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!

1796, y Edward Jenner conducted the famous trial that proved inoculation could prevent smallpox. Jenner s trial was the first step toward mass vaccinations that conquered epidemics such as typhoid, yellow fever, polio and measles. 1931, y First documented CT in the U.S. using a matched control group, randomization, placebo, and blinding . y It used gold in the treatment of pulmonary TB.

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

Nuremburg Code in 1947 1. Study participants must give voluntary consent 2. Must be no reasonable alternative to conducting the experiment 3. The anticipated results must have basis in biological knowledge & animal experimentation 4. Procedure should avoid unnecessary suffering & injury 5. 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

Subjects are protected against even a remote possibility of death / injury. 8. Study must be conducted by qualified scientists. 9. Subject can stop participation at will. 10. Investigator has obligation to terminate the experiment if injury seems likely.
7. y y

Provides groundwork for standards of ethical conduct Do not distinguish between therapeutic & purely scientific experimentation

Durham-Humphrey Amendment of 1951 y Exempted certain drugs from requirement that their labeling contains adequate directions for use. y Be taken safely under medical supervision were exempted provided they were sold under the order of a licensed prescriber / administered under prescribed supervision. y Such exempted drugs, 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, launched on 1 October 1957, y was found to act as an effective tranquilizer and painkiller and was proclaimed a "wonder drug" for insomnia, coughs, colds and headaches. 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

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

Declaration of Helsinki, 1964 y Adopted by 18th WMA general assembly, Helsinki, Finland, 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, 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 . (conflicting) y Major landmark in evolution of GCP.

Good clinical practice y Set of guidelines for biomedical studies y Encompasses design, conduct, termination, audit, analysis, reporting & documentation of studies involving human subjects. y Fundamental tenet: Research on man, interest of science & society should never precedence over considerations related to the well being of the study subjects . y 2 cardinal principles:
y protection of right of human subjects & y authenticity of biomedical data generated.

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, Japan & United states to facilitate mutual acceptance of clinical trial data.

y Principles of GCP 1. 2. 3. 4. 5. 6.

CT in accordance with ethical principles(1. autonomy, 2. beneficence, 3. justice) Before trial, foreseeable risks & inconveniences should be weighed against benefit for individual trial subject & society Rights, safety & wellbeing of the trial subjects are most important. Available non-clinical & clinical information of product: adequate CT: scientifically sound, described in a clear, detailed protocol CT conducted in compliance with protocol that has received prior institutional review board (IRB) / independent ethics committee (IEC) approval

7. 8. 9. 10.

11. 12. 13.

Medical care / medical decision for subjects: always be responsibility of qualified physician. Each individual involved in conducting: be qualified Freely given informed consent should be obtained from every subject. CT information should be recorded, handled & stored in a way that it allows its accurate reporting, interpretation & verification. Confidentiality of records Investigational products should be manufactured, handled & stored in accordance of GMP. Procedures that assure quality of every aspect of trial should be implemented.

y Before the age of clinical trial, Ivy(1948) suggested that y y y y

patient is always an experimental subject. Conflict for physician: desire for academic & financial success - complete with both patient care & research. Trials are ethical in setting of uncertainty. Research & practice are not separable. Double standards
y Investigator studying randomized

comparison knows superior drug. y Treatment not thoroughly studied (thalidomide) y Some cultural places have fewer restrictions (US Vs Asia)

y There are legitimate ethical concerns about Clinical

trials
y Randomization ( if no equipoise , not justified) y Treatment preference (if pt prefers a t/t should they be y y y y

persuaded) Informed consent (e.g. test of radioactive substances 1945-1975 / sick - dying pt new treatment ?) Monitoring (one t/t superior evidences - stop) Active Vs Placebo (not be justified if effective t/t exist) Demonstration trial (ample evidence already-unethical)

1. Difficulty of determining whether an outcome represents a

true signal or just background noise. e.g. giving a new compound to 1-10 patient recovers from pneumonia -doesn t 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 of patients Clinical trials, with (usually) large aggregate data sets, randomization, and blinding, can often overcome these issues of variability and noise

2) Relying on informal observations or nonrandomized

studies is the difficulty in distinguishing between a result due to a bias vs. a result due to a real effect. e.g. when a patient and/or the treating physician know that a therapy is being administered, there may be a placebo effect. e.g. Imbalance between t/t groups (younger & healthier) Clinical trials can ameliorate or eliminate these biases & issues.
y y

Blinding can reduce the placebo effect and Randomization can reduce imbalances in patient characteristics between the groups.

3)

Source of medical knowledge could be the hazards of multiple post hoc analyses. If the data is analyzed enough times in enough different ways, 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 a p value of 0.05 or less. Prospective clinical trials pre-specify one primary endpoint. This minimizes the risk of spurious results.

4)

Knowledge based on retrospective data - need to establish causation. Mostly it is not possible to establish causation without randomized intervention. e.g. pts ingest aspirin - low incidence of cardiovascular events. Its possible to postulate that aspirin lowers the risk of CV events, but other explanations cannot be ruled out. An alternate reason : pts who exercise > : injure their knees > ; tend to take aspirin for their aching joints. Or, A diet low in fat - cause dental caries & take more aspirin to relieve the dental pain.

The opposite is also true: confounding may mask 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.

The two most critical limitations are

y Generalizability
Generalizability refers to the appropriateness of extrapolating the results from a study to the general patient population as a whole. CT -truly generalizable - random sample of patients with a disease, (reflect population at large, m/m physician in clinical practice.)

y Effectiveness.
Clinical trials test efficacy, not effectiveness, of a drug. goal : difference between a drug and placebo frequent visits, extra attention, compliance, prohibition of concomitant medications,. overestimate or underestimate of the effect be seen in true clinical practice.

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

2)

Case series

A demonstration of certain possibility related clinical events

But subject to large selection biases.

3)

Database analysis

Treatment is not determined by Data unlikely to have experimental design but by factors such collected specifically as physician/ patient preference. to evaluate efficacy. Investigator takes advantage of Lack key design natural exposures / treatment strength of selection & chooses a comparison group experiments Treatment assignment is by design. End point ascertainment is actively performed & analysis is planned in advance.

4)

Observational studies

5)

Comparative clinical trials

Invariant requirement of hypothesis-testing clinical trials Prospective intervention

Variable properties of hypothesis-testing clinical trials Randomization vs. other ways of assignment Number of treatment groups

Assignment to treatment groups At least one control group Null hypothesis

Superiority vs. other testing Type of outcome being tested

y A sample is a portion or subset of a population. y When populations are very large, observing or testing every

single member of the population becomes impractical. y Sample must have similar diversity of all relevant characteristics as the total population. E.g. 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. Usually the study population is a sample of the total population

Larger study sample sizes mean greater study power. Increasing the sample size is costly Therefore, investigators must balance increasing study power with expense.

Many factors affect the sample size Power : commonly used power threshold is 80%, which means that a false null hypothesis is successfully rejected 80% of the time. Significance level : The most commonly used significance levels are 5% ( p 0.05) and 1% ( p 0.01), which means that there is a 5% or 1% probability, respectively, of a chance difference mistakenly being considered a real significant difference. Clinical event rate : The relevant clinical event depends on what you are studying. If you were studying a treatment to alleviate severe diarrhea, then the clinical event is an episode of diarrhea.

Event rate is the frequency of the relevant clinical event in your 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 study s power depends on the difference between the expected effect size and the actual observed effect size.

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

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

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:

where Z is the Z -score, 2 is the population variance, and e is the margin of error (i.e., the desired precision).

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

where Z is the Z -score, p is the estimated proportion of an attribute that is present in the population, and e is the margin of error
Softwares for sample size calculation EPI 6.. Open info..

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, and it reduces potential bias from patients. Single blinding Double blinding Triple blinding

y It s a document that specifies the research plan for a CT y Difficult part of writing:
1. 2.

Formulating & developing an important, feasible scientific question Being certain that resource are available (funds, pt, time)

y y

Developing a written research protocol- crucial step Functions :

y y y y

quality control tool Way to communicate research idea to others Quantum unit of research Legal document

1)

Title page
a)Study title b)principal investigator c)other study collaborators d)Administrative officer

2) Contents / Index 3)

Protocol synopsis
One page description

4) Schema 5) Objectives of study 6) Introduction & background 7) Drug information 8) Staging criteria

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, management & monitoring

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)