The thalidomide tragedy of the 1960s is today recognised as one of the most horrific examples of the side effects of medicines. Prescribed to relieve morning sickness in early pregnancy, the world was shocked by its side effects, when babies exposed in utero to thalidomide were born with serious deformities and congenital defects.
Until the thalidomide tragedy, drugs were not monitored for their possible impact on foetuses, even though it was already recognised that alcohol could across the placental barrier and affect foetal development. Thalidomide was subsequently banned and the incident marked a landmark change in the drug monitoring process. Teratogenicity testing and safety laws were framed to monitor medicines for safety and quality.
Today, drug safety monitoring has evolved into a separate branch of pharmacology – pharmacovigilance (PV) – defined as the detection, assessment, understanding and prevention of adverse effects, particularly long-term and short-term adverse effects of medicines. Regulators and governments rely on such data to evaluate the benefit:risk ratio of a particular molecule when considering it for marketing approvals.
Many drugs have been withdrawn from the market due to safety issues. The biggest drug recalls in recent history are Rofecoxib (Vioxx) which was withdrawn in 2004, natalizumab (Tysabri, 2005), and valdecoxib (Bextra, 2005.)
An analysis of reasons published by the US FDA and previous reports regarding drug recalls and withdrawals list the top nine safety reasons for withdrawals as hepatotoxicity (27.9 per cent), cardiovascular toxicity (17.4 per cent), haematologic toxicity (10.4 per cent), cutireaction (7.0 per cent), carcinogenicity (6.3 per cent), neurotoxicity (6.3 per cent), nephrotoxicity (5.6 per cent), allergy (3.5 per cent) and drug abuse (3.5 per cent).1
 “It is very critical for India to have her own PV monitoring system.”Imran Ali Senior Director & Global Head, Safety Operations, Global Data & Safety Monitoring, Quintiles |
One of the prime reasons for pharma companies to invest in PV systems is to proactively monitor their products’ safety profile, as drug recalls result in substantial loss in revenues as well as reputation of the company concerned. Imran Ali, Senior Director & Global Head, Safety Operations, Global Data & Safety Monitoring, Quintiles lists the long term benefits of PV saying, “The benefits for biopharma companies from PV are primarily the ability to maximise drug safety and secure and maintain public trust and confidence. PV helps in proactively assessing drug risk through its product lifecycle, evaluating drug to drug interactions and designing risk mitigation strategies.”
Drivers of change
Bioharmaceutical companies have thus had no choice but to invest in a PV strategy. The escalating costs of getting a molecule to market have seen most pharma companies outsource key components of the R&D and clinical trials process and PV requirements too have gone the same way. This has led to a growth in the demand for PV services.
 “Globally, with new regulations and greater safety awareness, PV is becoming an increasingly important activity for all pharma companies.”Nidhi Saxena Chief Executive Officer, Karmic Lifesciences |
The global PV market was worth $1.86 billion in 2008 and is estimated to touch $2.25 billion in 2015, says Nidhi Saxena, CEO, Karmic Lifesciences quoting from a Frost & Sullivan report on the World Pharmacovigilance Markets. The PVG market is thus growing at a CAGR of about 15 per cent. “Globally, with new regulations and greater safety awareness, PV is becoming an increasingly important activity for all pharma companies and we are seeing see a rapid growth in this area,” explains Saxena.
 “Indian companies are now open to have PV systems in order to enter US and EU markets.”Moin Don Executive Director & Founder PVCON Pharmacovigilance Auditing Consulting Services |
Confirming this trend, Moin Don, Executive Director & Founder, PVCON Pharmacovigilance Auditing Consulting Services, observes that Indian companies are now open to have PV systems in order to enter US and EU markets where, without such PV system registration or re-registration, and hence marketing of their products is not possible.
Building a case for PV in India
Given that investments in PV are linked to regulatory oversight, it is safe to assume that since India’s PV system is still in evolution, companies have not yet taken it too seriously. India’s PV framework (or rather the lack of it) was once again in the spotlight recently, with various industry representatives protesting that a ban on pioglitazone was unwarranted as there was no data of pioglitazone-related adverse drug reactions (ADRs) in India. The ban has since been rolled back but these arguments reflected the loopholes in the country’s mechanisms to report incidents concerning drug safety and the dire need to build and strengthen a countrywide PV system.
 “A company’s compliance is an extrapolation of the country’s culture and does not depend on whether the company is an innovator or a generic player.”Dr J Vijay Venkatraman Managing Director & CEO, Oviya MedSafe |
Even though he points out that pioglitazone has not been globally banned or even wholly withdrawn from Europe or North America, Dr J Vijay Venkatraman, Managing Director & CEO, Oviya MedSafe, agrees that the long-term solution to such critical issues concerning the safety of patients is establishing a robust PV system that includes all stakeholders of drug safety with the sole aim of ensuring that the benefit-risk ratio is in favour of the patients.” (For more reactions after the revocation of the ban, see story, ‘Pioglitazone: the saga continues’, pages 33-36)
As he explains, Indian data for pioglitazone becomes significant because the drug’s role in the development of bladder cancer is still a matter of controversy, contrary to the case of rosiglitazone for which there was global evidence in favour of its withdrawal from the market.
India’s first steps towards a PV framework was in 1986 when an ADR monitoring system was put in place with 12 regional centers serving a population of 50 million each. This system was not so successful and India’s next attempt was in 1997 when the country joined WHO’s ADR monitoring programme based in Uppsala, Sweden. But India’s contribution to the global ADR database was too scant, pointing to the lack of traction within the industry at that point of time. India’s third attempt, in 2004, the National Pharmacovigilance Programme, with WHO funding had to be re-conceptualised. Renamed the Pharmacovigilance Programme of India (PvPI), it has been operational in this avatar since July 2010. Dr Vijay says that today, the PvPI is the main repository of suspected post-marketing adverse drug reactions in India.
 “Today PvPI is strong on paper, however the question is, how many centers are actually collecting the data and submitting the same?”Dr Deven V Parmar Chief Scientific Officer, Karmic Lifesciences |
Unfortunately India’s PV system has not evolved as fast as it could have. Dr Deven V Parmar, Chief Scientific Officer, Karmic Lifesciences points to data released by the Uppsala Monitoring Centre, where India does not feature in the list of active Individual Case Safety Reports (ICSRs) in the WHO global ICSR database from March 2008-2013. (See chart: List of active ICSRs in the WHO global ICSR database from March 2008-2013)
Explaining the basis of PV systems, he quotes from Cicero in ancient Rome who said, “Salus populi suprema lex esto,” meaning that ‘the welfare of the people is to be the highest law.’ But he alleges that only a handful of Indian companies have a basic PV programme in place. “By and large, not many Indian companies feel a PV system or department is a necessity. Only Indian companies who have products being sold in emerging and established markets where the regulation mandates them to submit Periodic Safety Update Reports (PSURs) would have a rudimentary system in place,” he says.
Even with these systems Parmar questions the accuracy of the data since for instance, the collection of the data for a PSUR would be through medical representatives, who are more focused on reaching their targets, as compared to collection of data.
This lack of commitment to a PV strategy is critical when one considers the various complications that could arise. Ali of Quintiles stresses this aspect of PV data saying, “It is very critical for India to have her own PV monitoring system on account of our ethnic variability, demographic profile, cultural differences, indigenous systems of medicine, etc which can all impact the safety and efficiency profile of the drug with the Indian population.” His reading is that given the Indian regulatory authorities’ increased focus on PV, biopharma companies are increasing their efforts to align with stringent Indian and global safety PV norms.
A will but no clear way?
Dr Vijay observes that in general, biopharma companies want to be compliant with regulations. A prime reason is that with globalisation, “compliance with one country’s regulation helps a biopharma company get into the good books of another, which is vital for their business expansion.”
He sees no difference in the attitudes between innovator and generic companies abroad as both treat compliance issues with equal importance. However, in India, the enforcement of the laws governing compliance issues is “ambiguous” and only the companies that are keen to remain compliant with Indian regulations choose to be compliant. Thus he feels that a company’s compliance is an extrapolation of the country’s culture and does not depend on whether the company is an innovator or a generic player.
 “India’s PV system looks like a cut and paste job without taking into consideration the Indian scenario and needs improvement and refinement.”Dr Pipasha Biswas Principal Consultant, Director & QPPV of Symogen |
If the recent outcry protesting the ban on pioglitazone and other drugs like the popular painkiller Analgin were any indication of India’s PV culture, the country still has a long way to go. Experts with experience of global PV systems like Dr Pipasha Biswas, Principal Consultant, Director & QPPV of Symogen, argue that India’s PV system “looks like a cut and paste job without taking into consideration the Indian scenario and needs improvement and refinement.
Comparing other emerging and developing countries like China and in the ASEAN region like Thailand, Singapore etc Biswas comments that India is lagging behind in terms of regulations, implementation, funding, human resources, the desire to make it happen and several other reasons.
For instance, she points out that China’s PV reporting has increased significantly since 2005. The Chinese government has built a robust infrastructure and is working in sync with healthcare professionals, hospitals and various provincial agencies to take it to the next level. The Chinese government has also increased the monetary funding and is serious about PV activities.
According to Biswas, this is the case with other ASEAN countries as well, who have a far more reporting rate of adverse events to their respective regulatory agencies than India.
These regulators obviously see the benefits of these investments because as Biswas reasons, increased (PV) reporting from within the country helps the regulatory agencies in that country to make effective decisions about the product when there are issues with the products. Secondly, the poor quality of human manpower is a difficult situation in India that does not help either.
Peer to peer comparisons
But India is not the only country with teething trouble on the PV front. Parmar quotes from a paper comparing PV systems in 55 low and middle income countries which shows that 45 percent of the PV centres (114) in the analysis were established during the 1990s and 49 per cent were set up later; 69 per cent were affiliated with their Drug Regulatory Agency, 20 per cent with the Ministry of Health and 9 per cent with a university or other scientific body. Less than half of the countries (23 of 55) have any budget allocated for PV. Public health programmes (44 per cent), the Global Fund to fight AIDS, Tuberculosis and Malaria (36 per cent), universities (26 per cent), poison centres (21 per cent), Management Sciences for Health (18 per cent) and Rational Use of Drugs networks (15 per cent) sponsor some PV activities.2
Having worked across geographies, Ali lists the several issues and challenges faced by developing countries as compared to the developed world pointing out that there is no data on ADRs that may occur due to the interaction between established medicines and traditional, herbal medicines and vaccines used locally. ADRs reporting for traditional and herbal medicines, especially the multicomponent and adulterated ones, is not addressed seriously enough.
Also, in a predominantly generic market, there is no accountability of PV when innovator products are taken off the market. Many admit to not investing in ADR monitoring considering that they deal with off-patent products, observes Ali.
| List of active ICSRs in the WHO global ICSR database from March 2008-2013 |
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Further analysing the performance gaps in India’s PV system, Dr Vijay says that though the PvPI is a huge step forward in the right direction for collating Indian drug safety data, it is currently restricted to the approved medical college hospitals in India, public health programmes, and autonomous institutes like the Indian Council of Medical Research (ICMR).
Moreover, he points out that the data received by the PvPI by way of ICSRs is shared only with the World Health Organization (WHO) but not with the concerned pharma companies thereby denying them of the opportunity to become aware of adverse events associated with the drugs they market and take corrective actions.
Apart from PvPI, some Indian pharma companies too receive adverse events, process them and report them to the CDSCO. The CDSCO headed by the Drug Controller General of India (DCGI) mandates the submission of PSURs for new drugs but not all biopharma companies are compliant, says Dr Vijay.
Creating a PV culture
Ali too feels that the objective, planning and focus of PvPI “hold great promise” as it has considered the challenges faced in the previous programmes and the collaboration with medical institutions and corporate hospitals and is slowly creating an ADR reporting culture and practice.
But he points to the challenges in reporting ADRs like lack of awareness of reporting systems and not knowing what exactly to report. “Reporting of ADRs is considered low priority. The fear of impact on reputation and medico legal issues is also a deterrent. This is compounded by the existence of numerous brands from various companies, multiple unapproved combination drugs and concomitant use of Indian system of medicine that complicate the entire reporting process,” says Ali elaborating on the many interconnected issues.
Giving the doctor/clinician perspective, Dr Vijay says, “The overall awareness of PV or rather the lack of it is the first challenge. The perception that any approved drug is unconditionally safe is widespread not only among the patient population but also among the medical fraternity. Doctors and other healthcare professionals should be motivated to report any untoward occurrence that happens after the administration of a drug, without wondering if it would be biopharmacologically possible, in order to identify hitherto unknown adverse drug reactions.”
However, he is optimistic that the Indian regulators have begun to show positive signals to energise Indian PV. He sees this as a “transition phase” as the Indian biopharma industry adapts to global drug safety standards in line with the country emerging as an ‘innovator market’ and shedding its image of being just another huge ‘generic market’.
Regulatory gaps
Parmar of Karmic Lifesciences sums up the current scenario when he says, “Today PvPI is strong on paper, however the question is, how many centers are actually collecting the data and submitting the same?”
Don points out that the Indian PV regulations are not in synchronisation with ICH or international guidelines. The latest update on safety reporting requirement from clinical trials would result in many fold reporting of SAEs, both relevant as well as irrelevant to the trials, to DCGI’s office. He feels that the current PV programme is doing much better but there are still centres around India where reporting numbers are abysmally low or nought and therefore we need to create awareness, and educate the stake holders in appropriate manner.
India’s sheer geographical mass also adds another dimension to the regulator’s task, because as Biswas of Symogen points out, the PvPI programme currently lacks the infrastructure needed for such a vast country. Thus the overall sense is that there would be more openness to the idea of implementing PV systems if the regulations were better framed.
Involving all stakeholders
There is consensus that if the PvPI needs to succeed, there needs to be greater involvement at the grass roots level. Ali points out that there is a need to increase awareness of healthcare professionals and the public in the understanding and importance of PV. This should include proactively demonstrating the benefits of collecting ADRs to medical professionals and creating awareness amongst the general public through product inserts/labeling sheets on PvPI and where to report ADRs as also introduction of a toll free number for reporting ADRs.
Besides doctors/clinicians who have an important part in identifying and reporting ADRs, Ali says that the accountability of biopharmacists and paramedics in reporting ADRs should also be enhanced.
At another level, Ali says that academic curricula should be enhanced to include PV for all healthcare and paramedical courses and the practice of reporting ADRs should be inculcated during internship and postgraduate programmes which will ensure strong foundational training.
At the regulator level, he opines that the PvPI workforce needs to be strengthened to handle incoming ADRs and ensure the processing of these events on time and there needs to be ongoing collaboration with various stakeholders for enhancing the programme.
Finally, Ali stresses that there is a strong need to create fora where regulators and the biopharma Industry interact with clinicians, patient groups and the general public to create awareness of the ADR reporting system and the immense benefit it has in patient safety. The PvPI’s involvement in these stakeholder partnerships would help create great and sustained value in the near future, according to Ali.
Industry associations should also be harnessed to drive this change. Parmar suggests that national bodies like the Indian Medical Association, Association of Medical Consultants, and others such as Association of Physicians of India, etc. can be roped in to strengthen the links between the various parts of the ADR system. Most consultants are not aware of PV practices in India and in fact, Parmar opines that the Medical Council Of India should make it a compulsory learning for all doctors in order to renew their licenses. In a similar vein, he recommends that the authorities should seek the cooperation from their counterparts in Unani, Ayurveda, Pharmacy & Allied branches of medicine as well.
The way forward
As the biopharma sector is a heavily regulated sector, it follows that rules and laws are a major driver of change. Thus regulators are no doubt aware that the guidelines and laws they frame today will dictate the destinies of the sector going forward. Therefore industry stakeholders are unanimous that the DCGI/CDSCO are on the right path but have many suggestions to improve /refine the framework.
Dr Vijay reasons that though PvPI is emerging as one of the largest and reasonably structured PV programmes in Asia, India does not have specific guidelines for PV as are available in the EU and the US. Schedule Y primarily focuses on clinical trial safety but not much mention is made in it about post-marketing PV, unlike emerging and developing countries similar to India such as Brazil and Saudi Arabia, which have formed their own PV guidelines by customising the guidelines of the matured markets.
Taking this thought further, Dr Vijay says, “With globalisation being the rule today, we would always benefit with our regulators getting to discuss more and more with their counterparts across the globe, as it would result in earlier awareness in India about any global drug safety issue and increased possibility of prior adoption of global drug safety strategies by India also.”
He also suggests that our drug regulators could call for proactive Risk Management Plans from biopharma companies that market drugs which have been implicated in safety issues to understand and evaluate the risk minimisation procedures put in place by them, as is the case in many other countries, instead of abruptly suspending a drug just on the basis of suspicion. This would provide a fair chance to quantify how safe or unsafe a drug is before deciding for it to be banned and this decision would be particularly important in the case of life-saving drugs since recalling them from the market would anyway impact the patients directly, he reasons, obviously referring to the aftermath of the pioglitazone episode.
PV solutions: options galore
Biopharma companies looking at setting up PV systems have the option of doing it themselves or outsourcing the entire process or parts of it to a growing list of PV specialists. Services and solution providers can be broadly categorised into CROs which offer end to end services, BPOs who have offer selected services like case processing activities for safety services along with additional safety knowledge and reporting services.
Ali also points out to a more recent trend of small scale consulting groups who have started to offer a wide range of safety services. In addition, some large biobiopharma companies have captive PV units to deliver safety services.
Enumerating the hallmarks of a good PV solution, Ali of Quintiles says the solution must take into account all the core services of safety from case intake, case processing, medical review to regulatory reporting, aggregate reporting, benefit risk evaluation and mitigated safety risks. A good PV solution should be able to provide accepted PV systems (example Argus, ARISg, etc) and standardised operating procedures to avoid the need for companies to invest in their own systems and procedures. This ability should be available at a global, scalable model and be able to meet the requirements of an ever changing and stringent regulatory environment. All this should be available at reasonable costs and within acceptable compliance and quality standards, he concludes. Besides these, Saxena believes that companies working to exceed client expectations should have a robust voice of customer process where clients can provide their feedback.
Quintiles’ global reach can be gauged by its 1000+ safety professionals across the globe, with dedicated staff in the US, Ireland, Switzerland, India, Singapore, China and Japan. The company has been providing PV services for 150+ biopharma companies for over two decades and has processed over 1.5 million adverse events globally as per industry leading quality and compliance metrics. According to Ali, the company has been audited by several global regulatory agencies with no critical findings. The level of services ranges from advanced specialist support as also PV consulting services for new entrants or small players wanting to establish a PV service as well as outcomes research abilities by harnessing public health.
Homegrown CROs too are as active in the PV space. According to Saxena, Karmic Lifesciences’ current PV team, with 180+ person years’ experience, offers a PV portfolio encompassing end-to-end PV and safety services to support US FDA, EMA and local reporting requirements, combined with full service CRO offerings to offer a complete solution to sponsors. The Mumbai-based company, processes approximately 5000 cases in a year, comprising serious, non-serious and clinical trial cases as well as literature search.
Karmic Lifesciences’ PV system was designed and put in place by Don’s firm, who says he has worked with a variety of clients ranging from Indian and global MNCs. His client roster includes giant generic biopharma companies, CROs and some KPOs with whom he has been associated with, as a strategic advisor and consultant. Besides these assignments, Don has been conducting PV audits round the year in the Asia-Pacific and CIS region as his preferred geography.
A global approach
“The growth prospects for PV solution providers is immense for the next three years or so,” says Don. He sees more business coming to Indian KPOs and PV solution providers like himself, with cost effectiveness as the biggest driver. Thus, services such as end to end case processing of cases, authoring of reports etc has grown many fold in the previous few years due to cost effectiveness of outsourcing vis-a-vis in house processing of cases by foreign MNCs. The expenditure on PV operations per company would largely depend on multiple factors such as nature of operations, magnitude, product portfolio, etc, he explains.
Though PV auditing services from India is a rarity, Don acknowledges that his clientele beyond the country is a testimony to his ability to leverage his personal global networking and brand name / goodwill to tap this potential. Clearly, India does not lack the PV know-how; what’s lacking is the ADR reporting culture and regulatory push.
Another breed of solution providers are clinicians-turned-PV specialists like Dr Vijay, a diabetologist who set up Coimbatore-based Oviya MedSafe along with other clinicians in February this year, to provide PV services. Initially operating in the European and the North American markets, the company won their first contract in the the Middle East market in June, and will to work on Corrective And Preventive Action plans (CAPAs) for one of the largest drug distributors in the region. The company also bagged its first India client in the same month, reportedly one of India’s largest biopharma companies, to write their PSURs for submission to the DCGI.
A problem of plenty?
In fact, far from a dearth, biopharma companies in India may be faced with a problem of plenty when it comes to choosing PV solution providers. Gauging the merits of each may prove difficult.
Biswas of Symogen cautions that the sector has a the high attrition rate and points out that the “poor quality of work is always in the news.” She stresses that as PV is a highly regulated area with increased audits and inspections, there are bound to be repercussions sooner rather than later if the quality (of PV work) suffers. “Unless there is improvement by providing Western standard training and increasing knowledge, it will be difficult to continue doing PV (in India),” she says.
To meet this issue head on, one of Symogen’s main principles since its inception in 2007 is to train and make their staff knowledgeable in all the spheres of PV especially with worldwide PV regulations so that seamless quality of work can be delivered to clients. The firm has its main offices in the US and Europe, and advocates proactive PV to meet regulatory demands. Symogen’s client list comprises large, mid-size and small biopharma and biotech companies as well as international CROs and BPOs, the likes of Roche Pharmaceuticals, Valeant, Shire Pharmaceuticals, Takeda, Genzyme, and Solvay.
The evolving regulations in the country maybe be a deterrent but pharma companies with global ambitions have no choice but to put a PV strategy in place. So a change in attitude is a given, driven by business realities rather than altruism. And the fact that Ma Foi Strategic Consultants picked up a 17.5 per cent stake in Oviya Medsafe less than a year after its inception is a clear indication of the value addition and long term growth prospects of PV solution providers.
The final argument in favour of a robust PV system is that drugs which were previously banned for safety reasons, are being approved, albeit with very strict controls, for certain conditions. For instance, thalidomide is currently approved under the US FDA orphan drug rules to treat leprosy, even as it remains a subject of ongoing research to treat other cancers and autoimmune conditions . Its use is minutely supervised to prevent the tragic birth defects associated with its first outing in the 1950-60ties.
Thus the business case for PV is very clear, both for the biopharma clients as well as PV solution providers. But going by the recent history of regulations for clinical trials, India needs nothing short of a patient uprising, led by pharmacovigilantes, to push the PV agenda forward. Any takers?
References:
1. Man F, Thornton A, Mybeck K et al; Evaluation of the characteristics of safety withdrawal of prescription drugs from worldwide pharmaceutical markets-1960 to 1999. Source: Drug Inf. J. 35, 293–317 (2001).
2. Sten Olsson, Shanthi N. Pal, Andy Stergachis and Mary Couper; Pharmacovigilance Activities in 55 Low- and Middle-Income Countries. A Questionnaire-Based Analysis. Drug Saf 2010; 33 (8): 689-703
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