Surrogate Endpoints

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Surrogate endpoints

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

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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.

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• 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

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• 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.

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HOW THEY RELATE ?
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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)

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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.

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• 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.

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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

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• 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

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• 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)

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• 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).

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• 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

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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.

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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.

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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
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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.
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• 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.

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• 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.

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• 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).

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• 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)

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• 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.

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• 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.

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• 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.

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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.

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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
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• 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
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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.

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• 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.

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• 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.

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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.

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