User:AbhiSuryawanshi/Clinical Trials in India

In India, clinical trials (or clinical studies) are series of organized medical tests carried out with innovatively promising drugs, as a means of ascertaining their effect and efficiency levels for human use, primarily in the Indian market. The discipline of clinical studies in its modern understanding was born around middle of the twentieth century in the western world, where anticipatory medical practices were performed decades earlier: in 1753, English physician James Lind demonstrated that citrus fruit are effective in curing scurvy. Since it promises discoveries that would facilitate medicine, clinical trials quickly began to gain prominence, and several pharm companies in the West including the US pursued its hope. In 1948, British researchers published the first clinical trial, and ever since, clinical trials have continued to rise and become mature as leading researchers employ both creativity and criticism. Clinical studies grew in several areas around the globe including India, owing to its ill-health burden and its economical implications on the nation on various levels. Today, there are volumes of trials on various drugs for various conditions in India.

Indian Advantage
In recent times, pharmaceutical companies have found it difficult to bring enough patients on board for drug testing in their clinical trials. In practice, the Food and Drug Administration (FDA) in the US necessitates that at least 4000 patients should take part in a clinical study for a promising drug to receive license for its market intended purposes. In the United States, the population willing to participate in Clinical Trials amounts to a total less than 5% within the patient demographic. More than 85% of clinical studies in the US usually lag roughly by a period of one year owing to deficiency of satisfactory participants, and this regularly leads to drag in product launching and weekly loss in revenue running in their millions of US Dollars. The regulation according to International Organization of Medical Services (CIOMS) recommends the offering of monetary incentives to volunteers to make up for inconvenience, lost time and personal expenses associated with taking part in the research. US and other nations of the West find it difficult to sustain a healthy clinical trials industry within this matrix of rigid regulations, extravagant safety and reimbursement stipulations, and inadequate volunteers. This is worsened in the US by a drop in investigators. For much of its earlier life, the clinical studies industry was not favored on the Indian terrains. However, for more than a decade some period after the turn of the century, attention continued to swing to India for running clinical trials, as a result of a multiplication in the international demand for world class CT management in capacity and productivity.[1] India CT indices includes an abundant professional resource pond, relative feasibility, profitable economic possibility in securing large populations of patients to participate, and the variety of genetic structure in its enormous population. And this provides international players in the biomedical and pharmaceutical industry with a comparative advantage in terms of cost and duration for drug discovery and development, which averages an annual 15% increase in R&D expenditure. In India, the middle-income demographic already crossed the 300 million mark, and it continues to gain momentum numerically and economically, presenting a lucrative market to the industry. As a result, clinical research outsourcing to India is experiencing faster growth and has brought cumulative investment on clinical research in the country to around USD 13 million and increased the bio statistical and clinical trial logistics services.

Incentives for Clinical Trials in India
The largest demographic of mild and malignant cancer patients, type I and II diabetes patients, and those with other major bad health conditions are found within the India population. This makes the country a hub for the international market of outsourced CTs.[1] Biotech companies are forming partnerships and setting up new operations. Leading organizations are taking steps to establishing research centers of the highest standard in the country. Within months of revising the schedule Y in 2005, contract research rose to a value ranging between USD 100-200M and continued to grow at a rate of 20-25% annually.[1] Over two dozen Contract Research Organizations (CROs) and several major international pharmaceuticals organization have begun conducting full-fledged clinical trials, since last 3 years. Several independent CROs conduct clinical trials in various therapeutic segments (like anti-inflammatory, allergic disorders, cardiovascular, central nervous system and oncology) and provide a wide range of clinical development services.[4] Favorable conditions facilitating this fortunate situation include a wide range of races living in different climatic conditions and affected by various diseases as a result of socio economic, environmental and seasonal changes; cheaper cost of technical services; abundant availability of well-trained medical workers and technical personnel; preponderance of top-notch medical facilities; extensive high-taste IT infrastructure; a favorable IPR environment; and a general culture in both the medical and the business spheres that largely runs on the English language.[1] Over the past two decades, India has speedily evolved to join the ranks of leaders in the IT industry, paring up with nations like the US and other western nations. This advantage is already been enjoyed in bioinformatics and employed to optimize the drug development process. Other players in the pharmaceutical industry also employ the IT advantage to provide data management systems for clinical trials. A few are on the verge of extending its use to cover safety monitoring and post marketing surveillance. In 2007, the total volume of clinical studies conducted in India was valued at an estimate of US$200 million.[1]

Clinical Trials Evolution in India
The national and local experience of clinical research in India is drawn out over several decades. Recently, major pharmaceutical companies recognize and have begun to exploit the clinical trials favorable terrain and situations in the land. Indians’ indigenous medicine is well known for its rich heritage. Typical texts that constitute canonical records and instructions of the Ayurveda regularly detail meticulous annotations on various ailments and thorough remedial instructions. A handful of personnel within the medical world are convinced of a high probability that these accounts qualify as penned down firsthand information and documentation by ancient Ayurveda experts. However, clinical studies in India are accounted for within modern medicine, since no recording of clinical experimentation is recognized from ancient texts. A number of momentous accomplishments of the Indian Council of Medical Research (ICMR) serve, in a number of ways, as markers of advancement of research in the field of medicine in the country during previous and current centuries. At the Plague laboratory in Bombay, on November 15, 1911, a team of experts that make up the core leadership of the Indian Research Fund Association (IRFA) had their inaugural conference which was chaired by Sir Harcourt Butler. A subsequent meeting held in 1912 saw a turning point conclusion that was reached by the organization’s core leadership which birthed the Indian Medical Research Journal. The last three years of that decade witnessed numerous projects that sustained the developing of indigenous meds to treat malaria, kala azar, beriberi, among others. Another milestone step was taken in 1945 when a clinical research unit was set up at the Indian Cancer Center in Bombay—the first research unit of IRFA physically and professionally connected to a medical organization. Four years later, the department was reconstituted into the Indian Council of Medical Research. The next six decades that followed were focused on setting up more national research centers in various medical disciplines on diet, TB, leprosy, virus infections, cholera, enteric illness, reproductive complications, toxicology, malignancy, trad-medical treatment, gas tragedies, gene, HIV/AIDS etc. The Central Ethical Committee of ICMR on Human Research was put in place few years approaching twentieth century’s close, instituted with the leadership and auspices of Honorable Justice (Rtrd.) M.N. Venkatachaliah. The committee convened in September 1996, and its main implementation was the instituting of various subcommittees to address the fundamental moral matters in particular disciplines in the medical field; Research in Epidemiology, Clinical Product Evaluation and Human Genome Projects were chosen areas of focus among many others. A catalogue of Ethical Guidelines for Biomedical Research on Human Participants was published by the core committee as the millennium turned and was revised six years later. Earlier in 1988, Schedule Y of Drugs and Cosmetics Act was put into operation and it provided guidelines that regulated the procedure of endorsing clinical studies. Important highpoints of the schedule emphasized mandating players in the industry to conduct Phase III clinical studies as part of the new-drug registering process, and providing support for the advancement of a principally typical Indian pharmaceutical industry. Only CT phases that lagged behind the international status received permission, which introduced an obstruction to the incorporation of clinical studies in India with clinical studies in international frontiers. Due to the restrictions of Schedule Y and its economic complications that stalled the Indian CT industry, a revised version was published in January of 2005 which altered the defining of clinical studies into a broader and freer category. This revised version was earmarked by logical and practical characterizations for Phase I to IV. Boundaries on patients’ recruitment and centers were repealed ensuring that sponsor companies were free to reach decisions based on the uniqueness of each clinical study and its requirement. Phase II and III in local CTs were permitted to run at par with international counterparts under revised version. Schedule Y 2005 authorized and codified Indian GCP guidelines that came in to operation four years prior, specifying the GCP roles of the ethics teams, research personnel and patrons, and endorsed formats for essential documents e.g. consensus, report, EC approval, reporting of serious adverse event. These alterations in Schedule Y formed a quintessential move in the right direction towards GCP compliant studies and afforded GCP guidelines its necessary supervisory support. On the Indian frontier as with the rest of the world, several decades into the field of clinical studies have seen studies evolve into a series of standardized procedures that emphasizes scientific valuation of efficiency while protecting the patient’s safety.

Growth Factors
A European group, India, and 74 other nations came together in 1995 in Uruguay for a round of GATT (General Agreement on Trade and Tariffs) discussions. The convention reached a consensus and all participants were signatory to the newly forged coalition, the World Trade Organization. WTO required all nations and signatory parties to align and organize each nation’s intellectual property rights under one united organization and undertaking with the establishment of “TRIPS” (Trade Related Intellectual Property Rights). This treaty guaranteed that patent rights obtained in one of its treaty nations are covered and secured for patent owner across party nations. It’s influence and effect stretched to patents in the biopharmaceutical disciplines. An article included within the treaty about “Intellectual Property Rights” guaranteed that such patent security is binding for 2 decades from the day patent rights are secured. With the acknowledged aim of aiding “them to create a sound and viable technological base”, developing nations including India were offered a ten-year duration to integrate patent laws with the TRIPS requirement. The 2001 Doha series of negotiations on TRIPS and Communal Health further extended this period up to 2016. Within the first quarter of 2005, India successfully began integrating its local patent laws into the TRIPS stipulation, and officially began acknowledging product patents. These product patents were implemented in every industrial sector under the ‘‘Patents (Amendment) Act 2005.’’ The former ‘‘Indian Patent Act, 1970’’ provided only process patent, which allows an inventor or company to develop or even patent a product or drug in India that had been discovered and patented by another in western nations.[26] This change in patent regulations were performed alongside the modification of the schedule Y regulations, which loosened its tough restrictions with the handling of volunteers participants in clinical trials by the industry players.

Regulatory Requirements
The Indian Council of Medical Research (ICMR) being the apex board is saddled with the important tasks of formulating, overseeing and promoting experimental studies in biomedical fields. This committee receives all financial aid from the GOI through one of its agencies, the Ministry of Health and Family Welfare and the Department of Health Research. The Drugs and Cosmetics Acts (DCA) was initially formulated in 1940 and it provided regulation for importation, manufacturing, and dissemination of pharmaceutical products in India. Its main goal was to guarantee safety, effectiveness, and best quality for both drugs and cosmetics. Regularly, the Act is revised to sustain and improve these standards. Several instructions in the DCA are applied alongside regulations from Schedule Y to provide overarching rules for ordering clinical research in the nation. In addition to its 12 appendices, it contains formats for CTs, consent documents, license templates and related documents. The ICMR guidelines underwent transformation in 2006 into 'Ethical Guidelines for Biomedical Research on Human Participants'. Its stipulations are being professionally adopted and usually considered for revision at least once within a decade. This guideline addresses 2 wide categories of clinical studies: overarching regulations that apply to all clinical studies; and specialized directives employed to provide a guide for research in specific areas, such as children healthcare and or herbal medicine. These scientific investigators bear responsibility for familiarizing with both documents and keeping to instructions contained in them as a rule of practice. The Good Clinical Practice (GCP) guideline published in 2001 by the CDSCO aimed at an Indian terrain specificity, though in contrast to the ICH GCP guideline, still awaits its first revision. The Schedule Y revision published in January 2005 included monumental changes that aimed at getting India on par with globally predominant regulations. Highlights of important changes ranged from the redefining of a clinical study (CT), permission for organizing such studies in India in phase with the practice elsewhere around the globe, clarification and delineation of tasks and duties for each party involved with the drug development process, requiring informed consent with every participant, prerequisite for studies in certain demographics and instructing that procedure modifications secure sanction from the desk of the DCGI.

Overview of Clinical Trials Industry
Subsequent to achieving TRIPS compliance and Schedule Y revision in 2005, gatekeepers of the clinical research field in India achieved the restructuring of policy framework and reorganizing of the regulatory environment. Such modifications provided several incentives for global Clinical Research Organizations (CROs) to widen the scope of their clinical studies projects in India. Approximately 20% of all clinical trials conducted across the world take place in India, and this provides an enormous potential for financial and scientific advantages. CROs are properly appropriating the present matrix for clinical trials in the India terrain: wide pool of participants, adequately skilled medical researchers, more cost-effective drug development process, and early conclusion of clinical studies. In India, professional conversations on ethics within the clinical research practice is receiving greater engagements by major stakeholders in the industry. International pharmaceutical firms who outsource their CT projects to counterparts in India are encouraged by incentives that come under the discussion on ethics, such as: prioritizing profit, reducing costs involved in developing drugs, shortening the approval process time, facilitating a much friendlier environment among the world’s disadvantaged ill. among others. Conducting clinical studies in India is estimated to cost less than half of its costs in most developed nations. Several factors facilitate cheaper drug development in India ranging from less expensive human labor and low onboarding costs to smaller compensation and lower rates for any harm, physical or related, caused to participants during the trial process. Moreover, a larger percentage of the demographics of clinical trials participants in India have no formal education. Hence, they are easily enlisted without an official commitment to be compensated by these CROs who promise them free healthcare and financial incentives. These participants are not aware of the pros and cons of participating in clinical trials nor can they make a distinction between medical treatment processes and clinical trial processes. Also, the concept of informed consent before enrolling in a trial is not very clear. The GOI’s mission for technological and economic advancement in the nation motivates it to continue proffering ways that incentivize international companies to bring their clinical trial projects into the country. This partly helps to achieve the central aim of clinical research which is to ensure that the benefits of clinical trials are reaching the wider society. Cumulative long-term effects of these changes in policy and regulation exists. The percentage of total clinical studies carried out in India experienced a sizeable growth from 0.9% to 5% between 2008 and 2013. This growth is similar to that observed in other south Asian nations like China, whereas, the Indian and South Asian gain in CT programs is paired by a decline in the US and other Western nations. A number of international pharma companies are reorganizing their operations and activities to run majorly in India, partly to take hold of the huge market opportunities among other advantages. The pharmaceutical firms have an unending supply of volunteers for their clinical studies on the Indian frontier. A matrix of important factors that are weighed when considering a locality for clinical trials put India as a preferable option. These factors range from location of institutional partner, internal facilities, prospect of future product launches, revenue, time of return on investment, potential edge over competitor. The Indian population averages around one-sixth of global population, and among them is found about 20 percent of worldwide disease problem. This statistic on disease burden is a larger context for the nation’s maternal, infant and children mortality which are the highest in global evaluation. All these are also spread out into a dual national burden of infectious and non-infectious disease. In 2012, WHO reported that non-infectious diseases are causative for over 65 percent of all morbidity issues and more than half of total mortality in India. A large proportion of individuals that fall into these disease burden categories are socio-economically disadvantaged locals who often go without proper healthcare. This makes them ready candidates for clinical studies. An estimate once revealed India as one of the leading nations in terms of volunteer patients for clinical trials, and they were only second to China by this estimate. The more cost-effective process of clinical studies in India is also an important factor that has brought about rise in the Indian facet of this industry. Coming behind Russia, Argentina and China, India provides a platform for ample cost reduction in clinical studies. Employing clinical nurses and related practitioners is also meaningfully cheaper in India than other destinations. The ratio of sum-total in costs of clinical studies between the Indian average and the US-American average is pegged at 0.11 units to 1 unit respectively. Expenses by CROs have also been estimated to have a lower index value at 0.11 in India than anywhere else. In terms of availability of physicians and other medical practitioners alongside the presence of CROs in the country, India falls behind nations like the US, China and Russia in this order. Lack of adequate statisticians to underwrite these clinical studies remains the only drawback for India. A string of other important factors that facilitate the move by companies in the West to operate more from India in areas of clinical research include a hundred percent FDI in CTs permitted by the Indian Government. R&D expenditure accrued by these big pharma firms within a period a little over a decade from the turn of the century approximates US$0.92B. Other multinational firms teamed up with local companies in India on R&D purposes. This enormous growth was paired by a significant 44% growth rate in the clinical studies industry that occurred from 2003 to 2009. The CT industry has generally received great capital investment to establish a large industrial infrastructural base both in research and healthcare. CTRI statistics reveal that, as a result of a greater demand for drugs and meds for non-communicable diseases in India and some developed countries, 110 of 116 non-indigenous companies focused research on non-infectious diseases. Indigenous Indian companies also focused efforts on developing and producing pharmaceutical medications for such conditions as diabetes, metabolic difficulties, allergies, cancerous build-ups, cardiac complications, bodily inflammations etc. The tremendous growth in the clinical research industry in India has brought drug development and production of the pharmaceutical industry in the nation to exporting capacity; 90% of their products are generic and over 30% of drugs are exported, occurring alongside a 20% market growth annually. India has consistently demonstrated the ability to manufacture more cost-effective generic drugs: its drug manufacturers are responsible for 40% in volume of generic drug imports to the US and 39% of the all generic drugs that approved for marketing in the US by the Food and Drug Administration (FDA), an agency of the US federal government. This growth is happening amidst controversies that surround the industry. Issues about ethics are the most concerning complications plaguing the industry. Generally, these controversies are a result of complications arising with regulations and policies stipulated by the GOI through its agencies. A growing concern is the trail of clinical trials related deaths are have gone uncompensated, either fully or partially. A very small number of cases have received any attention and concerned individuals are offered very discouraging compensations. One instance that occurred in 2004 involved the recruitment of several gas accident survivors by doctors at a renowned medical and research institution without ensuring informed consent, and the report indicates that 14 mortalities were recorded among these patients during the course of the trials. Throughout the second half of that decade, 32 mortalities were recorded in relation to clinical trials that were conducted at an Indore‐based hospital. A pharma franchise company reported that large proportions of the clinical studies that are conducted in India are not done according to global standards. The Indian government has publicly acknowledged that between 2005 and 2012, around 2,644 mortalities were recorded during clinical studies for new drugs, of which 80 deaths were directly attributed to the items tested. Another 500 experienced serious adverse reactions.