bernhard huitfeldt 24 oct 20121 fms and the development of biostatistics during 25 years (mostly...

Bernhard Huitfeldt 24 Oct 2012 1

FMS and the development of biostatistics during 25 years

(mostly from a pharma industry perspective)

FMS jubilee conference at Utö, 25 October 2012

Bernhard Huitfeldt

BH Statistical Consulting


Your future depends on your history

Janus:The Roman god of beginnings and transitions and …… time and he looks to the future and the past.


By-law aims for FMS

• Contribute to improved use of statistical methods within medicine

• Be a forum for discussions about statistical applications, primarily within drug industry

• Promote exchange of professional skills between the members

• Represent Swedish medical statistics in international relations such as EFPSI (from 2004)


The first FMS members elected on November 27, 1987 (n = 17)

• Tore Haglund Astra Alab• Stephan Ogenstad Astra Alab• Carl Johan Lamm Astra Draco• Klas Svensson Astra Draco• Mats Lörstad Astra Hässle• Sören Romare Astra Hässle• Christina Eskilsson Kabi Vitrum• Olivier Guilbaud Kabi Vitrum• Leif Trulsson Kabi Vitrum• Örjan Nordle Leo Läkemedel• Göran Nilsson Pharmacia• Ingemar Selinus Pharmacia• Alexandra Tsipogianni Sahlgrenska sjukhuset• Sture Holm Göteborgs Universitet• Ann-Sofie Matthiesen Stockholm Universitet• Marie-Louise Nordström Uppsala Universitet


FMS presidents 1987 - 2012

1987-1989 Mats Lörstad Astra Hässle - Mölndal1989-1991 Bernhard Huitfeldt Pharmacia - Uppsala1991-1993 Stephan Ogenstad Astra Arcus - Södertälje1993-1996 Hans Wedel Nordiska hälsovårdshögskolan1996-1998 Eva Kelty CDC - Lund1998-2000 Juni Palmgren MEB, Stockholms Universitet2000-2002 Elisabeth Svensson Örebro Universitet2002-2005 Ziad Taib AstraZeneca - Mölndal2005-2007 Tom Britton Stockholms Universitet2008-2009 Stig Johan Wiklund AstraZeneca - Södertälje2010-2012 Anna Torrång AstraZeneca - Södertälje2012- Anna Ekman Sahlgrenska sjukhuset -

Göteborg


Membership

• 1987 (n = 17)• 1996 (n =175)• 2012 (n > 200)

Category Number

Pharma Industry 74

CRO 13

Other Industry 2

Hospitals 21

University 46

Authorities 6

Unspecified 13

Total 175

Distribution 1996


Main activities

• Spring and autumn meetings with a scientific program (n = 50)

• Workshops (n = 9)• Courses (n = 11)• Guidelines reviews - ICH, EMA, FDA (n ≥ 8)

• Founding member of EFSPI (1989)


Workshops

• Intention-to-treat, Adverse drug effects: Bob O’Neill, 1990• Meta-analysis of clinical trials: John Lewis, Peter GØtzsche,1991• Sampling designs for public health investigations:

(Surveysektionen), 2003 • Adaptive design: Christopher Jennison, 2007• Methods for consultations: 2008• Statistical methods for cancer patient survival: 2009• Statistical issues in medical statistics: (DSBS), 2010• Model based drug development: (SSL), 2011• Benefit-risk assessment methodology: (DSBS), 2012


Courses

• Repeated measurements: Mike Kenward & E. Allen, 1990• Crossover-trials: Mike Kenward, E. Allen 1991• Ordered categorical data: John Whitehead, 1992• Meta-analysis: Anne & John Whitehead, 1993• Survival analysis: Per K Andersen, Niels Keiding, 1994• Dose-response: Aage Völund, Juni Palmgren, Sture Holm, Philip

Hougaard, 1995• Repeated measurements: Juni Palmgren, Sture Holm, Dietrich v

Rosen, 1996• Bayesian methods: Don Berry, 1997• Missing data: Rod Little, T Raghunatan, 1999• Mixed models: Robert Prescott, Helen Brown 2004• Non-linear mixed effects models: Ed Vonesh, 2009


Themes at spring and autumn meetings

• Bioequivalence, 1987• Design of experiments, 1988• Development of diagnostic methods, 1989• Quality of life, 1991• Survival analysis and chaos, 1992• Epidemiology, 1993• Health economy, 1994• Authorization of statisticians, 1995• Genetic statistics, 1998• Bioinformatics, 1999• The role of statistics and statisticians in drug development, 1999• Design and analysis of equivalence and non-inferiority trials,

2000


Themes at spring and autumn meetings (cont’d)

• Competing risks and multivariate survival data, 2000• Current biostatistics research in Sweden, 2002• Risk evaluation of drugs and food, 2002• Bayesian inference in biostatistics (David Spiegelhalter), 2003• Statistical issues in drug development (Stephen Senn), DSBS,

2004• Modern statistical methods in medical research (Sir David Cox),

MEB, 2004• Statisticians in the medical debate – shut up or speak up, 2005• Current biostatistics research and education, 2005


Themes at spring and autumn meetings (cont’d)

• Statistical issues applicable in drug development (Peter Diggle), 2006

• Important statistical issues in the drug industry, 2006• Epidemiology and genetics (SSL, FSB), 2007• Animal and statistics, 2007• Jubilee conference 20 yrs (Andy Grieve), 2008• Healthy statistics – ethical issues on the border between

statistics and medicine (SSFr), 2008• Multivariate 2.0, 2009• Multiplicity (Yudi Pawatan), 2010• Statistical issues in medical statistics (DSBS), 2010• Register based statistics, (Surveyföreningen), 2011


Guideline reviews

• 1995: ICH guideline E3, Structure and content of clinical study reports

• 1999: ICH guideline E10, Choice of control group in clinical trials

• 2002: EMA points to consider, Adjustment for baseline covariates

• 2004: EMA points to consider, Choice of non-inferiority margin

• 2004: ICH guideline E 14, QT/QTc interval prolongation• 2005: EMA guideline on data monitoring committees• 2010: FDA guideline on non-inferiority studies• 2010: FDA guideline on adaptive designs


FMS partners (2009 -)


Holders of scholarships (stipendiater)

2009 Therese AnderssonCaroline DietrichAnna Genell

2010 Sandra ElorantaAnna JohanssonSharon Kühlman Berenzon

2011 Anna EkmanAnna Lindam

Rebecca RylanceHalef Darabi

2012 Anna JohanssonAchilles Tsounamis

Adnan Noor

(15 000 kr)

(15 000 kr)

(25 000 kr)

(25 000 kr)


Situation 1987

• Relatively simple statistics in design and analysis used in clinical trials 1987.

• Regulatory authorities started to become more demanding (FDA mostly).

• Almost no statistics provided by professional statisticians existed in preclinical research.

• Computer facilities rather primitive, start of advanced database technology (Oracle), SAS, BMDP, lack of harmonization on data standards.


Phase 1 Phase 2a,b

Phase 3a Phase 4

Phase 3b

Stages in drug development


Preclinical

Phase I

Phase II

Phase III

Registration

11.1.

9 %

12%

19%

64%

100 %

8.6 5.3 1.6 1

Success RatesSource: R&D General Metrics 2007, Pharmaceutical Benchmarking Forum, slide 248

Success Rate to Approval

Number of drugs needed in each phase to achieve one approval


Processes in clinical trials

Clinical Study Protocol incl. SAP and CRFs

Database design Data capture

Data management

Reporting Database

Analysis&

ReportingOutput database

Clinical Study

Report andPublication

•Processes

•Tools

•Roles & Responsibilities

•Patient data listings

•Summary tables & graphs

•Statistical analysis output


Roles and responsibilities

• From p-value producer to strategic project partner• Expert adviser• Leadership roles and decision maker

• Study statistician• Project statistician• Global project statistician• Research statistician• Expert roles – therapeutic area, adverse

effects, pharmacokinetics etc


Statistical methodology 1987 -2012

• Bioequivalence• Generalized Linear Models, Mixed models, Random

effect models, Repeated measures etc.• Missing data• Meta-analysis• Non-inferiority• Bayesian statistics, decision analysis• Adaptive designs including group sequential trials• Modeling & simulation• Outcome studies, mega-studies• Observational studies, non-intervention studies


Computer technology and software 1987 - 2012

– Increase of speed and capacity of computers• Database technology, increased volumes of data,

bioinformatics, computer intensive methods

– General statistics software packages, new procedures in

• SAS, SPSS, S-plus, R etc.

– Special statistics software• East, nQuery + interim, ADAPT, BUGS etc.


Regulatory guidelines 1987 - 2012

– International Conference of Harmonization (ICH)

• Safety, Quality, Efficacy (E9 and E10 etc.)

– Food Drug Administration (FDA)

• General methodology and disease specific guidelines

– European Medicines Agency

• Points to consider


ICH/E9


Dagens Industri 14 september 2004

“När sedan FDA:s statistikexpert gick till angrepp blev det den sista spiken i kistan ……..”


Globalization

• Global companies and global markets, multinational studies, bridging• Cooperation between authorities (FDA, EMA, Japan…)• Strong professional organizations (ISCB, DIA, EFSPI, ASA, PSI..)• International conferences• Biopharmaceutical statistical science becomes global with dedicated journals

- J. of Biopharmaceutical Statistics (US, 21st year)

- Pharmaceutical Statistics (PSI, 10th year) - Statistics in Biopharmaceutical Research (ASA, 3rd year)


Public trust challenged

• The JAMA story

• Ethics code

• Authorization of statisticians


Quotation from a related area

• “The work during the past 30 years in has in the best case been

sensationally worthless or in the worst case directly detrimental”

• “… the more frequent use of these models implied that the became less interested in the reality and more fascinated of mathematical relations”

macroeconomy

economists


The evolution of biostatistics?


Happy birthday!

• We can be proud of what we have achieved so far

• We have many challenges to tackle in the future

bernhard huitfeldt 24 oct 20121 fms and the development of biostatistics during 25 years (mostly...

Documents

courses n

workshops n

fms members

scientific program n

statistical issues

statistical applications

fms presidents

survival analysis