# Presentation: 224052

## Making Better Use of All Clinical Studies in an NDA*

***Charles Anello, Sc.D.***
**Deputy Director**
**Office of  Biostatistics/CDER/FDA**

**Presented at PhRMA Biostatistics Subcommittee, Biostatistics and Clinical Data Management, Opportunities and Challenges for Industry and FDA Annual Workshop**
**November 9 - 11, 1998, Bethesda, Maryland**
*** ****The views expressed are those of the author and not necessarily those of CDER/FDA**

## Motivation

**The focus will be on the following two questions:**
**Are there legal and/or ethical requirements to report all data collected in a clinical trial?**
**Are there reporting strategies that might be useful?**

## Topics

**Impact of PDUFA, FDAMA & ICH **
**Data Reporting Requirements**
**Use of Data (individual studies, collectively)**
**Electronic Submission**
**Conclusions**

## Impact of PDUFA, FDAMA and ICH

**Shortened review time**
**Move towards an electronic NDA**
**Move towards common international submissions**
**Reduce time to evaluate the totality of information collected**
**Move towards Good Review Practices**

## Are there legal and/or ethical requirements to report all data collected in a clinical trial?

## Yes, there are legal requirements.

## Reporting Requirements

**(Ref 353 FD&C Act)**

**(a)  No person shall introduce or deliver for introduction into interstate commerce any new drug, unless an approved application is filed persuant to section (b) or (j) this section is effective with respect to such drug.**
**(b)(1)(A)  ****Full reports of investigations**** which have been made to show whether or not such drug is safe and whether such drug is effective in use.**

## Reporting Requirements (cont.) Under

**(1)****	****...do not include ****adequate tests by all reasonable methods**
**(4)****	****...****insufficient information**** to determine whether such drug is safe**
**(5)    ...lack substantial evidence of effectiveness**

**Reporting Requirements (cont.) Under**

**(FD&C Act Subpart V Drug & Devices)Part A Section:  353)**

## Missing Data

**May make it difficult to interpret a study’s finding**
**May make it impossible to do an intention-to-treat analysis**
**No unique and generally accepted method for analyzing clinical trials with substantial missing data**
**Results in multiple (sensitivity) analyses**

## Full reporting may only be possible when there is complete follow-up of patients entered into clinical trials.

## Are there ethical reasons for full reporting?

## CDER’s Mission

**Promote and protect public health by assuring that safe and effective drugs are available to Americans.**

## Both Industry and FDA have an interest in protecting public health.  

**Reporting full information serves this goal.**

## Yes, there are ethical reasons to fully report the information collected during drug development.  It may be the best way to protect the public health.

## Changes in What Constitutes Full Reports

**Prior to 1987 all case reports**
**After 1987 case reports on only deaths and dropouts**
**1998 proposed for abbreviated reports when information not intended to contribute to the evaluation of product effectiveness**

## Guidance for Industry

**“****Submission of Abbreviated Reports and Synopses in Support of Marketing Applications”**

**(Aug. 1998)**

## Guidance

**Intended to meet the requirements of Section 118 FDAMA**
**In the past, less than full reports provisions exist in both Clin/Stat Guidelines and ICHC**
**Studies not intended to contribute to evaluation of effectiveness or support information included in labeling**

## Studies for Which a Full Report Should be Submitted

**Studies providing the basis for dose recommendations**
**Controlled studies contributing directly to substantial evidence of effectiveness**
**Controlled studies that support intended comparative claims**
**Controlled studies evaluating effectiveness for the indication that failed to show an effect**

**For clinical effectiveness studies**

## Examples of Studies for Which an Abbreviated Report Could be Submitted

**Studies with active controls that do not provide substantial effectiveness**
**Studies for related indications for which market approval is not being sought**
**Studies not designed as efficacy studies**
**Studies of doses or dosage forms not intended for marketing**

## Examples of Studies for Which Synopses Should be Submitted

**Studies of unrestriced indication for which marketing approval is not being sought (unless they form a significant portion of the safety data base)**
**Studies evaluating routes of administration for marketing is not sought**
**Incomplete studies, unless stopped for safety reasons**
**Uncontrolled studies not specifically identified as needing abbreviated or full study reports**

## What can be learned from a fully documented single, adequate and well designed clinical trial?

## What Can be Learned Depends on

**the clinical setting**
**the criteria for selecting patterns**
**the choice of dose**
**the duration of the trial**
**the choice of endpoints**
**Analysis Plan (intention-to-treat, handling of missing data)**

## Full Reports for an Individual Study Includes But is Not Limited To:

**Overall design**
**Study population**
**Choice of control groups**
**Method of treatment assignment**
**Dose selection**
**Blinding**
**Variables measured for safety and efficacy, potential confounder, completeness of follow-up)**
**Analysis Plan (intention-to-treat, method of handling missing data)**

## Full Reporting Also Involves a Summary of Collective Evidence

## Collective Evidence

**Usually applications that are approved contain more than 1 clinical trial.  Multiple studies needed are needed to answer many questions about the drugs safety and effectiveness.  Full reporting includes making better use of the collective evidence.**

## The Collective Evidence is Contained in the Integrated Summary of Effectiveness (ISE) and the Integrated Summary of Safety (ISS)

## Collective evidence is important in evaluating subgroups like age, gender and ethnicity.

## Collective Evidence is Important For:

**Safety evaluation**
**Generating hypotheses**
**Better estimates of treatment effects**
**Subgroups**
**Additional endpoints**
**Dose response**
**Duration of response**

## Collective Evidence May InvolveCombining Inferences, Studies or Data

**Protocol (objective, method and analytical plan)**
**Methods to avoid Bias**
**Methods to assess Heterogeneity**
**Various statistical approaches:**
**Estimating a common effect**
**Fixed effect:  (Peto)**
**Random effect:  (Dersimonian and Laird)**
**Explaining heterogeneity (regression methods)**
**Mixed effects:  (Huque)**

**Full reporting of collective evidence might involve:**

## Electronic Submissions

## Electronic Submission (ERSR) Goals

**By the year 2002**
**All submissions can be received and archived electronically**
**All electronic submissions and reviews accessed from the reviewer’s desktop computer**
**Standardized data analysis and tools**
**FOI material available on the internet**

## Archive Submissions

**CRT/CRF - in effect now**
**Full NDA as PDF - for comment**
**SAS/Transport for data submission**
**Future guidance - IND, ANDA, DMF, Annual Reports**

## Today’s Archive Electronic Submission

**NDA Archive Guidance**
**www.fda.gov/cder/guidance**
**PDF for text**
**Specific guidance on PDF options**
**File names and directory structures**
**Navigation aids - hyperlinks, bookmarks, searchable indexes**

## Good Review Practices

## A Good Reporting Strategy Supports Good Review Practices

**Reviews of submitted application involve both individual studies and collective analysis.**

## Good Review Practices

**Quality of the data**
**Protocol and completed studies**
**Adequate and well controlled studies**
**Potential sources of bias**
**Ruling out chance**
**The collective evidence**
**The conclusions**
**The proposed label**

**Focus on**

## The Goals of the Analysis

**Rule out bias (due to design, conduct or imbalance in prognostic factors)**
**Rule out chance (based on the Type I and Type II errors)**
**Estimate the important clinical treatment effects (or variables as related to the safety and efficacy of the drug and the standard errors of the estimates)**
**Draw inferences from the study result**

## Are there reporting strategies that might be useful?

## Good Reporting Strategies

**Meet ethical and regulatory requirement to report all relevant data**
**Good indexing of the NDA**
**Pre-NDA discussion on data requirements**
**Report in a manner that conserves resources of both FDA and sponsor**
**Are there optimal reporting strategies**

## Reporting Strategies (cont.)

**Excessive reporting works against objective of accelerated drug development**
**Avoid unnecessary data collection**
**Avoid unnecessary summarization**
**All subjects who entered the trial should be accounted for**
**Well thought out descriptive statistic (demographics and prognostic variables)**
**Limit unplanned analysis**

**(ref:  ICH, E3, E9)**

## Reporting Strategies (cont.)

**Blind analysis prior to modification of analysis plan**
**Describe and report changes in analysis plan**
**Detailed aspects of presentation and tabulation at time of blind review**

**(ref:  ICH, E3, E9)**

**Reporting Strategies (cont.)**

## Reporting Strategies for Clinical Data

**Individual trials large enough to satisfy their objective**
**Series of trials may be useful for some goals (e.g. age, gender, ethnicity)**
**Safety data from all human exposures**
**May be useful to combine data which use comparison groups (e.g. placebo, active controls)**
**Appropriate survival analyses to exploit the potential relationship of incidence of adverse events, duration and follow-up**

**(ref:  E9, 7.2)**

## Reporting Strategy Including Intention to Treat Analysis

**All randomized patients**
**Only exclusion on prespecified criteria measured at baseline**

## Conclusion

**There are legal and ethical reasons for reporting all relevant data collected during the drug development process**
**Some reporting strategies already exist in the 1988 Guidelines, ICH E3 and E9**
**Electronic Submissions and desktop review capabilities will help all of us make better use of clinical data in NDA’s**
**There may be better strategies and these should be considered**