Biostatisticians lead the way

Kit RoesBiostatistics UMC Utrecht

BMS-ANed 22oktober 2009Biostatistics as conscience of the life sciences

François Chifflart (1825–1901), La Conscience (after Victor Hugo)

Conscience

Is an ability or a faculty that distinguishes whether one's actions are right or wrong.

It leads to feelings of remorse when a human does things that go against his/her moral values, and to feelings of rectitude or integrity when actions conform to moral values.

The extent to which such moral judgments are, or should be, based wholly in reason has been a matter of controversy almost throughout the history of Western philosophy.

Perspective(s)(and potential conflicts of interests?)

This presentation

Biostatistics in pharma industry

Examples Data irregularities FDA Advisory Committee DSMB & stopping studies

Roles & responsibilities: are statisticians sufficiently equipped?

Concluding remarks

Biostatistics in pharma R&D

Research Development

DiscoveryExploratory

DevelopmentFull Development

and Launch

Target Lead RegistrationLeadOptimization

Pre-clinical / CMCDevelopment

Pre-clinical / CMCDevelopment

Marketing & Sales

ClinicalDevelopment

ClinicalDevelopment

IIIa

IIbIII

Statistics / Quantitative modeling

Early Stage

Pharmacology and toxicologyBiomarkers, Pharmacogenetics &omics

Bio-analysis & assay validationEarly clinical development

Late Stage Clinical Development

Integrated analyses for submissions Interaction with regulatory authorities,

Phase IV, safety monitoring & signal detection

and publication support

Statistics LeadershipAt R&D Leadership level

Collaborating scientistsRelatively unstructured

Scientists also analyze dataStatisticians more advanced

Quality control

Clinical teams with clear roles & responsibilities

Statisticians analyze dataRoutinely involved in

interaction with authoritiesTeams within statistics

collaborate on same project

Quality control

Pharmaceutical statisticians

Little Use of Statistics

“Required” use Statistics

Tactical use of Statistics

Strategic use of Statistics

& “Statistical thinking” 1955 2009

Rockhold, 2002Rockhold, 2002

Regulated Confirmatory trials

ICH E9 Additional guidance (FDA, EMEA)

DMCs, Non-inferiority, Flexible designs, Missing data ……

All registrations in US: re-analysis of key results, publicly available, including critical assessments (Advisory Committees)

EMEA: Critical assessment (including statistical issues), publicly available.

Obligation to report results of all analyses performed (also post-hoc)

Perfect world?

Data irregularities

Electronic patient diaries (ePRO) Huge amounts of data

Graphical checking asinitial data analysis

Can reveal patterns With elaborate algorithm identified sites

suspect of clustering of entry times See also O’Gorman (DIA Clinical Forum,

2009)

As it should be…

Pattern emerges……

Data irregularities

Through internal Advisory Committee on suspected fraud (with statistician):

Sites investigated / audited / confirmed Reporting to authorities, including solution for

analysis

Pro-active measures for all new trials with similar devices

FDA Advisory Committee

Independent experts Advise FDA on approval

Questions Efficacious in… Safe in… (Benefit / Risk?)

Vote

FDA Briefing

Company Briefing

Question and answer

FDA Advisory Committee

DR. SZEGEDI: With regard to suicidality, be it completed suicide or suicide attempts, we have done several analyses and I would like Dr. Kit Rous from Biometrix to explain them to you.

DR. RUES: Thank you, Dr. Szegedi.If I understand your question correctly, I think the concern is that actually the rates of suicide to suicide attempts might differ in short and long term where actually as a result, the comparison across all time versus placebo would not provide the correct picture. We have addressed that question and we have done so by actually comparing suicides and suicide attempts because there are only very few suicides to draw any conclusions comparatively for asenapine and olanzapine,

http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/PsychopharmacologicDrugsAdvisoryCommittee/UCM179980.pdf

Topics of statistical nature

Missing data / drop-out Survival analysis / hazard rate assumptions

Treatment by Center and US vs Non-US Strength of evidence (positive/negative/failed

trials)

Key roles and challenges

Prepare for and address the “statistical” questions.

Communication

(Help) Ensure the whole team does not go beyond what the data allow to conclude.

Maintain integrity (while you cannot have everything your way)

The LIFT study (NEJM, Aug 14, 2008.The Effect of Tibolone in Older Postmenopausal Women, S.R. Cummings et al.)

Randomized, placebo controlled study in 4538 osteoporotic, postmenopausal women to evaluate the effect of 3 yrs treatment for prevention of vertebral fractures.

Primary endpoint: Incident vertebral factures after 3 years of treatment

Secondary: Clinical fractures

Key safety (pre-defined, partly): Endometrial hyperplasia Breast cancer, All cancer CHD, Stroke or TIA VTE

DSMB LIFT

DSMB Charter

Membership, responsibilities, procedures, reports, unblinding, conflict of interest.

Key efficacy data and key safety data to be monitored. Sequential monitoring of incidence of vertebral

fractures (Lan-Demets with a symmetric 5% O’Brien-Fleming-type spending function).

Additional considerations when interpreting the data:“No single statistical decision rule or procedure can take the place of the well

reasoned consideration of all aspects of the data by a group of concerned, competent and experienced persons with a wide range of scientific backgrounds and points of view.”

(1): A safety concern

August 2005 (average follow up 2.4 years) the LIFT DSMB:

Indicates shortly before their August 26, 2005 meeting that they might share a safety concern with representatives of Steering Committee and Sponsor.

That may involve (partial) unblinding.

Steering Cee & Sponsor procedure

Written and dated agreement was made to the following procedure (statistician responsible):

Potential unblinding to full report if needed: Two key Steering Committee members (incl. chair). The (non voting) Steering Committee member on behalf of the

sponsor. Two senior managers from the sponsor (Medical Affairs (MD)

and statistician), not involved in trial.

Subsequently, a larger group could be unblinded to limited information, if necessary for execution of the DSMB recommendation.

(1): What happened?

DSMB recommends: Inform LIFT participants and scientific community of observed

increased risk of stroke associated with tibolone in this study. Include rates, relative hazards, CI’s and p-values. Participants to re-consent. Continue the trial for important additional scientific data.

Steering Committee and sponsor representatives: Decided not to be further unblinded (beyond what will be

made public).

BMJ 2005, 8 October. LIFT study to continue as planned. D.E. Grobbee.

(2): Stopping the trialFebruary 2006 (6 months later) DSMB recommends discontinuation:

Increased risk of stroke persisted in the LIFT study. Primary endpoint established, crossing the pre-defined

stopping boundary.

Sponsor representatives and key Steering Committee members enabled to review unblinded report (after written confidentiality statement and over the weekend).

Sponsor and Steering Committee reach same conclusion and support DSMB recommendation.

BMJ 2006,18 March, LIFT study is discontinued. S.R. Cummings on behalf of LIFT Steering Committee

DSMBs

Key area where statisticians continue to make a huge contribution to clinical research integrity.

Innovation in statistical methodology Impact on DSMB operation and status Typically area where statisticians are in the lead

(although not the chair) Ellenberg, Fleming & De Mets, Whitehead, Pocock EMEA Guideline, FDA Guidance Internal pharma SOPs

Roles & responsibilities

Adequately equipped? Technical knowledge and continuous innovation Non-quantitative (biology, medicine, regulations) Collaboration and teamwork

Communication Leadership Integrity (ethics….)

Unscientific: Google hits

Chemistry and Ethics 5.5 M Physics and Ethics 6 M Mathematics and Ethics 7 M Statistics and Ethics 12 M Psychology and Ethics 15 M Medicine and Ethics 19 M Law and Ethics 40 M

Professional standards

ISI Declaration of Professional Ethics ASA Ethical Guidelines for Statistical Practice RSS Code of Conduct Statistics Netherlands (CBS), and Norway,

and……

………..

ISI Declaration of Professional Ethics

Society

Paymasters

Colleagues

Subjects

Conflicting interests Guarding against misuse and misinterpretation Benefits as large as possible Objective, transparent about limitations

Clarity in roles and responsibilities Impartial assessment of alternative methods No pre-emption of outcomes Safeguard privileged info while revealing methods

Maintaining confidence in statistics Transparency of methods Knowing ones own ethical principles and those of

collaborators

Principles of Informed Consent

ASA and RSS

Add:

Statistical analysis should be open to assessment, limits and source of data analyzed visible.

Data available for analysis by appropriate others

Acknowledge that statistician can be overruled by others (RSS)

Concluding remarks

Keep our own conscience clear Peer review and collaborative work on projects* Innovate Integrity maintained as part of group shared value Organization and seniority to facilitate

Educate ourselves (if not already done) Statistics and ethics (curricula available)

* Registration of VVS-Biostatisticians