# Presentation: 141720

## Developing Chronic Disease TherapiesPresentation to the FDA Science Board

**Robert M Califf MD**
**Director Duke Clinical Research Institute**
**Details in: Health Affairs: 23:77-88; 2004**

## Key Points

**Chronic diseases will be (are) the dominant health issue in our society**
**Predicting whether a chronic disease therapy causes net benefit or harm is difficult**
**Biomarkers and imaging are the way to go**
- But mostly as a screen
- Cannot substitute for clinical outcomes in most circumstances
**Tremendous inefficiency in clinical trials**

## Life Expectancy

**Years**

**Years**

**Life Expectancy**

## Global Burden of Disease: Top 10

**Global Burden of Disease: Top 10**

## Age-Standardized Distribution of Disability

***Manton KG et al. Proc Natl Acad Sci 2001;98:6354-9***

## Total Number of Persons Age 65 or Older in the United States: 1900-2050

- 1900

- 1950

- 2000

- 2050

**0**

**20**

**40**

**60**

**80**

**Millions **
**of people**

**Year**

***projected**

*****

- US Census Bureau, Decennial Census Data and Population Projections

**Age 65 or older**

**Notes:**
Total Number of Persons Age 65 or Older in the United States: 1900-2050
The population of persons over 65 years is growing rapidly. Improvements in medical care and survival rates have led to improved life expectancy resulting in a proportionately larger population of elderly patients. Current and projected numbers of people over the age of 65 years in the United States are shown.  It is expected that by the year 2050 the number of people over the age of 65 years will double from 40 to 80 million as compared to today.

## Medicare Growth 2002–2030

**Medicare Growth 2002–2030**

**Medicare enrollment**
- 		2002:	40 million
- 		2030:	77 million
*	**—**N Engl J Med 2001;344:928–31*
**Worker : beneficiary ratio**
- 		2002:	4.0 : 1
- 		2030:	2.3 : 1
- 		2070:	2.0 : 1
*	**—**www.whitehouse.gov*

## Annual Report to Congress, the Medicare Board of Trustees

- “The financial status of the fund has deteriorated significantly, with asset exhaustion projected to occur in 2019 under current law compared to 2026 in last year's report.”** **
- Medicare will grow much faster than the economy as a whole, increasing from 2.6 percent of the gross domestic product last year to 3.7 percent in 2010, 7.7 percent in 2035 ...
- Projected Medicare costs would exceed those for Social Security in 2024 ...

*-- March 23, 2004*

## Drivers of Healthcare Consumerism

## Slide 10

## The Cycle of Clinical Therapeutics—New Model

**Concept**

**Outcomes**

**Clinical Trials**

**Guidelines**

**Performance**
**Indicators**

**Performance**

**The Cycle of Clinical Therapeutics—New Model**

**Education**
**and**
**Feedback**

## Principles for Trials Designed to Define Balance of Risk and Benefit of Therapy

**Treatment effects usually modest**
**Qualitative interactions are uncommon**
**Quantitative interactions common**
**Unintended targets common**
**Long-term vs. short-term effects may differ**
**Combinations are unpredictable**
**Class effect may not be valid**
**Most treatments produce a mixture of benefits and risks**
- Califf and DeMets  Circ 2002

## Principles of Trials Designed to Elucidate the Balance of Risk and Benefit of Therapies

**Most beneficial therapies do not save money, but create incremental benefit for incremental cost**
**Applying the results of clinical trials is beneficial**
**Some areas of CV medicine are underserved and therefore lack evidence to guide practice**
**Our current method of doing trials is unnecessarily expensive**
**Participation is critical**
- Califf and DeMets Circ 2002

## Sample Size

**0-50****	****< 500****	****> 0.9****	****Utterly inadequate**
**50-150****	****1000****	****0.7-0.9****	****Probably inadequate**
**150-350****	****3000****	****0.3-0.7****	****Possibly inadequate**
**350-650****	****6000****	****0.1-0.3****	****Probably adequate**
**> 650****	****10000****	****< 0.1****	****Adequate**

**Sample Size**

***Yusuf Progr CV Dis 1985***

**Probability of failing to achieve p < .01 if risk reduction = 25%*

**9503CG01**

## CAST

**CAST**

***Echt, N Engl J Med, 1991***

**Days after Randomization**

**Patients without Event (%)**

**Placebo (n = 743)**

**Encainide****or Flecainide****(n = 755)**

**p = 0.0004**

## Unintended Targets

## Unintended Targets

## Time

**Time**

## Time

**A**

**B**

**Time**

**Disease**

- SurrogateEndpoint

**True ****Clinical****Outcome**
**Flemming and Demets**

*Intervention*

**Disease**

- SurrogateEndpoint

**True ****Clinical****Outcome**

## Time

**D**

**Time**

**Disease**

- SurrogateEndpoint

**True ****Clinical****Outcome**
**Flemming and Demets**

*Intervention*

**Disease**

- SurrogateEndpoint

**True ****Clinical****Outcome**

*Intervention*

## Therapies Always Cause a Combination of:

*Good Effects*

*Bad Effects*

*Adapted from Furberg*

**Therapies Always Cause a Combination of:**

## Troponin and Risk Stratification in ACS:GUSTO-IIa and TIMI-IIIb

**TnT +**

**TnT -**

**Mortality Rates**
- TnT Pos: 14%
- TnT Neg: 5%

**p < 0.001**

- Troponin I (ng/ml)

- p < 0.001

*—**Ohman EM, et al. NEJM 1996*

*—**Antman EM, et al. NEJM 1996*

## Combined All-cause Mortality and Morbidity

**Event-free probability**

**13.3 % risk reduction **

**0**

**3**

**6**

**9**

**12**

**15**

**18**

**21**

**24**

**27**

**Months**

**65**

**0**

**70**

**75**

**80**

**85**

**90**

**95**

**100**

**Placebo**

**Valsartan**

***P*****=0.009**

**Cohn, et al. *****N Engl J Med*****.  2001.**

**n=5010**

## Subgroup Results

**1.25**

**Subgroup****	****% pts**
**Overall****	****100**
**Beta blocker (yes)****	****35**
**no beta blocker ****	****65**
**ACEI (yes)****	****93**
**no ACEI* ****	****  7**

**1.0**

**0.75**

**0.50**

**.87**

**.77**

**.97**

**Valsartan better**

**Valsartan worse**

**Mortality and Morbidity**

**44.0% ********, *****P*****=.0002**

**Cohn.  *****N Engl J Med*****. 2001; *FDA analysis/package insert**

**	****RR of death ****	*****P***
**no ACEI ****	******** 41%****	****<0.05***
**ACEI + Beta blocker ****	******** 42% ****	****0.009**

**Subgroup Results**

***n=366**

## Valsartan Approved for CHF(But with 3 subgroup provisos)

- Indications and Usage
**Diovan is indicated for the treatment of heart failure (NYHA class II-IV) in patients ****who are intolerant of ACEIs.**** In a controlled clinical trial, Diovan significantly reduced hospitalizations for heart failure. ****There is no evidence that Diovan provides added benefits when it is used with an adequate dose of an ACEI.**
**Concomitant use with an ****ACEI and a beta blocker is not recommended.**

## Subgroup analysis: a machine for generating false negatives

- -- Richard Peto

***Lancet*****. 1988**

- ISIS-2	ASA	Placebo	RR	*P*
- Gemini or Libra	11.1%	10.2%	1.09	NS
- Others	9.0%	12.1%	0.72	<0.00001

## Small Trials (low number of deaths) are Unreliable

## Mortality 1 year-GUSTO 4

**22,4**

**18,3**

**15,7**

**12,8**

**6,9**

**7**

**9,3**

**7,9**

**4,1**

**3,8**

**4,1**

**3,5**

**2,7**

**1,2**

**2,7**

**1,6**

**0**

**5**

**10**

**15**

**20**

**25**

**<= 237**

**237- 669**

**669- 1869**

**>1869**

**NT-proBNP,**
**quartiles ng/L**

**> 0.47**

**0.12 - 0.47**

**0.01 - 0.12**

**<= 0.01**

**Troponin T, quartiles ug/l**

**Mortality 1 year-GUSTO 4**

**%**

## Mortality 1 year-GUSTO 4

**23,4**

**15**

**17,2**

**16,7**

**9**

**8,1**

**6,4**

**7,1**

**4,8**

**4,9**

**3,6**

**2,7**

**2,8**

**0,5**

**2,7**

**1,6**

**0**

**5**

**10**

**15**

**20**

**25**

**<= 237**

**237- 669**

**669- 1869**

**>1869**

**3.96- 9.62**

**>9.62**

**CRP, quartiles mg/L**

**<= 1.84**

**1.84- 3.96**

**%**

**NT-proBNP,**
**quartiles ng/L**

**Mortality 1 year-GUSTO 4**

## Mortality 1 year-GUSTO 4

**25,7**

**16,4**

**12,3**

**8,2**

**12,2**

**8**

**6,9**

**3,1**

**8,2**

**5,2**

**2,1**

**1,8**

**6,8**

**2,9**

**1,6**

**0,3**

**5**

**10**

**15**

**20**

**25**

**30**

**0**

**<= 237**

**237- 669**

**Creatinine clearance, ml/min**

**%**

**NT-proBNP,**
**quartiles ng/L**

**Mortality 1 year-GUSTO 4**

**<=51**

**51-66**

**66-84**

**>84**

**669- 1869**

**>1869**

## Mortality 1 year

**17,8**

**10,2**

**11,6**

**8,8**

**14,1**

**8,9**

**5,1**

**7,7**

**13,8**

**7,7**

**5,6**

**5,8**

**6,1**

**3,2**

**5,1**

**1,7**

**0**

**2**

**4**

**6**

**8**

**10**

**12**

**14**

**16**

**18**

**3.96- 9.62**

**>9.62**

**CRP, quartiles mg/L**

**<= 1.84**

**1.84- 3.96**

**%**

**Mortality 1 year**

**Troponin T, **
**kvartiler ug/l**

**> 0.47**

**0.12 - 0.47**

**0.01 - 0.12**

**<= 0.01**

## “Information systems can now draw meaningful statistical inferences pertinent to each individual from massive data sets that include genomic data, imaging results, and biomarker analyses along with traditional clinical variables.  Such evidence, made available to clinicians working at the point of care, can direct the most appropriate preventative and therapeutic actions.”

- “Information systems can now draw meaningful statistical inferences pertinent to each individual _from massive data sets that include genomic data, imaging results, and biomarker analyses_ along with traditional clinical variables.  Such evidence, made available to clinicians working at the point of care, can direct the most appropriate preventative and therapeutic actions.”

*—**RS Williams, Science, April 2003*

## Predicting Clinical Benefit and Toxicity

**Biomarkers and imaging—the pathway**
**If we don’t develop effective approaches to “interoperability” of these data we will suffer**
- Multivariable nature of biology increases needed sample sizes  by log orders
- No single entity (corporation or institution) has enough cases to validate complex biological predictive models
**Allowing the market to “sort it out” is playing Russian roulette with the public health**

## Background

- Estimated $26.4 billion spent annually for R&D, $4.1 billion on Cardiovascular trials
- Hypothesis: design of the operational plan impacts overall costs, and operational plans are put together in a risk averse manner
- Objective: assess the importance of trials functions to total costs and estimate cost savings through changes in trial design and management

## Background - cont’d

- Methods - two clinical trials case studies were prepared
**participants completed a simple 16 question survey based on budget drivers, not the science**
**applied a “ballpark” pricing model**
- “Think-tank” meeting including government agencies, academicians, and industry

## Slide 36

## Slide 37

## Slide 38

## Waste in Clinical Trials

**Imagine building bridges without engineering schools**
**Lack of clinical research as a discipline **
- Lack of standards
- Lack of empirical analysis of value of changes

## Changes In Lipoproteins

**Changes In Lipoproteins**

- Percent Change fromBaseline to Year 1

- LDL

- HDL

- Triglycerides

## HERS/HERS II and WHI: Clinical Outcomes

## WHI: HRT and Quality of Life

- Hayes, N Engl J Med 2003

## Hormone Therapy and the Coagulation System

**	****	****	****	****   ****Estrogen****	****	****+ Progestin**
**Factor XII****	****	****   Increases****	****	****         ?**
**Factor VIIa****	****	****   Increases****	****     Decreases/Neutral**
**Fibrinogen****	****	****   Decreases****	****  Decreases**
**F1.2****	****	****	****   Increases****	****	****  Increases**
**Fibrinopeptide A****	****   Increases****	****	****          ?**
**Protein C****	****	****   Variable****	****	****  Variable**
**Protein S****	****	****   Variable****	****	****  Variable**
**Antithrombin III****	****  Decreases****	**** Decreases**

## WHI: Results Interpretation

**How large are the treatment effects?**
- In 10,000 women treated for one year:
*CHD**	**	**	**7 more*
*Stroke**	**	**           8 more*
*PE/DVT**	**	**8 more*
*Breast CA**	**	**8 more*
*Colorectal CA**	**6 fewer*
*Hip fracture **	**           5 fewer*
- Cumulative differences will increase with time
*100 excess events over 5 years*
*60,000 excess events in 6 million users*

## Therapies Always Cause a Combination of:

*Good Effects*

*Bad Effects*

*Adapted from Furberg*

**Therapies Always Cause a Combination of:**

## Key Points

**Chronic diseases will be (are) the dominant health issue in our society**
**Predicting whether a chronic disease therapy causes net benefit or harm is difficult**
**Biomarkers and imaging are the way to go**
- But mostly as a screen
- Cannot substitute for clinical outcomes in most circumstances
**Tremendous inefficiency in clinical trials**