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Dr Pallavi Dhanvijay

Date : 03/09/2010

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y Clinical trials are studies performed with human

subjects to test new drugs or combinations of drugs,

new approaches to surgery or radiotherapy or

procedures to improve the diagnosis of disease andthe quality of life of the patient.

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Egypt 1550 BCy Ancient Egyptians regularly documented their prescriptions,

but there was no proof they worked.600 BCy In the Book of Daniel, the Bible describes that

Daniel tested two diets to see which was healthier, avegetarian diet or a diet rich with meats and wine.After a 10-day test, vegetarian diet was judged healthy.

1st century B.C.y Cleopatra devised an experiment to test theory

y

it takes 40 days to fashion a male foetus fullyy 80 days to fashion a female foetus.

y Handmaids were sentenced to death under governmentorder, Cleopatra had them impregnated and subjected themto subsequent operations to open their wombs at specifictimes ofgestation

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1747:y Captain James Lind performed a clinical

trial using citrus to find the cure for scurvy

in his sailorsa. One/four British sailors who took saltedmeat during voyages died of scurvy.b. German sailors who ate fruits andvegetables didnt get scurvy

y He ultimately saved thousands of Britishsailors.

y This was the first chemo-preventiveclinical trial known in modern history!

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1796,

y Edward Jenner conducted the famous trial thatproved inoculation could prevent smallpox.

Jenners trial was the first step toward massvaccinations that conquered epidemics such astyphoid, yellow fever, polio and measles.

1931,

y First documentedCT in the U.S. using a matchedcontrol group, randomization, placebo, andblinding.

y It used gold in the treatment of pulmonary TB.

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Past abuses:y 1932: TuskegeeEffect ofuntreated syphilis

y Jewish chr. Disease hospital22 delibated elderly injected cancer cells

Without their knowledge to see if theywould immunologically reject the cells

y Willowbrook State Schoolinfected in mentallyretarded children with viralhepatitis (natural history of disease)

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y Hippocratic tradition does not proscribe CT

y In World war IIy The evidence of criminal & unscientific behavior of

physicians in camps of Nazi Germanyy Incidents of torture, murder & experimental atrocities

by physiciansy Tried at Nuremberg : Nuremberg trialsy Judges presiding outlined 10 principles required to

satisfy ethical conduct for human experimentation

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Nuremburg Code in 19471. Study participants must give voluntary consent

2. Must be no reasonable alternative to conductingthe experiment

3. The anticipated results must have basis inbiological knowledge & animal experimentation

4. Procedure should avoid unnecessary suffering &injury

5. No expectation for death/ disability as a result oftrial

6. Degree of risk for the patient is consistent withthe humanitarian importance of study

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7. Subjects are protected against even a remotepossibility of death / injury.

8. Studymust be conducted by qualified scientists.

9. Subject can stop participation at will.10. Investigator has obligation to terminate theexperiment if injury seems likely.

y

Provides groundwork for standards of ethicalconduct

y Do not distinguish between therapeutic &purely scientific experimentation

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Durham-Humphrey Amendment of 1951

y Exempted certain drugs from requirement thattheir labeling contains adequate directions for use.

y

Be taken safelyunder medical supervision wereexempted provided they were sold under the orderof a licensed prescriber / administered underprescribed supervision.

y Such exempted drugs, instead of adequatedirections for use, must have on its label

Caution: Federal law prohibits dispensing without aprescription.

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Thalidomide disaster of 1962

y Thalidomide, launched on 1 October 1957,

y was found to act as an effective tranquilizer

and painkiller and was proclaimed a "wonderdrug" for insomnia, coughs, colds andheadaches.

y Effective antiemetic with effect on morning

sicknessy Thousands of pregnant women took the drug

y No thought given : drug could pass placentalbarrier and harm the developing fetus

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y Durham-Humphery 1951 amendment was inadequate toprotect the public

y Large prescribers relied on manufacturers for their informationabout drugs

Kefauver-Harris Amendment of 1962y K/a drug efficacy amendmentsy Registration ofmanufacturers & inspection ofmanufacturing

sitesy Beforemarketing any new drug ,

to supply a) proof of effectivenessb) proof of safety

y Good manufacturing practices (GMP)y Else drug adulterated

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Declaration of Helsinki, 1964

y Adopted by 18thWMAgeneral assembly,Helsinki, Finland, June 1964

y It binds physician with the words the health of

my patient will bemy first considerationy International code ofmedical ethics declares

that,

A physician shall act only in the patients interestwhen providingmedical care which might havethe effect of weakening the physical & mentalcondition of the patient.

(conflicting)

y Major landmark in evolution of GCP.

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Good clinical practice

y Set ofguidelines for biomedical studies

y Encompasses design, conduct, termination, audit, analysis,

reporting & documentation of studies involving humansubjects.

y Fundamental tenet: Research on man, interest of science &society should never precedence over considerations relatedto the well being of the study subjects.

y 2 cardinal principles:y protection of right of human subjects &

y authenticity of biomedical data generated.

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ICH-GCP of 1997

y Guidelines were prepared under Internationalconference on harmonization of technical

requirements for registration of pharmaceuticals forhuman use (ICH)

y Objective: unified standard for European union, Japan& United states to facilitate mutual acceptance of

clinical trial data.

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y Principles of GCP

1. CT in accordance with ethical principles(1. autonomy, 2.beneficence, 3. justice)

2. Before trial, foreseeable risks & inconveniences should be

weighed against benefit for individual trial subject & society3. Rights, safety & wellbeing of the trial subjects are most

important.

4. Available non-clinical & clinical information of product:adequate

5. CT: scientifically sound, described in a clear, detailed protocol6. CT conducted in compliance with protocol that has received

prior institutional review board (IRB) / independent ethicscommittee (IEC) approval

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7. Medical care / medical decision for subjects: always beresponsibility of qualified physician.

8. Each individual involved in conducting: be qualified9. Freelygiven informed consent should be obtained from

every subject.10. CT information should be recorded, handled & stored ina way that it allows its accurate reporting, interpretation& verification.

11. Confidentiality of records

12. Investigational products should be manufactured,handled & stored in accordance of GMP.13. Procedures that assure quality of every aspect of trial

should be implemented.

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y Before the age of clinical trial, Ivy(1948) suggested thatpatient is always an experimental subject.

y Conflict for physician: desire for academic & financialsuccess - complete with both patient care & research.

y

Trials are ethical in setting ofuncertainty.y Research & practice are not separable.y Double standards

y Investigator studying randomizedcomparison knows superior drug.

y

Treatment not thoroughly studied(thalidomide)y Some cultural places have fewer

restrictions (US Vs Asia)

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y There are legitimate ethical concerns about Clinicaltrialsy Randomization ( if no equipoise, not justified)

y

Treatment preference (if pt prefers a t/t should they bepersuaded)

y Informed consent (e.g. test of radioactive substances1945-1975 / sick - dying pt new treatment ?)

y Monitoring (one t/t superior evidences - stop)

y Active Vs Placebo (not be justified if effective t/t exist)

y Demonstration trial (ample evidence already-unethical)

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1. Difficulty of determining whether an outcome represents atrue signal or just background noise.

e.g. giving a new compound to 1-10 patient recovers frompneumonia -doesnt establish - drug cured.

Reasons: diseases have variable outcome;

evidence tremendous biases & confounding factors;

?spontaneously recovered

e.g. M. leprae exposure few contract leprosy ;

e.g. Statins prevent cardiovascular events in fraction ofpatients

Clinical trials, with (usually) large aggregate data sets,

randomization, and blinding, can often overcome these

issues of variability and noise

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2) Relying on informal observations or nonrandomizedstudies is the difficulty in distinguishing between a resultdue to a bias vs. a result due to a real effect.

e.g. when a patient and/or the treating physician knowthat a therapy is being administered, there may be aplacebo effect.

e.g. Imbalance between t/t groups (younger & healthier)

Clinical trials can ameliorate or eliminate these biases &

issues.y Blinding can reduce the placebo effect and

y Randomization can reduce imbalances in patient characteristicsbetween the groups.

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3) Source ofmedical knowledge could be the hazards ofmultiplepost hoc analyses.

Ifthe data is analyzed enough times in enough differentways, one can often find a convincing association between

therapy and outcome.

e.g. its possible to find correlations : zodiac signs &response rate.

looking data in 20 different ways can be expected to yield

one spurious association with ap value of 0.05 or less.Prospective clinical trials pre-specify one primary endpoint.

This minimizes the risk of spurious results.

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4) Knowledge based on retrospective data - need toestablish causation.

Mostly it is not possible to establish causation withoutrandomized intervention.

e.g. pts ingest aspirin - low incidence of cardiovascularevents.

Its possible to postulate that aspirin lowers the risk of CVevents, but other explanations cannot be ruled out.

An alternate reason : pts who exercise > : injure theirknees > ; tend to take aspirin for their aching joints.

Or, A diet low in fat - cause dental caries & take moreaspirin to relieve the dental pain.

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The opposite is also true:

confoundingmaymask causal association.

e.g. MI pts: > sicker :> likely to receive thrombolytic

who received thrombolytic - different characteristics.group with intervention may not do better, despite the

intervention being effective.

Multivariate analysis can tease out effects d/t differences

in the patient population.CT ideally, a randomized prospective clinical trial is the

optimal way of establishing clear causation.

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y Randomized/blinded trial

y Randomized/double blinded trial

y Non-randomized concurrent controlled trial

y Placebo trial

y Historical controlled trial

y

Crossover Trial

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y Experimental design is a way to advance knowledgeefficiently & reliably

y The foundation of design are observation & theory

y Several types of clinical observationsy They help in generating a hypothesis.

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Types of clinical observations

1) Case reports Demonstrate that an event is of someinterest

Weakest clinicalevidence

2) Case series A demonstration of certain possibilityrelated clinical events

But subject to largeselection biases.

3) Database analysis Treatment is not determined byexperimental design but by factors suchas physician/ patient preference.

Data unlikely to havecollected specificallyto evaluate efficacy.

4) Observationalstudies

Investigator takes advantage ofnatural exposures / treatment

selection & chooses a comparison group

Lack key designstrengthof

experiments

5) Comparativeclinical trials

Treatment assignment is by design. Endpoint ascertainment is activelyperformed & analysis is planned inadvance.

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Invariant requirement ofhypothesis-testing clinicaltrials

Variable properties ofhypothesis-testing clinicaltrials

Prospective intervention Randomization vs. other ways

of assignment

Assignment to treatmentgroups

Number of treatment groups

At least one control group Superiority vs. other testing

Null hypothesis Type of outcome being tested

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y Asample is a portion or subset of a population.

y When populations are very large, observing or testing everysingle member of the population becomes impractical.

y

Samplemust have similar diversity of all relevantcharacteristics as the total population.

E.g. Jackie Chan action movies are not a representativesample of Hong Kongmovies

y Samples must be random to be representative

y The study population is a group of patients who are part ofa clinical study. Usually the study population is a sample ofthe total population

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Larger study sample sizes mean greater study power.

Increasing the sample size is costly

Therefore, investigatorsmust balance increasing studypower with expense.

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Many factors affect the sample size

Power : commonly used power threshold is 80%, which meansthat a false null hypothesis is successfully rejected 80% ofthe time.

Significance level : The most commonly used significancelevels are 5% (p 0.05) and 1% ( p 0.01), whichmeans thatthere is a 5% or 1% probability, respectively, of a chancedifference mistakenly being considered a real significant

difference.Clinical event rate : The relevant clinical event depends on

what you are studying. If youwere studying a treatment toalleviate severe diarrhea, then the clinical event is an

episode of diarrhea.

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Event rate is the frequency of the relevant clinical event inyour study population.

A low event rate = large sample size.

Higher event rates = smaller sample sizes.Predicting the event rate can be very difficult and is

usually based on prior studies.

Expected effect size : A studys power depends on the

difference between the expected effect size and theactual observed effect size.

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Compliance and drop-out rates :

Subject allocation ratio :

The allocation ratio is the ratio of the number of patients

assigned to each arm. 1:1 / 2:1 etc

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Potential strategies include using:Most of the Population

Entire population of pts with certain conditions orcharacteristics is small enough to serve as the sample

few = fulfill the selection criteria.Using the entire population

The Sample Size of a Comparable Study

Sample Size Tables and Software

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Sample Size Formulae

The final method for choosing a sample is using sample size

formula. The following formula calculates sample

size when you are comparing the means of two groups:

whereZ is the Z -score, 2 is the population variance, and e

is the margin of error (i.e., the desired precision).

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The following formula calculates sample size when youare comparing the proportions of two groups:

whereZ is the Z -score, p is the estimated proportion of an

attribute that is present in the population, and e is the margin oferror

Softwares for sample size calculationEPI 6..Open info..

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y Randomization is the process ofusing chance orprobability to assign subjects to different study arms

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Blinding ormasking achieves two things: it reducespotential bias from investigators, and it reducespotential bias from patients.

Single blindingDouble blinding

Triple blinding

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y Its a document that specifies the research plan for a CT

y Difficult part of writing:1. Formulating & developing an important, feasible scientific

question

2. Being certain that resource are available (funds, pt, time)

y Developing a written research protocol- crucial step

y Functions :y quality control tool

y Way to communicate research idea to othersy Quantumunit of research

y Legal document

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1) Title pagea)Study title b)principal investigator c)other study

collaborators d)Administrative officer

2) Contents / Index

3) Protocol synopsisOne page description

4) Schema

5) Objectives of study

6) Introduction & background7) Drug information

8) Staging criteria

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9) Patient eligibility criteria

10) Registration / randomization procedures & stratification

11) Treatment program

12) Dosage modification / side effects13) Agent information

14) Treatment evaluation

15) Serial measurement / study calendar

16) Statistical considerations17) External collaboration / reviews

18) Data recording, management & monitoring

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19) Special instructions

20) Communication & publication of data

21) Patient consent forms

22) References23) Data forms

24) Other appendices (ethical review documentation,toxicity criteria etc.)

25) Glossary (definition ofunfamiliar terms)

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