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One Framework to Rule them All

For many years, the area of benefit–risk assessment of pharmaceutical products was almost a taboo – there was no transparency, no audit trail, and no systematic approach. Compared with 15 years ago, there is now a more systematic approach being taken in many regulatory agencies. High-profile tragedies involving approved drugs, such as Vioxx, have led to revised legislation and a new emphasis on benefit–risk assessment. But there are still many regions where these complex decisions come down to a single individual. We did a survey as recently as 2013 to find out whether regulators were using any specific criteria/model when assessing benefit and risk – we found that qualitative approaches still dominate (1).

The thrust of my work over the past decade has been promoting more collaborative decision making, based on a systematic, transparent process. Nine years ago, my collaborators and I proposed a quantitative model, starting a debate about benefit–risk assessment of medicines that led to a consultation paper from the EMA in support of our model. Around the globe, regulatory authorities have been debating the issues, and we have been invited to take part in many of these internal discussions.

Opening the dialog with regulators and pharmaceutical companies has been tremendously valuable in itself. But while our original model was very thorough, its mathematical complexity meant that it was only likely to be used by the most sophisticated regulatory bodies – and then only in a handful of the most challenging decisions. We wanted to create a framework that could be used globally – a common language.

High-profile tragedies involving approved drugs, such as Vioxx, have led to revised legislation and a new emphasis on benefit–risk assessment.

Our recently published “universal framework” was designed for this purpose (2). It is a streamlined, semi-quantitative framework that can be easily integrated into the assessment processes of pharmaceutical companies and regulators worldwide. The framework was developed in collaboration with regulatory authorities in Australia, Singapore, Canada, UK and Europe. It looked good on paper, but to be sure of its practical value, regulators tested the model as part of their routine assessment of pharmaceutical products. It proved to be a very robust, user-friendly and relevant tool. In case studies and retrospective analyses of past approvals, the framework has often uncovered new issues, which in some cases could well have led to a different decision.

Another important issue that we hope this framework will address is the discordance between the decisions made on the same drug in different parts of the world. There are long waits for patients in some countries to get a drug that may have been approved months or years earlier in another region. In some respects, the gap is widening between the mature regulatory authorities in countries like the US, Europe, Australia, and those in emerging economies, with potentially life-saving drugs taking months or years to reach poorer nations, even aside from the affordability issues they present.

The framework lays out eight key steps to make an informed decision based on an impartial assessment of the benefits and risks, applicable for any product, in any part of the world.

  1. Determine the decision context
  2. Build a value tree
  3. Refine the value tree
  4. Look at the relative importance of benefits and risks
  5. Evaluate the options available to you
  6. Evaluate the level of uncertainty
  7.  Summarize the results, preferably involving visualization
  8. Communicate the results to relevant stakeholders

The resulting documentation includes background information on the product, summaries of the non-clinical, pharmacological and clinical study results, identification of the benefits and risks, the criteria considered and a clear conclusion. It is worth highlighting the importance of visualizing the results of the assessment using graphs, such as forest plots. Graphical information is much easier for people to absorb, and a key component of the framework is its transparency.

The time has come for pharmaceutical and regulatory professionals around the world to speak the same language.

Like any such system, the universal framework will be most valuable in situations where the risks are high and the benefit–risk trade-off is not clear cut. Consider a drug for migraine headache with a number of serious potential side effects. Migraines are not life-threatening, but can be very debilitating – for example, a surgeon who develops severe migraines may be forced to abandon their career for fear of putting patients at risk. By using a framework like ours, regulators can take into account the minutiae of the benefits and risks and make an informed decision.

The time has come for pharmaceutical and regulatory professionals around the world to speak the same language. By increasing communication and exploring joint review of pharmaceutical products, we could save time and money and, most importantly, improve access to medicines worldwide.

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  1. J. Leong et al, “Is There a Need for a Universal Benefit-Risk Assessment Framework for Medicines? Regulatory and Industry Perspectives”, Pharmacoepidemiol. Drug Saf. 22(9), 1004–1012 (2013).
  2. J. Leong, S. Salek and S. Walker, “Benefit-Risk Assessment of Medicines”, Springer (2015).
About the Author
Sam Salek

Sam Salek is Professor and Chair, Pharmacoepidemiology, University of Hertfordshire, UK.

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