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Surrogate Endpoints

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Title: Surrogate Endpoints


1
Surrogate endpoints
  • By Dr. Swapnil Chube
  • JR2, Dept. of Pharmacology,
  • SRTR GMC, Ambajogai.

2
DEFINATIONS
  • Biomarker
  • A characteristic that is objectively
    measured and evaluated as an indicator of normal
    biological processes, pathogenic processes, or
    pharmacological responses to a therapeutic
    intervention.
  • Clinical Endpoint
  • It refers to a disease, symptom, sign or a
    laboratory measurement that constitutes one of
    the target outcomes of a trial.

3
  • Clinical Endpoints -
  • Primary endpoint endpoint for which subjects are
    randomised and for which the trial is powered
  • Secondary endpoint endpoints that are analysed
    post hoc for which the trial may not be powered
    nor randomised.
  • Humane endpoint
  • The point at which pain/distress is terminated,
    minimised or reduced for an entity (such as
    experimental animals) in a trial.
  • This may necessitate withdrawal from the trial
    before the target outcome of interest has been
    fully reached

4
  • Surrogate endpoint
  • A biomarker intended to substitute for a clinical
    endpoint NIH.
  • A laboratory measurement / physical sign, used as
    a substitute for a clinically meaningful
    endpoint, that measures directly how a patient
    feels, functions or survives.
  • Combined endpoint
  • This merges a variety of clinical outcomes in one
    group.

5
HOW THEY RELATE ?
6
Biomarkers Categories
  • Pharmacodynamic markers
  • Determines whether a drug hits the target and has
    the expected impact on the biological pathway.
  • Used to evaluate mechanism of action, PK/PD
    correlations determine dose schedule
  • Predictive markers
  • Used to identify patients most likely to respond
    or are least likely to suffer an adverse event
    when treated with a drug
  • Prognostic markers
  • Associate with the disease outcome regardless of
    the treatment
  • Surrogate endpoints
  • Endpoints suggesting clinical outcomes (e.g. LDL
    cholesterol, HbA1c)

7
Timeline of key events in the history of
biomarkers
  • Late 1980s Experimental medicine groups set up
    in few companies to develop surrogate endpoints
    and link with discovery.
  • Late 1998 Realization of economics of attrition
    started the drive to take attrition earlier, to
    manage failures and investing more in biomarkers.
  • 2000 Industry productivity begins to dip despite
    increased target generation, combinatorial
    chemistry and high-throughput screening.
  • Increased investment in biomarkers and
    technology greater focus on quality and
    standardization, advances in molecular diagnosis,
    human genome and concepts of personalized
    medicine.

8
  • Early 2000s Standardization of a language for
    biomarkers
  • FDA critical path paper Stagnation/Innovation
    signals that regulators perceive biomarkers as an
    important improvement in the drug development
    process.
  • Late 2000s future
  • Human target validation will be the main driver
    for development of novel drugs,
  • preclinical studies will be focused on
    translational biomarkers,
  • Drugs developed for disease subtypes with the aid
    of molecular diagnostics.

9
Biomarkers
  • Physiological responses or laboratory tests that
    occur in association with a pathological process
    and have putative diagnostic and/or prognostic
    utility
  • Biological criteria
  • Must be consistent with known pathophysiology
  • Must be indicative of disease prognosis
  • Must lie on the intervention pathway
  • Statistical Criteria
  • Changes must be correlated with clinical outcome
  • But correlation does not equal causation

10
  • Biomarkers are considered to be surrogate
    endpoints that is, they act as surrogates or
    substitutes for clinically meaningful endpoints
    (pulse, BP, CD4 count, viral load, Brain
    Natriuretic Peptide, PSA, Endothelin-1, VEGF)
  • Not all biomarkers are surrogate endpoints
  • They provide an interim evidence about the safety
    and efficacy of treatments while more definitive
    clinical data is collected
  • Advantages
  • Allow researchers to design smaller, more
    efficient studies
  • Shortening the time for approval of new
    treatments

11
  • Some Applications of Biomarkers
  • Phase I-II clinical studies
  • to demonstrate pharmacological activity in
    humans
  • to define dose or plasma level response
    relationships as a basis for later studies
  • Phase III clinical studies
  • as a basis for stratifying patients
  • for safety monitoring
  • as basis for interim analysis of patient
    response
  • as basis for conditional regulatory approval
  • Phase IV clinical studies
  • Used as a basis for regulatory approval of
    generic drugs (e.g. blood levels)

12
  • Surrogate Endpoints
  • Biologically plausible
  • Measurable in all patients with the disease
  • Predictive of disease progression / remission
  • Subject to standardization and validation ?
    reliability.
  • Reproducible
  • Effect of treatment on surrogate endpoint should
    translate into effect on true endpoint (criteria
    of validity).

13
  • Advantages
  • Enables more rapid evaluation of treatment
    effects
  • Trials designed with smaller sample size
  • Reduces duration of the study
  • Reduces cost of the study
  • ? Examples Blood sugar, serum cholesterol,
    blood pressure, negative
  • cultures
  • Pitfalls
  • May not be a true predictor of clinical outcome
  • Adverse effects may outweigh clinical benefit
  • May not be useful for all patient populations or
    in all stages of a disease
  • May still need to follow up for true endpoint
  • Short term study small no. of patients ? May
    not reveal rare adverse effects

14
SURROGATE ENDPOINT
  • An ideal surrogate endpoint is one in which all
    mechanisms of action to the true endpoint are
    mediated through the surrogate endpoint.
  • In practice, this is often not possible.

15
Criteria For Validity
  • Validity is decided through stringent
    examination of, consistent
  • performance of the surrogate endpoint, in
    META- ANALYSIS of
  • MULTIPLE PHASE III trials.
  • For a surrogate endpoint to be accepted as a
    valid substitute for the
  • true endpoint, the following conditions must
    be met
  • Informative there must be evidence that the
    surrogate predicts the true endpoint.
  • Specific the interventions effect on the true
    endpoint must be mediated through the surrogate
    endpoint.
  • Complete study involving the surrogate endpoint
    must also capture all the information on adverse
    effects associated with the intervention.

16
Examples Of Surrogate And True Endpoints
MEDICAL DISEASE TRUE ENDPOINT SURROGATE ENDPOINT
Heart Disease Survival rate Cholesterol level
HIV infection Survival rate CD4 counts
Hyperthyroidism Weight loss, bulging eyeballs, tremors Serum T3 level
Lung cancer Survival rate Tumor shrinkage
17
Failure Of Surrogate Endpoints
  • They fail because of the following physiological
    reasons
  • Surrogate endpoint NOT ON THE CAUSAL PATHWAY of
    disease process.

Here the surrogate measures a symptom unrelated
to the final outcome.
18
  • E.g. mechanisms leading to the development of
    macrovascular complications in type II DM may not
    involve change in HbA1c levels.
  • Thus measuring the change in HbA1c levels as a
    surrogate endpoint for evaluating effects of
    intervention on the macrovascular complications
    like TIA, atherosclerosis, etc. induced by type
    II DM, isn't validated as a surrogate endpoint.

19
  • 2. Surrogate endpoint NOT ON ALL PATHWAYS of the
    disease process.
  • The intervention in this case may show an effect
    on surrogate endpoint, but not on an unrelated
    pathway to the true endpoint.
  • In some cases, a particular intervention may have
    opposite effects on the 2 pathways ? exactly
    wrong conclusions.

20
  • E.g. evaluation of level of cytokines as an
    indicator of inflammation, after use of a mouth
    rinse in a patient suffering from peri-odontitis.
  • In this case, a true endpoint is tooth loss or
    increased tooth mobility
  • Even if the mouth rinse is helpful in reducing
    cytokine levels, a patient can still end up with
    tooth loss or increased tooth mobility (true
    endpoints)
  • This is because the disease may be progressing
    through other pathways involving PGs,
    collagenases, etc. (alternate pathway to true
    endpoint).

21
  • 3. Surrogate endpoint NOT ON INTERVENTIONS
    PATHWAY
  • Here the surrogate endpoint is completely
    oblivious to the intervention.
  • E.g. study effect of mouth rinse on gingivitis
    which has signs and symptoms like halitosis and
    gingival index (gum swelling, bleeding and
    redness)

22
  • Gingival index is regarded as a surrogate marker.
  • A mouth rinse ( intervention) can reduce
    halitosis ? implies reduction of gingivitis (
    true endpoint ) but has no effect on gingival
    index ( surrogate endpoint)
  • Thus if only the surrogate (gingival index) is
    considered here as a measure of treatment of
    gingivitis by mouth rinse, then there seems to be
    a false negative result with the particular
    intervention (mouth rinse) ? i.e. no reduction in
    gingivitis.

23
  • 4. Surrogate endpoint IN MULTI-FACTORIAL DISEASE
  • Here a surrogate endpoint is only on one pathway
    of a multi-
  • factorial disease
  • The disease process here operates with complex
    interaction in
  • multiple pathways.
  • The same study may yield different results at
    different times, owing
  • to multiple underlying mechanisms.

24
  • E.g. a study of a multi-factorial disease like
    Dental caries, ?reduction in salivary bacterial
    count - surrogate marker
  • ?pain, sensitivity, food lodgment - true
    endpoints
  • Dental caries is a multi-factorial disease.
  • ?Causative factors - diet, size and shape of
    the tooth, salivary factors like pH, viscosity,
    buffering capacity and bacterial counts.
  • Even if a particular intervention reduces the
    salivary bacterial counts (surrogate endpoint
    here), it wont stop / reduce / have an effect on
    the true endpoint, because of the persistence of
    the other unaffected causative factors.
  • Thus salivary bacterial counts becomes a weak
    surrogate endpoint in this case.

25
An Endpoint Hierarchy For Outcome Measures
  • Level 1 a true clinical-efficacy measure
  • Level 2 a validated surrogate endpoint (for a
    specific disease
  • setting and class of
    interventions)
  • Level 3 a non-validated surrogate endpoint, yet
    one
  • established to be reasonably
    likely to predict clinical
  • benefit (for a specific disease
    setting and class of
  • interventions)
  • Level 4 a correlate that is a measure of
    biological activity but
  • that has not been established
    to be at a higher level.

26
SURROGATE ENDPOINTS OFTEN USED IN CLINICAL
PRACTICE 1. Generally accepted as valid -
SURROGATE MARKER PREDICTS
HbA1c Diabetic MICROVASCULAR complications
FEV1 Mortality in COPD
Blood pressure Primary and secondary cardiovascular events
Viral load Survival in HIV infection
Cholesterol concentration Primary and secondary cardiovascular events
Intraocular pressure Visual loss in glaucoma
27
  • 2. Doubt still exists about validity -

SURROGATE MARKER PREDICTS
HbA1c Diabetic MACROVASCULAR complications
Bone Mineral Density Fracture risk
PSA Prognosis of prostate cancer
Suppression of arrythmia Long term survival
Carotid intima-media thickness Coronary artery disease
Albuminuria Cardiovascular disease
28
Accelerated Approvals Controversy
  • In 1992 the FDA formulated a new regulatory
    process, often referred to as accelerated
    approval" provision (AA).
  • Found at Subpart H of 21 CFR (Code of Federal
    Regulations)
  • It became critical during search for effective
    treatments of AIDS and HIV related disease in
    early 1990s.
  • Under the AA process, marketing approval can be
    provided for interventions when they have been
    shown to have compelling effects on Level 3
    biological markers, where these effects are
    reasonably likely to predict clinical benefit.

29
  • Once AA has been granted to an intervention, the
    sponsor then is responsible to complete, in a
    timely manner, one or more clinical trials that
    will validate that the intervention truly does
    provide meaningful benefit on tangible measures
    of clinical benefit.
  • These validation trials should meet all of the
    usual criteria for quality of trial conduct and
    reliability of conclusions, including usual
    levels for statistical strength of evidence,
    which would be required for providing full
    regulatory approval in non-AA settings.
  • AA is to provide patients earlier access to
    promising new interventions for diseases that are
    life-threatening or induce irreversible
    morbidity, when the inadequacy of existing
    therapies leaves an important unmet clinical
    need.

30
  • Although this motivation is easily justified, the
    actual implementation of the AA process is
    controversial.
  • Controversies are
  • The average time between the granting of
    marketing through AA and the completion of
    ongoing validation trials was projected to be ten
    years.
  • Initial validation trials that had been completed
    indicated minimal treatment benefit, yet
    marketing of the intervention continued.

31
CONCLUSION
  • Surrogate markers are born of phase II trials and
    are not necessarily ideal for use in clinical
    decision making. Phase III trials should be the
    true testing ground for the validity of surrogate
    markers.
  • There are some valid surrogate markers of disease
    progression which can be reliably used to monitor
    chronic conditions and as treatment goals.
  • However, the clinical utility of many surrogates
    is open to questions and their validity is
    largely untested.
  • Practitioners need to keep in mind that some
    widely used surrogate markers of disease have not
    been adequately validated for use in clinical
    situations.

32
REFERENCES
  1. Department of Health and Human Services. Food and
    Drug Administration. New drug, antibiotic, and
    biological drug product regulations accelerated
    approval. Federal Register Vol 57 No 73. 1992. p.
    13234-42.
  2. Fleming TR, DeMets DL. Surrogate end points in
    clinical trials are we being misled? Ann Intern
    Med 1996125605-13.
  3. Barnes D. How prescription drugs are developed.
    Aust Prescr 200629159-61.
  4. Dolan S, Varkey B. Prognostic factors in chronic
    obstructive pulmonary disease. Curr Opin Pulm Med
    200511149-52.

33
  1. Berger VW. Does the Prentice criterion validate
    surrogate endpoints? Stat Med 2004231571-8.
  2. Krumholz HM, Lee TH. Redefining quality
    implications of recent clinical trials. N Eng J
    Med 20083582537-9.
  3. Biomarkers Definitions Working Group. Biomarkers
    and surrogate endpoints Preferred definitions
    and conceptual framework. Clinical Pharmacol Ther
    2001698995
  4. Buyse M, Molenberghs G, Buzykowski T, Renard D,
    Geys H. The validation of surrogate endpoints in
    meta-analyses of randomized experiments.
    Biostatistics 200014967.

34
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