# Presentation: 583366

## Integrated Analyses and the CTD Sections Addressing Safety

- Robert J. Temple, M.D.
- Associate Director for Medical Policy
- Center for Drug Evaluation and Research
- U.S. Food and Drug Administration

- June 16-20, 2002
- DIA - 38th Annual Meeting

## Plan

- Review contents and purpose of the ISS
- Contrast ISS with contents of Module 2, section 2.7.4:  Summary of Clinical Safety
- Conclusions

## ISSIntegrated Summary of Safety

- A very important part of an NDA
- _Required_ by regulation since 1985 [21 CFR 314.50(d)(5)(vi)] but explained and described only in 1988, in the Guideline for the Format and Content of the Clinical and Statistical Section of NDAs (The Clin-Stat Guideline)
- Represented a _revolution_ in our approach to safety assessment [Temple R.  The Regulatory Evolution of Integrated Safety Summary.  Drug Information Journal. 1991; 25:485-92]

## ISSIntegrated Summary of Safety

- Misnamed (as Justina always tells you) and it was mostly my fault (as Justina also always tells you).  It is, in fact, an integrated _analysis_.  That, however, became fully apparent only in 1988.
- It is the way we analyze safety in the typical multi-trial data base of an NDA, not primarily study-by-study, but as an integrated overall view.

## How Else Could You Do It?

- After 1962 focus on adequate and well-controlled studies for efficacy, with little attention to _theory_ of safety review
- Safety is distinct from hypothesis-testing effectiveness model
- descriptive rather than rigorous
- rarely hypothesis-testing

## How Else Could You Do It?

- Single studies usually cannot give the answer
- Large safety data base allows
- 1.	Study-by-study comparison of more common events
- 2.	Pooled estimates of common and rarer events
- 3.	Pooled analysis of effects in subgroups, dose response
- 4.	Overview of deaths and adverse dropouts
- These are new analyses, not summaries of something else

## Integrated Summary Regulation21 CFR 314.50(d)(5)(vi)

- “Integrated summary of all available information about the safety of the drug product, including pertinent animal data, demonstrated or potential adverse effects of the drug, clinically significant drug-drug interactions, and other safety considerations, such as data from epidemiological studies of related drugs.”
- In 1998 there was added a specific requirement for analysis of adverse effects by age, gender, and race.
- In fact, the ISS has both elements of a summary and elements of new analysis.

## Clin-Stat Guideline (IIH, page 32-46)

- 1.	Overview:
- Integrates safety information from all sources (animal, clin pharm, controlled and uncontrolled studies, epi data).
- “While other parts of the application present safety results of each study, the integrated summary is an overall analysis, examining all studies together.  This allows examination of differences among population subsets not possible with the relatively small numbers of patients in individual studies, and, especially important, allows evaluation of more serious adverse effects too rare to be [seen] in single studies.”
- “Thus, the ISS is, in part, simply a summation of data from individual studies and, in part, a new analysis that goes beyond what can be done with individual studies.”

## 2.  Detailed AnalysisGeneral Concept

- a.	Extent of exposure:  a detailed description of who was exposed to the drug, to what doses, and for how long.  Relates to legal requirement of “All tests reasonably applicable to evaluate safety.”   Also see ICH E-1 (which, by the way, deserves a current look).  Implicit in asking for this information is the possibility that a reviewer could conclude there are “not enough” severely ill people, people with particular concomitant illness, people studied for long enough, or people who received the recommended dose.  If no problems are seen, the drug can be said to have attained “safe passage” (Leber).  This presentation allows us to consider whether exposure was sufficient to make such safe passage meaningful.

## General Concept (cont.)

- b.	Assessment of Common Events
- 	The common events are usually easily assessed because rates can be compared in Rx and control.  They usually are not critical to approval but to proper use of the drug, so that relation to dose, demographic characteristics, renal and hepatic function is important.  Individual study rates are of interest, but pooled rates give better precision and allow exploration of dose, demographics, etc.
- 	While this analysis requires effort it is, in a sense, always successful.  These rates and subset effects _can_ be found (exception:  trials fail to detect abnormal sexual function and impaired cognition, unless special efforts are made).

## General Concept (cont.)

- c.	Serious events and the search for the “needle.”
- 	If a drug had an obvious major liability, and this was recognized, an NDA would probably not be submitted.  But we _know_ that sometimes important ADRs are missed during development, or are seen but not appreciated.
- 	Review of total data base is a search for the needle in a haystack, without knowing whether there is a needle or what it looks like.  A critical part of the search is looking at deaths and adverse dropouts, where _unexpected_ important adverse effects should be.

## General Concept (cont.)

- c.	Search for the “needle” (cont.)
- 	We are good at looking for events drugs have caused in the past, or at least we eventually get good at them.
- Only recently appreciate ominous nature of transaminase elevation accompanied by elevated bilirubin, so _now_ search for that combination.
- Only now appreciate import of prolonged QT.
- 	_Before_ we understand, we need to look for things we haven’t appreciated yet and the place to look is within the deaths and adverse dropouts, particularly at events considered intercurrent illness, because anything really important should show up there.  Recent example:  discovery that an Alzheimer’s drug caused proximal weakness, breathing difficulties, was not recognized by sponsor, yet was critical reason for NA.

## General Concept (cont.)

- c.	Search for the “needle” (cont.)
- 	This means that the ISS will need to present those patients in detail.  Some deaths, of course, are expected and will not merit close analysis, but many others will.  The ISS asks that the location of narratives be given (i.e., narratives _can_ be in study reports) but suggests that it might be good to put _all_ the narratives in the ISS (much better, I think).  Also, of course, there are CRFs available for all deaths and dropouts.

## General Concept (cont.)

- When you’ve assessed the adequacy of exposure, classified and analyzed the common events, and searched the serious events and deaths and dropouts (including review of narratives and CRFs) for possible problems, you (the reviewer) have done all you can.  You are finished (at least with the analysis - you still have to reach conclusions).  That is a very good thing to know.
- One note:  The ISS is not as good as it should be in describing the overall approach to safety evaluation (e.g., how liver injury, QT prolongation, cataract development were assessed).  Module 2.7.4 does this better.

## Detailed Analysis

- A full description of the detailed analyses is “beyond the scope” of this discussion, but:
- They are numerous, and not all will be productive or worthy of a display in a summary document.
- It is important, for example, to place narratives of deaths and dropouts _somewhere_  (in an ISS, for example) for review but many will prove uninformative and should not be placed in a summary.
- Many analyses (of overall ADR rates, for example) will be presented as alternatives, will be accompanied by statistical presentations, etc., not all of which will be needed in detail in a summary.

## ISS vs. Clinical Summary

- Module 2 of the CTD contains a brief Clinical Overview (section 2.5 about 30 pages) and a much more detailed Clinical Summary (section 2.7, 50-400 pages, excluding attached tables).
- There is a clear distinction between description of a study in the Summary of Results of Individual Studies (2.7.3.2) and the full report (ICH E-3), found in module 5.  The summary should be relatively brief (like an abstract in a journal) and it is even suggested these can be extracted from the E-3 synopses (I don’t believe that).
- In sum, clear distinction between summary of a study and full report.

## ISS vs. Clinical Summary

- Similarly, although the summary of Clinical Safety (2.7.4) has all of the sections of an ISS (actually better than current ISS because it was constructed to be similar to the ICH E-3 document, which improved on the Clin-Stat guideline study report) and is very detailed, it is not a complete ISS in most cases (few narratives, e.g.), and will _usually_ not fit into the Clinical Summary.
- By analogy with the reports of individual studies the Clinical Summary contains the essential safety conclusions and analyses but it is not the full ISS study report, which is contained in module 5, and would usually be distracting if shoehorned into the Summary.

## Need for Both Documents

- If the full scope of an ISS (and we owe an updating on this) can fit comfortably into the Clinical Summary, then placing it there is fully acceptable.  It may be possible to put certain expanded sections in module 5, with the bulk of the presentation in module 2.
- But leaving out parts of the ISS to squeeze the material into a summary document serves no one’s interests and can only lead to later questions.
- Given typical length of ISS (and ISE, both hundreds of pages), they do not seem easily fitted into a 50-400 page Clinical Summary.