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European Pharmaceutical Contractor

Worth the Risk?

“Some benefits are not worth the risk, and some risks are worth taking” (1). This certainly applies to pharmacovigilance. In an authorised product, there is usually an implicit understanding by the consumer that the benefit/risk profile of a product is positive. Or should that be a misunderstanding?

For many patients, the approval and availability of a medicinal product carries a perception of no associated risk. However, at the point of marketing approval, many risks will not have been detected due to the inherent, exclusive nature of clinical trials that have the power to only detect more common adverse events.

There are also huge challenges in the differences in perception between the public and healthcare professionals (HCPs). For example, Patient A presents to his physician with severe rheumatoid arthritis (RA), having failed with previous disease-modifying anti-rheumatic drug therapies, and the physician determines that treatment with a monoclonal antibody is appropriate. Patient B presents to his physician with moderate to severe plaque psoriasis, and his physician determines that the addition of the same monoclonal antibody is indicated.

Both patients are prescribed the same product. Assuming all other factors are equal – for example, comorbid conditions and concomitant medications – is the benefit/risk to the psoriasis patient the same as the benefit/risk for the RA patient? This depends on the HCP perception versus that of the patient.

The ability to educate patients through risk communication is often poorly and inconsistently applied. Communications about the safety of medicines are complex and generally poorly performed. Discussions may not be initiated by HCPs and the lack of a ‘common language’ to express risk can cause confusion. In the event of a serious adverse drug reaction, prior failures in communication can cause difficulties, and patients may fail to receive adequate information about the nature of their experience (2).

European and US Regulation

It is clearly time to implement mandatory reporting of adverse drug reactions by HCPs, and to make product information available on the internet which is free from commercial information and accessible to all patients in all countries in which the product is marketed. However, the solution is not as simple as it may at first seem.

Current regulatory guidelines related to pharmaceutical risk minimisation put most emphasis on risk communication and control of the use of drugs. Little, if any, consideration is given to those aspects of an adverse drug reaction that ultimately determine whether the risk can be minimised (3).

Risk management activities now taking shape, such as the development of a European Union (EU) Risk Management Plan (RMP) and/or a US Food and Drug Administration (FDA) Risk Evaluation and Mitigation Strategy (REMS), will establish a more proactive approach to learn and confirm cycles through the drug lifespan. However, there will be a need for conducting repetitive benefit/ risk assessments.

The context of a benefit/risk evaluation should consider medical needs and alternatives. Each indication and population should be considered in the context of use/key benefits and risks driving the evaluation, and the methodology should be clear and succinct.

The new periodic benefit-risk evaluation report – introduced in the EU in July 2012 as the result of the European Medicines Agency (EMA) guidance on good pharmacovigilance practices – has the mindset of cumulative benefit/risk evaluation, rather than an interval safety review. Local government regulations within Europe limit the access by patients to medicinal product information, although the advent of publishing the RMP on the EMA portal will improve patient education.

Balanced Information

It is important to realise that what the marketing authorisation holder (MAH) can communicate about benefits and risks is strongly influenced by the obligations of companies to the market and investors (4). In the US, the FDA permits the development of a productspecific website. Significant safety risks must be readily available on the site, but these sites are often clouded by commercial activities.

Although the MAH provides patient information leaflets and medication guides, this is done after the decision to treat has been made and the product has been dispensed to the patient. The decision to treat by the patient should occur before the dispensing process using information about the current risks in an uncluttered, understandable and non-commercial format.

Pharmaceutical websites are unlikely to completely communicate risk information (5), so it may be time to consider social media as a tool for HCPs to communicate this information to patients. In order to promote more balanced coverage and avoid unnecessary scares, professionals working in drug safety should rethink their strategies for this. There is significant lack of evidence about the effectiveness of social media and the internet in communicating with patients. Part of risk management activities should include an objective, evidencebased evaluation of the effi cacy in risk communication.

Another issue is that, as studies show, on average only 5-10 per cent of actual adverse drug reactions are reported to the competent authorities. This situation must improve. Currently, HCPs, pharmacovigilance centres, poison control centres, and so on, are asked to voluntarily submit suspected adverse drug reaction information – for example, through the FDA MedWatch or the UK Medicines and Healthcare Products Regulatory Agency’s Yellow Card system. A regulatory solution should be considered, providing the burden is minimised.

Informed Choices

The advent of new EU legislation on pharmacovigilance aims to give the consumer/patient more awareness and more informed choices – and is prompting a growing openness in the communication of safety information.

Applying elements from social marketing and patient-tailored approaches to support behaviours of safe medicine use in patients and HCPs should help the pharmacovigilance community to minimise risks with medicines and improve patient safety (7). Social media can provide balanced information regarding significant safety issues, but we must be wary that any reactive and sensationalised reporting will provide little guidance to patients.

This pharmacovigilance issue is something of a double-edged sword. On the one hand, it is not uncommon for solicitors to over-report adverse drug reactions to regulatory authorities. Conversely, applying a risk mitigation strategy, such as an FDA-mandated REMS, may overwhelm the patient and reduce access to a proven therapy. As such, HCPs must be capable and willing to provide objective information to support the patient’s informed consent to initiate therapy.

Patient Participation

The EMA Human Scientific Committee’s Working Party with Patients and Consumers Organisations (PCWP) was established in 2005 to provide recommendations to the EMA on all matters of direct or indirect interest to patients in relation to medicinal products. In January 2006, the PCWP consisted of 10 consumer and patient organisations; this number has now grown to 15.

Involvement includes assisting with the preparation of communication material, as well as disseminating information after publication. Patients and consumers are systematically invited to participate whenever the agency prepares communications on emerging safety issues addressed to patients/consumers, or when they have been previously involved in the product’s benefit/risk evaluation. In fact, patients have been involved in several safety communications over drugs such as Viracept and Tysabri.

The rights of the patient/consumer is very much the priority. It is recognised that there are currently health inequalities in access to care and in particular to newly marketed medicinal products – and the aim is to have ‘empowered patients’ with healthy lifestyles who are not discriminated against. Continued dialogue with patient and healthcare organisations is central to achieving this.

A PCWP survey carried out in 2009 revealed a need to communicate benefits and risks together; to give a clear description of both qualitative and quantitative aspects; and to identify factors which may influence a benefit or a risk in an individual. Areas for improvement were identified for the summary of product characteristics, labelling and the package leaflet; the public assessment report; and product safety announcements.

Both RMP and REMS provide positive guidance for identification, monitoring and minimisation of risk to patient safety. However, at present, neither the EU nor the FDA provides specific guidance on how risk should be related to benefit either qualitatively or quantitatively (8). When outcomes from these programmes are evaluated, compliance falls below 50 per cent.

The EMA and FDA are instigating measures to begin an overall evaluation of safety and the benefit/risk profile. Mandatory reporting by all stakeholders is required. Sponsors should be able to actively provide information to the patients, but the content and format must be non-commercial.

Global pharmacovigilance is growing and dynamic, and should be a ‘living’ process that is constantly reviewed, analysed and updated. In the end, the true focus of all pharmacovigilance activities is better patient focus by simply providing the patient with sufficient information to decide whether to participate in treatment.

1. Hamburg and Sharfstein, New England Journal of Medicine, 360(24): pp2,493-2,495, 2009
2. Hugman B, Protecting the people? Risk communication and the chequered history and performance of bureaucracy, Drug Saf 35(11): pp1,005-1,025, November 2012
3. Callréus T, On pharmaceutical risk minimizatiom, Drug Saf 31(9): pp737-742, 2008
4. Edwards B and Chakraborty S, Risk communication and the pharmaceutical industry: what is the reality? Drug Saf 35(11): pp1,027-1,040, November 2012
5. Davis JJ, Cross E and Crowley J, Pharmaceutical websites and the communication of risk information, J Health Commun 12(1): pp29-39, January-February 2007
6. Hirst C, Cook S, Dai W, Perez- Gutthann S and Andrews E, A call for international harmonization in therapeutic risk management, Pharmacoepidemiol Drug Saf 15(12): pp839-849; discussion pp850-851, December 2006
7. Bahri P and Harrison-Woolrych M, How to improve communication for the safe use of medicines? Discussions on social marketing and patient-tailored approaches at the annual meetings of the WHO Programme for International Drug Monitoring, Drug Saf 35(12): pp1,073- 1,079, December 2012
8. Lis Y, Roberts MH, Kamble S, J Guo J and Raisch DW, Comparisons of Food and Drug Administration and European Medicines Agency risk management implementation for recent pharmaceutical approvals: Report of the International Society for Pharmacoeconomics and outcomes research risk benefit management working group, Value in Health 15(8): pp1,108-1,118, December 2012

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Lisa Bolitho is Director of Medical and Safety Services at ICON Clinical Research and has more than 16 years of industry and pharmacovigilance experience. She was educated at Cardiff University, where she gained a BSc in Pharmacology and Therapeutics at its School of Medicine and an MSc in Clinical Research at its School of Pharmacy. Lisa began her career in drug safety at GSK and then joined Chiron Vaccines (now Novartis Vaccines) before moving to ICON in 2006.

Mark Nelson Tyrrell currently serves as Director of Drug Safety within Medical and Safety Services at ICON Clinical Research. He has 20 years of experience in drug safety, risk management and medical information in both pharmaceutical and contract research environments. Mark joined ICON in 2012, having previously served as Subject Matter Expert/Director of Global Pharmacovigilance at HCL Technologies and Director of Global Risk Management at PRA International. He holds a BSc in Pharmacy from Saint John’s University in Jamaica, New York.
Lisa Bolitho
Mark Nelson Tyrrell
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