Benefit-Risk Evaluation

This content was archived on June 24, 2013.

• A Tiered Approach to an Enhanced Scope for Safety, Efficacy, and Quality Evidence
• Goals of a New Approach to Benefit-Risk

The scientific standard of evidence for safety and efficacy to support market authorization of a drug requires positive, validated outcomes from adequate, randomized, and controlled clinical studies. These studies involve large groups of test patients in trials designed according to accepted standards. The results are extrapolated to the general population and communicated through drug labelling. The controlled nature of this type of trial design reflects fundamental aspects of the scientific method to test cause and effect.

A Tiered Approach to an Enhanced Scope for Safety, Efficacy, and Quality Evidence

A marketing standard based on a tiered approach to the evidence is proposed. This standard would continue to require, as the first tier of evidence, the traditional, scientifically accepted, foundational evidence of safety, efficacy, and quality for a drug under the proposed conditions of use. It would also superimpose an express requirement for a second tier of evidence demonstrating an overall favourable benefit-risk balance.

Benefit-risk evaluation is founded on scientific evidence of safety and efficacy, but also encompasses a larger scope of contributing circumstances. The broader issues that factor into the second tier of evidence can fall into the following general categories:

• benefit-risk issues that provide a more complete perspective on the safety, efficacy, and quality of a drug and its potential clinical utility; and
• Higher-level benefit-risk matters related to public health and individual health, including societal, ethical, or constitutional considerations.

Examples of these benefit-risk considerations can include

• the availability and performance of other therapies;
• domestic and international clinical practice environments;
• anticipated patterns of use that may lie outside the conditions of use studied in pre-market trials, including duration, real-world target populations, indication, and dosing;
• anticipated manageability of risks, including potential therapeutic impact of remaining uncertainties about the drug;
• the seriousness of the disease or condition for which the drug is proposed to be used;
• the nature of the target population and whether it includes vulnerable populations, such as children and the elderly;
• patient or consumer access issues to the drug in the pre-market environment;
• the ability to conduct randomized controlled clinical trials for scientific, logistical, or ethical reasons; and
• risk or uncertainty acceptance by decision makers outside the federal regulatory authority.

Health Canada attempts to consider many of these factors in assessing drugs. However, with assessment focused narrowly on safety, efficacy, and quality, benefit-risk assessment is not well supported within the current regulatory structure. Although a number of methodologies have been developed for benefit-risk assessment, there is no generally accepted standard for determining the benefit-risk profile of a new drug.

See also the discussion paper, Evidence Standards for New Drug Marketing Approval.

Goals of a New Approach to Benefit-Risk

A progressive licensing framework would continue to require substantial evidence for safety, efficacy, and quality, but also would incorporate other kinds of evidence for a full benefit-risk evaluation. The new standard would remain evidence based while accommodating broader considerations about the acceptability of a drug for the marketplace. The new standard would clarify the basis upon which decisions are made. Formalizing the application of benefit-risk concepts to the pre-market and post-market licensing standard would establish a single and stable standard reflecting a life cycle approach to drug regulation.

Maintenance of market authorization could require a continuing favourable benefit-risk profile for the authorized conditions of use throughout the drug's life cycle. The favourable benefit-risk profile would be based on the same elements required for initial market authorization, with some possible additions.

There would be circumstances allowing a drug to depart initially from the first tier of evidence for safety and efficacy, recognising the overall requirement for a favourable benefit-risk profile based on exceptional drivers for initial market authorization. In such situations, there would be a requirement for an evidence-based, compelling and broadly accepted case that the potential benefits of bringing a drug to market outweigh uncertainties regarding safety and efficacy. The intention of the new model is to provide a rigorous framework for the consideration of flexibility in achieving evidence of safety and efficacy for drugs with exceptional benefit-risk profiles so that

• the best proven methods and techniques for gathering evidence are adopted across a drug's life cycle and as drug development technologies mature;
• the global nature of drug development and regulation can be taken into account; and
• critical Canadian decision makers can exert influence over the process.

There have been widespread calls for greater involvement of decision makers beyond the federal regulator and the industry in the drug regulatory process. Expanding the benefit and risk concepts beyond the core efficacy and safety perspective would legitimize the involvement of various key decision makers in the planning and decision-making processes for drugs seeking flexible departure. This broader involvement also would address the need for greater transparency in drug regulation.

See also the section on Good Planning.

Contact information for the Progressive Licensing Project.