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Benefits vs. Risks: Telling the Story in the Clinical Overview May be Changing

October 6, 2015 | Tim Garver, PhD, EVP/COO | Medical Writing Services

Are you scheduled to work on or submit a marketing application in the second half of next year? If so, you’ll need to be prepared for some potentially big changes in what’s required when making the benefit-risk argument in your Clinical Overview.

A Bit of Background

In November of 2000, the Steering Committee of the ICH recommended that the clinical sections of all marketing applications prepared in the European Union, Japan, and the United States be structured based on the guideline developed within the ICH’s Expert Working Group on this topic – this guideline was called M4E. The guideline was subsequently modified, without further public consultation, to implement numbering and section heading changes, and is called M4E(R1).

The FDA issued a final guidance document in August of 2001 adopting the recommended technical requirements for all clinical sections of New Drug Applications (NDAs) to ensure harmonization with marketing applications submitted in the European Union and Japan.

The Clinical Overview (Module 2.5)

One of the documents covered by these guidelines is the Clinical Overview, a document that resides within Module 2 of the Common Technical Document (CTD) structure.

The Clinical Overview is the location in the marketing application where a Sponsor is expected to provide a critical analysis of their clinical data and, hopefully, establish that the expected benefits of their compound outweigh its potential risks.


Proposed Changes to Risk-Benefit Section of Clinical Overview

Based on the guidelines noted above, the critical analysis presented in the Clinical Overview should include a rationale for the product, as well as overviews of biopharmaceutics, clinical pharmacology, efficacy, and safety, and a critical appraisal of the potential benefits and risks of using the medicinal product in clinical practice.

For regulators, this benefit-risk assessment is vitally important in making the determination as to whether or not a marketing application is worthy of approval.

While the original ICH and FDA guidelines provide general recommendations on the topics that need to be covered in the benefit-risk section, over the years regulators have found a high degree of variability in how Sponsors address this section of the Clinical Overview. This variability has, at times, resulted in inefficient communication and poor facilitation of benefit-risk assessment discussions between Sponsors and regulators.

As a result, the ICH Expert Working Group has been in the process of revising M4E(R1) in order to provide greater specificity on the format and structure of the benefit-risk section, and the Step 2 version of this updated draft guideline – called M4E(R2) – was released on August 5th of 2015. (Not sure what “Step 2” means? Hang on, I’ll explain at the end of this post.)

M4E(R2) provides significantly more guidance on how to write Section 2.5.6 (Benefits and Risks Conclusions) of the Clinical Overview, including the adoption of new “sub-headings” that were not included in M4E(R1). M4E(R2) also provides additional guidance regarding Section 2.5.1 (Product Development Rationale), though the changes to Section 2.5.6 are the focus of this post.

Benefit-Risk Subheadings in Section 2.5.6

Therapeutic Context

As noted above, the draft guideline indicates that the new therapeutic context section be sub-divided into sections addressing the disease or condition the medicinal product is intended to treat along with a discussion of current therapies for that disease or condition.

For the disease/condition section, the guideline suggests the Sponsor describe which characteristics of the disease or condition are most relevant to, or have the greatest impact on, the intended population. This discussion may begin with a broad perspective of the disease but should ultimately focus on the specific aspects of the disease that would be addressed by the proposed indication of the medicinal product.

pills M4E(R2) also suggests including a summary of the “major therapies” (those therapies used most frequently and/or recommended in clinical guidelines) that are currently available for the target patient population, although other interventions such as surgical procedures and off‑label drug use may also be discussed.

A discussion of the medical need for a new therapy in the context of the efficacy, safety, tolerability, convenience, or preference (if applicable) of the currently available therapies is also suggested.


Within the newly-proposed Section, the key benefits of the medicinal product that will be used in the overall benefit-risk assessment need to be discussed.

While a “benefit” is typically described by a primary efficacy endpoint, in some cases the benefit may be described by a combination of study endpoints. Furthermore, the benefits of the medicinal product may be related to convenience of use and, therefore, improved compliance.


It’s suggested that the following characteristics be considered when identifying the key benefits:

  • Nature of the benefit (Does the medicinal product prolong life? Cure the disease? Provide symptomatic relief?)
  • Clinical importance of the benefit (Less frequent hospitalization? Prevention of disease progression?)
  • Absolute difference in the new therapy’s treatment effect versus the comparator(s)

The benefits section should also include an analysis of the strengths and limitations of, and the potential uncertainties in the evidence related to each key benefit (eg, consistency of results across trials, generalizability of results to clinical practice).


cube With regard to risks (Section, M4E(R2) suggests Sponsors summarize the key risks associated with the use of the medicinal product that will be discussed in the evaluation of the overall benefit-risk assessment.

In this context, “risk” refers to the frequency and severity of an unfavorable effect associated with the medicinal product, including the seriousness of potential outcomes of the risk.

The risk section does not need to describe every risk that has been discussed throughout the application – only those that are deemed to be the “key” risks. When identifying “key risks”, the draft guideline suggests the following be considered for each adverse drug reaction:

  • Seriousness and/or severity
  • Frequency in the study population versus the comparator(s) and/or background rate in the patient population
  • Reversibility
  • Tolerability

Similar to the benefits section, in the risks section the guideline suggests that an analysis of the strengths and limitations of, and the uncertainties in, the relevant safety information also be included.

Benefit-Risk Assessment

Section, as per draft M4E(R2), will be the Sponsor’s overall benefit-risk assessment and should include a concise description of the reasoning and clinical judgment that is used in assessing and weighing the key benefits and key risks of the medicinal product.

While other portions of the newly proposed Section 2.5.6 can include factual descriptions of the clinical data, the benefit-risk assessment should focus on interpreting the data.


The draft guideline suggests that Sponsors can take various approaches for conducting the benefit-risk assessment, and states that a descriptive approach that overtly explains how the data, in aggregate, have been interpreted may be adequate.

Beyond this the guideline does not define a specific methodology that should be followed, although it suggests that, in certain circumstances, a quantitative approach may be acceptable.

Finally, the guideline clarifies that, if the Sponsor so chooses, summary tables and/or graphical displays to help communicate the clinical importance of the key benefits and risks, and the resulting benefit-risk assessment, are permitted in Section

What Are The Next “Steps”?

As I said at the beginning of this post, as of August 5th of 2015, this draft guideline is at the completion of “Step 2” of the formal ICH procedure, which consists of a 5-step process.


Source: Formal ICH Procedure

Step 3 (Regulatory consultation) is scheduled to run from September of 2015 through March of 2016, and the ICH Expert Working Group will review all comments on the current draft guideline from March of 2016 through June of 2016.

If all goes well and, depending on the extent of public comments received, an Expert Draft Guideline will be available by the end of Step 3, with Step 4 (Adoption of an ICH Harmonized Guideline) currently targeted for June of 2016.

Step 5 (Implementation) would then immediately occur. Implementation of the new guideline is carried out according to the same national/regional procedures that apply to other regional regulatory guidelines and requirements.

Stay Tuned!

If your work in any way entails having knowledge of marketing applications, you’ll need to keep your eyes and ears open for how all of this all works out in the next 9 months or so to see if big changes are forthcoming in how the benefit-risk argument needs to be detailed in future submissions. And when the final guideline is issued, please visit our website – you’ll be sure to find a blog post about it!

One last thing – IMPACT has extensive experience writing the various components of marketing applications, including Clinical Overviews, across a wide range of therapeutic fields. So if you or someone you know is in need of our medical writing services, we’d love to help! Don’t hesitate to contact us, we can’t wait to hear from you.

Category: Medical Writing Services
Keywords: Clinical Overview, M4E(R2), Benefit-Risk, New Drug Applications, Marketing Applications