Over the last five years, India has emerged as a favourite destination for off-shoring of global clinical trials. The number of global trials in India registered in clinicaltrials.gov, jumped to 149 during 2001-05 from one during 1996-2000. However, 2005-08 saw the number of global clinical trials in India quadrupling to 542. One of the major reasons for this exponential growth is the reforms in the regulatory system and processes. The reforms, which began with amendments in Schedule Y in 2005, are continuing in the direction of making Indian regulatory processes robust and globally acceptable.
Schedule Y amendment (2005): The amendments in Schedule Y were the first major step towards streamlining the Indian clinical trial review process and improving the quality of Indian trials. Some of the important changes were:
Phase II-IV trials: The 2005 schedule Y removed the phase lag in clinical trials, thus permitting concurrent phase II-IV trials in India. This facilitated Indian pharma industry to participate in global clinical development programmes
● Good clinical practice (GCP): The Schedule made compliance to Indian GCP guidelines mandatory by defining roles and responsibilities of the sponsor, investigator and ethics committees. It also recommended formats for key documents - consent, ethics approval, safety reporting, trial report etc.
● Pharmacovigilance: The amendments laid down reporting time lines of 14 calendar days for serious adverse events to regulatory agency and other investigator sites. For marketed drugs, periodic safety update reports became compulsory
Improvements in processes (2006): In October 2006, drug controller general of India (DCGI) office initiated several steps to streamline the clinical trial application process and make it time bound. The initiatives included:
● Categorisation of global clinical trials: For category A clinical trials, whose protocols have been approved by well known regulatory agencies like US Food and Drug Administration (FDA), UK Medicines and Healthcare products Regulatory Agency (MHRA), European Medicines Agency (EMEA) etc., clinical trial permission is granted in approximately four weeks time. All other applications not covered under category A fall under category B. The regulatory approval time for such applications is expected to be around 12 weeks
● Clinical trial application process: The Central Drugs Standard Control Organisation (CDSCO) introduced a 16-item checklist for clinical trial applications covering study details, documents and data requirements, and international regulatory status. This has brought clarity and uniformity in the submission of clinical trial application
● Protocol amendments: These have been classified into categories. Some important amendments such as recruitment of additional patients, major changes in protocol and change in selection criteria require approval from DCGI office before implementation. Some amendments can be implemented after notification, eg., addition of sites or change in investigator or amendment of IB/consent documents. Protocol amendment approval is a time consuming process. The classification of protocol amendments will reduce the time and efforts for both sponsor companies and the regulators.
Drugs and Cosmetics Bill (2007): The bill contains a penalty provision for any individual conducting clinical trials without approval of CDA. The penalties include imprisonment for a term up to five years and fine up to ten lakh rupees. In case the offence is repeated, the imprisonment and fine are doubled. This new provision is expected to compel the clinical trial professionals to conduct the clinical trials as per regulatory guidelines.
Proposed Schedule Y amendment (2008): In July 2008, CDSCO held consultations with industry, academia and non-government organisations (NGO) to discuss amendments to Schedule Y of 2005. Some of the proposed amendments include:
n Phase I clinical trials may be permitted in India for new molecules discovered in other country, if the intellectual property (IP) is owned by an Indian company or if the drug is developed by Indian company and IP holder under a valid agreement
● Phase 0 clinical trial or micro-dosing, which is useful in gaining early information on pharmacokinetics, pharmacodynamics and metabolism, may be permitted
● Phase III clinical trials data generated in India as part of the global clinical trial may be accepted for the purpose of new drug approval in the country
● The pharma companies will be required to intimate the licensing authority about change in regulatory status of the drug, i.e., withdrawal or restrictions on usage within 30 days and within 60 days of any change in the package insert
Other initiatives
● CDSCO has introduced the system of keeping the daily issued letters in public domain by displaying them on the CDSCO website. It encompasses all types of letters, i.e., permission to market, clinical trial / bioequivalence approval export permission, import license etc. This is a step towards bringing transparency
● CDSCO is taking proactive role to ensure compliance to regulatory guidance. Recently, DCGI office stopped a clinical trial in which a child with a cardiac problem died
● CDSCO is investing in planning for future expansion of manpower and infrastructure. It is also developing systems for ensuring compliance, e.g., clinical trial inspection
As India becomes a major global player in the field of clinical trials, it is necessary that the Indian trials meet global scientific, ethical, regulatory and quality expectations. This requires a state-of-the-art regulatory framework. The regulatory reforms of last 3 years are making the Indian regulatory system responsive to expectations of diverse stakeholders and are providing the right thrust to modernise the regulatory framework. This renaissance of Indian regulatory system heralds a bright future for Indian society and industry.
(The authors are with Clininvent Research Pvt. Ltd)