Solving the global benefit-risk assessment dilemma

Professor Sam Salek, School of Medical and Life Sciences, University of Hertfordshire, calls for a “universal framework” to speed up the disjointed decision-making process around the commissioning of new drugs

The regulation of medicines is essentially conducted to fulfil the criteria of quality, safety and efficacy. As patients are not equipped to make a scientific assessment, regulators play a crucial role in controlling access to safe and effective medicines.

Key elements highlighted by the World Health Organisation (WHO) for effective regulation of medicines include strong cooperation and collaboration between stakeholders, transparency and accountability. The latter is deemed critical for communication of the basis of decisions and building public confidence.

Despite this, there are many problems with the current regulatory system, meaning that a huge gap exists between countries when it comes to patients accessing new, potentially life-saving medicines.

The review of medicines by regulatory agencies is largely based on the submission of clinical data collected from clinical trials phases I to IV.

Assessment of the clinical efficacy of a medicine is supported by studies designed to provide a reliable conclusion through the scientific investigation of suitable endpoints, which it is expected would be translated to meaningful benefits to the patients.

However, owing to practical reasons — namely time restrictions — these measured endpoints are often surrogates of the actual clinical benefits. For example, parameters like blood pressure, cholesterol levels or microbial eradication may not actually translate to reduced cardiovascular events or a faster recovery from an infection.

To establish the utility of a medicine, trials are required to produce clinical endpoints that could directly benefit a patient, such as overall survival, reduction in hospital stay or an improved quality of life from a chronic debilitating disease.

Indeed, the definition of a benefit may differ among physicians, patients and between diseases.

This may be owing to differences in severity of the disease itself and the subjective perception of the expectations arising from the treatment.

Moreover, a benefit should also take into account the trade-off incurred from the potential adverse effects of the treatment.

As a result, a proven clinical efficacy in a study may not always translate into a benefit for the patient.

In the assessment of risk or harm, safety data is collected alongside clinical studies that are primarily designed for the purpose of proving clinical efficacy.

Given the limitations and uncertainties in confirming the individual benefits and risks to patients, it is challenging to prove the likely safety outcomes for a patient. The traditional method of assessing efficacy and safety separately cannot be logically collated to provide a balanced view.

It can be assumed that agencies go through much deliberation on the trade-offs between the benefits and risks, but these are generally not documented or made known to the public. 

It has therefore been emphasised by the major regulatory agencies that qualitative evaluation and expert judgment should not be replaced by quantitative benefit-risk assessment. Instead they recommended that a model for benefit-risk assessment should be structured, of a qualitative approach and be able to describe explicitly the importance of benefits and risks in the context of the decision.

Though stakeholders acknowledge that a universal framework would provide a structure and consistency in decision-making, their efforts in achieving this have largely been independent.

There is no common framework, which as a result compromises the consistency of the assessment of benefits and risks and decision-making. The lack of such a system could in turn result in inconsistency in approval of new medicines, making them available to patients in some parts of the worlds and denying them in others.

There is now a need to identify a common framework that can be used by both regulatory agencies and pharmaceutical companies to improve communication to stakeholders and overcome the difficulty faced by agencies and companies when it comes to explaining the outcomes of the assessment.