CV SAFETY IN PHARMACEUTICAL DEVELOPMENT – ACADEMIC PERSPECTIVE

1. CV SAFETY IN PHARMACEUTICAL DEVELOPMENT – ACADEMIC PERSPECTIVE Rob Califf MD Vice Chancellor for Clinical ResearchDirector, Duke Translational Research Institute

2. Academic“Of theoretical interest, but of no practical value”

3. Years 3 6 9 12 15 Compound Success Rates Source: PhRMA, 2006 Industry Profile

4. 100 – 80 – 60 – 40 – 20 – 0 – Source: Device firms Biotech firms Funding ($ in billions) Pharma firms Private State/local Federal—non-NIH NIH 1994 1995 1996 1997 1998 1999 2000 2001 2002 2003 Reproduced from Moses et al., JAMA 2005;294:1333-42

5. Comparative Pre-Approval Capitalized Costs per Approved New Molecule ** All R&D costs (basic research and preclinical development) prior to initiation of clinical testing *** Based on a 5-year shift and prior growth rates for the preclinical and clinical periods DiMasi et al. 2003

6. Innovation Gap Getting Wider Pharma Innovation Gap Burrill & Company

7. Drug Safety System • Requires complex synergy between first rate science and first rate operational management on many levels in a complex supply chain • Components Manufacturers/distributors including multiple subcontractors Practitioners/hospitals/health systems/insurers/payers/public health systems Researchers Patients and consumers • A regulatory agency dealing with this complexity needs adequate staffing for routine function and first rate scientists for complex functions • Globalization, new understanding of clinical effectiveness and genomic sciences have made this job much more difficult (and interesting)

8. Safety • the condition of being safe from undergoing or causing hurt, injury, or lossMerriam-Webster Dictionary • The difficulty with safety of medical products Hurt, injury or loss occurs due to use or can occur due to lack of use Often the patient with the most to gain also has a high risk of toxicity • Accordingly Minimizing risk does not maximize safety

9. Safety Effectiveness Balancing Safety and Effectiveness Conceptual Goal: Not a ratio that can be calculated the same way for every person!

10. Domains of Cardiovascular Safety Assessment • Preclinical • Early clinical observation • Registration trials • Comparative Effectiveness PCTs Observational data • Safety surveillance Active Passive

11. Preclinical Cardiac Safety • Can we develop reproducible models that truly inform the human condition when exposed to a drug? • Human genetic disease models? • Transgenic models? • Can we link probabilistic information from preclinical models to the human condition?

12. The Real Question: What is the probability of this in clinical use relative to the probability of benefit?

13. Take the QT interval and Channel Testing • If QT is long and biological channel testing positive there is very likely a risk of torsades • We currently have no way of translating those signals into a quantitative risk of torsades/death • The epidemiology simply has not been done! • Without a quantitative estimate Decision makers tend to revert to “safe mode” Even the most rational person cannot make rational decisions

14. Early Clinical CV Safety • Can we develop effective biomarker signatures of cardiac toxicity in humans? • Can we understand the mechanistic/systems basis for observations with biomarkers?

15. Why do we need Systems Biology to identify and predict Biomarker Sets? Disease and drug action originate at the level of cellular components but physiological effects (e.g. symptoms, drug action) are at the organismal levels. Unraveling such complexity requires a systems approaches

16. Move from “Phase I” to true biological proof of concept! • Patient populations highly characterized • Reclassify disease characteristics • Define novel biological targets Target/Disease Intervention 2 Data Integration 4 1 3 5 • Research Tool Box • Easy access • Best of its kind • Define biological effects of drug/device • Early response • Toxicity • Move discovery into human testing • Best technology with efficient management • Highly professional, reliable staff • No “limits” on what can be done • Academic design • Results • Better biological understanding • Signatures of response, non response, toxicity and prediction • New Research Methodologies • IT & Bioinformatics deployed to collate and organize the array of results so they can be interpreted through statistical analysis

17. Protein Biomarkers and ‘Omics Goal: Detect molecular events in blood as a surrogate of local tissue responses

18. Gene Expression Predicts VTE RiskAntiPhosphoLipid Syndrome/Antibody • 57 APS pts + VTE • 32 APS pts - VTE • 32 aPLA - VTE • 8 controls • RNA processing, microarrays informatics • 100% accuracy VTE Blood 2006 107:1391

19. “Registration Trials” • Can we develop effective publicly transparent methods of deciding when registration trials must Provide threshold data for CV safety Provide definitive data regarding CV safety

20. Intervention True ClinicalOutcome Fleming and Demets Annals Int Med Disease SurrogateEndpoint Time

21. Time Disease True ClinicalOutcome A SurrogateEndpoint Intervention True ClinicalOutcome Flemming and Demets Disease B SurrogateEndpoint

22. Time Intervention Disease True ClinicalOutcome C SurrogateEndpoint Intervention True ClinicalOutcome Flemming and Demets Disease D SurrogateEndpoint

23. ? neurohormones Vesnarinone Systolic Function? Neurohormones Calcium Blockers Arrhythmia PD Inhibitors Neurohormones Epoprostenol Unintended Targets

24. ? neurohormones TNF- blockers Systolic Function? Neurohormones Moxonidine Neurohormones Flosequinon Fluid retention Doxazocin Unintended Targets

26. Pre-Approval Development Program • Pre-approval trials of sufficient size andduration to rule out a HR of 2.0 for MACE(upper 95% confidence interval). • Required: Pre-specified pooling of CVoutcomes in all trials with adjudication by anindependent clinical endpoints committee. • Useful: At least one study in patients at highCV risk, perhaps 1000 patients for 1-2 years

27. Pre-Approval Cardiovascular Studies MACE = major adverse CV events including death, MI, stroke, and hospitalization for revascularization

28. 87 Events to Exclude Upper 95% CI of 2.0 0.98 1.23 0.67 1.56 0.4 0.5 0.67 1.0 1.5 2.0 2.5 Active better Control better Nissen

29. Comparative Effectiveness (Pragmatic) • Can we get rid of the useless regulation and response to regulation that is stifling our ability to generate critical RCT data? • Can we convince policy makers that randomization is critical to sort out modest, but important differences in treatment effect? • Can we convince the US health system to incorporate evidence generation into practice?

31. Clinical Trial Cost Estimates $ In US 2007 Millions Full Cost Industry Streamlined Industry More Streamlined

32. Bureaucracy • 1 a : a body of nonelective government officials b : an administrative policy-making group • 2 : government characterized by specialization of functions, adherence to fixed rules, and a hierarchy of authority • 3 : a system of administration marked by officialism, red tape, and proliferation

33. Bureaucrats • Bureaucrats write memoranda both because they appear to be busy when they are writing and because the memos, once written, immediately become proof that they were busy Charles Peters • Hell hath no fury like a bureaucrat scorned Milton Friedman (1912 - )

34. Bureaucracy • The only thing that saves us from the bureaucracy is inefficiency. An efficient bureaucracy is the greatest threat to liberty Eugene McCarthy (1916 - ), Time magazine, Feb. 12, 1979 • Bureaucracy defends the status quo long past the time when the quo has lost its status Laurence J. Peter (1919 - 1988) • Any sufficiently advanced bureaucracy is indistinguishable from molasses. • Unknown

35. Comparative Effectiveness (Observational Studies) • Is there really way to make chicken salad out of chicken $%^@? • Can we develop a sentinel surveillance system that provides instantaneous Validation or refutation of observational comparisons Public review of whether efforts to “adjust” have been adequate Launching of proper RCT if needed

36. Consider Hemoglobin and Erythrpoieten • Anemia is bad The worse the anemia the worse the prognosis • Erythropoieten is a “natural product” • When erythropieten is given the higher the Hgb, the better the outcome • When people are randomized to higher or lower Hgb targets, lower does as well or better!

37. Safety Surveillance (Active) • Can we develop embedded systems in electronic health records that will enable rapid collection of well defined data? • What will happen with consumer driven reporting of drug events?

38. Fundamental Informatics Infrastucture--Matrix Organizational Structure Disease Registries—Granular, Detailed Integrated at “enterprise level” Primary Care Mental Health Cancer Cardiovascular Etc… Health System A ElectronicHealth Records Adaptable to all! Health System B Etc…

40. Expected Number of ADEs Background AEs Target Population All AEs ADEs = +DRUG = =

41. Expected Number of ADEs ADEs prevented Smaller safety database Less power ADEs prevented ADEs prevented ADEs prevented Larger safety database More power ADEs prevented ADEs prevented

42. Safety Surveillance (Passive) • Can we develop more effective methods of sorting signal from noise? • How will we deal with the ubiquitous nature of data warehouses that will be able to link use of a drug with adverse outcomes?

43. Risk Communication • Can we develop more effective methods of presenting uncertainty (probabilities) to The public? Professional audiences? The press? Congress?

44. Therapies Always Cause a Combination of: • Good Effects • Bad Effects Adapted from Furberg

45. Numeracy is the ability to reason with numbers and other mathematical concepts. To be numerically literate, a person has to be comfortable with logic and reasoning. Some of the areas that are involved in numeracy include: basic numbers, orders of magnitude, geometry, algebra, probability and statistics.

46. Poll: 7/5 of Americans Don't Bother To Do The Math A new poll shows that seven out of every five of Americans don't bother to do the math. "When asked, 53% percent said that, when reading or hearing anything that involves two or more numbers, they don't even rtry to do the math," said lead pollster Bradley Noel. "Another 49% said they will often think about doing the math but ultimately decide against it. Only 19% said they will actually add things up to see if the report makes sense.“ Source: innumeracy.com

47. Inaccurate reporting of news stories and insufficient skepticism in assessing these stories Financial mismanagement and accumulation of consumer debt, specifically related to misunderstanding of compound interest Loss of money on gambling, in particular caused by belief in the gambler's fallacy Belief in pseudoscience. According to Paulos, "Innumeracy and pseudoscience are often associated, in part because of the ease with which mathematical certainty can be invoked, to bludgeon the innumerate into a dumb acquiescence." Poor assessment of risk, for example, refusing to fly by airplane (a relatively safe form of transport) while taking unnecessary risks in a car (where an accident is more likely) Limited job prospects Consequences of Innumeracy

48. “I skate to where the puck is going to be, not to where it has been.” Wayne Gretzky(the Puck Stops Here!)