With amended Schedule Y and changed regulatory environment (with planned inspections by local regulator), the Indian pharma industry [including other stake holders like clinical research organisations (CROs)] is expected to be more 'pharmacovigilant'.
The Drugs and Cosmetics Act of India, which was formulated in 1940 and which subsequently underwent amendments in 1982, 1986 and 1995, contains the Schedule Y, which lays down guidelines for the conduct of clinical trials in India as well as guidelines for import and manufacture of new drugs.
With the latest amendment (January 20, 2005) to the Schedule Y of Drugs and Cosmetic Act 1945, the reporting of adverse events from clinical trials has not only become unambiguous, but also mandatory, which is a quantum leap and a clear reflection that the Indian regulatory agency Drug Controller General of India (DCGI) is now more serious about safety regulations.
The schedule Y now clearly spells out the responsibilities of the sponsors as well as the investigators vis-à-vis adverse events reporting during a clinical trial. Besides, it also describes the data elements in which SAEs have to be reported.
The safety reporting responsibilities of the sponsors
"Any unexpected serious adverse event occurring during a clinical trial should be communicated promptly (within 14 calendar days) by the sponsor to the licensing authority and to the other investigator(s) participating in the study."
The safety reporting responsibilities of the investigators
"Investigator(s) shall report all serious and unexpected adverse events to the sponsor within 24 hours and to the ethics committee that accorded approval to the study protocol within 7 working days of their occurrence."
One can argue that insistence on reporting 'unexpected serious events' from clinical trials is against the internationally accepted norm of reporting 'suspected unexpected serious adverse reactions' (SUSARs) to regulatory authorities. However, it is a conscious effort from the regulators to usher in reporting culture in India, but it's clear that it adds a tremendous burden on all the stake holders, including the office of DCGI.
Till date, the post marketing surveillance remains the weakest area and suffers on account of 'underreporting' like any other country. The amended schedule Y has made an attempt to address this problem by making periodic safety update reports (PSURs) submission mandatory for all new drugs for a period of four years after approval (marketing authorisation) and expedited reporting of SUSARs from such drugs. Quite often, one gets to hear from the industry people, that submission of PSURs makes a post marketing safety (PMS) study as a superfluous exercise, which is not true.
PSURS as per amended Schedule Y (2005)
● For all new drugs
● To be submitted every six months for the first two years after approval
● Subsequent two years the PSURs need to be submitted annually
● To be submitted within 30 calendar days of the last day of the reporting period
The national pharmacovigilance programme (NPvP) should be considered as a very positive and 'potentially effective' measure in a country like India in developing pharmacovigilance awareness, inculcating reporting culture.
The national pharmacovigilance programme is largely based on the recommendations made in the World Health Organisation (WHO) document titled - "Safety monitoring of medicinal products - guidelines for setting up and running a pharmacovigilance centre."
The programme aims to foster the culture of adverse drug effects (ADE) notification in its first year of operation and subsequently aims to:
● Generate broad based adverse drug reaction (ADR) data on the Indian population and share the information with global healthcare community through WHO-UMC
● Ensure optimum safety of drug products in the Indian market
● Provide technical expertise for evaluating statutory AE reports furnished by sponsors conducting clinical trials in India
The programme today has a total of 35 centres scattered throughout the country, which comprises of zonal, regional and peripheral centres.
To effectively deal with the expected scale of operations in the country, national pharmacovigilance programme envisages several peripheral pharmacovigilance centres pooling their data at five regional pharmacovigilance centres, which in turn funnel their data to the two zonal pharmacovigilance centres. Zonal pharmacovigilance centres are expected to analyse the data and submit consolidated information to the national pharmacovigilance centre, where national pharmacovigilance advisory committee would evaluate the data and recommend appropriate regulatory interventions. The response generated by the NPvP can be gauged from the recently published report by the regional pharmacovigilance centre (south), which says, "Its eight peripheral units have reported around 2000 adverse drug reactions (ADRs) within 9 months of its existence". This was largely possible by conducting awareness programmes among doctors, nurses and pharmacists.
All the efforts have had a feeble to moderate effects on pharmacovigilance activities in India. Most of the sponsors and marketing authorisation holders have started reporting SAEs in some earnestness, and there are training programmes, seminars and a spurt in clinical research related educational courses. Post graduate, certificate, diploma and degree courses conducted by private academic institutions like Institute of Clinical Research - India and Academy of Clinical Exllence have included pharmacovigilance module in their curriculum.
Big Indian multinational pharma companies have already set up or are in the process of setting up their own global pharmacovigilance departments, (like Ranbaxy & Dr Reddy's) fully equipped with most advanced software, in order to comply with stringent international regulatory reporting requirements. The business process outsourcing (BPO) segment looks to be benefited most, thanks to outsourced pharmacovigilance work from US and EU.
There have been some ice-breaking outsourcing alliances like the one between Tata Consultancy Services (TCS) to support Roche's global capacity building initiative by providing support on drug safety (as per the press release from TCS). Also, Bristol-Myers Squibb (BMS) extended its current outsourcing relationship with Accenture with a new "multiyear agreement" in which Accenture will provide services, including support for BMS's global pharmacovigilance HQ. The fact that about more than 100 people are already deployed in these two ventures, speaks volumes for its business potential, along with growth of pharmacovigilance professionals in this segment.
Indian pharma companies, the ever growing CRO and KPO sector are looking for several trained pharmacovigilance professionals. And this requirement would increase exponentially, as more pharmacovigilance work will be outsourced to Indian market. It's not so much from the safety reporting requirement from the clinical trails, which forms only 30 to 40 per cent of the ADRs reported, but the largest chunk comes from the post marketing surveillance for the approved drugs. The US Food and Drug Administration (FDA) alone gets over 200, 000 AE reports annually, not to talk about its European and Japanese counterparts, where the reporting requirements are as rigid, if not more.
The entire pharmacovigilance process, not to speak of the scientific aspect of pharmacovigilance, particularly the low end pharmacovigilance service basket comprising mainly individual case processing segment (from receipt to data entry, quality check, medical & regulatory assessment), involves a good number of working hands, as the operation is immensely labour intensive. Considering the fact that the discipline of pharmacovigilance in India is still in its infancy stage, where only a few pharmaceutical companies and CROs can claim to have a robust, fully dedicated pharmacovigilance group, it's very difficult to get professionals with hands on training in this niche discipline. What at the most you get is the CRA, Sr.CRA, project leads, who have done safety monitoring as part of their job.
Realising this, most of the institutes offering a variety of post graduate (PG) diploma or certificate courses have included pharmacovigilance (PV) in the curriculum, which for obvious reasons is inadequate. Of late Symogen India has started a PG certificate course in PV & PE, first of its kind in India, which should give all those who want to be PV professionals an advantage and head start ahead of others.
Taking Indian PV to greater height would be an arduous task, where all the stake holders have to contribute, perhaps much more than the statutory requirements. The responsibility of DCGI as the custodian of public health is most critical. While we appreciate the changes brought about by safety reporting, a great deal of harmonising activity needs to be done. Some of the grey or untouched areas that need to be looked into are:
● The need to be in line with international reporting norms, that has expedited reporting of SUSARs and not USAE
● The inconsistent way of USAEs reporting by sponsors (Append. XI, /CIOMS I / MedWatch forms / internal company formats complying the appendix XI are being used). This will make data capture into an electronic system most difficult, if not impossible
● To address internal discrepancies that exist between the stipulations with regards to safety reporting instruction as per the Schedule Y and that as described in NOC for clinical trials.
● Provision should be made to cover other important molecules, with known unsafe profile to be brought under the purview of PSURs besides the 'new drugs' and should not be limited to 4 years alone.
The current amended schedule is quiet on certain aspects like:
● About diligence and to submit follow up reports, where the initial SAE report was incomplete
● Reporting of SUSARs from foreign sites
● Provision of waivers for expedited reporting, with respect to deaths and other SAEs which are ' efficacy outcomes' and captured as such
● Safety surveillance of herbal, alternative medicines and that of the medical devices
Given the India healthcare scenario, the safety surveillance of alternative medicines, medical devices and medication errors are the most neglected and potentially most dangerous areas. There is a clear need to expand scope of safety monitoring system to include these areas. The WHO guidelines of 2004 could be the basic document to make a beginning. So also NPvP should be closely linked to national drug regulatory system.
The biggest and most critical measure would be to strengthen DCGI's hands through adequate trained manpower and access to most modern E2BM compliant PV software. Considering that the data collected through NPvP is going to be shared with Uppsala Monitoring Centre (WHO), the most obvious choice could be the tested VigiBase system. One cannot think of making any sense, or derive a signal manually from the heap of data that is expected to come to DCGI's office, unless such validated and tested software are being used.
(The author is associate director (Asia Pacific), Pharmacovigilance QA, Johnson & Johnson Ltd)