Problematiche connesse all’analisi ongoing Il ruolo della CRO come INDEPENDENT STATISTICAL ANALYSIS CENTER

VIII CONGRESSO NAZIONALE BIAS

CONFINDUSTRIA Verona

29 Giugno – 1 Luglio 2016

Valeria Bandiera

Senior Biostatistician

CROS NT

Introduction

Primary responsibility of the DMC is to ensure, throughout the duration of the study that risks to patients in the trial are reasonable in relation to anticipated benefit.

HOW?

Periodically reviewing and evaluating of the accumulated study data for safety, study conduct and progress, efficacy (when appropriate), scientific validity and integrity of the trial

Making recommendations concerning the continuation, modification or termination of the trial

Maintaining the confidentiality of DMC internal discussion and activities as well as the contents of reports provided to it

One of the main problems for data monitoring (including DMC deliberations) and any release of results/interim analysis is

CONFIDENTIALITY

CONFIDENTIALITY as a MUST

Absolute confidentiality is of extreme importance to the work of the DMC to prevent evolving trial results from impacting the execution of the trial

Objective: «to preserve confidentiality while maximizing the opportunities for interaction

with all individuals who would have valuable input for the committee» (9)

Confidentiality is one of the highest priority for the regulatory authorities!

Guidelines FDA and EMEA Guidance (5),(6) ICH E9 , E6 (4),(3)

Other Guidelines/papers with a lot of indications and suggestions National Institute of Health (NIH) Guidelines (8) DAMOCLES study group indications(2) Practical papers (10), (9)

BUT

No defined rules, flexibility depending on study designs and purposes

How to ensure confidentiality?

Masked study groups for DMC review (X vs. Y instead of experimental vs. control) -> however key to the grouping coding must be available for immediate unmasking, if deemed necessary

DMC Meeting format including both Open and Closed sessions has proven to be useful

Open session allows for interaction and discussion of study logistical matters between the IDMC and investigator representatives, the sponsor, DM and stat team and, if appropriate, regulatory agencies.

Any data must be presented without grouping by treatment assignment

Outcome results must not be discussed during this session

Closed session (and eventually Closed Executive session), which is restrict to IDMC voting members and Stats only, where data presentation by treatment group are discussed and recommendations/actions will be agreed

Grouped safety data and, if appropriate, efficacy data presented by coded treatment arm

Closed Executive session is restricted to voting members only to ensure complete objectivity as they discuss outcome results, make decisions, and formulate recommendations

Closed Session Report is confidential and marked accordingly

DMC operating procedures in place at the start of the trial, describing how DMC works and how it communicates with the other study participants

how the integrity of the study with respect to preventing dissemination of unblinded study information is ensured

administrative as well as methodological aspects of the DMC work

data flow

Possible conflicts of interest of DMC members

and adherence to these procedures is essential for all persons involved in DMC activities (12)

Independence increase objectivity

The standard policy used in the large majority of trials is to keep accumulating data confidential to DMC and statistician who prepares the report

Trial statistician?

Independent Statistician?

Independent Organization (academic group, CRO,…)?

« … the integrity of the trial is best protected when the statistician preparing unblinded data for the DMC is external to the sponsor…»FDA guideline (5)

Arguments in favor of using an independent statistician: retains the principle of keeping blind all those involved with the trial

prevents placing the trial stat in a difficult position

but

what’s the risk if this independent statistician is from the same company who is managing the data or the main analysis?

Protection measures: restricted areas for documentation and results for DSMBs

Consultancy

«New»/alternative approach/model -> ISAC and/or different CROs managing blinded and unblinded data / separate CRFs/DBs…

The NIH model vs. the Industry-Modified NIH Model

Members external to both the study and its sponsor

Independence of the committee is best maintained when the individuals responsible for the statistical analysis for the IDMC are ALSO INDEPENDENT of the sponsor

• External to, and independent of, the Sponsor

• Participate to both open and closed IDMC sessions

• Responsibility for data collection, site monitoring, data quality control and management

• Remains blinded to treatment assignments

Datasets without treatment assignments periodically transmitted for interim analysis

One-time transmission of the study randomization code to the (I)SAC before the study starts

IMPORTANT*: channel of communication for the discussion of data issues should be established between (I)SAC and DMgtC and/or sponsor before the trial begins!

* NHI= National Institutes of Health

Ref. (1), (11)

The role of ISAC: more than an analysis performer

Critical link between the IDMC and the Clinical Trial and/or Sponsor

Primarily responsible for producing interim data analysis and the reports for the IDMC (and analysis of the final data)

Protocol development support/review especially with regard of statistical aspects of study design and analysis

Interim Analysis Plan preparation or review

Development of statistical guidance for the interim monitoring (in collaboration with the sponsor and/or the IDMC)

Verification of key data items (randomization and primary endpoints) when data collection and management are not independent of the industry sponsor

Identification of topics of potential interest or concern to the IDMC, also during open sessions

Other functions supporting IDMC like preparing draft written operating procedures for the IDMC (IDMC charter), agendas and summary notes of IDMC meetings, general assistance in assuring that the IDMC functions smoothly, effectively, and confidentially

Involvement in the preparation of the final analyses and publication(s) in collaboration with the steering committee and the sponsor

Interim Monitoring reports

Information necessary for the IDMC in order to Monitor occurrence of AEs with the goal of ensuring patient safety

Monitor performance of the study (recruitment, baseline characteristics, adherence to the protocol,..) to asses whether modifications of the design and/or the study protocol might be appropriate to increase the likelihood of the trial’s success

Monitor evolving evidence regarding treatment efficacy to allow the IDMC to consider recommendations for early study termination for either efficacy or futility

(1)

Focus on Safety: Not only Statistical Analysis Tables

In most cases, safety monitoring is the major task for a DMC

Requests on DMCs:

not only

stopping rules/interim analysis/sample size re-estimations

but also

good overviews of safety (Data Safety Monitoring Boards)(8)

For DSMBs – different way to present data – PATIENT ORIENTED

Usual Stat tables

GRAPHS: Large amounts of info communicated in a manner that is maximally informative and easy to

review in a short period of time

Treatment comparisons, both at baseline and over time, easily examined as are time-related

trends in the data

Categorical data – bar charts (percent of pts in a particular category); continuous data –

boxplots; time-to-event data – Kaplan-Meier estimates of survival curves

Customized graphs - for example to display interim analysis boundaries

PT PROFILES, Pt profiles by graphs

OUTLIERS (SINGLE PT DATA AVAILABLE for outliers – conc

diseases/meds, SAEs,…)

Focus on Safety: Not only Statistical Analysis Tables

Demographic Information

Date of

Enrolled

Date of

Birth

Weight

(kg)

Height

(cm)

Age

(YEARS) Sex Race Ethnicity

DDMMM

YYYY (V1)

DDMMM

YYYY

xxx.x xxx.x xx FEMALE xxxx Hispanic

or Latino

Dosing Information

Was study

drug

dispensed?

Drug

Name

Drug

Unit

Date

study

drug

dispensed

How many

tablets

were

dispensed?

Was study

drug

returned?

Date study

drug returned

Number of tablets

taken

Yes/No xxxxxx xx DDMMMY

YYY (V X)

x Yes/No DDMMMYYYY

(V X)

x

Subject Summary

Subject Status

Completion/With

drawal Date

Reason for

Withdrawal

Duration of

Exposure (days)

Completed/Withdrawn DDMMMYYYY xxxx xxxx

Vital Signs

Date of Assessment

Diastolic Blood

Pressure (mmHg)

Systolic Blood

Pressure (mmHg)

Pulse Rate

(beats/min)

Temperature

(°C)

DDMMMYYYY (V X) xxx xx xx xx.x

Laboratory Test Results - Hematology

Sample Taken?

(Yes/No)

Date of Sample

Taken

Test

(units) Result (L/N/H) Normal Limits

Change

from

Baseline

Yes/No DDMMYYYY (V X) Test 1 (xxx) xx.x (x) xx.x-xx.x x.x

Adverse Events

SOC/PT/Verbatim Term

Start Date Stop Date Severity/ Serious? Relationship Outcome

Action

Taken Duration

Days to

Onset

DDMMYYYY DDMMYYYY Mild/Moderate/Severe/

Yes/No Rel/Not Rel

Recovered/ Recovered with Sequelae/Not

yet Recovered/Death/Unknown … xx xx

Case study – additional parties in the model

When the IMP, for its nature, can reveal easily, at least at certain points of the treatment period (usually at the very beginning), the treatment arms of the study (HIGHT UNBLINDING RISK)… independent parties can be involved in the data management and analysis processes

and

also the CRF and the DB can be split

and

SAPs and data analysis

Case study: Multicenter, randomized, double-blind, parallel-group, active-controlled, superiority study to compare the efficacy and safety of DRUG A to DRUG B in subjects with DISEASE X

The study was based on two CRFs and databases, i.e. main and first day monitoring database, in order to avoid unblinding of the Sponsor trial team.

Dedicated SAP for variables with unblinding potential: all analyses for the data that potentially could lead to unblinding, as defined in the Central Clinical Monitoring-Plan (CCMP) for the study

SAP was drafted by the Sponsor and forwarded, for review and usage, to a Biostatistics CRO that covers first dose monitoring and has access to the first dose monitoring database.

Sponsor Biostatistics do not have access to this data until after the final database-lock.

Case Study – data flow

Independent

CRO n.3 (Create ADaM and

Blinded Outputs)

Independent CRO

n.2

(SDTM and specs

for First Monitoring

data + pooling with

main data)

Pooled SDTMs

Potential Duplicates (es. Aes)

removed or managed by specific

flags)

Independent CRO n.1

(First Day Monitoring

eCRF)

LABs

[Main]

ISAC

(CRO)

Data

Management

department

Biostatistic

department

ADaM (all

datasets except

First Day

monitoring data)

Data

Collection

center

IDMC

Sponsor (Main eCRF)

SDTM + specs for

entire main

database

RAW data

[First Day monitoring]

Pooled ADaM

ECG:

[Main]

aCRF and SDTM specs for both

Main and First Day Monitoring;

SDTM for entire Main eCRF

Blinded

CCMP/IDMC

outputs

ADaM Cross

Compare

(excluding data

with unblinding

potential)

First Dose Monitoring

Outputs (to first dose

Monitors)

Case Study – difficulties and successes

Coordination several parties

Communication

Tight timelines

Data quality

Group of experts serving

DMC for this (and future)

studies

Possibility for the Sponsor

to review blinded data

results

Efficient secure platforms

for data exchange with

restricted access measures

When analysis of unblinded data are prepared by a

third party, the DMC working procedures should

clearly describe who performs these analyses and

the measures foreseen to avoid dissemination of

unblinded treatment information(6), (12)

Summary

ISAC as valid support for confidentiality in DMCs

There are several ways that the ISAC can facilitate the

work of the IDMC and the interactions between IDMC,

Sponsor and steering committee, in addition to

producing the interim monitoring reports

An Independent Statistical Analysis Center can be

responsible for a broad range of activities in support

to an IDMC and good clinical trial conduct, preserving

essential features of the well-established NIH clinical

trial model

Independency of the Stat team for IDMCs is well seen

by regulatory authorities and contributes to

effectively and efficiently to preserve confidentiality

References

(1) The role of an Independent Statistical Analysis center in the Industry-Modified National Institutes of Health model, Marian R. Fisher, PHD, Ellen B. Roecker, PHD, and David L. DeMets, PHD – Drug Information Journal, Vol. 35, pp. 115-129, 2001

(2) Issues in data monitoring and interim analysis of trials, AM Grant, DG Altman, AB Babiker, MK Campbell, FJ Clemens, JH Darbyshire, DR Elbourne, SK McLeer, MKB Parmar,SJ Pocock, DJ Spiegelhalter, MR Sydes, AE Walker, SA Wallace and the DAMOCLES study group – Health Technology Assessment 2005; Vol. 9: No. 7

(3) International Conference of Harmonization. E6: Guideline for Good Clinical Practice. Federal Register, 9 May 1997, Vol. 62, No. 90, p. 25691-25709. Available at: http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Efficacy/E6/E6_R1_Guideline.pdf

(4) International Conference on Harmonisation. E9 Statistical Principles for Clinical Trials. Federal Register, 16 September 1998, Vol. 63, No. 179, p. 49583. Available at: http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Efficacy/E9/Step4/E9_Guideline.pdf

(5) Guidance for clinical trial sponsors - Establishment and Operation of Clinical Trial Data Monitoring Committees. Federal Register, 28 March 2006. Available at: http://www.fda.gov/downloads/RegulatoryInformation/Guidances/ucm127073.pdf

(6) Guideline on Data Monitoring Committees, 27July 2005, EMEA, CHMP/EWP/5872/03. Available at: http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2009/09/WC500003635.pdf

(7) Data Monitoring Committees in Clinical trials – Guidance for Research Ethics Committees, May 2010 National Patient Safety Agency. Available at: http://www.hra.nhs.uk/documents/2013/10/data-monitoring-committees-in-clinical-trials.pdf

(8) Data and Safety Monitoring Board (DSMB) Guidelines. National Institute of Health (NIH), National Institute of Dental and Craniofacial Research (NIDCR). Available at: http://www.nidcr.nih.gov/Research/ToolsforResearchers/Toolkit/DSMBGuidelines.htm

(9) Fleming TR. Data monitoring committees and capturing relevant information of high quality. Stat Med 1993;12:565–70.

(10) Ellenberg S, Fleming T, DeMets D. Data monitoring committees in clinical trials: a practical perspective.Chichester: John Wiley; 2002.

(11) Heart Special Project Committee. Organization, review and administration of cooperative studies (Greenberg Report): A report from the heart special project committee to the National Advisory Council, May 1967. Control Clin Trials 1988;9:137–148.

(12) A proposed charter for clinical trial Data Monitoring Committees: helping them to do their job well, DAMOCLES study group. The Lancet 2005; 365:711-722.