Published: 6 December 2019


The Medsafe Files – Episode 12: Benefit-risk (of harm) review

Prescriber Update 40(4): 70–72

December 2019

Key Messages

  • Medsafe approves medicines based on a favourable balance of benefit to risk of harm for the intended treatment population. The evidence supporting this decision is outlined in the data sheet.
  • For each individual patient, the benefits and risks of harm of a medicine need to be personalised for their specific needs and circumstances to make sure the medicine is right for them.


Medsafe reviews the benefit and risk of harm of medicines at different stages of the product lifecycle. For example, the benefit-risk balance is assessed:

  • prior to approval
  • for new indications or changes to indications
  • following identification of a significant new adverse reaction
  • following identification of new information suggesting a lack of (relative) efficacy or quality issue.

Medsafe reviews the benefits and risk of harm for medicines at the population level. The benefits and risks of harm may be different for an individual considering treatment with that medicine.


The benefit of a medicine is the sum of its efficacy and the context of use. Medsafe considers the following information when assessing the benefits of a medicine.

The epidemiology and natural history of the disease targeted by the medicine

Understanding the target condition helps to put the benefits and risks of harm of a medicine into perspective. Tolerance of harm is generally greater for life-threatening conditions such as cancer than self-limiting conditions such as a cold.

The purpose or intended outcome of treatment

Treatments that can cure a disease tend to be associated with a higher harm tolerance than those that reduce the symptoms of a disease. Similarly, vaccines are generally given to healthy people and therefore must be highly effective and safe to satisfy regulatory requirements.

The evidence for benefits

The efficacy of the medicine is a major consideration. The strength of the evidence is a significant part of the evaluation and Medsafe looks at not just the quality of the clinical trial(s) but also the choice of endpoints (outcomes or surrogate markers), the absolute effect of the intervention and its comparison to the background rate of remission for that condition, placebo effects and other interventions (if that data is available).

Also important are quality of life measures and patient views on acceptability and tolerability.

The generalisability of the clinical trial results may be reflected in the approved indication. Indications for medicines when the trials involved very specific patient groups will often restrict use to these groups.

For reviews taking place after the medicine has been approved and used in non-clinical trial populations, data on effectiveness (ie, the benefit in real world use) and comparison with other treatments will also be considered.

Risk of harm

When assessing the risk of harm both the frequency and severity of the harm are considered.

The strength of the evidence for the adverse reaction

During the pre-market approval phase this will generally be the information generated in the clinical trials. The collection of safety information in trials may be driven by prior knowledge of other medicines in the same class, pharmacokinetics, pharmacodynamics and pre-clinical information.

Once the medicine has been approved, additional information becomes available – for example, from case reports and observational studies – enabling the identification of rarer side effects.

Identification of the reaction(s) which are the risk driver(s)

For most medicines there are one or two reactions that have the greatest impact on the balance of benefits and harms. Examples of reactions considered to be risk drivers include: liver toxicity, renal toxicity, haematological toxicity, malignancy, QT-prolongation, and Serious Cutaneous Adverse Reactions (SCAR). A change in the frequency or seriousness/severity of these reactions is likely to prompt a risk benefit review.

Nature of the reaction

The ability to predict and therefore prevent an adverse reaction is an important consideration. If it is possible to predict a reaction by monitoring factors such as white cell count, the risk may be considered acceptable. These factors are often described in the contraindications or warnings in the data sheet.

Other reactions may be reversible on stopping the medicine or be treatable, and again this will influence their importance relative to the benefits of the medicine. Other reactions may be viewed as more minor or rare enough not to impact the benefit-risk balance.

Risk comparison

It may be possible and appropriate to compare the risks of harm of a medicine with the risks of other medicines used to treat the same condition, as well as the potential effects of not treating the condition.

Risk quantification

The frequency of a reaction may be estimated in clinical trials. However, this can be harder for rarer events only detected once the medicine is in use. When a frequency estimate can be made this is detailed in the data sheet. A change in the frequency of significant reactions can impact the benefit-risk balance and it is important therefore to study the safety of medicines throughout their life cycle.

Overall conclusions on benefit risk

The benefit-risk balance cannot be expressed as a number because while some of the considerations are quantitative, others are qualitative. The unit of measurement differs between benefit and risk. In particular, long-term benefits may have to be weighed against short term risks or vice versa. The tolerance for risk will also differ according to the expected benefit of the medicine. Therefore, concluding whether the benefits outweigh the risks of harm for a medicine comes down to a value judgement. Decision making tools can be useful to identify how different value judgements may influence the interpretation of the benefits and risks. Where a medicine has more than one indication, the benefit-risk balance is likely to be different for each indication and depends on its context of use.

Other factors that may be considered by the regulator are the ability to impose risk management strategies such as regular blood monitoring or pregnancy prevention programmes, and the statutory power of the regulator.

What about individual patients?

The acceptability of a medicine for an individual patient will depend upon their personal objectives and lifestyle. Therefore, patients need to be involved in the decision-making process.

When considering harm from the patient perspective, drawbacks such as any requirement for routine monitoring or dietary precautions should also be discussed. The route of administration may be unacceptable, or the patient may have difficulties understanding complex administration instructions.

The applicability of the clinical trial benefits will depend on how closely the patient fits the trial inclusion and exclusion criteria. The patient may be in a known higher risk group for harms or may be taking other medicines or natural health products that may interact to cause harm.

When discussing the evidence for benefit and harm, the data should be communicated in a transparent way. Explaining the change of benefit may be best understood using the number of patients needed to treat. Explaining risk may need to include the risk of harm and the risk of not having the reaction. For example, 1 in 10 people who take this medicine experience a headache; 9 in 10 people who take this medicine do not experience a headache. The decision to take the medicine is essentially a gamble by the patient as to whether they will be in the group who will the experience the benefit and/or harm. Different patients will have different views on the acceptability of this gamble.

The benefit-risk balance can change over time and the use of medicines should be reassessed periodically and discussed with the patient. Some medicines are known to have a different benefit-risk balance in patients with particular genetic profiles. For example, patients with HLA-B*57;01 should not take abacavir3.

Further reading

  1. CIOMS Working Group IV. 1998. Benefit-Risk Balance for Marketed drugs: Evaluating Safety Signals. Switzerland: Council for International Organizations of Medical Sciences (CIOMS). Available at:
  2. Mussen F, Salek S, Walker S. 2009. Benefit-Risk Appraisal of Medicines: A Systematic Approach to Decision-Making. UK: Wiley-Blackwell.
  3. Medsafe. 2018. Pharmacogenomics – helps reduce rash decisions. Prescriber Update 39(2): 25–7. URL: (accessed 22 October 2019).
Hide menus
Show menus
0 1 2 4 5 6 7 9 [ /