“Diseases continue to be the major cause of death, disability and social economical disruption worldwide but the bottom line is that these can all be cured through the availability of effective and affordable medicines”

Diseases are the major cause of death, disability and sufferings worldwide. Emergence of new diseases without effective prevention or control as well as growing ineffectiveness of available medicines pose a serious threat to mankind and may potentially be the end of road for modern medical treatments. According to WHO 2004, global burden of disease report the leading global risk for the mortality are high blood pressure (13% death globally), tobacco use (9% death globally), high blood glucose (6% death globally), physical inactivity (6% death globally), over weight and obesity (5% death globally). It is predicted that for low income countries, Non Communicable Diseases (NCD) will contribute half of the total disease burden in 2030 making HIV/AIDS a major cause of death (12%) followed by prenatal disease (6%), depression (4%) and ischemic heart disease (4%). It is also predicted that lung, stomach and liver cancer will appear as a leading causes of death in 2020. Almost 79% of all death cause by NCD occurs in low income countries. Hence there is a need to provide newer, safer and effective medicines to almost 5.6 billion people of the world in a single segment of NCD. Apart from this, emerging new infectious disease such as severe acute respiratory syndrome, ebola, avian flu, swine flu as well as antibiotic resistant strains of already known bacteria and various other diseases require the availability of newer and effective medicines on an urgent basis.

Why do we need Clinical Trials?
Clinical trials are the mainstay for bringing out newer, better and safe medicines to serve the mankind. It is the most expensive and time consuming component of the drug discovery process and constitute approximately 70% of the total time and money spent in the overall development process. Typically it takes approximately 12 years and US$ 900 million to bring one new drug from conception to market out of which 6-7 years are spent in various phases of clinical trials. The first documented evidence of clinical trial dates back to 1747 when James Lind discovered citrus fruit as a cure for scurvy. In the modern world, clinical trials are conducted in four different phases (I, II, III, and IV), where each phase is aimed at addressing a scientific question. While the initial safety of a new drug is established in Phase-I of clinical trial the later phases establishes the efficacy of the drug along with the safety. As clinical trials moves in a phase-wise manner, the next phase is initiated only if the drug passes the earlier phase.

Drug discovery process- A long journey
In order to understand the significance of clinical trials, it is imperative to understand the new drug discovery process by and large. The drug discovery process begins with the generation of a new idea that is targeted towards chemically modifying a disease process via a drug. The first step is selection and validation of a disease ‘target’ which is followed by selection of ‘drug’ that has the ability to interact with the target. Tens of thousands of potential drug substances (obtained from massive compound libraries) are tested against the target in a robotic process called High Throughput Screening (HTS). HTS yields ‘hit compounds’ that are further studied in detail for their physical, chemical and biological properties. Hit compounds with suitable physical, chemical and biological properties become the ‘lead candidates’ which are then chemically modified to obtain the compounds with suitable pharmacodynamic and pharmacokinetic properties. The compound with best profile is then chosen for further investigation in the form of preclinical and clinical testing.

While preclinical tests are performed in the laboratory, using a wide array of chemical and biochemical assays, cell-culture and animal models, the clinical testing is done via four phases (I, II, III and IV) of clinical trials. The knowledge gained from one phase is assessed before progressing to the next phase. However, research in a particular phase may continue even after the drug has progressed to further stages of development.

Phase-I clinical trials are conducted to establish initial safety, maximum tolerance and pharmacokinetics of a new drug in 20-80 healthy human volunteers (with the exception of cancer drugs where Phase-I trials are done on cancer patients). These are also called as ‘First in Man’ and acts as a basis of validating the findings from pre-clinical testing in to human beings. Usually Phase-I trials are initiated with a very low dose (1/10th of the optimal animal dose) which is gradually increased to determine the maximum tolerated dose. During Phase-I trials, sufficient information about the drug’s pharmacokinetics and pharmacological effects is obtained to plan a well-controlled, Phase-II trial.

Phase-II clinical trials are universally accepted as a standard requirement for the evaluation of efficacy and safety of a new drug. Careful observations are made to determine the dose and adverse reactions in 100-200 patients with the relevant indication. If a new drug is found to be effective and safe in Phase-II trials, it is moved to next phase of development. In case of lack of efficacy the development of drug is stopped at this phase itself.  

Phase-III clinical trials are the final pre-marketing phase of clinical trials. These are large, multi-centric trials to establish the safety and efficacy of a new drug vis-à-vis existing standard of care/placebo to form the basis for regulatory submission. If a new drug is found to be safe and effective in Phase-III trials, a New Drug Application (NDA) is filed to regulatory authorities for seeking marketing permission.

Phase-IV clinical trials are post marketing studies that are conducted for generating additional safety data on a drug once it is marketed. Regulatory authorities can withdraw the marketing authorization of a drug any time if there are safety concerns on its usage.

It is estimated that out of every 10,000-30,000 drug molecules screened; only 250-300 enters the pre-clinical testing, 5 enters the clinical testing and only 1 reaches the market.

Clinical research market (size and trends)
Global
The worldwide pharmaceutical market is estimated at US$ 427 billion with its research and development (R&D) spent estimated roughly at US$ 60 to 65 billion. Currently, the size of clinical research market worldwide is worth over US$ 52 billion of which 70 percent of the business is generated within the US, employing an estimated 210,000 individuals. UK is considered as the hub for clinical trials in Europe with over 70,000 individuals in the industry. Asia is fast emerging as a preferred destination for the conduct of global clinical trials and is projected to have the requirement of skilled manpower in big numbers. Contract research organizations (CROs) are fast gaining importance because of their global presence, specialized local expertise as well as competitive pricing strategies. CROs serving the pharmaceutical industry generated revenues of US$ 21.69 billion worldwide in 2010 which is expected to reach US$ 32.73 billion in 2015 and US$ 65 billion in 2021, with the top ten CROs accounting for more than half of the overall market.

Indian
The Indian pharmaceutical market is expected to grow at a CAGR of approximately 13.2% during 2009-14 to reach a value of US$ 15,490 million in 2014. According to a Frost and Sullivan report, the domestic clinical research organization market was worth US$ 485 million in 2011 and it is set to cross US$ 1 billion-mark by 2016.

Site ClinicalTrials.gov (a registry and results database of publicly and privately supported clinical studies of human participants conducted around the world) enlists a total of 144308 clinical trials across 182 countries at the end of April 2013. Of the 144308 studies the open and closed studies constitutes 31.5% and 68.5% respectively. In terms of number of clinical trials United States tops the list with 47% of all clinical studies followed by Canada and Germany with 7% each and France and United Kingdom with 6% and 5% studies respectively. India is ranked at 23rd position both under ‘All Studies’ as well as ‘Open Studies’ category.

India has a listing of 2212 clinical trials of which 548 studies are currently in the enrolment phase. Of the 2212 studies, 45% are phase-III, 21% are phase-II and 12% are phase-I clinical trials. Oncology tops the therapeutic area list with 24% share followed by infectious diseases (17%), CVD (12%), diabetes (10%), CNS (8%), and others (28%) respectively.

India clearly provide strategic advantage due to the availability of large patient populations, highly educated manpower, a wide spectrum of disease, lower operational costs, English speaking population and a favourable economic and intellectual property environment. A steadily increasing number of clinical trials over past few years have confirmed this belief and the clinical research industry has witnessed exponential growth during this period. However, there has been a lot of turmoil on the conduct of clinical trials in India of late, and various new regulations/requirements have been imposed without a balanced approach leaving the hundreds of million dollar industry at the verge of extinction.

Regulatory landscape and recent policy initiatives
The general recommendations for carrying out clinical trials in India are specified in Schedule-Y of Drugs and Cosmetics Act 1940. The controlling authority is Central Drugs Standard Control Organization (CDSCO) that functions under the Directorate General of Health Services (DGHS). CDSCO is headed by Drugs Controller General of India (DCGI) and contains separate sections such as New Drugs, Subsequent New Drugs, Biological-Vaccine and r-DNA, Cosmetics, Medical Devices, FDCs, Global Clinical Trial and BA/BE for export etc. The application for the permission of carrying out a clinical trial is made to the office of DCGI. Once the dossier is submitted, it takes approximately 7-10 working days for an application to reach the respective section. After the initial review, the application is referred to the respective New Drug Advisory Committee (NDAC) or Medical Device Advisory Committee (MDAC) or IND Committee if it is complete in all regard. The Applicant is required to present the study in a scheduled committee meeting and based on the recommendation of the committee, the final decision of approval or modification or rejection is taken by the DCGI.

In light of recent turmoil on the conduct of clinical trials in India the Drugs and Cosmetics Rule, 1945 has been amended as follows:
i.    Drugs and Cosmetics (First Amendment) Rules dated 30th January 2013
ii.    Drugs and Cosmetics (Second Amendment) Rules dated 1st February 2013
iii.    Drugs and Cosmetics (Third Amendment) Rules dated 8th February 2013

Drugs and Cosmetics (First Amendment) Rules dated January 30, 2013
This new rule specifies the provision of compensation for injury or death during a clinical trial. As per the new rule, any injury or death to a clinical trial subject due to the following reasons shall be considered as clinical trial related injury or death:

1. Adverse effect of IP
2. Violation of the approved protocol, scientific misconduct/negligence by sponsor/investigator
3. Failure of IP to provide intended therapeutic effect
4. Use of placebo in  a placebo-controlled trial
5. Adverse effects due to concomitant medication as part of protocol excluding standard care
6. Injury to a child in-utero because of the participation of parent in CT
7. Any procedure involved in the study

Following provisions of compensation has been specified in the new rule:
i.    Any injury occurring to a clinical trial subject: Sponsor (or his representative, whosoever has obtained permission from the Licensing Authority for conduct of clinical trial) to provide free medical management as long as required
ii.    Clinical trial related injury to a trial subject: Sponsor (or his representative, whosoever has obtained permission from the Licensing Authority for conduct of clinical trial)  to provide free medical management as long as required + financial compensation
iii. Clinical trial related death: Sponsor (or his representative, whosoever has obtained permission from the Licensing Authority for conduct of clinical trial) to provide financial compensation to the Nominee + cost of medical management (if any)

Drugs and Cosmetics (Third Amendment) Rules dated February 8, 2013 mandates the registration of Ethics Committee as per the requirements of Rule 122 DD.

Further, two committees have been constituted by the Ministry for supervising the clinical trials on new chemical entities:
A.    An apex committee under the Chairmanship of Secretary, Health and Family Welfare to take stock of new approvals and to supervise and monitor the conduct of the clinical trial in the country
B.    A Technical Committee to give inputs to Apex Committee for supervising and monitoring the conduct of clinical trials in the country and to monitor the number of approvals done by NDAC and MDAC
In addition to above, following two Expert Committees have also been constituted on the recommendation of Parliament Standing Committee:
1.    Expert Committee to formulate policy guidelines and SOPs for approval of new drugs, clinical trials and banning of drugs
2. The Expert Committee to formulate policy guidelines and procedures for approval of fixed dose combinations

The DCGI and Ministry of Health and Family Welfare have also formed three expert committees for the examination SAEs of death in clinical trials.

These new Policy initiatives in addition to the mandatory registration of clinical trials on Clinical Trials Registry-India (CTRI) as well as inspection of trial sites by the regulatory agency has lead to the evolution of a robust regulatory system for the vigilance and conduct of clinical trials in the Country. This will ensure that all clinical trials in India are conducted to the highest standards along with appropriate indemnity and insurance to cover the occasions when harm might be suffered by a participating subject.

Though the spirit of new regulations is a welcoming move but some of the provisions as well as aftermath are posing turbulent times for the entire clinical research industry in the country. There have been several unjustified and unanswered questions that are posing a threat to the existence of industry itself especially when some of the provisions are not even covered by the scope of clinical trial insurance.

Conclusion
Emergence of new diseases as well as growing resistance to the available medicine pose a serious threat to the mankind that needs to be addressed on a priority basis.  Since, clinical trial is the only way to make newer treatment options available to the mankind; no one can imagine a world without it unless we feel that available treatment options are adequate and we no longer need any new medicine or therapy for the current or future generations. Imagine a world when a person will survive a complex surgical procedure but will die of post-surgical infections caused by the micro-organism that are resistant to the available antibiotics. Hence, there is an unmet medical need to develop newer drugs or therapies. Like other developing countries, some key barriers exists in India that includes limited technical know-how on drug discovery, poor compliance to the regulatory framework, patient’s rights and safety, lack of training at the level of various stakeholders, infrastructural challenges etc. and needs to be addressed in a similar fashion.

Ethical companies set globally consistent standards and conduct trials only in the countries where GCP compliance is assured and where they can market the product on a later date. Indian investigators and clinical research professionals have already demonstrated their medical and scientific competence by participating in several global registration trials as well as by publishing their research work in peer-reviewed scientific medical Journals of repute. Over the years, thousands of patients in India have benefited by participating in clinical trials and there is no reason why we should not make newer treatment options available to them especially for diseases like cancer, critical care, infectious diseases, cardiovascular diseases, diabetes etc. It is unjustifiable to penalize somebody for adverse event(s) that a clinical trial subject experiences during the period that he/she would not have lived otherwise had he/she not participated in the clinical trial.

It’s time now that above issues are addressed on an urgent basis and in an unbiased fashion thereby providing a lifeline to this noble profession in India. Otherwise, this field will vanish from India and will continue to grow in the neighbouring countries leaving Indian patients helpless against deadly diseases.