Facultades Particulares

Part II - Development of the Benefit-Risk Template

The importance of communication between companies and agencies is frequently highlighted. There is also a need for a better understanding of why different agencies come to different conclusions when faced with essentially the same application data.

Improved transparency is required as both companies and agencies hold different skillsets and interpret efficacy and safety information differently. There is further pressure on agencies to increase transparency and accountability and to establish an appropriate documentation system for the basis of their decisions. It was therefore important to have a document that enables the effective communication of benefit-risk information amongst stakeholders in addition to having a universal framework for the assessment of benefits and risks. The communication of risks without the communication of benefits may serve to undermine public discourse and for this purpose, a template was proposed to be used in accordance with the principles outlined in the universal framework.

The Centre for Innovation in Regulatory Science had identified the need for a template to be used in conjunction with their 7-step framework for the assessment of benefits and risks. They searched for a guidance document for the assessment of benefits and risks of medicines, which led to the identification of the published reflection paper by EMA (EMA, 2008). In the absence of the principles and methodologies for benefit-risk assessment from other major regulatory authorities, there would be issues of consistency, transparency and communication of the outcomes of assessment and the basis of decisions. Hence EMA undertook the task of revising the CHMP assessment report templates and incorporating a structured list of benefit and risk criteria.

In order to recognise demonstrated benefits, important results should be critically assessed and the unresolved issues or uncertainties be identified (Table 4.9). For the assessment of safety (Table 4.10), important non-clinical and clinical findings should be discussed with the background of potential pharmacokinetic and pharmaco

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dynamic interactions, the potential for overdose or for abuse, as well as the misuse and off-label use of the medicine. The extent of the contribution to the risk should also be stated.

Table 4.9 EMA criteria for assessing efficacy

1. Efficacy (primary endpoint) versus comparator and its clinical relevance 2. Magnitude of treatment effect

3. Clinical relevance of the primary endpoints 4. Statistical significance of the efficacy results

5. Representiveness of the studied population for the population targeted in the label 6. Discussion of dose

7. Evidence for the efficacy in relative subgroups 8. Design conduct and statistical adequacy of the trial

9. Confirmation of treatment effect by results of non-primary endpoints 10. Validation of scales and outcome measures

11. Patient preferred outcomes

12. Confirmation of efficacy by results of relevant non-pivotal trials and extensions 13. Anticipated patient compliance (and patient convenience)

14. Clustering (consistency) of results of the pivotal trials

Table 4.10 EMA criteria for assessing harms

1. Overall incidence of adverse effects (from clinical trials) 2. Overall incidence of serious adverse effects (from clinical trials 3. Discontinuation rate due to adverse effects (from clinical trials)

4. Incidence, seriousness and duration of specific adverse effects (from clinical trials and post-marketing surveillance)

5. Interaction with other drugs and food 6. Safety in subgroups (e.g. race and sex)

7. Potential for off label use leading to safety hazards

8. Potential for non-demonstrated additional risk due to limitations of clinical trials and/or short market exposure.

9. Potential for non-demonstrated additional risk due to safety issues observed in pre-clinical safety studies but not in humans

10. Potential for non-demonstrated additional risk due to safety issues observed with other medicines of the same pharmacological class

In determining the benefit-risk balance (Table 4.11), EMA decided that this should be put in perspective regarding alternative therapies or interventions (where possible and relevant) and to conclude as to whether the benefit-risk balance is positive in the specified target population. The evaluation of the balance should also take into account the observed benefits and harms as well as the uncertainties and risks. The perspectives of different stakeholders should be taken into account in the assessment of the benefit-risk balance, in particular the perspectives of patients and prescribing physicians.

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Table 4.11 Criteria for assessing benefit-risk balance

• Amount of evidence to characterise the benefit-risk balance:

o Availability of comparative data and their limitations and potential deficiencies

• Interpret key benefits and risks

o from perspectives of different stakeholders, including patients and treating physicians

• Level of risk acceptability

o corresponding to the perceived degree of clinical benefit in the specific context

• Relating the benefits to the risks when possible:

o Using logical comparisons e.g. potential lives saved as a result of treatment compared to potential lives lost as a result of adverse reactions

• Factors affecting the benefit-risk balance:

o Situations that may alter the current balance e.g. different patient or disease characteristics

• Sensitivity of the benefit-risk balance:

o Discussion of the potential changes to the balance if the fundamental assumptions are to be amended

• Other appropriate discussions:

o Effectiveness of proposed treatment compared to available options

o For negative benefit-risk balance, describe the potential harm incurred upon exposure for the claimed indication

o Evolution of benefit-risk balance over time

o Outstanding issues, submission or reports to address identified issues

o Evaluation of pharmacovigilance plan, risk mitigation plan or other post-marketing commitments including need for further studies

o Opinions from scientific experts, patients, consumers or advocates and other stakeholders in the benefit-risk assessments

• Conclusion on the benefit-risk being positive or not for every claimed indication.

*adapted from EMA reflection paper

A workshop was conducted by CIRS to seek opinions on the use of the EMA’s criteria in the reflection paper and these were deemed appropriate in the absence of other authoritative guidance. Therefore, a developmental version of the template based on the criteria from the EMA reflection paper was produced by CIRS.

The developmental version was in Microsoft Word format and was tested for functionality by the Consortium. This was carried out as a retrospective feasibility study between two pairs of agencies, with each pair testing the template on a

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common product. Major amendments to the developmental version included the addition of an overall summary, inclusion of summaries of relevant non-clinical, quality and clinical findings and changes to the presentation of study results. Other changes were made at the suggestion of the Consortium to improve user experiences and included functional tabs at the top of each page and an active content page that linked directly to the corresponding sections of the template.

The second version of the template was again subjected to evaluation by the Consortium. It was in an active PDF format to facilitate the user experience. This phase was conducted as a retrospective exercise using a product submitted for review to all four partner agencies. A new section 6 for visualisation was included at the suggestion of the Consortium, which would further align the template with the universal framework. There were no other major changes, and amendments were made to improve user experience (functional icons to print, email and view the template). Hence the final version of the template consisted of two sections, namely the “Proforma” and “Benefit-risk summary” (Table 4.12). The final template, namely the Benefit-Risk Template or BR Template, is attached as Appendix I.

The potential use of the BR Template was reviewed as to whether this would be able to fulfil the core elements of the universal framework, namely framing the decision (section 1), identifying the benefits and risks (section 2 and 3), assessing benefits and risks (section 4), interpretation (section 5) and recommendations (section 6). In relating to the universal framework, this template fully supports these requirements (Table 4.13).