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In February 2013, FDA released a new document outlining their “structured approach to benefit risk assessment in regulatory decision making”.  This document was released as a result of requirements and commitments for FDA from PDUFA V.

Here is a review of the contents followed by some comments on it and its implications.


Starting in 2009 FDA has been developing a systematic approach to benefit-risk (BR) assessment for drug review.  It has set several requirements for this new policy.  It must operate within the legal, regulatory and policy framework of FDA as it now exists; use a systematic approach for life cycle benefit risk assessment; and decide on a new approach.  FDA has decided, in regard to the approach, that quantitative decision modeling is sometimes useful but rather they will use a “structured qualitative approach” and integrate the new methodology into the existing work processes.

FDA’s framework for doing each analysis will now include the following components:


Assess severity of the condition

Analysis of other options

Primarily clinical trials: 1o and 2o endpoints, subpopulation analysis

Adequacy of the safety database, the severity and reversibility of AEs, and the potential for sub-optimal management in the post-market setting

Graphically it will look like this for each factor in the decision:

They performed a pilot project in 2012 in which six new NDA/BLAs were analyzed using this framework.  This permitted FDA to refine and test the process and integrate into the current work flow.

In 2013 they will revise the Clinical Review Templates that are currently used for product review.  Here is an example of a current one: https://www.fda.gov/downloads/BiologicsBloodVaccines/BloodBloodProducts/ApprovedProducts/LicensedProductsBLAs/FractionatedPlasmaProducts/UCM343981.pdf

The basic contents of such templates are usually as follows:

Table of Contents


1. Executive Summary

2. Clinical and Regulatory Background

2.1 Disease or health related conditions Studied

2.2 Currently Available, Pharmacologically Unrelated Treatment(s)/Intervention(s) for the Proposed


2.3 Safety and Efficacy of Pharmacologically Related Products

2.4 Previous Human Experience with the Product (Including Foreign Experience)

2.5 Summary of Pre and Post submission Regulatory Activity Related to the Submission

2.6 Other Relevant Background Information

3. Submission Quality and Good Clinical Practices

3.1 Submission Quality and Completeness

3.2 Compliance With Good Clinical Practices And Submission Integrity

3.3 Financial Disclosures

4. Significant Efficacy/Safety Issues Related to Other Review Disciplines

4.1 Chemistry, Manufacturing, and Controls

4.2 Assay Validation

4.3 Nonclinical Pharmacology/Toxicology

4.4 Clinical Pharmacology

4.4.1 Mechanism of Action

4.4.2 Human Pharmacodynamics (PD)

4.4.3 Human Pharmacokinetics (PK)

4.5 Statistical

4.6 Pharmacovigilance

5. Sources of Clinical Data and Other Information Considered in the Review

5.1 Review Strategy

5.2 BLA/IND Documents That Serve as the Basis for the Clinical Review

5.3 Table of Studies/Clinical Trials

5.4 Consultations

5.4.1 Advisory Committee Meeting (if applicable)

5.4.2 External Consults/Collaborations

5.5 Literature Reviewed (if applicable)

6. Discussion of Individual Studies/Clinical Trials

6.1 Trial #1

6.1.1 Objectives (Primary, Secondary, etc)

6.1.2 Design Overview

6.1.3 Population

6.1.4 Study Treatments or Agents Mandated by the Protocol

6.1.5 Directions for Use

6.1.6 Sites and Centers

6.1.7 Surveillance/Monitoring

6.1.8 Endpoints and Criteria for Study Success

6.1.9 Statistical Considerations & Statistical Analysis Plan

6.1.10 Study Population and Disposition

6.1.11 Efficacy Analyses

6.1.12 Safety Analyses

6.2 Trial #2

(as above with trial #1)

7. Integrated Overview of Efficacy

8. Integrated Overview of Safety

8.6 Safety Conclusions

9. Additional Clinical Issues

9.1 Special Populations

9.1.1 Human Reproduction and Pregnancy Data

9.1.2 Use During Lactation

9.1.3 Pediatric Use and PREA Considerations

9.1.4 Immunocompromised Patients

9.1.5 Geriatric Use

9.2 Aspect(s) of the Clinical Evaluation Not Previously Covered

10. Conclusions

11. Risk-Benefit Considerations and Recommendations

11.1 Risk Benefit Considerations

11.2 Risk Benefit Summary and Assessment

11.3 Discussion of Regulatory Options

11.4 Recommendations on Regulatory Actions

11.5 Labeling Review and Recommendations

11.6 Recommendations on Postmarketing Actions


Thus many of these sections will be revised.  A major addition now will be the consideration and use of the drug in the post-marketing setting as this use is critical to understanding the drug’s profile, particularly regarding safety.  A new draft guidance will be developed on how to apply this methodology to whether a REMS is necessary to ensure that the benefits of a drug outweigh its risks.  This will then be used for FDA’s post-marketing review of the drug’s BR assessment when new information arrives.

FDA will need to consider the utility of new post-marketing data that comes from sources which are, as they put it, of “varying levels of rigor” and how well the previous BR assessment based on pre-marketing data compares with the post-marketing data.

This new methodology will be implemented beginning in 2014 when it will be used for NDAs on new molecular entities and original BLAs.  In 2016 efficacy supplements for new and expanded indications will be evaluated using this framework and in 2017 all original NDAs will then also use this methodology.

FDA will create various internal boards to track the changes and look at the outcomes and results of the assessments with the new methodology.  There will be a CDER and a separate CBER Advisory Group with members from multiple disciplines including New Drugs, Surveillance & Epidemiology, Medical Policy, Clinical Science, Planning & Informatics and others.  Evaluations will begin in 2015 and 2016 after several applications have been handled this way.

FDA will hold two public workshops with the first in 2014 covering the framework and methodology and the second at an unspecified date focusing on the results of the implemented frameworks.

Another interesting aspect is that FDA will hold four public meetings over five years to look at this framework for four disease areas which are in the process of being chosen.

FDA will obtain the patients’ perspectives on:


This interesting document describes how FDA will look at benefit and risk.  It is a bit confusing (to me) but gives the broad strokes of where FDA is heading.  How it will integrate post-marketing data at the time of approval is unclear as this data does not yet exist.  It appears the likely uses in the post-marketing setting will influence whether a REMS is needed and, if so, what will be required.

This approach resembles, in many ways, the approach that is being undertaken by the EMA, Health Canada, the UK’s MHRA and others.  There is a broad approach of looking at the benefits and risks from all stakeholders’ points of view.  Clearly the NDA/MA submission presents the pharma company’s benefit profile (usually with a touch of marketing thrown in…), as well as the patients, the FDA and other interested parties including, in some cases, an Advisory Committee.  The big picture will be examined in terms of the disease and its clinical course, what other therapies there are and whether they can modify the disease, off label use (and presumably abuse) and other factors.  As with the EMA, the idea of folding in the post-marketing picture in addition to the clinical trials pre-marketing data will now be formally included.  The EMA makes the distinction between (pre-marketing) “efficacy” and (post-marketing) “effectiveness”.  The FDA does not use these words but the concepts are similar.  The EMA has also included these concepts in the new format Risk Management Plans (RMPs) and in the new format PSURs (PBRERs-Periodic Benefit Risk Evaluation Reports).

Thus the concept of continuous and continuing benefit risk analysis during the full life cycle of the drug is now the “new normal”.  There is likely to be much overlap between FDA and EMA processes though surely each will have its own peculiarities and twists.  The challenge for the industry is to marry the two such that the conclusions and mitigation procedures are in harmony.

Another tricky area will be to see how bureaucratic and detailed the requirements will be.  Whether the same depth of BR analysis is needed, for example,  for a “benign” anti-histamine and a toxic oncology drug remains to be seen.  How generics, biologics and biosimilars will be handled in this framework also is not yet defined well on either side of the Atlantic.

We are in the infancy of the benefit risk paradigm.  As large databases and electronic health records come on-line there will be enormous amounts of data available.  How one sifts through the data and how one separates the needle from the haystack remains to be seen.   Hopefully the agencies will actually measure the effectiveness of the new processes and keep what works and discard what doesn’t.  It’s a reasonable start but if we don’t have a reasonable finish the system won’t fly.

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