1. The Feasibility of Personalized Medicine Steffen Stürzebecher, M.D., Ph.D. Global PGx, Biomarker Development and Non- Clinical Statistics

2. Global Pharmacogenomics, Schering AG ACCP and AGAH 2006 joint meeting page AGHA_February 2006 20.02.062 The „hope vs. hype dilemma“ of the „Personalized Medicine“ claim One has to admit that the early promises have been as much an overestimation as the recent warnings appear to be overly cautious, that a relevant contribution of predictive personalized medicine will take another one or two decades to materialize......with regard to a broad use of tools to improve the personalized use of drugs, we face, however, more than only the challenges of “omics” tools, biomarker validation and proof of utility, i.e. the whole spectrum of societal aspects from cost utility of “response testing” to orphanized disease sub-entities

3. Global Pharmacogenomics, Schering AG ACCP and AGAH 2006 joint meeting page AGHA_February 2006 20.02.063

4. Global Pharmacogenomics, Schering AG ACCP and AGAH 2006 joint meeting page AGHA_February 2006 20.02.064 What have we learned yesterday already? There are quite a number of different meanings of BM and their respective purpose BM may be useful in drug development at different stages without delivering tools for personalized medicine in clinical practice (more the rule than the exception) even BM that had been around for a long time, e.g. PSA or Prolactin do not correlate (good enough) with treatment outcome only very few BMs are considered (true) surrogate markers a growing number of companies have adopted policies that require BM strategies to be in place before a drug is further promoted through the development pipeline (e.g. Pfizer) with regard to risk reduction and improved benefit/risk profiles, regulatory agencies will put more pressure on the development of predictive markers and you should have a 15 minutes training unit with the remote control before you give your talk

5. Global Pharmacogenomics, Schering AG ACCP and AGAH 2006 joint meeting page AGHA_February 2006 20.02.065 not yet

6. Global Pharmacogenomics, Schering AG ACCP and AGAH 2006 joint meeting page AGHA_February 2006 20.02.066 Two „extremes“ of personalized medicine (PM) Clinical Development approach: Better stratification or selection of patients in clinical trials = better prediction for a GROUP e.g. by sub-entity of disease, polymorphisms of target, polymorphisms in ADME can also be applied if selected group has only gradually better benefit than „all-comers“ Clinical practice: improve the use of the existing armamentarium of therapeutic and preventive drugs = better prediction for an individual patient

7. Global Pharmacogenomics, Schering AG ACCP and AGAH 2006 joint meeting page AGHA_February 2006 20.02.067 More than two options: The potential bridge between clin. dev‘t and medical practice: stratification marker with moderate/marked increase of probability to respond phase II stratification marker (moderate) used and confirmed; effect in „non-carriers“ = minimal phase III better worse post approval since minimal response in „non-carriers“, marker becomes „test“ and label requires prior testing accordingly

8. Global Pharmacogenomics, Schering AG ACCP and AGAH 2006 joint meeting page AGHA_February 2006 20.02.068 Current and future contribution of „omics“ to personalized medicine The new „omics“ tools certainly broaden the scope and increase the chances (beyond their research and dev. use) of re-defining disease subentities discovering new prognostic markers of the disease finding prediction markers of treatment outcome and tolerability improving treatment monitoring guiding escalation therapy approaches and drug combinations by BM monitoring

9. Global Pharmacogenomics, Schering AG ACCP and AGAH 2006 joint meeting page AGHA_February 2006 20.02.069 The idea of PM is not new in principle! Drug development as well as medical practice have always tried to select and „enrich“ patients with regard to the following aspects: early in drug development, e.g. more homogenous patient population in phase II than in phase III inclusion criteria that give the drug the „best chance to be effective“ more effective less tolerable drugs to be used later in treatment schedules

10. Global Pharmacogenomics, Schering AG ACCP and AGAH 2006 joint meeting page AGHA_February 2006 20.02.0610 The new era of „omics“ based search for BMs to eventually enable PM is different with regard to: biostatistical and bioinformatic approach to interpret and control the data hypothesis free vs. hypothesis driven approach multiplicity of data and pathway context of data Regulatory environment Public perception, e.g. overly optimistic or critical expectations

11. Global Pharmacogenomics, Schering AG ACCP and AGAH 2006 joint meeting page AGHA_February 2006 20.02.0611 Current and future contribution of „omics“ to personalized medicine The first examples beyond the „famous“ Herceptin, Gleevec, Irinotecan, Abacavir, Iressa stories appear to support that there is „justified hope“ Example of prognostic RNA Expression Profiling Signature in Breast Cancer (van de Vijver et al.) Example of RNA Expression Profiling Signature to predict treatment outcome of Taxane therapy in breast cancer Example of ovarian cancer diagnostic proteomics signature Example of DNA Methylation Marker (PIXT 2) in Breast Cancer prognosis and prediction of treatment outcome...most of them have still to stand up to independent confirmation and to proof of clinical validity and utility...

12. Global Pharmacogenomics, Schering AG ACCP and AGAH 2006 joint meeting page AGHA_February 2006 20.02.0612 The example of Breast Cancer A signature clearly distinguishing risk GROUPS overall and for LN + and LN- patients could be confirmed in three consecutive studies (van de Vijver et al., van‘t Veer et al),

13. Global Pharmacogenomics, Schering AG ACCP and AGAH 2006 joint meeting page AGHA_February 2006 20.02.0613 The example of Breast Cancer However, when trying to predict individual patients‘ outcome, the high odds ratios (13.7-15.3) and low p-values (p<0.001) don‘t translate into high accuracy of individual outcome:

14. Global Pharmacogenomics, Schering AG ACCP and AGAH 2006 joint meeting page AGHA_February 2006 20.02.0614 The example of Breast Cancer However, when trying to predict individual patients‘ outcome, the high odds ratios (13.7-15.3) and low p-values (p<0.001) don‘t translate into high accuracy of individual outcome: Initial study n=78 Test + (pos. progn.) Test – (neg. progn.) Disease free > 5 yrs. 2618 Disease dist. met. < 5yrs. 331 SensitivitySpecificityPPVNPV Initial study N=78 59%91%89%63% Confirmatory Study N=295 52%93%96%38% a Biomarker short of fulfilling the criteria of becoming a Surrogate marker can still contribute a lot to increase certainty in treatment option selection and treatment montitoring as compared to established prognostic criteria and scores (NIH etc.)

15. Global Pharmacogenomics, Schering AG ACCP and AGAH 2006 joint meeting page AGHA_February 2006 20.02.0615 Current and future contribution of „omics“ to personalized medicine Careful bridging from the infancy of a new biomarker era to a new paradigm in drug development and public health is necessary to avoid disappointment of public expectations with the consequence of e.g. withdrawal of public money, e.g. in the European FPs, Innovative Medicines Initiative to avoid overly optimistic expectations within pharmaceutical companies with the consequence of reduced budgets for „omics“ and biomarker search in development projects

16. Global Pharmacogenomics, Schering AG ACCP and AGAH 2006 joint meeting page AGHA_February 2006 20.02.0616 Current and future contribution of „omics“ to personalized medicine... to mitigate the notion that drug development will become less expensive in the short term to avoid the notion – or to adequately address- that diseases will be subsegmented to a point where part of them will no longer be in the focus of drug development – orphan indications of the reverse type

17. Global Pharmacogenomics, Schering AG ACCP and AGAH 2006 joint meeting page AGHA_February 2006 20.02.0617 Hurdles : (company) internal hurdles: the usual fear in Marketing of sub-segmenting the market the extra burden for Clinical Development to safeguard sampling for PGx (and the extra budget, e.g. for a middle-size phase III trial ~200-300 TEU for sample and save alone) uncertainty (unjustified) regarding IRBs‘ reaction to supplement pharmacoGENETIC protocols the extra „miles“ colleagues in Reg. Affairs and in Project Management have „to go“ A (few) word(s) on Incentives and Hurdles

18. Global Pharmacogenomics, Schering AG ACCP and AGAH 2006 joint meeting page AGHA_February 2006 20.02.0618 Hurdles : potential IRB/EC and other ethical hurdles: harmonization of IRBs/ECs with regard to pharmacogenetic studies still lacking (although not a major issue in our experience ) once a „probable valid biomarker“ e.g. predicting response and non-response to a drug has been identified, it may be considered unethical to still perform studies in all-comers (even if drug were effective on an all-comers basis but with a strong impact of the „predictor“) A (few) word(s) on Incentives and Hurdles

19. Global Pharmacogenomics, Schering AG ACCP and AGAH 2006 joint meeting page AGHA_February 2006 20.02.0619 „ Genetic Exceptionalism“ – a few cautionary remarks Altough one can argue for good reasons that genetics don‘t represent data of different „weight“ and sensitivity as compared to any other medical data,...

20. Global Pharmacogenomics, Schering AG ACCP and AGAH 2006 joint meeting page AGHA_February 2006 20.02.0620 „Genetic Exceptionalism“ There is the perception in the public (including IRBs/ECs and policy/law makers like the Council of Europe) that genetic data including pharmacogenetic data deserve special (data) protection long term storage and use of samples for „genetics“ with large scale analysis of genes potential new prognoses/diagnoses, e.g. of course of disease becoming possible (not revealed by phenotype) Industry will have to cope with this perception It is all the more important to distinguish between disease genetics and e.g. pharmacogenetic research between DNA related tests and dynamic genomic tests

21. Global Pharmacogenomics, Schering AG ACCP and AGAH 2006 joint meeting page AGHA_February 2006 20.02.0621 Disease geneticsPharmacogenetics

22. Global Pharmacogenomics, Schering AG ACCP and AGAH 2006 joint meeting page AGHA_February 2006 20.02.0622 Disease geneticsPharmacogenetics

23. Global Pharmacogenomics, Schering AG ACCP and AGAH 2006 joint meeting page AGHA_February 2006 20.02.0623 Disease geneticsPharmacogenetics Expression profiling, Proteomics, somatic mutations..

24. Global Pharmacogenomics, Schering AG ACCP and AGAH 2006 joint meeting page AGHA_February 2006 20.02.0624 Hurdles: regulatory and legal hurdles even embarking on PGx sampling and associated „claims“ in a study protocol can constitute the problem of being challenged to make best use of the samples and findings Regulatory agencies can re-define the level of impact of PGx data (regardless of what the sponsor‘s claims are) on a drug‘s dossier (e.g. FDA‘s GDS guidance)  which is, of course, appropriate given their duties to protect public health A (few) word(s) on Incentives and Hurdles

25. Global Pharmacogenomics, Schering AG ACCP and AGAH 2006 joint meeting page AGHA_February 2006 20.02.0625 Hurdles: regulatory and legal hurdles Push of regulators and/or e.g. third party payers to develop a validated test to „translate“ PGx findings into a routine testing tool.  Including the requirement of validation studies for PGx biomarker development Non-harmonized legislation e.g. regarding data protection and biobanking A (few) word(s) on Incentives and Hurdles

26. Global Pharmacogenomics, Schering AG ACCP and AGAH 2006 joint meeting page AGHA_February 2006 20.02.0626 Potential Incentives: (company) internal focussed indication rather than no indication at all (salvage of drugs by PGx based stratification) increased confidence of doctors and patients in treatment with perdictive test; improved adherence to treatment earlier attrition through employing PGx based biomarker related endpoints in early development last but not least (rather not in our/Schering‘s case) the additional commercial value of a Dx (use) patent extension for Dx/Rx combinations improved image of pharmaceutical industry re good care for the patient and for public health A (few) word(s) on Incentives and Hurdles

27. Global Pharmacogenomics, Schering AG ACCP and AGAH 2006 joint meeting page AGHA_February 2006 20.02.0627 Schering’s approach exemplified: overall: 1900 RNA samples

28. Global Pharmacogenomics, Schering AG ACCP and AGAH 2006 joint meeting page AGHA_February 2006 20.02.0628...this study can be used to develop prognostic markers of natural course of disease to discover predictors of treatment outcome to search for markers that help monitor disease activity to search for markers that help monitor treatment efficacy to further investigate the MoA of the drug of interest....

29. Global Pharmacogenomics, Schering AG ACCP and AGAH 2006 joint meeting page AGHA_February 2006 20.02.0629 In case of doubt, treat the patient Our favorite scenarios for the performance characteristics of a test in this case: high sensitivity - in identifying all responders to drug treatment...  more important to treat / enhance compliance of the maximum number of patients...  minimum number of false negatives, i.e patients falsely excluded from / taken off drug... at the price of limited specificity - i.e. rather accepting false positives since the drug has a good benefit/risk profile

30. Global Pharmacogenomics, Schering AG ACCP and AGAH 2006 joint meeting page AGHA_February 2006 20.02.0630 Potential Incentives: by regulators, legislation, reimbursement policies: Re-consideration of „patient subgroup based orphan drug status“ Option for patent extension (comparable to pediatric indications) based on new biomarkers guiding treatment decisions (consider re-defined biomarker dependent use of a drug as a label extension) Special reimbursement policy for drugs with biomarker guided prescription schemes Promotion of research and development of new biomarkers for better and safer treatment by public health policies A (few) word(s) on Incentives and Hurdles

31. Global Pharmacogenomics, Schering AG ACCP and AGAH 2006 joint meeting page AGHA_February 2006 20.02.0631 Beyond the development of new medical entities and research- how do deal with the drugs used today? Consequent use of ADME relevant pharmacogenetics Public funds needed to promote the pharmacogenetics around generic drugs! Laboratory, reporting and counseling standards and qualtity controls have to be established and different purposes of BM use should be considered with regard to stringency of requirements for certification

32. Global Pharmacogenomics, Schering AG ACCP and AGAH 2006 joint meeting page AGHA_February 2006 20.02.0632 courtesy Ron Zimmern

33. Global Pharmacogenomics, Schering AG ACCP and AGAH 2006 joint meeting page AGHA_February 2006 20.02.0633 The ethical and societal dimensions of PM: Learning more about disease outcome prognostic markers and treatment outcome predictors will gradually change the paradigms of medicine again rendering molecular medicine much more a routine application may change paradigms of cost-utility analyses and quality assurance in the public health sector needs more and better health and disease conscience education  increased need for counselling to enable patients to chose from options together with their doctors may lead to re-consideration of private insurance risks  and may need legislation or self-control to avoid „unjustice“ may leave certain subgroups of patients untreated (sub-optimally treated)

35. Global Pharmacogenomics, Schering AG ACCP and AGAH 2006 joint meeting page AGHA_February 2006 20.02.0635 Old and new tools of „Personalized Medicine“ Anatomical & functional imaging - CT, MRI, PET, SPECT mechanism of action: PTK-ZK --> early changes in vascular permeability (DCE-MRI) hints for clinical efficacy: number / size of MS brain lesions under treatment Classical Biomarker application - Physician‘s Eye & Ear clinical symptoms / scores & their change under therapy assessing the response to / outcome of treatment

36. Global Pharmacogenomics, Schering AG ACCP and AGAH 2006 joint meeting page AGHA_February 2006 20.02.0636 Old and new tools of „Personalized Medicine“ Molecular Biomarkers - *-omics, biochemical assays, clinical chemistry discovery - validation - routine laboratory test open “*-omics“ analyses - signatures / panels - single analytes All of these „tools“ have been used to stratify clinical studies as well as to select optimal treatment for patients in clinical routine use

37. Global Pharmacogenomics, Schering AG ACCP and AGAH 2006 joint meeting page AGHA_February 2006 20.02.0637 General Definition of Biomarker Biological marker - Biomarker A characteristic that is objectively measured and evaluated as an indicator of normal biologic processes, pathogenic processes, or pharmacologic responses to a therapeutic intervention Biomarkers Definitions Working Group “Biomarkers and Surrogate Endpoints: Preferred Definitions and Conceptual Framework“ Clinical Pharmacology & Therapeutics 69, 2001

38. Global Pharmacogenomics, Schering AG ACCP and AGAH 2006 joint meeting page AGHA_February 2006 20.02.0638 Early Dis-Proof Scenarios “weak“ compound (phase I)  BM detects no / weak biological drug effect related to desired MoA @ MTD in phase I  BM detects sub-maximal biological drug effect @ MTD in phase I good compound & bad target (phase I & phase II)  BM detects strong / maximum biological drug effect (phase I/II)  but: desired MoA not translating into clinical effect (phase II) “bad compound“ signal by early markers of toxicity / lack of tolerance (preclinical / phase I) Lack of Tolerance (Marker) / SAEs Dose Type I BM MTD Dose MTD Dose Optimal Dose Clinical Reponse (Marker)

39. Global Pharmacogenomics, Schering AG ACCP and AGAH 2006 joint meeting page AGHA_February 2006 20.02.0639 Drivers of Personalized Medicine In addition to a growing need to better steer and control health budgets, to avoid unnecessary or harmful drug treatment, the needs and „musts“ in pharmaceutical development will be a major driver to explore the options of PM

40. Global Pharmacogenomics, Schering AG ACCP and AGAH 2006 joint meeting page AGHA_February 2006 20.02.0640 „Internal needs“ Speed, early attrition / selection of development candidates, risk reduction in Clinical Development External Demands Ethics (committees) & scientific interest Regulators  may demand BM development where improvement of Tx risk / benefit evident or likely  e.g. from own PGx, external PGx data submissions, literature, state of the art  may not accept “exploratory“ status of submitted data  have established guidelines for biomarker development (GDS guidance) and offer support and collaboration (e.g. PG Briefing Meetings with CHMP, FDA; FDA “Critical Path Initiative“) PM needs and demands in drug development:

41. Global Pharmacogenomics, Schering AG ACCP and AGAH 2006 joint meeting page AGHA_February 2006 20.02.0641 Economics  future reimbursement policies: patient stratification as key to product sales  new response predictor can support LCM of mature product  earnings from commercialization of BM test as non-strategic “by- product“ PM needs and demands in drug development:

42. Global Pharmacogenomics, Schering AG ACCP and AGAH 2006 joint meeting page AGHA_February 2006 20.02.0642 availability of BMs may reduce duration of phase II  support dose finding in phase I / phase II  focus on biological response rather than on MTD, smaller dose range  shorter exposure to effect by use of early response / tox markers or surrogate endpoints  less activities in toxicology needed to cover exposure time in patients  option of staggered designs (phase I / IIa): early-into-patients  dose escalation in volunteers narrowly preceding dose escalation in patients BM in phase IIb and III may allow for development in (highly) enriched patient populations & may shorten time to first approval BM may rescue a compound only active in a sub-population of patients

43. Global Pharmacogenomics, Schering AG ACCP and AGAH 2006 joint meeting page AGHA_February 2006 20.02.0643 The protection of the patient from misuse of pharmacogenetic data is key to the progress in this field As unlikely as it is today that pharmacogenetic testing may lead to predictors of disease and/or treatment outcome with high enough probability to draw consequences regarding insurance coverage, this cannot be completely ruled out and, therefore, it is of utmost relevance to the progress in the field - that there are/is: Moratoria by private health and life insurers to not regard results of genetic testing in decision on insurance coverage or insurance premium (e.g. Netherlands, UK, Germany) Legislation banning the use of genetic test results by employers, insurers or in any other context of potential discrimination (e.g. Austria, France, Italy, Netherlands)