Surrogate Endpoints. The Surrogates Story 3 Drug Trials 2 FDA Policy Issues 1. CAST Trial –Cardiac...

Surrogate Endpoints

The Surrogates Story 3 Drug Trials

2 FDA Policy Issues

• 1. CAST Trial –Cardiac Arrhythmias • 2. Concorde – AZT for AIDS• 3. Erythropoietin for Dialysis Pts

• 1. Accelerated Approval (AA)• 2. Patient-Reported Outcomes (PRO)

Managing the “Wild Card” of Cardiovascular Disease-

Sudden Cardiac Death

• Up to half of the ½ million cardiovascular deaths are “sudden” deaths

• Known risk factors for sudden death– Cardiac ischemia (esp recent) – Poor ejection fraction fraction– Ventricular arrhythmias

Rigorous testing of new anti-arrhythmics

Antiarrthymics in the late 80’s

• Antiarrthymics for PVCs & V-Tach widely prescribed– Between ¼ - ½ million patients/yr were taking

• “New” antiarrthymic drugs more effective in suppression arrthymias

• Scientific EPS selection of best therapies– Encainide Flecainide Moricizine

• Placebo controlled trials considered unethical – Even tho no trails showing reduction of arrhythmias led to

reduction of sudden death

Cardiac Arrhythmia Suppression Trial

CAST-ing doubt on the

dominant pradigms

High Risk Patients Require Treatment

• “Unethical” not to treat such high risk patients

• Have to do something• How would you feel if one of these

patients you “ignored” suffered sudden death– Plus legal ramifications



dominant pradigms

CAST trial 1987

• Randomized, Double-Blind, Placebo Control • 27 clinical centers, 4,400 patients

– Open-label titration to select drug-responsive patients:

• 1,727 randomized to Encainide, Flecainide or Moricizine

• Trial is discontinued early – Encainide and Flecainide 1989– Moricizine 1991

http://clinicaltrials.gov/ct/show/NCT00000526

CAST Results

Sudden Death Total Death

Drug 43 63

Placebo 9 23



dominant pradigms

Surrogate Endpoints• Change in a clinical variable

not experienced directly by the patient – Blood pressure – Serum cholesterol – Serum Glucose – PVC’s

• Not itself a direct measure of clinical harm or benefit– Patient does not necessarily feel better or worse

Clinically Relevant Endpoints

• Mortality or survival benefit• Clinically important change experienced

directly by the patient– Reduced pain – Improved functional status – Improved quality of life

• Directly measures clinical benefit or harm

Hierarchy of endpoints

Level 1: True clinical-efficacy measure

Level 2: Validated surrogate endpoint

Level 3: Non-validated surrogate endpoints reasonably likely to predict clinical benefit

Level 4: A correlate that measures biological activity but whose clinical relevance is not well established

Fleming, T. Surrogate endpoints and FDA’s accelerated approval process: the challenges are greater than they seem. Health Affairs (2005) 24(1) 67-78

Why Use Surrogate Endpoints?

• Reduction in sample size, duration of trial and cost– Easier to show benefits: weeks to mos vs. years

• Assess benefits of drug where measurement of clinical outcomes would be unethical/invasive

• Because death and other “harder” outcomes are uncommon or delayed well into future

Surrogate Reductio ad absurdum

• Elevated WBC count – surrogate for severity of pneumonia

• So, why not give cytotoxic agents to reduce the white count?!

Limitations of Surrogate Endpoints

• Surrogates may not be valid predictors of actual clinical outcomes

• Rests upon physiologic assumptions– Persuasiveness of biologic plausibility

• May be statistically significant but not clinically significant

• Provide only partial picture of totality of drug’s effect

• Lend themselves to manipulation by PhARMA• Many turn out to be misleading “red herrings”

Fleming, T. R. et. al. Ann Intern Med 1996;125:605-613

Reasons for failure of surrogate end points

Surrogate is not involved in disease pathway

Disease has multiple pathways and intervention effects only one pathway mediated through surrogate

Surrogate is not affected by/ insensitive to intervention’s effect

Intervention has mechanisms of action independent of disease process

Prostate Biopsy Finasteride Trials

Ventricular ArrythmiasEncainide and Flecainide Trials

CD4 levelsHIV drugs

Ventricular ArrythmiasEncainide and Flecainide Trials

Effective antimicrobial treatment or Useless surrogate?

• 4,000 surgical patients • Treated patients for nasal staph carriage • Treated pts 4.6% vs. 21.3% control (p<.001)

• No difference in surgical infections: 2.3% in treated vs. 2.4% in controls

Perl NEJM 2003

Zidovudine -- AZT

• Thymidine Analogue• Synthesized 1964• Drug in the public domain• 1984 scientists approach

drug companies to expedite R&D

• Got Burroughs Wellcome to patent (w/ difficulty)

Mitsuya, H. et al., 3'-Azido-3'-deoxythymidine (BW A509U): An antiviral agent that inhibits the infectivity and cytopathic effect of human T-lymphotropic virus

type III/lymphadenopathy associated virus in vitro, Proc. Natl. Acad. Sci USA (82) 1985

Pathophysiology of HIV

http://research.bidmc.harvard.edu/vptutorials/HIV/home.htm

AZT

The Evidence it “Works”

AZT uM

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ells

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Mitsuya, H. et al., 3'-Azido-3'-deoxythymidine (BW A509U): An antiviral agent that inhibits the infectivity and cytopathic effect of human T-lymphotropic virus

type III/lymphadenopathy associated virus in vitro, Proc. Natl. Acad. Sci USA (82) 1985

HIV positive T cells

HIV negative T cells

AZT surrogate endpoints: the context

• No treatments for AIDS desperation– Bribery to enter trials– Difficulties of obtaining accurate results– Drug smuggling rings

• Cook County: 100’s of deaths per quarter• Regan administration largely ignores HIV

AZT- The Hopes

• New public private partnership • Burroughs Wellcome submits AZT application

in 3 stages over 7 months

• Drug companies, scientists and regulatory agency working together for good of the public– Sets stage for accelerated approval of other drugs

AZT: The Doubts

• The myth of public health altruism– Burroughs Wellcome charges $10,000/year– Largely assumes credit for innovation

• Despite doing relatively little of R & D

• Clinical trials on limited population– White, gay males

• Difficult to adhere to regimen – Initially 6x/day

• Controversies and questions about role of the drug

1994 CONCORDE Study

Kaplan-Meier Plot for all causes of death

Kaplan-Meier Plot for time to AIDS or Death

Kaplan-Meier for time to ARC AIDS or death

Kaplan-Meier for time to reduction in CD4 count less than half of baseline, AIDS or death

The small but highly significant and persistent difference in CD4 count between the groups was not translated into a significant clinical benefit. Thus, analyses of the time until certain concentrations of CD4 were reached revealed significantly shorter times in the Deferred AZT treatment group. Had such analyses been regarded as fundamental, the trial might have been stopped early with a false-positive result.

CONCORDE Conclusions

This discrepancy in the differences between Immediate and Deferred AZT treatment groups in terms of changes in CD4 count and of long-term clinical response casts doubt on the uncritical use of CD4 counts as "surrogate endpoints" in trials, although their value as a prognostic marker for disease progression in cohorts and trials is beyond dispute. The reason for this discrepancy is unclear.

CONCORDE Conclusions II

This discrepancy in the differences between Immediate and Deferred AZT treatment groups in terms of changes in CD4 count and of long-term clinical response casts doubt on the uncritical use of CD4 counts as "surrogate endpoints" in trials, although their value as a prognostic marker for disease progression in cohorts and trials is beyond dispute. The reason for this discrepancy is unclear.

Conclusions Continued

History of Erythropoietin

• U of C scientist Eugene Goldwasser starts research on erythropoietin 1960s

• Purified in 1970s

Erythropoietin and Biotech Revolution

• Amgen works with Goldwasser to sequence and clone erythropoietin

• 1985 Amgen files patent• Orphan Drug • 1989 approved for marketing• Decade later $5b in profits

Erythropoietin

Blood’s Life-Blood

Policy Context: Not that simple

• Natl Kidney Foundation guidelines– Progressively raised Hb level w/out clinical

evidence of benefit– Strong conflicts of interest

• 10/18 panel members w/significant financial interest

• 57% of NKF funding from industry

• Medicare reimbursements source of profit for dialysis centers

CHOIR and CREATE Studies

• Researchers in US and France simultaneously conduct erythropoietin studies w/ clinical endpoints

• Funded by Amgen’s competitors– Roche Johnson & Johnson

• To get their “me-too” drugs to market

Singh A et al. N Engl J Med 2006;355:2085-2098

CHOIR: Enrollment and Outcomes

Mean Monthly Hemoglobin Levels


Kaplan-Meier Estimates of the Probability of the Primary Composite End Point


Kaplan-Meier Estimates of Secondary Endpoint of Death


Drueke T et al. N Engl J Med 2006;355:2071-2084

CREATE: Enrollment, Randomization, and Study Completion


Median Hemoglobin Levels in the Intention-to-Treat Population during the Study


Changes from Baseline to Year 1 in SF-36 Quality-of-Life Scores

Changes from baseline to Year 1 in Time to Dialysis during the Study


Lower Hb Group remains off dialysis longer

Current FDA issues with Regulation of Surrogate Endpoints

• Accelerated approval (1992)– Formal acceptance of surrogates– Endpoints “reasonably likely to predict clinical

benefit”– Early marketing approval contingent upon post-

marketing studies confirming clinical benefit

• Patient-Centered Outcomes– Lancet commentary, controversies

Pressures for Accelerated Approval (AA)

• 1962 Kefauver-Harris Amendments require demonstration of efficacy

• Alleged “drug lag” – Drug industry and free market economists

want less regulation– Patient groups demand more available

treatments for AIDS and cancer

ACT UP Demonstrations

http://aidshistory.nih.gov/search_for_treatments/demonstration.html

http://www.actupny.org/documents/FDAhandbook1.html

1988 FDA Headquarters

1990 NIH Headquarters

Accelerated Approval --Issues

• More lenient criteria-slipping into surrogates

• Lack of urgency to complete post-marketing study commitments

• No “teeth”– Unwillingness and lack of power to pull

drugs off the market

Oncology Drug Advisory Committee Report

• Review 8 products approved under AA in first five years AA available for oncology rx (3/03)

• Average time for completion of post-approval studies = 10 years

• Marketing of interventions shown to have little benefit, continued

Accelerated Approval, Animal Efficacy Rule and Pediatric Research Equity Act

Open Post-Marketing Commitments

Behind Schedule

On schedule

Submitted

Concluded

64%13%

10%

13%

• How to handle cases where validation studies don’t conclusively support the drug?

• What to do if no tangible benefit in face of well documented toxicities or safety risks

CAST-ing about for

better pradigms

Patient-Reported Outcomes (PRO)

• Attempt to weigh patient-centered quality of life outcomes

• Step forward: care about more than just death – Want to value and measure quality of life (QOL) – Respect and weight for how patients are feeling

• True valued outcomes ……….or “back door” surrogates?

• Susceptible to manipulation• How to achieve validated measures/scales?

Revicki, Lancet 2/17/2007

Policy analysis found this study & related promotional activities resulted in increase sales worth $375-450 million

Take Home Points

• Misconception that if an outcome is a “correlate” it is a valid surrogate end point – “A correlate does not a surrogate make”

• Lowering risk marker: ? masking or killing the messenger

• Multiple other “unintended” effects to drugs besides putative “neat” mechanisms of action

• Even best surrogates, risk misleading in various ways

2 Criteria for Valid Surrogate

• Biologic marker must be correlated with the clinical endpoint

• Marker must fully capture the net effect of the intervention on the clinical-efficacy endpoint

Fleming, Health Affairs 2005

Searching for Surrogates in JAMA Ads

• How many drug ads (denominator)?• How many ads have efficacy outcome data

of any sort (numerator 1)?• How many of the outcomes are actual clinical

outcomes; how many are surrogates?• Pick out 1 or 2 and analyze them

– As a pharmaceutical researcher design surrogate tools and studies to show how well the drug “works”

– As an FDA reviewer critique/discuss real or implied surrogate issues related to the drug and the ad .

Surrogate Endpoints. The Surrogates Story 3 Drug Trials 2 FDA Policy Issues 1. CAST Trial –Cardiac...

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