EFFICIENT INTEGRATED SUMMARIES PREPARATION: FROM

BIOSTATISTICS TO MEDICAL WRITING

CROS NT looks at the regulatory requirements from both the EMA and FDA with regards to

Integrated Summaries of Safety & Efficacy and how to successfully prepare these analyses

from a statistical and documentation point of view.

Integrated Summaries of Safety and

Efficacy are not only required for New Drug

Applications, they are considered some of the

most important documents for submissions.

They are not simply summaries, but rather

they are analyses of results that determine

the safety and effectiveness of drugs in

development, including rare adverse events

(AE). ISS and ISE analyses also play an

integral part in the CTD/eCTD. Therefore, the

biometrics team – from Statistician to Medical

Writer – needs to work together and

communicate effectively in the preparation of

Integrated Summaries.

The FDA requires both ISS and ISE submissions for New Drug Applications. Within the

CTD, this includes both an overview and summary of clinical efficacy and safety. Within

the Clinical Study Report, submissions must contain reports of analyses of data from more

than one study (including any formal integrated analyses, meta-analyses and bridging

analyses).

At the end of 2015, the FDA finalized guidance on Integrated Summaries of Effectiveness

for NDAs and BLAs. The FDA officially defines ISE as a “comprehensive integrated analysis

of the effectiveness of a study drug”. The guidance released in 2015 differentiates ISE from

the Summary of Clinical Efficacy stating that ISE should be a “self-contained, detailed

analysis that comprehensively examines relevant data from multiple sources intented to

provide the substantial evidence of effectiveness for a given drug, and describes additional

information related to the effectiveness, such as dose-response, effects in population

subsets, or timing or response”. The ISE is meant to provide a clear understanding of

responses across studies.

Meanwhile, the EMA also requires both ISS and ISE for New Drug Applications in the

European Union and has specific questions that must go into the CTD regarding clinical

overview and summary and integrated summary. EMA submissions include statistical

analyses of safety data and meta-analyses of efficacy data and require expert medical

writing.

ICH guidelines for eCTD submissions (supported by both the EMA and FDA) prefer the use

of CDISC standards, particularly SDTM and ADaM.

The requirements laid out by the regulatory authorities make collaboration between

biostatisticians and medical writers inevitable. The challenge is understanding what roles

they play in the planning and preparation of integrated summaries and the best way of

collaborating.

Statisticians and Statistical Programmers

Statisticians need to be involved in the planning stages of integrated summaries, Ideally,

statisticians should attend pre-submission meetings with regulatory authorities to discuss

the statistical analysis aspects of the integrated summary including sample size and trial

design.

From a statistical perspective, the statisticians produce a statistical analysis plan while

the programmers focus on integrated datasets. The statistical analysis plan includes an

analysis of aggregated data and an explanation of the methodology chosen. The

biostatistician needs to highlight any inconsistencies or limitations in the sample size. In

the meantime, statistical programmers pool datasets from all relevant studies. The best

way to get full value from an integrated summary is to have the methdological

biostatistician involved in all phases of an integrated summary life cycle.

Biostatisticians and statistical programmers collaborate to select the data to be pooled and

ensure correct data formatting.

Medical Writers

The Medical Writer ties the pooled datasets and analyses together into the final Clinical

Study Report. Logically, if data is centralized and integrated, this makes writing easier.

Medical Writers should work closely with biostatisticians in attendance at pre-submission

meetings to understand what is expected of regulatory authorities. In terms of document

structure, the EMA and FDA both have guidance on what should be included in the CSR

in terms of length and content. Medical Writers need to be familiar with “Module 2″ of the

CTD – “the CTD Clinical Overview and Summary in Module 2 will not usually contain the

level of detail expected for an ISS (…) if, the requirements of 21 CFR 314.50 can be met for a

particular application by what is in the CTD Module 2 summary, then the CTD Module 2

section would fulfill the need for an ISS/ISE”.

Centralizing clinical data is key to successful Integrated Summaries

preparation

Biostatisticians, Statistical Programmers and Medical

Writers should be working together on Integrated

Summaries from the beginning. While the

biostatistician sets out an analysis plan and the

programmers are pooling data, the medical writer

should have a summary of analysis considerations.

Consistency is the key to ensuring Integrated

Summaries are produced within budget and on time.

Centralizing clinical data with one data centric vendor

across a program of studies ensures data traceability,

data quality and standardization. Statisticians and

programmers work more efficiently when they can use

previously developed programs. For example, programmers can work quicker if they do not

need to rename dataset variables.

Centralizing data with a full biometrics team – including in-house biostatistician,

programmer and medical writer – ensures a consistent approach to integrated summaries

and surefire final product to be submitted to regulatory authorities. The dedicated team

can follow a project from conception to submission, deploy the same programming macros,

use the same writing style and create an ISS/ISE document template in line with company

branding to be used for future summaries.

Overview

CROS NT has prepared numerous integrated summaries for both EMA and FDA submission.

As a data centric CRO, we know what issues to anticipate when working with distributed

data and have an excellent track record in a centralized approach to Integrated Summaries.

We have statisticians, programmers and medical writers in-house with extensive experience

in ISS/ISE preparation, and our biometrics teams have integrated large numbers of studies

providing data mapping, warehousing, analysis, reporting and medical writing services.