 مريضات لأنسولين إنسانيّة وأنسولين. أوصلت محاكمات سريريّة يكون على [أنكلوج] ويطوّر جزيء جديدة لسرطان الرّئة.

محاكمات سريريّة على 300 مريضات على جديدة ملاريا "كوكتيل" عقار أنّ يضمّ كلوروكين (إلى الذي إجهادات هنديّة [ملريل] قد طوّروا مقاومة) و [أزيثرومسن], مضادّ للجراثيم. أوصلت محاكمات سريريّة أيضا يكون لعقارات أن يعامل [أستيوبوروسس], [برست كنسر] وإنفصام الشخصيّة.

محاكمات شاملة فوق في هند لمعالجة من [فرينت] خاصّة سرطان الرّئة. واحدة من الأسباب ل يعتبر هند أنّ يتلقّى هو السّكان ضخمة صبور يعدى ب هذا نوع السرطان الرّئة, أيّ يكون أوّلا أطلقت بواسطة تبغ منتوجات. اعتبرت هند أيضا يكون موقعة مستقبلية لمحاكمات مقبلة سريريّة يتضمّن عقارات جديدة ومعالجة لمعالجة من [فرينت] مختلفة من دم سرطان وأمراض [كلوركتل].

المحاكمات في هند في الأغلب في مناطق مختلفة مثل [أنكلوج], علم الغدد الصّم, طبّ رضّ, رياضات الطبّ, أمراض رئويّة, أمراض خاصّ بطبّ الأطفال, وأمراض معدّة.

أوصلت ال [أوس] كبيرة سريريّة تجريبيّة خارجيّة لعقار تسليم أداة يتلقّى يكون في هند.

وضع من محاكمة سريريّة في هند:

الصناعة هنديّة صيدلانيّة واحدة من السريعة ينمو قطاعات من الاقتصاد هنديّة ويجعل خطوات سريعة على السنون. من يكون إستيراد صناعة متدلّية في ال 1950, قد حقّق الصناعة [سلف-سوفّيسنسي] ويكسب تمييز شاملة كمنتج من تكلفة منخفضة [هيغقوليتي] شحن عقارات وصياغة. يتلقّى يبرهن طبعه في السوق دوليّة, هند الآن على الدفة من يقصّر التحدي من يبرهن فعاليته كالرأس مال لآثار شاملة سريريّة. يؤيّد [ا نومبر وف] عاملات التمييز هند كصرة لبحث سريريّة, واجبة إلى أيّ الشركات متعدّد أجناس قد عيّنوا هو بما أنّ غايتهم مثاليّة, غير أنّ في 1988, الحكومة جعل هو إجباريّة لكلّ جديدة عقار تقديمات كمتطلب تنظيميّة ل يحصل [نس] يوافق. برمجت [ي] اشترط أنّ القبضة مقدّم طلب ل أيّ عقار جديدة سوفت ولدت معطيات في محاكمات محلّية سريريّة يوصل في تقريبا 100 مريضات في 4 [تو] 5 مراكز. يشير هذا جدول أيضا أنّ إذن ل هذا محاكمات سريريّة كنت أعطيت لواحدة طور خلف التطوير وضع في ال [رست وف ث وورلد]. مهما, لثاني ومقدّم طلب لاحقة ل ال نفسه مركبة, ما من تطلّبت محاكمة سريريّة كنت, بما أنّ هم استطاع أبديت [بيو-قويفلنس] إلى المنتوج أولى يوافق ويقدّم إشارتهم من العامّة في السوق. واجبة إلى هذا افتقار الحماية, مبتكرة شركات قد كان مال خاسرة بفضل لا [ب] يمكن أن يقدّم هم جديدة و [كتّينغ دج] بحث في الهنديّة سوق واجبة إلى الوجود من إشارات عامّة من مبتكرة مركبات.
فضلا عن ذلك, ثبّط هو أيضا ال [فرمسوتيكل كمبني] من يوفي دراسات شاملة سريريّة بفرع تابعهم محلّية في هند وفضّل أن ينتظر ل هم مبتكرة إشارات أن يكون وافقت في [سورس كونتري] وبعد ذلك وفيت محدودة يجسر يدرس لموافقة محلّية. بالتّالي, قد كان هناك ثغر بين تقديماتهم في هند مع الإستراحة من الأسواق عالميّا.

طاولة 1: إنتقال في [رغلتوري وثوريتي] إمكانيات في هند

قبل 2005 بعد 2005
معامل براءة اختراع قانون منتوج سمحت براءة اختراع لعقارات, طعام وزراعيّة مادّة كيميائيّة
طور [إيي] [إييي] محاكمات كان فقط عقب أنّ أطوار كان أتمّت في مكان آخر (طور تأخر)

عدّل جدول [ي] لمحاكمات [مولتي-سنتريك] متواقتة سريريّة طبقا [غكب] يحسن جدول [م.].
تسجيل سريريّة تجريبيّة - هند ([كتري]), يموّل معا ب [دست], [وهو] و [إيكمر] يبدأ.
[غلب] [مونيتور] سلطة تركيب ل [بر-كلينيكل] ([توإكسيكلوجكل]) دراسات.
وافق عقارات جديدة, إستيراد, محاكمات سريريّة, عقار معايير ب [سنترل غفرنمنت] إنفاذ بدول.
[كدسك-وهو] وطنيّة [فرمكفيجلنس] أطلق برنامج.

منتوج براءة اختراع نظامة:
المسوّدة وطنيّة مستحضرات صيدليّة ارتكبت سياسة 2006 إلى يجعل هنديّة قانون وسياسات [رلتينغ تو] [إيبر], بما في ذلك معطيات حماية, كلّيّا شكوى مع رحلات إحتياطات. قد وقع هند التجارة يرتبط [إينتلّكتثل بروبرتي] حقوق (رحلات) إتفاق كجزء من ال [وتو] نظام تعديل, أيّ سيضمن [إينتلّكتثل بروبرتي] حقوق وبراءة اختراع حماية إلى شركات يمسك البراءة اختراع من 2005. في الحاضرة [إينتلّكتثل بروبرتي] حق ([إيبر]) نظامة, قد أصبح هو جدّا مهمّة ل يوصل بحث في الوقت المناسب سريريّة. بدرجة متزايدة, منحت إذن ل [فس-ي] محاكمات يكون بعد تقييم كاملة من البروتوكولات, منتوجات وإدعاءات. بإيجاب, يسترخي الحكومة يتلقّى أيضا الواجب رسم أنّ يكون فرضت على سريريّة محاكمات عينات. يشير هذا [ستبس] التعهد من الحكومة في يقوّي هند موقعة ويدفع هو كعالم زعيمة في بحر سريريّة.

[بيوثيكس]:
بينما يوصل المحاكمات سريريّة, ال [كرو] أعلم حاجة أن يحمل المبدأ تالي في [ميند-سّنتيليتي], [فولونترينسّ], رضاء, [نون-إكسبلويتأيشن], عزلة, خطر [مينيميزأيشن], كفاءة محترفة, مسؤولية, تحقيق أفضل من فائدة عامّة وكلية من مسؤولية وإستجابة ([إيكمر], 2000). ال يقترح محاكمة سريريّة يضطرّ كنت راجعت ووافقت بتشريعيّة علم خلق لجنة ([إيك]), أو [رفيو بوأرد] تشريعيّة ([إيرب]). بعد موافقة أخلاقية, الاقتراح يضطرّ كنت قدّمت لموافقة إلى عقارات جهاز تحكّم جنرال هند ([دكج]), بما أنّ ضروريّة تحت الجدول [ي] من عقارات ويتصرّف مستحضر تجميل, 1940.
في يناير - كانون الثّاني 2005, تبنّى هند قاعدة جديدة أنّ سيسمح [فرمسوتيكل كمبني] أن يبدأ طور [إيي] [إييي] محاكمات مع محاكمات من ال نفسه طور يوصل في الخارج, هناك ب يقلّد [دفلوبمنت تيم] سريريّة. تحت القديمة قاعدة, طور [إيي] [إييي] سمحت محاكمات كان فقط عقب أنّ أطوار كان أتمّت في مكان آخر. نويت القواعد كان أن يخلق "طور تأخر" بين هند وال [رست وف ث وورلد] أن يمنع [فرمسوتيكل كمبني] أجنبيّة من يستعمل هنديات أن يختبر معالجتهم غيرمثبت. مع التعديل متأخّرة ([20ث] يناير - كانون الثّاني 2005) إلى الجدول [ي] من عقارات وعمل

تجميليّة 1945, قد أصبح ال يفيد من حادثات عكسيّة من محاكمات سريريّة واضحة وغير غامض. هناك [أف كورس] كم رمي بين القديمة والصيغة جديدة والنيات جدّيّة من ال [دكج] بخصوص إستجابة [ستريكتر] بوضوح ملموسة.

[إيش-غكب] إستجابة:
ممارسات جيّدة سريريّة ([غكب]) أخلاقية وعلميّة نوعية معيار ل يصمّم, يوصل ويسجّل محاكمات أنّ يتضمّن المشاركة ال [هومن سوبجكت]. يزوّد إستجابة مع هذا معيار تأمين إلى جمهور أنّ الحقوق, أمان و [ولّ-بينغ] من مواضيع تجريبيّة حميت. رفيع المستوى من [إينترنأيشنل كنفرنس] على حالة توافق ([إيش]) من [تشنيكل رقويرمنت] لتسجيل المستحضرات صيدليّة لإستعمال إنسانيّة, ممارسة جيّدة سريريّة ([غكب]) و [أوس] طعام وعقار إدارة ([فدا]) معايير [كمبلينس-سنس] 2001, ال [دكج] قد طبّق توافق إلى [إيش] [غكب/غود] مختبرة ممارسة ([غلب]) [غيدلينس]. عموما, سيجد كثير [كمبتنت وثوريتي] ([ك] [س]), بما في ذلك ال [فدا], المعايير من محاكمات هنديّة سريريّة مقبولة.

تسجيل سريريّة تجريبيّة:
سطّر اثنان حادثات مستقلّة الحاجة أن يتلقّى جدّيّة [ر-لووك] في الطريق محاكمات سريريّة يكون أوصلت وأفدت. مرحلة مبكرة ذهب محاكمة ال [تن1412], جسم [مونوكلونل] أن يعامل سرطان دمّ, بجدّيّة على نحو خاطئ في بريطانيا مع اثنا عشر مريضات يدخل واجبة إلى يتعدّد جهاز إخفاق يقتضي إدخال إلى المستشفى. أتيت بما أنّ هو أغلق على الكعوب من الجدال شديدة أنّ [مرك] مع يمسك معطيات حرجة من محاكمات ال [فيوإكسإكس], هذا حادثات وضع [فرما] صناعة بشدّة في الحوض سفينة. [إين فكت], قد كان هناك عدّة تقارير أنّ كلّ ليس جيّدا مع محاكمات سريريّة, أنّ هدف أن يطوّر جديدة [ثربيوتيك] أو إجراءات وقائيّة, قدّمت أو قيّمت موجودة [مديكل ترتمنت] وتقنيات [فيس--فيس] [نو ون].
تجلّى ك [سري] الحدوثات من حادثات تعيسة يصحب مع محاكمات سريريّة, هناك قد كان ينمو دعوة لشفافية, مسؤولية وميسوريّة من محاكمات سريريّة ونتيجاتهم [إين وردر تو] [ر-ستبليش] ثقة عامّة في معطيات سريريّة تجريبيّة. كلّ يظهر هذا أن يكون يمكن فقط

بتسجيل إجباريّة من كلّ محاكمات سريريّة, مع الهدف نهائيّة من يضمن أنّ كلّ محاكمة نتيجات, [بوستيف] أو أحفور سلبيّ كنت سيطلقون إلى الجمهور. عدّة تسجيلات تجريبيّة سابقا [إين بلس] العالم على, مثل ال [أكتر], ClinicalTrials.gov, [إيسكرتن], [إتك.]. Furthermore the WHO is promoting an international initiative to develop a Meta register of controlled trials that would offer a one step search portal fed from existing registers and provide a unique identification number for clinical trials from certified registers that needs standard criteria for the exchange of essential trial data. Keeping with the times and its demands, a registry, Clinical Trial Registry-India (CTRI), funded jointly by DST, WHO and ICMR has been initiated. The CTRI has been set up at NIMS (ICMR), New Delhi to provide a platform for registration of all clinical trials in India. Primary objectives are to establish public record system by registering all prospective clinical trials conducted in India on health products including drugs, devices, vaccines and herbal drugs which will made publicly available on the internet at no cost.

National pharmacovigilance programme:
The government of India, with the World Bank, has initiated the National Pharmacovigilance Programme. The Central Drugs Standard Control Organization (CDSCO) is coordinating the country wide pharmacovigilance programme under the aegis of DGHS, Ministry of Health and Family Welfare, New Delhi. With the number of new drugs being regularly approved for marketing in India, there is a need for a vibrant pharmacovigilance system in the country to protect our population from the potential harms that may be caused by some of these new drugs. Besides, with the patent regime coming in force from 2005, it is widely believed that India would become the global hub for new drug trials. These situations make it pertinent for the Indian central drugs regulatory authority to have a vibrant pharmacovigilance system in the country.

The Regulatory Approval process:
Clinical trials are now regulated by the Drugs Controller General of India (DCGI), whos is responsible for assuring that all clinical trials comply with the requirements of the International Conference on Harmonisation (ICH) of Technical Requirements for Registration of Pharmaceuticals for Human Use, as well as Good Clinical Practices. The DCGI approval process categorizes clinical trials into two types. If the study protocol has already been approved by a recognized regulatory authority in more or more developed countries (such as the U.S., Canada, U.K., Switzerland, Germany, Australia, Japan, and South Africa), the study is classified as a Type A trial and can be approved using a fast track process within two to six weeks after the required documentation has been submitted. All other studies are classified as Type B, for these, the approval process is generally 8 to 12 weeks. The Institutional Review Board (IRB) approval process can be conducted in parallel with the DCGI review and, if import licenses are needed, the applications for these can also proceed in parallel. These provisions facilitate the process of getting study protocols in place and quickly initiating the trials.

Bridging the Needs:
Western Pharma companies need to increase productivity, decrease costs, and shorten the time to market for new drugs. One solution is conducting clinical trials that provide lower cost and faster recruitment without compromising the quality of the research. India clearly offers this solution. In the past, several constraints have limited the number of clinical trials conducted in India:
• Communication can be an issue because of cultural differences between Western countries and India.
• The difference in time zones creates further difficulties in communication and monitoring of work.
• There are some significant differences between Western and Indian business cultures.
• Indian researchers need to clearly understand the requirements of Western pharmaceutical companies and their regulatory requirements.
• Western companies need to overcome their perception of India as a non-traditional “developing” nation that is the “land of the generics” with limited capacity and uncertain quality of work.
These issues are not unique to clinical trails. Similar issues have been faces and successfully addressed in fields such as information technology (IT) and business process outsourcing (BPO), where India is now a leading provider of services to western clients.

Barriers:
The overall time and cost advantage in bringing a drug to market by leveraging India’s resources could be as high as US $200 million, 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 at US $ 2billion. CROs themselves are fast gaining importance because of their global presence, specialized local expertise, and competitive 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.

Patients’ Rights and safety:
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 eight 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 then 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. This phase process is particularly important in developing countries if carefully understood and explained to potential subjects.

Regulatory Framework:
Multinational pharmaceutical companies and CROs are able to conduct good quality clinical trials in India despite infrastructural challenges at the regulatory departmental level. They can do so because of required professional training and the professional’s 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.

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.

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 offers value-added infrastructural incentives to the country.

Functioning of ethics committees:
According to a survey conducted by ICMR, ECs are functioning in over 200 institutions. However, there is no accreditation of ECs. Besides, some ECs have an irregular schedule of meetings, lack standard operating procedures, and do not have a composition in line with GCP guidelines. The ICMR has planned to review and audit the functioning of ECs and to introduce a national accreditation system for them. Additionally, the ICMR has also established an Independent Forum for Ethics Review Committees, which will organize training programs for the members of ECs. The revised schedule Y of Drugs and Cosmetic Rules devotes significant attention to the roles and responsibilities of ECs, prescribes the composition of ECs as per the ICMR guidelines and provides formats for the approval letter of ECs. These government initiatives are likely to improve the current situation.

Responsibilities of investigators:
In 2002, there were 200-250 GCP trained investigators and 40-50 GCP clinical studies were conducted. These small numbers imply that many potential clinical investigators do not have the experience of conducting GCP trials. Though this is not considered negative, it does require a major investment in training during study start-up. For the investigators struggling to balance patient care and research activities, compliance to GCP is an additional new responsibility. In addition, low literacy levels and poverty amongst the patients and the pressure of quick patient recruitment from the sponsors pose significant challenges to an investigator making efforts to obtain proper informed consent from the patients. The stress on documentation of the informed consent process in the GCP training programs, and the adverse media publicity to several recent clinical trial mishaps and subsequent government enquires have increased the awareness amongst the investigators about ethical and regulatory issues and the need for adequate patient protection.

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 motivate them to develop research protocols for domestic health care issues. This, in turn, is nurturing a culture of medical research that can match international standards.

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:
 The purchasing power of the customers;
 The existence of unpatented drugs and cheaper substitutes; and
 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.

CASE STUDY:

Indian Guinea Pigs for Sale: Outsourcing Clinical Trials
This article was shown different perspective what type of unethical clinical trial business occurred in India
1) Two Indian pharmaceutical companies conducted trials of genetically engineered drugs without proper approvals, have renewed fears about unethical drug research in India. This case involved Bangalore-based Biocon and Hyderabad-based Shantha. Biotech conducted Phase III trials of genetically engineered drugs (insulin for diabetes by Biocon and streptokinase for heart attacks by Shantha) without appropriate prior approval of both the Drug Controller General of India (DGCI) and the Genetic Engineering Approval Committee. Press report was said that approval letter DCGI got or not. Also both companies applied to the GEAC only after the trials started.
Result of this study: Some people died in the Shantha trial, conducted on seriously ill patients. This study was conducted in 2003.Company does not followed Indian GCP regulation and ICH-guideline when recruiting patients in trial. In emergency situation company does not obtained proper informed consent process. Also company did not provide compensation to trial related injury.
2) Mumbai-based Sun Pharmaceutical Industries Limited bypassed the DCGI altogether and got private doctors to prescribe the anti-cancer drug Letrozole to more than 400 women for ovulation induction. They used the results to promote this drug through medical representatives for this unapproved usage. While there are debates about doctors' legal and ethical right to prescribe a drug off-label, off-label research done without following proper procedure is outright illegal. Letrozole is patented by Novartis. There is nothing to indicate that Novartis was involved in the illegal trial.

Conclusion:
Although it typically takes 10 to 12 years and millions of dollars to bring one new drug to market, 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 development programs.
The evolution of GCP in the west- from the Nuremberg Trials till the development of ICH-GCP guidelines-took almost five decades. India’s involvement in global GCP trials is only about a decade old. ICMR’s Ethical Guidelines for Biomedical Research on Human Subjects were launched in 2000 and Indian GCP guidelines became available in Dec 2001. The experience of conducting global GCP trials limited. GCP is a shared responsibility amongst sponsors, investigators, regulators and ethics committees. As all stakeholders are still learning, the journey towards achieving global quality is unlikely to be smooth. The efforts of the government and industry to create awareness through GCP workshops and to provide training to the investigators and ECs will go a long way in creating a culture of global GCP quality trials.
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.

BIBILOGRAPHY:-
1. “Outsourcing clinical studies advantage of India” by S K Gupta Chronicle Pharmabiz Page no 51 September 28.2006.
2. “Clinical Research in India” by Dr Swapneel Anaokar in Pharambiz.The author is Head - Clinical Research and Regulatory Affairs, GlaxoSmithKline Pharmaceutical Limited, India Tuesday, February 12, 2002 11:16 IST
3. Outsourcing in Clinical Research - The Indian Perspective” by Kapil Parab
4. Research Analyst-Healthcare Practice Frost & Sullivan, India published in med India.
5. History of clinical research published in med India.
6. “Clinical trials and regulatory tribulations” by Bhatt AD. Express Pharma Pulse 2002-Nov 21:32-3
7. “Outsourcing clinical trials to India rash and risky, critics warn” by Jayaraman KS. Nat Med 2004; 10:440.
8. “DCGI guidelines a booster shot for clinical drug trials” by Raghu Balakrishnan published in DNA new paper Wednesday, November 29, 2006 22:11 IST
9. Global Clinical Trials in India – Challenges and Opportunities” a report by Dr Dhananjay Bakhle in Business briefing Pharmatech 2003
10. Indian Guinea Pigs for Sale: Outsourcing Clinical Trials by Sandhya Srinivasan
11. India Resource Center September 8, 2004
12. Fenn CG, Wong E, and Zambrano D.2001. The contemporary situation for the conduct of clinical trials in Asia. International Journal of pharmaceutical Medicine 15: 169-73.
13. Wax PM. 1995. Elixirs, diluents, and the passage of the 1938 Federal Food, Drug and Cosmetic Act. Annals of Internal Medicine 122: 456-61.

14. Diggle GE.2001. Thalidomide: 40 years on. International Journal of pharmaceutical Medicine 55: 627-31.
15. U.S. Food and Drug Administration. Disqualified/ Restricted / Assurance List for ClinicalInvestigatorsAvailablefrom, www.fda.gov/ora/compliance_ref/bimo/dis_res_assur.htm.
16. Lamberti MJ, Space S, Gammbrill S. Going global. Appl Clin Trials 2004; 13:84-92.
17. Borfitz D. Lifting India’s Barriers to clinical trials. Center Watch 2003; 10(8): 1-9.
18. Jayaraman KS. Outsourcing clinical trials to India rash and risky, critics warn Nat Med 2004; 10:440.
19. Bhatt AD. Clinical trials and regulatory tribulations. Express Pharma Pulse 2002; Nov 21:32-3.
20. Mudur G. Johns Hopkins admits scientist used Indian patients as Guinea pigs. Br Med J 2001; 323: 1204.