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Bernhard Huitfeldt 24 Oct 20121 FMS and the development of biostatistics during 25 years (mostly from a pharma industry perspective) FMS jubilee conference.

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Presentation on theme: "Bernhard Huitfeldt 24 Oct 20121 FMS and the development of biostatistics during 25 years (mostly from a pharma industry perspective) FMS jubilee conference."— Presentation transcript:

1 Bernhard Huitfeldt 24 Oct 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

2 Bernhard Huitfeldt 24 Oct 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.

3 Bernhard Huitfeldt 24 Oct 20123

4 4 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)

5 Bernhard Huitfeldt 24 Oct The first FMS members elected on November 27, 1987 (n = 17) Tore HaglundAstra 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

6 Bernhard Huitfeldt 24 Oct FMS presidents Mats LörstadAstra Hässle - Mölndal Bernhard HuitfeldtPharmacia - Uppsala Stephan OgenstadAstra Arcus - Södertälje Hans WedelNordiska hälsovårdshögskolan Eva KeltyCDC - Lund Juni PalmgrenMEB, Stockholms Universitet Elisabeth SvenssonÖrebro Universitet Ziad TaibAstraZeneca - Mölndal Tom BrittonStockholms Universitet Stig Johan WiklundAstraZeneca - Södertälje Anna TorrångAstraZeneca - Södertälje Anna EkmanSahlgrenska sjukhuset - Göteborg

7 Bernhard Huitfeldt 24 Oct Membership 1987 (n = 17) 1996 (n =175) 2012 (n > 200) CategoryNumber Pharma Industry74 CRO13 Other Industry2 Hospitals21 University46 Authorities6 Unspecified13 Total175 Distribution 1996

8 Bernhard Huitfeldt 24 Oct 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)

9 Bernhard Huitfeldt 24 Oct Workshops Intention-to-treat, Adverse drug effects: Bob O’Neill, 1990 Meta-analysis of clinical trials: John Lewis, Peter G Ø tzsche,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

10 Bernhard Huitfeldt 24 Oct 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

11 Bernhard Huitfeldt 24 Oct 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

12 Bernhard Huitfeldt 24 Oct 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

13 Bernhard Huitfeldt 24 Oct 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

14 Bernhard Huitfeldt 24 Oct 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

15 Bernhard Huitfeldt 24 Oct FMS partners (2009 -)

16 Bernhard Huitfeldt 24 Oct Holders of scholarships (stipendiater) 2009 Therese Andersson Caroline Dietrich Anna Genell 2010 Sandra Eloranta Anna Johansson Sharon Kühlman Berenzon 2011 Anna Ekman Anna Lindam Rebecca Rylance Halef Darabi 2012 Anna Johansson Achilles Tsounamis Adnan Noor ( kr) ( kr)

17 Bernhard Huitfeldt 24 Oct Situation 1987 Relatively simple statistics in design and analysis used in clinical trials 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.

18 Bernhard Huitfeldt 24 Oct Phase 1Phase 2a,b Phase 3aPhase 4 Phase 3b Stages in drug development

19 Bernhard Huitfeldt 24 Oct Source: 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

20 Bernhard Huitfeldt 24 Oct Processes in clinical trials Clinical Study Protocol incl. SAP and CRFs Database design Data capture Data management Reporting Database Analysis & Reporting Output database Clinical Study Report and Publication Processes Tools Roles & Responsibilities Patient data listings Summary tables & graphs Statistical analysis output

21 Bernhard Huitfeldt 24 Oct 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

22 Bernhard Huitfeldt 24 Oct Statistical methodology 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

23 Bernhard Huitfeldt 24 Oct Computer technology and software –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.

24 Bernhard Huitfeldt 24 Oct Regulatory guidelines –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

25 Bernhard Huitfeldt 24 Oct ICH/E9

26 Bernhard Huitfeldt 24 Oct Dagens Industri 14 september 2004 “När sedan FDA:s statistikexpert gick till angrepp blev det den sista spiken i kistan ……..”

27 Bernhard Huitfeldt 24 Oct 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)

28 Bernhard Huitfeldt 24 Oct Public trust challenged The JAMA story Ethics code Authorization of statisticians

29 Bernhard Huitfeldt 24 Oct 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

30 Bernhard Huitfeldt 24 Oct The evolution of biostatistics?

31 Bernhard Huitfeldt 24 Oct Happy birthday! We can be proud of what we have achieved so far We have many challenges to tackle in the future

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