CDER Wants YOU to Tell It How to Improve the Integrated Review; We Have a Few Ideas of Our Own

FDA issued a Federal Register notice on September 13, 2024, seeking feedback on the Integrated Review format that the Center for Drug Evaluation and Research (CDER) began using as part of its New Drugs Regulatory Program (NDRP) modernization effort several years ago.

The NDRP focused on six strategic objectives one of which was the implementation of the Integrated Assessment which per CDER was designed to “critically, collaboratively, and consistently assess whether information in drug approval applications meets legal and regulatory requirements.”  These efforts included the adoption of a new review template for the assessment and documentation to be used in reviewing NDAs and BLAs with an overall goal of having a more collaborative inter-disciplinary approach to the process.  While much of the effect may have been on the internal processes of the review division and other disciplines tasked with evaluating the approvability of applications submitted to CDER, a significant change also occurred in how CDER conveys information about the internal review process and conclusions that lead to an application approval.  Specifically, CDER moved from sharing the reviews of the individual disciplines in the documents available to the public to sharing an Integrated Review which shares the conclusions but much less of the detail of each review.

Before FDA even asked, we had been considering an HPM FDA Law Blog post on this subject.  The appeal of distilling down the extensive process that goes into the decision to approve an application into a single package is easy to see, and some may be interested in only the ultimate distillation – an approval is issued or not. As frequent consumers of both the old-style Summary Basis of Approval (SBA) that includes the individual detailed discipline reviews and the newer leaner Integrated Assessments, however, we have found the more summary nature of the Integrated Assessments to be lacking information that can be critically important in identifying and understanding how resolution was reached on issues identified in the review.

For example, one cannot always discern the opinions of individual reviewers in an Integrated Review.  Those of us seeking to learn how FDA may approach a similar issue in another context want to understand what the differences of opinion were.  The Additional Analyses and Information section of the Integrated Review includes only the separate reviews of reviewers who “disagree with significant elements of the Executive Summary and Interdisciplinary Assessment sections or the decision of the Signatory Authority.”  89 FR 74966 at 74968 (Sept. 13, 2024).  Differences of opinion that were resolved before the action was taken would not be included.

Another potential problem with an Integrated Review is that we can never know what information was eliminated from the individual reviews.  For example, perhaps the Integrated Review simply agrees with some conclusion in an individual review but does not include the “why” rationale that the individual reviewer found persuasive.  Fully understanding FDA’s thought process and the basis of its conclusions (i.e., the “why”) is of particular import to those who seek to understand how FDA may view the issue in other situations.

We also have encountered instances where there was a mathematical or other objective error in the underlying review.  The Integrated Review includes the conclusions or results of various analyses, but there is no “show your work” feature.  Consequently, it can be difficult to follow how FDA came to its conclusion.

Some of the goals of the Integrated Review (including making information available to lay people) may be well-served by the more concise document.  Consolidation into a single review by its nature, however, will leave details of the individual review process on the cutting room floor.  There are those who are willing to read through the more extensive package consisting of all the reviews.  These individual reviews already exist and could be posted in addition to the Integrated Review or an even more concise version of the Integrated Review.

We look forward to seeing what others have found useful or frustrating about the Integrated Review, including in comments that provide responses to these specific questions FDA asks in the Federal Register notice:

1. We are interested in preserving for stakeholders what they find most useful in FDA reviews.
2. Comparing the Integrated Review to previous review documentation, is there any information you are having difficulty locating?
3. Are you able to use the Integrated Review for the same purpose that you used previous reviews? If not, please provide specific examples.
4. We are interested in specific recommendations about any areas of the Integrated Review documentation of the Integrated Assessment that can be improved to meet the needs of stakeholders.
5. We are interested in stakeholders’ views regarding the advantages and disadvantages of an interdisciplinary assessment presentation of key review issues and the resultant integration of the assessments of multiple disciplines into a single Integrated Review document.
6. We would like to know whether the new format of the Integrated Review documentation for the Integrated Assessment provides clarity of benefit-risk assessments and informs your knowledge of FDA’s basis for making decisions.
7. Based on the integrated review, were the issues that concerned the review team clear and understandable? If so, what helped achieve this? If not, what can be improved?

Comments are due by December 12, 2024.