Dr Pallavi Dhanvijay Date : 03/09/2010
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 and the quality of life of the patient.
Egypt 1550 BC y Ancient Egyptians regularly documented their prescriptions, but there was no proof they worked. 600 BC y In the Book of Daniel, the Bible describes that Daniel tested two diets to see which was healthier, a vegetarian 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 fully y 80 days to fashion a female foetus.
y Handmaids were sentenced to death under government
order, Cleopatra had them impregnated and subjected them to subsequent operations to open their wombs at specific times of gestation
1747: y Captain James Lind performed a clinical trial using citrus to find the cure for scurvy in his sailors a. One/four British sailors who took salted meat during voyages died of scurvy. b. German sailors who ate fruits and vegetables didn t get scurvy y He ultimately saved thousands of British sailors. y This was the first chemo-preventive clinical trial known in modern history!
. y First documented CT in the U. and blinding . y Edward Jenner conducted the famous trial that proved inoculation could prevent smallpox. 1931. polio and measles.1796. yellow fever. placebo.S. randomization. y It used gold in the treatment of pulmonary TB. using a matched control group. Jenner s trial was the first step toward mass vaccinations that conquered epidemics such as typhoid.
Past abuses: y 1932: Tuskegee Effect of untreated syphilis
y Jewish chr. Disease hospital
22 delibated elderly injected cancer cells Without their knowledge to see if they would immunologically reject the cells
y Willowbrook State School
infected in mentally retarded children with viral hepatitis (natural history of disease)
y Hippocratic tradition does not proscribe CT y In World war II
y The evidence of criminal & unscientific behavior of
physicians in camps of Nazi Germany y Incidents of torture. murder & experimental atrocities by physicians y Tried at Nuremberg : Nuremberg trials y Judges presiding outlined 10 principles required to satisfy ethical conduct for human experimentation
Study participants must give voluntary consent 2. The anticipated results must have basis in biological knowledge & animal experimentation 4. Procedure should avoid unnecessary suffering & injury 5. Must be no reasonable alternative to conducting the experiment 3. No expectation for death/ disability as a result of trial 6. Degree of risk for the patient is consistent with the humanitarian importance of study
.Nuremburg Code in 1947 1.
7. Subject can stop participation at will. 9. Study must be conducted by qualified scientists. y y
Provides groundwork for standards of ethical conduct Do not distinguish between therapeutic & purely scientific experimentation
.Subjects are protected against even a remote possibility of death / injury. Investigator has obligation to terminate the experiment if injury seems likely. 8. 10.
Durham-Humphrey Amendment of 1951 y Exempted certain drugs from requirement that their labeling contains adequate directions for use.
. y Such exempted drugs. y Be taken safely under medical supervision were exempted provided they were sold under the order of a licensed prescriber / administered under prescribed supervision. instead of adequate directions for use. must have on its label Caution: Federal law prohibits dispensing without a prescription .
Thalidomide disaster of 1962 y Thalidomide. colds and headaches. coughs. y Effective antiemetic with effect on morning sickness y Thousands of pregnant women took the drug y No thought given : drug could pass placental barrier and harm the developing fetus
. launched on 1 October 1957. y was found to act as an effective tranquilizer and painkiller and was proclaimed a "wonder drug" for insomnia.
y Durham-Humphery 1951 amendment was inadequate to
protect the public y Large prescribers relied on manufacturers for their information about drugs Kefauver-Harris Amendment of 1962 y K/a drug efficacy amendments y Registration of manufacturers & inspection of manufacturing sites y Before marketing any new drug . to supply a) proof of effectiveness b) proof of safety y Good manufacturing practices (GMP) y Else drug adulterated
June 1964 y It binds physician with the words the health of my patient will be my first consideration y International code of medical ethics declares that. Finland. Helsinki. (conflicting) y Major landmark in evolution of GCP.
.Declaration of Helsinki. A physician shall act only in the patient s interest when providing medical care which might have the effect of weakening the physical & mental condition of the patient . 1964 y Adopted by 18th WMA general assembly.
y 2 cardinal principles:
y protection of right of human subjects & y authenticity of biomedical data generated. audit. analysis.Good clinical practice y Set of guidelines for biomedical studies y Encompasses design.
. conduct. reporting & documentation of studies involving human subjects. interest of science & society should never precedence over considerations related to the well being of the study subjects . y Fundamental tenet: Research on man. termination.
Japan & United states to facilitate mutual acceptance of clinical trial data.
.ICH-GCP of 1997 y Guidelines were prepared under International conference on harmonization of technical requirements for registration of pharmaceuticals for human use (ICH) y Objective: unified standard for European union.
2.y Principles of GCP 1. 6. detailed protocol CT conducted in compliance with protocol that has received prior institutional review board (IRB) / independent ethics committee (IEC) approval
. described in a clear. 2. justice) Before trial.
CT in accordance with ethical principles(1. foreseeable risks & inconveniences should be weighed against benefit for individual trial subject & society Rights. 3. Available non-clinical & clinical information of product: adequate CT: scientifically sound. 3. safety & wellbeing of the trial subjects are most important. 5. 4. beneficence. autonomy.
Each individual involved in conducting: be qualified Freely given informed consent should be obtained from every subject. interpretation & verification. 12. handled & stored in accordance of GMP. 13.
. Confidentiality of records Investigational products should be manufactured. Procedures that assure quality of every aspect of trial should be implemented. 8. handled & stored in a way that it allows its accurate reporting. 10. 9. CT information should be recorded.
Medical care / medical decision for subjects: always be responsibility of qualified physician.
Research & practice are not separable. y Treatment not thoroughly studied (thalidomide) y Some cultural places have fewer restrictions (US Vs Asia)
.complete with both patient care & research. Ivy(1948) suggested that y y y y
patient is always an experimental subject. Conflict for physician: desire for academic & financial success . Double standards
y Investigator studying randomized
comparison knows superior drug. Trials are ethical in setting of uncertainty.y Before the age of clinical trial.
dying pt new treatment ?) Monitoring (one t/t superior evidences . test of radioactive substances 1945-1975 / sick .stop) Active Vs Placebo (not be justified if effective t/t exist) Demonstration trial (ample evidence already-unethical)
. not justified) y Treatment preference (if pt prefers a t/t should they be y y y y
persuaded) Informed consent (e.y There are legitimate ethical concerns about Clinical
y Randomization ( if no equipoise .g.
e.g.g. giving a new compound to 1-10 patient recovers from pneumonia -doesn t establish . with (usually) large aggregate data sets. M.g. ?spontaneously recovered e. e. Statins prevent cardiovascular events in fraction of patients Clinical trials.drug cured. and blinding. evidence tremendous biases & confounding factors. leprae exposure few contract leprosy . Difficulty of determining whether an outcome represents a
true signal or just background noise. randomization. can often overcome these issues of variability and noise
. Reasons: diseases have variable outcome.1.
e.2) Relying on informal observations or nonrandomized
studies is the difficulty in distinguishing between a result due to a bias vs.
Blinding can reduce the placebo effect and Randomization can reduce imbalances in patient characteristics between the groups. a result due to a real effect.g. when a patient and/or the treating physician know that a therapy is being administered.g.
. e. there may be a placebo effect. Imbalance between t/t groups (younger & healthier) Clinical trials can ameliorate or eliminate these biases & issues.
one can often find a convincing association between therapy and outcome.g.05 or less.
. This minimizes the risk of spurious results. its possible to find correlations : zodiac signs & response rate. e. Prospective clinical trials pre-specify one primary endpoint. If the data is analyzed enough times in enough different ways. looking data in 20 different ways can be expected to yield one spurious association with a p value of 0.3)
Source of medical knowledge could be the hazards of multiple post hoc analyses.
Its possible to postulate that aspirin lowers the risk of CV events.4)
Knowledge based on retrospective data . An alternate reason : pts who exercise > : injure their knees > .cause dental caries & take more aspirin to relieve the dental pain.g.need to establish causation. A diet low in fat .low incidence of cardiovascular events. e. Or. pts ingest aspirin . tend to take aspirin for their aching joints.
. Mostly it is not possible to establish causation without randomized intervention. but other explanations cannot be ruled out.
.g. MI pts: > sicker :> likely to receive thrombolytic who received thrombolytic . despite the intervention being effective. Multivariate analysis can tease out effects d/t differences in the patient population. a randomized prospective clinical trial is the optimal way of establishing clear causation.The opposite is also true: confounding may mask causal association. CT ideally. group with intervention may not do better. e.
The two most critical limitations are
Generalizability refers to the appropriateness of extrapolating the results from a study to the general patient population as a whole. goal : difference between a drug and placebo frequent visits.random sample of patients with a disease. compliance. CT -truly generalizable .. overestimate or underestimate of the effect be seen in true clinical practice. of a drug.)
Clinical trials test efficacy. prohibition of concomitant medications. extra attention. m/m physician in clinical practice. not effectiveness. (reflect population at large.
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
y Experimental design is a way to advance knowledge
efficiently & reliably y The foundation of design are observation & theory y Several types of clinical observations y They help in generating a hypothesis.
Types of clinical observations 1) Case reports Demonstrate that an event is of some interest Weakest clinical evidence
A demonstration of certain possibility related clinical events
But subject to large selection biases. to evaluate efficacy.
Comparative clinical trials
. End point ascertainment is actively performed & analysis is planned in advance. Investigator takes advantage of Lack key design natural exposures / treatment strength of selection & chooses a comparison group experiments Treatment assignment is by design.
Treatment is not determined by Data unlikely to have experimental design but by factors such collected specifically as physician/ patient preference.
Invariant requirement of hypothesis-testing clinical trials Prospective intervention
Variable properties of hypothesis-testing clinical trials Randomization vs. other testing Type of outcome being tested
. other ways of assignment Number of treatment groups
Assignment to treatment groups At least one control group Null hypothesis
Usually the study population is a sample of the total population
. y When populations are very large. observing or testing every
single member of the population becomes impractical. E. y Sample must have similar diversity of all relevant characteristics as the total population.y A sample is a portion or subset of a population. Jackie Chan action movies are not a representative sample of Hong Kong movies y Samples must be random to be representative y The study population is a group of patients who are part of a clinical study.g.
Increasing the sample size is costly Therefore. investigators must balance increasing study power with expense.
.Larger study sample sizes mean greater study power.
05) and 1% ( p 0. respectively. Significance level : The most commonly used significance levels are 5% ( p 0.01). which means that a false null hypothesis is successfully rejected 80% of the time. of a chance difference mistakenly being considered a real significant difference. If you were studying a treatment to alleviate severe diarrhea.
. which means that there is a 5% or 1% probability.Many factors affect the sample size Power : commonly used power threshold is 80%. Clinical event rate : The relevant clinical event depends on what you are studying. then the clinical event is an episode of diarrhea.
A low event rate = large sample size. Higher event rates = smaller sample sizes. Expected effect size : A study s power depends on the difference between the expected effect size and the actual observed effect size.
. Predicting the event rate can be very difficult and is usually based on prior studies.Event rate is the frequency of the relevant clinical event in your study population.
1:1 / 2:1 etc
.Compliance and drop-out rates : Subject allocation ratio : The allocation ratio is the ratio of the number of patients assigned to each arm.
Potential strategies include using: Most of the Population Entire population of pts with certain conditions or characteristics 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
. the desired precision). The following formula calculates sample size when you are comparing the means of two groups:
where Z is the Z -score.
. and e is the margin of error (i. 2 is the population variance.e.Sample Size Formulae The final method for choosing a sample is using sample size formula.
.. p is the estimated proportion of an attribute that is present in the population.The following formula calculates sample size when you are comparing the proportions of two groups:
where Z is the Z -score. Open info. and e is the margin of error
Softwares for sample size calculation EPI 6..
y Randomization is the process of using chance or
probability to assign subjects to different study arms
Blinding or masking achieves two things: it reduces potential bias from investigators. Single blinding Double blinding Triple blinding
. and it reduces potential bias from patients.
pt.crucial step Functions :
y y y y
quality control tool Way to communicate research idea to others Quantum unit of research Legal document
.y It s a document that specifies the research plan for a CT y Difficult part of writing:
1. 2. feasible scientific question Being certain that resource are available (funds. time)
Developing a written research protocol.
Formulating & developing an important.
a)Study title b)principal investigator c)other study collaborators d)Administrative officer
2) Contents / Index 3)
One page description
4) Schema 5) Objectives of study 6) Introduction & background 7) Drug information 8) Staging criteria
management & monitoring
.9) 10) 11) 12) 13) 14) 15) 16) 17) 18)
Patient eligibility criteria Registration / randomization procedures & stratification Treatment program Dosage modification / side effects Agent information Treatment evaluation Serial measurement / study calendar Statistical considerations External collaboration / reviews Data recording.
19) Special instructions 20) Communication & publication of data 21) Patient consent forms 22) References 23) Data forms 24) Other appendices (ethical review documentation.
toxicity criteria etc.) 25) Glossary (definition of unfamiliar terms)