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Spring 2016 Faculty Newsletter - Pharmacovigilance

Editorial

Hello and welcome to our first 2016 newsletter!

The present issue focuses on Pharmacovigilance; a science and art that has seen remarkable evolution and advancement in the last few decades. A vital discipline, that has a huge number of ever interested stakeholders and is relevant to anyone who has ever been subject to or can potentially be subjected to, a medical intervention – that means all of us!

This issue begins with an introductory article by Dr Sumit Munjal outlining some of the key concepts of pharmacovigilance. Dr Pipasha Biswas has written a noteworthy article summarising the complex subject of signals, which would be of particular interest to our readers with no prior exposure or expertise of the subject. Our international colleagues, Dr Vijay Venkatraman Janarthanan and Dr Vignesh Rajendran have written an insightful article on the history and development of this important discipline in India. Finally, I have written an article on the role of the EU Qualified Person for Pharmacovigilance (QPPV).

As I always say, this is your newsletter. Please feel free to contribute and yes, all suggestions for improvement are warmly welcome. Please contact myself or Ben Cottam in the Faculty office (b.cottam@fpm.org.uk) with your ideas.

Happy reading and enjoy the sunshine.

Dr Asad Khan MFPM
Editor of the Newsletter


Contents


President’s update

Professor Alan Boyd PFPM

It has now been just over 100 days since I became the President of the Faculty and as expected it has been a very busy time for me in assuming my role. One of the most significant things that has happened during this time is our move into the new offices at Angel Gate in Islington. We spent a lot of time over the past 12 months looking for new offices and when we found Angel Gate we knew that it would be a good place to relocate too – it was a bit like looking for a new home – when we first saw them we knew they would be right. I have to say, however, that so far, the premises have exceeded my expectations. Most people who have visited the new offices have been very complimentary about them and we have already started having meetings there. Kathryn Swanston and the staff have been working hard in getting everything sorted and on behalf of all the members I would like to thank them for doing this. We are looking forward to welcoming all members over the next few months. So when you do visit, we do hope you will like what you will see.

I have also been out meeting people from the other Medical Colleges and Faculties and other groups that are relevant to the Faculty in order to introduce myself and tell them about the Faculty and what our role and aims are. I am pleased to say that everyone that I have met so far has been very interested in hearing about the Faculty plans for the future, as I have laid out in my objectives, and the good thing is that no one has yet asked me ‘What’s the Faculty of Pharmaceutical Medicine??’, which has been satisfying. Also from my various discussions, people and groups from outside the Faculty have told me that they are very willing to collaborate with us on relevant activities, so I will be taking them up on this where we can.

Recently I also had the opportunity to meet Dr Margaret Chan, the Director-General of the World Health Organisation. Dr Chan delivered the Annual Lecture of the MHRA and gave a fascinating presentation about the work of WHO and covered topics such as how they dealt with the Ebola crisis and how they are currently handling the current Zika virus outbreak. After the lecture we talked about Pharmaceutical Medicine and she was particularly interested to hear about our PMST programme. She commented that as this is such a unique programme, she encouraged us to help other countries set up similar programmes for their pharmaceutical physicians – so there’s a challenge to us all!

In the last Faculty Newsletter, I laid out the objectives that I would like to achieve over the next three years and I have also started working on these too. I have recently met with Sharon McCullough (Chair of the Education Committee) and Peter Stonier (Director of Education and Training) to discuss Education and Training initiatives across the Faculty. We have put an outline plan together and this will be shared with all members in due course. In relation to the ‘Engaging with the Membership’ objective, Tim Higenbottam (Vice-President) and I have started our discussions about this and are formulating our ideas. One other key objective was a review of the Faculty structure and operations to make sure we are configured correctly in the future. To start this process we have already had discussions at the recent Faculty Board and Coordination Committee meetings and I am also having a meeting with all the chairs of the current Faculty Committees, including the Trainees Sub-Committee, during the first week in April, to continue the process. On the topic of entry of Non-Medical Members to the Faculty, this was also discussed at the recent Board meeting and we have initiated a project led by Tom Morris (Registrar) to consider this further.

For our ‘Outward Looking Objective’ one key piece of work is the Faculty involvement with the Choosing Wisely initiative being led by the Academy of Medical Royal Colleges. We have had several meetings already with the project team at the AoMRC in relation to our inputs covering adherence and improved prescribing practices, which are all relevant across medicine in general, whatever the specialty.

In terms of increased communications from the Faculty, we were consulted about our views on the recent issues surrounding the disaster that took place recently in a Phase I study being conducted in France. This experience has led me to think that, as a Faculty, we do need to think proactively about what views we might have and want to contribute to the key medical issues of the day such as antibiotic resistance, off-label use, early access to medicines, etc, etc. To this end we are organising a Faculty Policy Review Day on the 17th May to discuss this. This meeting will be open to all members of the Faculty to attend and further details will be circulated soon (please keep the afternoon of the 17th May free in your diary if you are interested in attending!).

As part of my new role I have also taken the opportunity to meet with Susan Bews, our Responsible Officer, and the revalidation team. I was impressed by their absolute willingness to provide whatever assistance, support, help and guidance they can to any of the 570+ doctors revalidating through the Faculty. It is clear that any doctor can sometimes face difficult or challenging situations, professional or personal that can affect their practice. Therefore, if such issues are raised with Dr Bews or the team in the office the sooner they will be in a position to offer advice or assistance. It might also be something quite simple such as a question relating to scheduling the meeting in the three-month window when you suddenly have a serious personal issue that has arisen (and I must point out workload and travel do not count as extenuating circumstances, even for the President – as I found out recently!), or questions about PReP or 360 feedback, or what happens post appraisal in the run up to your revalidation recommendation or what your next steps are, etc. So please do get in touch with the revalidation team as soon as you can and the sooner they know there is an issue, the sooner they can assist or put your mind at rest. So please do note that the team give support Monday to Friday 0900 – 1700 and a good way to contact them for most queries is via revalidation@fpm.org.uk.

You will read below about the newly launched GPMP Support Network. Since the launch of Good Pharmaceutical Medical Practice in November 2014, a working group chaired by Dr Tom Morris has been developing a ‘support network’ aiming to further guide pharmaceutical physicians who face ethical or medical dilemmas in their practice. An appointed panel of FPM Fellows have volunteered to give their views on relevant questions and queries submitted to the network by pharmaceutical physicians. The support network will provide a valuable source of confidential advice and I encourage all members to read the information below and on the website, and get in touch if you have any queries.

I do hope that you have found this update informative. I do intend to keep you informed about the activities of the Faculty on a regular basis. However, if anyone has any matters or comments that they would like to discuss with me, then please drop me an email at a.boyd@fpm.org.uk and I will look forward to hearing from you. Also I hope to meet as many members as I can at the various meetings that we hold or attend. For information I will be attending the forthcoming IFAPP Conference in Sao Paulo, Brazil from the 18-20th April, as I have been invited to give a presentation on ‘Good Pharmaceutical Medical Practice’ and how we developed these guidelines. So if you are attending this event I will look forward to meeting you there too. Finally, I do hope you enjoy reading the rest of this newsletter and in particular the articles relating to Pharmacovigilance and Product Safety – topics of importance no matter where you work within the specialty.


Launch of the GPMP Support Network

Dr Tom Morris
Chair of the GPMP Support Network

In November 2014 the FPM launched Good Pharmaceutical Medical Practice (GPMP – https://www.fpm.org.uk/policypublications/GPMP), which provides all doctors practising pharmaceutical medicine around the world with specific guidance and direction on expected standards, conduct and behaviour. However, it has been recognised that on occasions, further support and advice may be required. Strengthening high quality decision-making in pharmaceutical medicine is in the interests of the patient and society. Therefore, based on feedback from FPM members, the ‘GPMP Support Network’ has been established aiming to further guide pharmaceutical physicians who face ethical or medical dilemmas in their practice.

The network was opened this week and will be promoted to potential users in a phased manner over the coming weeks. An appointed panel of FPM Fellows have volunteered to give their views on relevant questions and queries submitted to the network by pharmaceutical physicians. The network will operate on a confidential basis, via email, and responses will be given in line with the FPM’s charitable objectives i.e. promote the science of pharmaceutical medicine and to develop and maintain competence, ethical integrity and high professional standards in the practice of pharmaceutical medicine. The network is free to use and is available to all members of the Faculty and all registered doctors involved in the practice of pharmaceutical medicine, anywhere in the World.

The scope of enquiries will include questions directly related to the interpretation and adoption of the standards set out in GPMP or other ethical guidelines. Enquiries considered out of the scope will include those related to the promotion of medicines, detailed scientific advice on the design or interpretation of trials, career, employment and legal advice. Enquiries will only be accepted if they link primarily to the health benefit to patients, healthy volunteers and/or the general public. The network is initially being launched on a pilot basis for one year, before consideration of permanent implementation.

To find out more about how the network will work, or to submit an enquiry, please visit the FPM website here https://www.fpm.org.uk/policypublications/GPMP or email GPMPsupport@fpm.org.uk.


An introduction to Pharmacovigilance

Dr Sumit Munjal
Takeda Development Centre Europe

According to World Health Organisation (WHO), Pharmacovigilance (PV) is defined as the science and activities relating to the detection, assessment, understanding and prevention of adverse effects or any other drug-related problem. It is a discipline that is ultimately responsible for patient safety and is considered an integral part of pharmaceutical industry. An adverse event (AE) is a medical occurrence temporally associated with the use of a medicinal product, but not necessarily causally related (ICH E2A guideline). An AE can be considered either non-serious, or, if it meets one of the criteria, serious – death, life threatening, hospitalisation (initial or prolonged), disability, congenital anomaly/birth defect or other serious (important medical) event (http://www.fda.gov/Safety/MedWatch/HowToReport/ucm053087.htm). Another important concept is causality assessment between the AE and the medicine and primarily it is determined as positive or negative for reporting a particular case to the health authorities (HAs). A case when reported by a health care professional (HCP) such as a clinician, pharmacist, nurse or a patient is called a spontaneous report. Whereas a case coming from a clinical trial, post-approval named patient use programs, other patient support or disease management programs would constitute a solicited report. An Individual Case Safety Report (ICSR) is considered valid when the four elements of an identifiable patient, an identifiable reporter, a suspect medicine, and an adverse event, are present.

There are a few key organisations that play a major collaborative role for PV on a global level. These are the WHO, the International Council of Harmonisation (ICH) and the Council for International Organisations of Medical Sciences (CIOMS). Then there are country level regulatory agencies such as US-FDA, UK-MHRA, Japan-PMDA, China FDA etc and European Medicines Agency (EMA). These regulators are responsible for ensuring safety, quality and efficacy of medicines in their country or region, providing regulatory guidelines or legislation and conducting inspection of pharmaceutical companies. There are also a number of other key stakeholders closely involved with PV such as patients, HCPs, academia, Contract Research Organisations (CROs), lawyers, media etc. A close collaboration between these various bodies and stakeholders is extremely important for effective management of patient safety.

A pharmaceutical company has many different functions at a global level, one of which is the Department of Global PV (GPV). Typically, in a medium to large size pharmaceutical company, there are sub-functions within GPV such as PV Operations, Standards Compliance & Training, Medical Safety, EU-Qualified person responsible for PV (QPPV), Drug Safety Officer & PV Business Partner relations and Risk Management with Pharmaco-epidemiology. Most of the safety decisions taken are applicable across the globe for patients; however, there may be some local exceptions based on patient needs/characteristics, disease epidemiology and individual country laws. These sub-functions work very closely with each other and other functions outside GPV of a pharmaceutical company. Databases and IT play a significant role in supporting PV systems, their quality and generally, the personnel within department of PV.

PV physicians work in a global matrix cross-functional team and provide medical input to manage drug safety issues. Some of the day-to-day work within a company PV department may involve single case safety assessment, signal detection, aggregate safety such as Periodic Safety Update Reports (PSURs/PBRERs), risk management involving Risk Management Plans (RMPs), responses to Health Authority (HA) queries, support for filing new licence submissions and ensuring compliance. PV work in HAs mainly involves guidance, assessing applications submitted by the pharmaceutical companies and taking decisions in the interests of patient safety in a particular country. CROs also play an important role in providing support to individual tasks of a larger company PV department.

Increasingly, PV is becoming an important aspect of early phase medicines development, and drug safety regulations are well in place once a medicine is licensed. It is important for companies to bring in PV colleagues earlier in the process of medicines development, ensuring appropriate safety requirements are met and considered for risk management. The concept of drug safety has changed over time and it has become more of a benefit-risk assessment that is conducted on an ongoing basis of a medicine’s lifecycle. An acceptable benefit-risk ratio can vary according to a therapeutic area and medical need of a medicine. A good example may be an oncology orphan drug vs a mature established medicine such as paracetamol. Disease epidemiology, patient survival and alternative treatment options may play a significant role in the decision making of benefit-risk assessment and licence approval or renewal of a particular medicine.

There are challenges within PV such as thorough evaluation of available data, identifying the appropriate benefit-risk balance, taking decisions in the interests of patient safety, timely communication and follow-up. There are also challenges in form of the lengthy process of medicines development, costs, resources, changing regulatory landscape and low reporting of adverse events by HCPs. More efforts are being made to encourage patient reporting of adverse events. Social media is playing an important role in today’s lives and there needs to be a strategy to capture this useful information whilst disregarding background ‘noise’.

Overall, the science of PV has come a long-way since the thalidomide disaster in 1960s and regulations around drug safety have been evolving. The scope of PV has increased and emerging markets constitute an important component of global PV now. This is both in form of outsourcing cost-efficiencies and more PV regulations around selling medicines in these rapidly growing emerging markets. This is leading to an interesting expansion of PV and rewarding experience of improving healthcare of patients around the world. More needs to be done to identify better strategies for collaboration, partnerships, harmonisation and taking this discipline forward in the interests of patients. Pharmacogenetics and personalised medicines are also work in progress to reduce the incidence of adverse drug reactions and make drugs more effective in individual patients.


Signal detection and benefit:risk assessment throughout the life cycle of a medicinal product

Dr Pippa Biswas MFPM
Director, Symogen Ltd.

No effective medicine is without risk and the use of medicines has become more complex than ever before! While they bring significant benefits, there are also inherent risks to public health and patient safety mainly due to adverse reactions. Adverse drug reactions (ADRs) are an important public health issue because of high morbidity, mortality and cost that they generate1. Specifically, every medicine can have both wanted and unwanted effects which may occur in some or all patients. It is precisely for this reason that the benefits of a medicine should always be weighed up against its risks and failing to manage the risks may have harmful consequences for patient safety and public health. Because of the strong impact on public health, regulatory authorities (RAs) worldwide have raised the bar and have implemented new pharmacovigilance legislation to protect public health by reducing the burden of ADRs through the detection of safety signals2. Although signal detection activities have mainly been performed based on spontaneous reporting databases, new pharmacovigilance legislation underlines the relevance of other sources of information e.g. scientific literature, epidemiology and large automated databases, for the evaluation of the benefit–risk balance of a medicinal product.

It is well known that not all safety issues relating to a medicinal product are identified during clinical trials and there is limited amount of information about a medicinal product’s safety profile before it comes on the market. Even though randomized controlled trials (RCTs) are the gold standard for assessing the efficacy of medicines, it is not necessarily so for drug safety, where narrow, well-defined patient inclusion criteria and inadequate power to detect either multiple or rare adverse events is a major limitation. Hence, at the time of approval of a medicinal product, knowledge of the full benefit-risk profile is incomplete thus making it more important to monitor the risks and benefits of medicinal products post-approval and throughout the product life cycle. Some risks become apparent only after approval of a medicinal product, when it is used in millions of patients in the “real world” population. In real life, a medicinal product is used in larger numbers of patients, in different types of patients (e.g. elderly patients, children, patients with more severe or even milder disease, patients on other medications which could interact etc.) and for longer periods of time, which can change the benefit-risk profile of the product substantially.

Signal Management in Pharmacovigilance

One of the main objectives in pharmacovigilance is proactively identifying previously unknown adverse effects that may not have been identified in pre-marketing clinical trials. The mechanism through which this exercise of finding unknown and rare adverse events is done is through proactive signal management. The signal management process can be defined as “the set of activities performed to determine whether, based on an examination of individual case safety reports (ICSRs), aggregated data from active surveillance systems or studies, literature information or other data sources, there are new risks associated with an active substance or a medicinal product or whether known risks have changed”2. The signal management process includes all steps from initial signal detection; through their validation and confirmation; analysis and prioritisation; and signal assessment to recommending action, as well as the tracking of the steps taken and of any recommendations made.

Signal detection methodology

Multiple methods exist for signal detection activities and there is no gold standard, however, the signal detection methodology falls broadly under two components:

Qualitative method: In this method, a case-by-case manual review of individual case reports or individual CIOMS (Council for International Organizations of Medical Sciences) forms is undertaken for a given period and a thorough analysis of the cases is done mainly by an assessor preferably a pharmacovigilance physician. Further, extensive literature reviews are also conducted for the events of interest. No comparison is made with cumulative data in this method.

Quantitative method: This method utilises statistical tools to identify drug-event pairs or combinations of a drug and an event that occur with disproportionately high frequency in large spontaneous databases. Traditional quantitative methods employed in spontaneous reports data have included reporting odds ratio (ROR), proportional reporting ratio (PRR) and Bayesian techniques, which are used by several marketing authorisation holders (MAHs). With the development of several administrative health claims databases, additional methods such as sequence symmetry analysis (SSA) are also employed routinely to confirm and validate the signals. Thus, the quantitative method utilises statistical outputs that help in data mining and analysis of signals.

Once a signal has been detected, it is then validated, analysed and prioritized. The validated signals are included in risk management plans (RMPs), which are used for benefit-risk assessments and to optimize the benefit-risk balance for a medicinal product.

Risk Management Process

Risk management in simple terms is a proactive approach to assessing and minimising risks that are detected through signal management activities. Per EU definition risk management is “a set of pharmacovigilance activities and interventions designed to identify, characterise, prevent or minimise risks relating to medicinal products, including the assessment of the effectiveness of those activities and interventions”.3

Risk management process consists of identifying and characterizing the nature, frequency, and severity of the risks associated with the use of a medicinal product, throughout a product’s lifecycle, from the early identification of a potential product, through the pre-marketing development process, and after approval during marketing. Pre-marketing risk assessment is the first step in this process, and it focuses on risk assessment prior to marketing mainly during clinical development in all phases of clinical trials. Regulatory authorities recommend that right from the start of development of a medicinal product MAHs need to pay careful attention to the overall design of the safety evaluation. Potential issues that may be suspected because of pre-clinical toxicological data or because of effects of related medicines should be targeted for further and detailed evaluation. As it is impossible to predict every important risk, MAHs should refine and modify safety evaluations as more data is received throughout the phases of clinical development and classify the risks as:

  • identified risk – adequate evidence of an association between the medicine and risk occurrence
  • potential risk – there is some basis for suspicion of an association between the medicinal product and the risk occurrence, though it is not confirmed; or
  • missing information – when there is insufficient or no data and additional data or evidence is needed to confirm the risk

This classification is essential in analysing and further understanding the actual risks of the medicinal products in detail. The strategy for risk management is thus based on the following and described below in Figure 1:

Safety profiles: All risks (identified or potential) are compiled, along with a record of what is missing in terms of safety information.

Risk assessment or pharmacovigilance plan: This is the plan for further identifying, characterizing, and assessing risks. It contains both routine and additional pharmacovigilance activities.

Risk Minimization Plan: This is the plan for minimizing the risk; it is an integral part of the risk management plan (see below). It contains both routine and additional risk minimization activities.

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Figure 1: Signal Management and Benefit-risk Assessment throughout the product life-cycle

Challenges for the future

One of the main challenges of signal management in the context of benefit-risk assessment is how to detect potential safety issues early during the clinical development phases and the analysis of the ever-increasing quantities of data effectively. The other challenge is how to get good quality and complete data from the ICSRs for robust analysis and evaluate potential signals quickly and how better methods in signal detection could best be applied in emerging safety issues. This especially includes consistent coding of event terms which is a key component of effective signal detection.

Conclusion

Benefit-risk assessment is a complex activity within pharmacovigilance, which includes all components of proactive signal management and risk management throughout a medicinal product’s life cycle. This is the central element of the scientific assessment of a marketing authorisation application. This increasingly complex activity is necessary to enhance the benefit-risk balance of a medicinal product in real life. Benefit-risk assessment, including signal management and risk management, can be challenging and expensive. However, it is an important aspect on which regulators decide the marketing authorization application of a product. Signal detection is an ongoing process where no single method will meet all needs and all potential signals need to be systematically investigated appropriately and addressed. There is no gold standard method available for either signal management or benefit-risk assessment; hence it is imperative to develop better multivariate methods of signal detection that can aid in benefit-risk assessment. Lastly, it is advisable to include combination of both robust qualitative and quantitative methodologies to fully include all aspects of benefit-risk assessment.

References

(1) Lazarou J, Pomeranz BH, Corey PN. Incidence of adverse drug reactions in hospitalized patients: a meta-analysis of prospective studies. JAMA. 1998; 279:1200–5.
(2) Guideline on good pharmacovigilance practices (GVP): Module IX Signal Management
(3) Guideline on good pharmacovigilance practice (GVP): Module V Risk Management Systems (Rev 1)


Pharmacovigilance in India - The Past, Present and Future

Dr J Vijay Venkatraman
Managing Director & CEO, Oviya MedSafe

Dr Vignesh Rajendran PhD
Pharmacovigilance Associate, Oviya MedSafe

The concept of pharmacovigilance (PV) in India traces its roots to 1986, in which year an official Adverse Drug Reaction (ADR) monitoring system involving 12 regional centres covering a population of 50 million each, was proposed. In the year 1989, six regional centres were set up for ADR monitoring, of which only two were eventually active.1 These early PV environments were complicated and the outdated systems meant that the amalgamation of data was unreliable and limited. After facing several roadblocks, India registered in 1997 as a member of the World Health Organisation (WHO) Programme for International Drug Monitoring, managed by the Uppsala Monitoring Centre (UMC). In November 2004, with funding support from the World Bank approved upon request of the Government of India, the Central Drugs Standard Control Organization (CDSCO) launched the National Pharmacovigilance Programme (NPP) with the immediate objective of nurturing a reporting culture amongst healthcare professionals (HCPs). Contrary to the overwhelming expectations from the policymakers, the programme did not progress, with the absence of continuous funding being a key reason. Recognising the need to re-conceptualise the NPP with more forethought and with a long-term strategy in place, the programme was rechristened the Pharmacovigilance Programme of India (PvPI) and commenced by CDSCO, the Directorate General of Health Services (DGHS) under the Ministry of Health and Family Welfare (MOHFW) in collaboration with the All India Institute of Medical Sciences (AIIMS). From April 2011, the Indian Pharmacopoeia Commission (IPC) took over as the National Coordinating Centre (NCC) for PvPI.

The focus of PvPI is towards establishing a unique drug safety ecosystem with a broad objective to safeguard the health of the 1.31 billion people of India by ensuring that the benefit of use of medicine outweighs the risks associated with its use. PvPI collects, collates, analyses the data, recommends regulatory interventions and communicates risks to HCPs and public.2 In a strategic move, PvPI has collaborated with a number of medical colleges and hospitals, which began to function as Adverse Drug reaction Monitoring Centres (AMCs) for collecting suspected ADR reports and forwarding them to NCC. The total number of AMCs currently functioning under the PvPI programme is 179, with 99 Causality Assessment Committees (CACs). IPC is in the process of enrolling additional centres under the PvPI such that the strength of AMCs will increase to 200 by the end of March 2016. It is remarkable that India became the first Asian country to report over 100,000 Individual Case Safety Reports (ICSRs) to VigiFlow, UMC's web-based PV system.3 Furthermore, India is currently the 7th largest contributor to the UMC's international drug safety database (Vigibase). Adding another feather to India’s cap is the UMC’s completeness score of 0.94 out of 1 assessed for Indian ICSRs, positioning India among the top-rankers in the completeness score criterion.4 The Regional Resource Centres for Training and Technical Support (RRCTTS) play a significant role in enhancing the awareness of PvPI among different stakeholders and motivating them to participate in it. Considering the significant role of RRCTTs, IPC is seriously contemplating to expand all its RRCTTS by undertaking requisite capacity building measures for infrastructural, technical, and logistical development based on PvPI recommendations, which will provide uniform training to all AMC(s) teams and enhance skill development for PvPI personnel while also strengthening the concerned AMC’s status. The Core Training Panel of PvPI interacts with international agencies for participation and implementation of training programmes related to pharmacovigilance.

Recent initiatives unveiled by PvPI include provision of a toll-free number, a revolutionary mobile application which simplifies the process of ADR reporting, adverse event reporting forms in six regional languages to encourage consumer reporting and a mandate to the pharmaceutical industry to submit reports in XML-E2B (Extensible Mark-up Language) format. It is worth noting that various Indian headquartered global pharmaceutical companies have established in-house PV units that operate by adopting global standards even before PvPI rolled out any mandates, in order to remain compliant with PV regulations outside India. PvPI has also set up a PV system in tuberculosis and HIV/AIDS-related health programmes with WHO support. The IPC is all set to become the first WHO Collaborating Centre for safety of medicines and vaccines in South-East Asia.5 It is evident that, by being a progressive program of the CDSCO and without the controls for any executive jurisdiction, PvPI has made positive strides. Earlier in 2015, the Drugs Technical Advisory Board (DTAB) recommended mandating pharmaceutical companies to report adverse effects of marketed medicines.6 Although recommendations were proactive, the legislation for mandate came in only in March 2016. The periodic communications and interactive discussions between PvPI and its stakeholders have brought progression in receiving ADR reports as many pharmaceutical companies consider reporting ADRs as an industry practice. As a result, the ADR reporting rate by the pharmaceutical industry to PvPI was 18.80 per cent in the year 2015.7

To broaden the involvement of the medical community in ADR reporting, IPC has started to collaborate with the IMA (Indian Medical Association), which represents over 360,000 medical practitioners. This will enable a greater role for the private practitioners and corporate hospitals since only government hospitals, institutions and colleges have been directly involved in PvPI until recently. Interestingly, ADR reporting by the corporate hospitals is mandatory for the National Accreditation Board for Hospitals & Healthcare Providers (NABH) accreditation of hospitals. To give further momentum to this initiative, both PvPI and IMA have agreed to celebrate a National Day of Patient Safety.8 The achievements of PvPI from 2010 to date is shown in Figure 1.

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Figure 1 Roadmap of Pharmacovigilance Programme of India

To analyse the benefit-risk ratio of marketed medicines, the Benefit-Risk Assessment Cell for drugs under the Risk Management Plan (RMP) of PvPI was recently launched as a strategic milestone to strengthen PvPI’s initiatives.9 The scope of PV, which is currently restricted to data collection and analysis on ADRs, is also soon expected to include pharmacogenomics as a part of the scientific component of PvPI, with the aid of the Indian Council of Medical Research(ICMR).10 The active functioning of the Signal Review Panel (SRP) under the PvPI program deserves appreciation as this apprises CDSCO about the signals generated and empowers CDSCO with evidence required to request drug manufacturers to make label changes. It is of relevance to remark that CDSCO’s March 2016 Gazette notification refers to the updates in Schedule Y, which has brought in a legal obligation for the pharmaceutical companies to have a PV system in place with qualified personnel for collecting, processing and forwarding the reports to the licensing authority for information on ADRs emerging from the use of the drug manufactured or marketed by them. It is now necessary for pharmacists to be available in every district hospital to ensure the monitoring of ADRs, which distinctly helps in boosting PvPI’s progress. India’s sustained commitment to patient safety is also palpable from the approval of the Health Ministry to begin the ‘Materio Vigilance Programme of India’ (MvPI) in March 2015 on the lines of similar programmes for Biovigilance and Haemovigilance, which were launched earlier in 2012.

India is likely to be among the top three pharmaceutical markets by incremental growth and the sixth largest market globally in 2020, and has been steadily evolving into one of the world’s most important pharmaceutical centres for clinical trials and research & development. It is worth mentioning that the PV outsourcing industry in India has grown by leaps and bounds in the past decade, with the number of PV professionals in the country amounting to almost 20,000 people. The talent pool in India has attracted global pharmaceutical companies, encouraging them to establish huge PV hubs to run their mainstream global PV activities, ranging from basic case processing activities to complex functions such as signal detection and analysis. The spectrum of PV capabilities available in India has expanded as expected and there is a need for interlinking the thinking of various stakeholders, who could devise an integrated multi-disciplinary approach in PV. The symbiosis of global talents available in the Indian pharmaceutical industry, professional bodies, academia and all other healthcare sectors, with the CDSCO/PvPI, under a common cause will be fruitful and could pave the way towards harmonisation and capacity building in the discipline. Some professional associations such as the Indian Society for Clinical Research (ISCR) have been vocal and proactive in offering their support to the PvPI through their PV Council. The two way communication between PvPI and statutory councils, professional societies, groups with mandates and industry associations has helped in sorting out various teething problems in integrating the flow of ADRs from various sources. The research and development initiatives by ICMR, Council of Scientific & Industrial Research (CSIR), Central Drug Research Institute (CDRI), The Society of Pharmacovigilance, India (SoPI), etc, have facilitated the support for the growth of PvPI. The imminent plan at the global level for the PvPI is to reinforce the collaboration with the WHO, UMC and harmonisation with the South Asian Association for Regional Cooperation nations (SAARC).11

To advance PV practices in India, it is now essential that the country undergoes a major transformation in its healthcare sector, putting patient safety at the forefront. India is keen to adopt the Internet of Things (IoT), with cloud-based apps that will bring efficiency and transparency in real-time with the active support of electronics, software and communication networks. India will need to develop specific national current reporting rate graphics and there is a pressing need for a country specific database for the public and a restructured online platform for doctors, to provide better awareness of drugs and their adverse effects. For PV as a practice to be inculcated, India needs to formulate standard guidelines, similar to European Medicines Agency’s Good Pharmacovigilance Practices (GVP), to ensure patient safety. With the intention of streamlining PV practices without compromising on patient safety, the European Medicines Agency's (EMA) RMPs, signal detection, concepts of Qualified Person for Pharmacovigilance (QPPV), the Marketing Authorisation Holder (MAH) paying the EMA for review of the submitted reports could be adopted. The EMA’s Medical Literature Monitoring Service (MLM) has become a hot topic of discussion in countries where PV responsibilities are emerging, since it is evident that literature cases contribute to a great extent to the volume of spontaneous cases. Adopting a system similar to the MLM could be an effective way of identifying ADRs in countries like India where pharmacovigilance is emerging, but the market is subjugated by drug manufacturers or distributors who may not have enough resources to perform literature searches. I hope that this article has given the reader an insight into where I think PV in India has come from and where it needs to go to be on par with global standards of drug safety.

References

(1) www.ipc.gov.in/PvPI/20.%20Pharmacovigilance%20programme%20for%20India.pdf
(2) http://ipc.nic.in/writereaddata/linkimages/PDF%20PV%20Toolkit-1898248681.pdf
(3) http://ipc.nic.in/writereaddata/mainlinkFile/File398.pdf
(4) Kalaiselvan V, Kumar R, Thota P, Tripathi A, and Singh GN. Status of documentation grading and completeness score for Indian individual case safety reports. IndJPharmacol2015; 47(3): 325–327.
(5) http://pib.nic.in/newsite/PrintRelease.aspx?relid=130201
(6) http://www.cdsco.nic.in/writereaddata/newMinutes%20of%2068th%20DTAB%20meeting.pdf
(7) http://www.pharmabiz.com/NewsDetails.aspx?aid=93772&sid=1
(8) www.pharmabiz.com/PrintArticle.aspx?aid=93462&sid=1
(9) http://pharmabiz.com/ArticleDetails.aspx?aid=93612&sid=1
(10) http://pharmabiz.com/ArticleDetails.aspx?aid=92820&sid=1
(11) www.pharmabiz.com/NewsDetails.aspx?aid=92775&sid=1

List of Figures

Fig 1 Roadmap of Pharmacovigilance Programme of India


EU Qualified Persons for Pharmacovigilance (QPPV); oversight, roles and responsibilities

Dr Asad Khan MFPM
Editor of the Newsletter

EU Qualified Persons for Pharmacovigilance (QPPVs) are a vital part of European pharmaceutical organisations, as they are responsible for the establishment and maintenance of the Marketing Authorisation Holders’ (MAH) pharmacovigilance systems, as described in the Pharmacovigilance System Master Files (PSMF). Such pharmacovigilance systems aim to fulfil an organisation’s legal tasks and responsibilities in relation to pharmacovigilance (PV) and are designed to monitor the safety of authorised medicinal products and to detect any changes to their benefit-risk balance. QPPVs and Safety teams interact with virtually all departments and functions within a company, as can be seen from Figure 1.

Figure 1: Interactions and interfaces of QPPVs and other departments / functions (Adapted from reference 6)

The key tasks, duties, interactions and interfaces of a QPPV with different departments and functions both within and outside a pharmaceutical organisation are summarised below:

1. Safety related activities

The EU Regulations require QPPVs to have sufficient authority to influence the performance of the pharmacovigilance activities and the quality systems of the MAHs. The said regulations also place an obligation on the MAHs to make available adequate structures, systems and processes, in order to ensure that QPPVs are able to carry out these important responsibilities. QPPVs should therefore be provided with full access to the PSMF as well as complete authority over these, and should be promptly notified of any changes to these files. The QPPVs should have full oversight of all the safety related processes and procedures which the MAH has in place at every level in order to ensure consistency and compliance across the organisation, for e.g. full overview of safety profiles of the medicinal product(s) including emerging safety concerns, benefit-risk evaluation, adverse reaction collection and reporting, provision of any safety information to the Competent Authorities, safety information from external and internal sources, contractual agreements, outsourcing of PV related activities, Periodic Safety Update Reports (PSURs) / Periodic benefit-risk evaluation report (PBRER) preparation and submission, marketing conditions and obligations, signalling activities and compliance metrics.

2. Risk management activities

It is vital that QPPVs should have sufficient authority over the content of risk management plans and risk minimisation measures and activities. Metrics from ‘Process’ and ‘Outcome’ indicators evaluating the effectiveness of risk management activities should be routinely reviewed by QPPVs to ensure that such activities and measures can be fine-tuned, modified and adjusted in a timely manner so that their objectives can be achieved.

3. Regulatory affairs activities

The interactions and interfaces between QPPV and Regulatory Affairs are extensive and last throughout the life cycle of medicinal products. These can be grouped as follows:

  • Safety variations and urgent safety restrictions
  • Responses to requests for safety information from regulatory authorities
  • Post-marketing commitments
  • Periodic safety reports (PSURs / PBRERs)
  • Product Labelling (summary of product characteristics (SPCs) / patient information leaflets (PILs))
  • Preparation of Marketing Authorisation submissions
  • Worldwide marketing authorisation status (approvals, divestments, acquisitions and changes to marketing authorisation of already existing medicinal products)

4. Medical information activities

Directive 2001/83/EC requires MAHs to have a medical information service about medicinal products that they have placed on the market. Such a service, being a company’s key interface with healthcare professionals, patients and the general public, is likely to receive a large proportion of adverse events (AEs) and other safety related information. It is, therefore, essential that the individuals working in such services are kept informed of the QPPVs, essential safety procedures, personnel and safety information so that key safety information is not only relayed both ways within the company but also externally.

5. Training activities

All product (and in some instances, non-product) and PV training material for internal and external stakeholders should be routinely validated by the QPPV. In addition, QPPVs should have an oversight of the training plans, electronic training systems and new entrants to the organisations, including contractors.

6. Quality assurance / Audit

The responsibility for the pharmacovigilance system means that the QPPV has oversight of the functioning of the system in all relevant aspects, including its quality system. The QPPV should be kept informed of scheduled pharmacovigilance audits and should be able to trigger an audit where appropriate. The QPPV should be provided with a copy of the corrective and preventative action plan (CAPA) following each audit. The QPPV should have an awareness of the quality control (QC) procedures that are used for key pharmacovigilance activities, for e.g. case processing and PSUR production. These procedures should be finalised with an input from the QPPV and must be adequately documented. Procedures and systems should also be implemented ensuring the necessary quality, including the correctness and completeness, of pharmacovigilance data submitted to the competent authorities in Member States and the EMA. The QPPV should be consulted in finalising these.

7. Clinical development and Medical affairs

QPPVs should be involved in the review and sign-off of protocols of post-authorisation safety studies (PASS) conducted in the EU or pursuant to a risk management plan agreed in the EU. QPPVs should also be kept informed of the emerging safety concerns and any other information relating to the evaluation of benefits and risks. This includes relevant information from the clinical trials e.g. recommendations from clinical trials safety monitoring boards that may have implications for the use of the products in authorised indications. Clinical trials Annual Safety Reports (ASRs) and Clinical Study Reports (CSRs) should also be promptly communicated to the QPPVs. Information about Phase IV Investigator Initiator Trials, non-interventional studies (NISs) and other Epidemiology / Observational studies should be made available to the QPPVs and any emerging safety concerns be promptly communicated.

8. Commercial / New business development

The QPPV should be promptly informed of the below so that the potential impact on the pharmacovigilance system can be assessed and the system be adapted accordingly:

  • Acquisition of another company
  • Purchasing individual products
  • Establishing a partnership with another MAH, organisation or person that has a direct or indirect impact on the pharmacovigilance system

The QPPV should be made aware of the sections of the contractual arrangements that relate to responsibilities for pharmacovigilance activities and safety data exchange and have the authority to request amendments.

References:

(1) Directive 2001/83/EC of the European Parliament and of the Council. Articles 1, 21a, 22, 22a, 28 c, 28 d, 98, 106(c) 104(3)(a), Art 1(28d), available at http://ec.europa.eu/health/files/eudralex/vol- 1/dir_2001_83_cons/dir2001_83_cons_20081230_en.pdf
(2) European Medicines Agency. Guideline on good pharmacovigilance practices (GVP) Module II – Pharmacovigilance system master file (Rev 1), EMA/816573/2011 Rev 1, 9 April 2013, available at http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2012/06/WC500129133.pdf
(3) The European Parliament and The EU Council. Regulation (EC) No 726/2004, Laying down Community procedures for the authorisation and supervision of medicinal products for human and veterinary use and establishing a European Medicines Agency, of 31 March 2004, Art 10(2), available at http://eur-ex.europa.eu/LexUriServ/LexUriServ.do?uri=OJ:L:2004:136:0001:0033:en:PDF
(4) European Medicines Agency. Guideline on good pharmacovigilance practices (GVP) Module I – Pharmacovigilance systems and their quality systems, EMA/541760/2011, 22 June 2012, available at http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2012/06/WC500129132.pdf
(5) European Medicines Agency.Guideline on good pharmacovigilance practices (GVP) Module V – Risk management systems (Rev 1), EMA/838713/2011 Rev 1, 15 April 2014, available at http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2012/06/WC500129134.pdf
(6) MHRA. Good Pharmacovigilance Practice Guide (The Purple Guide). Edition 2009, The Pharmaceutical Press.
(7) European Medicines Agency. Questions and answers on the risk management plan (RMP) summary, EMA/156738/2014. 5 May 2014, available at http://www.ema.europa.eu/docs/en_GB/document_library/Other/2014/05/WC500166101.pdf
(8) European Medicines Agency. Guideline on good pharmacovigilance practices (GVP)
Module XVI– Risk minimisation measures: selection of tools and effectiveness indicators (Rev 1), 15 April 2014, EMA/204715/2012 Rev 1*, available at http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2014/02/WC500162051.pdf