CLINICAL SAFETY DATA MANAGEMENT (ICH-E2 A)

This guideline is explaining the importance to gather and, if necessary, to take action on important clinical safety information arising during clinical development.It describes definitions, terminologies used in Clinical trial Safety, receipt and processing of SAE data from Sites and expedited reporting of SAEs to RA(s) and Investigators.

Adverse Event / Experience (AE)

Any untoward medical occurrence in a patient or clinical investigation subject administered a pharmaceutical product and which does not necessarily have to have a causal relationship with this treatment. An AE can therefore be any unfavourable and unintended sign (including an abnormal lab finding), symptom, or disease temporally associated with the use of a medicinal product.

SUSARs = Suspected Unexpected Serious Adverse Reactions terminology used in EU Clinical Trial Directive.A SUSAR is a suspected adverse reaction to an investigational medicinal product that is both unexpected and serious.

Adverse Drug Reaction (ADR)

All noxious and unintended responses to a medicinal product related to any dose should be considered adverse drug reactions

Response to a medicinal product” or Reaction = a causal relationship between a medicinal product and an adverse event is at least a reasonable possibility, i.e.,the causal relationship cannot be ruled out.

Unexpected Adverse Drug Reaction

An adverse reaction, the nature or severity of which is not consistent with the applicable product information (e.g., Investigator's Brochure for an unapproved investigational medicinal product).

Serious Adverse Event (SAE)

A SAE is any untoward medical occurrence that at any dose:

- results in death

- is life-threatening

-requires inpatient hospitalization or prolongation ofexisting        hospitalization

- results in persistent or significant disability/incapacity

- is a congenital anomaly/birth defect

Severe reactions involve an event (as in mild, moderate, severe MI).It may be a minor medical significance (such as a severe headache).

Serious reactions based on patient/event outcome or action criteria.usually associated with events that pose a threat to a patient’s life or functioning.

Expedited Reporting to RA(s)

ALL single cases of SERIOUS adverse events (of the same IP, regardless of source) that are UNEXPECTED AND RELATED.

Reporting Timeframes

Fatal or Life-threatening Unexpected ADRs-Initial notification in 7 calendar days from first knowledge followed by complete report in 8 additional calendar days.All Other Serious, Unexpected ADRs report within 15 calendar days from first knowledge.

How to report?

CIOMS-I Form (Med Watch 3500A for US).Analysis of similar events (IND safety reports in US only). FDA 1571 Form (IND safety reports in US only).Other safety information requiring rapid communication to RA(s):a major safety finding from a newly completed animal study (such as carcinogenicity),a significant hazard to the patient population, such as lack of efficacy with a medicinal product used in treating life-threatening diseases,an increase in the rate of occurrence of an “expected” serious ADR, which is judged to be clinically important.Expedited SAE reports will be sent to all active investigators (participating in protocols using the same IP) in the form of an Investigator Alert Letter. The alert letters will include a paragraph advising the investigators to inform their IRB of the expedited SAE report; and append the new safety information received to the IB  as appropriate. It is the PI’s responsibility to submit the alert letters to his IRB 

COSTART

The Coding Symbols for a Thesaurus of Adverse Reaction Terms (COSTART) was developed by the United States Food and Drug Administration (FDA) for the coding, filing and retrieving of post-marketing adverse reaction reports. COSTART provides a method to deal with the variation in vocabulary used by those who submit adverse event reports to the FDA. Use of this dictionary allowed for standardization of adverse reaction reporting towards the FDA in a consistent way. Recently COSTART was replaced by the MedDRA.

MedDRA or Medical Dictionary for Regulatory Activities is a clinically validated international medical terminology used by regulatory authorities and the regulated biopharmaceutical industry throughout the entire regulatory process, from pre-marketing to post-marketing activities, and for data entry, retrieval, evaluation, and presentation. In addition, it is the adverse event classification dictionary endorsed by the International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use MedDRA is used in the US, European Union, and Japan. Its use is currently mandated in Europe and Japan for safety reporting.MedDRA is managed by the MSSO (Maintenance and Support Services Organization), an organization that reports to the International Federation of Pharmaceutical Manufacturers and Associations (IFPMA). MedDRA is free for regulators and priced according to company revenue for industry. MedDRA is also available in Japanese. The Japanese counterpart for MSSO is called JMO.The MSSO releases updated MedDRA versions twice a year - in March and September. The March release is the main annual release and contains LLT and PT changes, and changes at the HLT level and above.The September release typically contains changes only at the LLT and PT level. The March 2010 Version 13.0 release is the current version.The MedDRA dictionary is organized by System Organ Class (SOC), divided into High-Level Group Terms (HLGT), High-Level Terms (HLT), Preferred Terms (PT) and finally into Lower-Level Terms (LLT). In addition, the MedDRA dictionary includes Standardized MedDRA Queries (SMQs). SMQs are groupings of terms that relate to a defined medical condition or area of interest.

MedWatch is the Food and Drug Administration’s reporting system for adverse events, founded in 1993. An adverse event is any undesirable experience associated with the use of a medical product. The MedWatch system collects reports of adverse reactions and quality problems, primarily with drugs and medical devices, but also for other FDA-regulated products (e.g., dietary supplements, cosmetics, medical foods, and infant formulas). Voluntary reporting by healthcare professionals, consumers, and patients is conducted on a single, one-page reporting form (Form FDA 3500). Reporting can be conducted online, by phone or by submitting the MedWatch 3500 form by mail or fax.

The Yellow Card Scheme is the UK system for collecting information on suspected Adverse Drug Reactions (ADRs) to medicines. The Scheme is run by the Medicines and Healthcare products Regulatory Agency (MHRA) and the Commission on Human Medicines (CHM) and has been in operation since 1964. Suspected ADRs are collected on all licensed medicines and vaccines, from those issued on prescription to medicines bought over the counter from a pharmacist or supermarket. The Scheme also includes all herbal preparations and unlicensed medicines. ADRs can be reported by anyone; this is usually done by healthcare professionals - including doctors, pharmacists and nurses - but patients and carers can also make reports.


Reference.
1.www.ich.org
2.www.wikipedia.org

OBSERVATIONAL CLINICAL STUDY DESIGN

An observational study is a study in which a researcher simply observes behavior in a systematic manner without influencing or interfering with the behavior. Observational studies are of four main types : case-control, cross-sectional(including surveys) and  cohort studies.

Case-Control studies

Case – a person with the disease of interest. Control – a person without the disease of interest (probably having the symptom or risk factor).A case–control study consists in comparing the frequency of exposure in a group of subjects having disease (the cases) Vs group free of that disease (the controls). Case-control studies determine the relative importance of a predictor variable in relation to the presence or absence of the disease. Case-control studies are retrospective and cannot therefore be used to calculate the relative risk; this a prospective cohort study. Case-control studies can however be used to calculate odds ratios, which in turn, usually approximate to the relative risk.

Advantages and Disadvantages

When conditions are uncommon, case-control studies generate a lot of information from relatively few subjects. When there is a long latent period between an exposure and the disease, case-control studies are the only feasible option

In case-control studies comparatively few subjects are required so more resources are available for studying each.

This flexibility of the variables studied comes at the expense of the restricted outcomes studied. The only outcome is the presence or absence of the disease or whatever criteria were chosen to select the cases.

The major problems with case-control studies are the familiar ones of confounding variables and bias. Bias may take two major forms.

Sampling bias-The patients with the disease may be a biased sample (for example, patients referred to a teaching hospital) or the controls may be biased (for example, volunteers, different ages, sex or socioeconomic group).

Observation and recall bias-As the study assesses predictor variables retrospectively there is great potential for a biased assessment of their presence and significance by the patient or the investigator, or both.

Cross-sectional Studies:

These are primarily used to determine prevalence. Prevalence equals the number of cases in a population at a given point in time. Cross-sectional studies can be thought of as providing a "snapshot" of the frequency and characteristics of a disease in a population at a particular point in time. This type of data can be used to assess the prevalence of acute or chronic conditions in a population. Surveys & polls are generally cross-sectional studies. The advantage of such studies is that subjects are neither deliberately exposed, treated, or not treated and hence there are seldom ethical difficulties. Only one group is used, data are collected only once and multiple outcomes can be studied; thus this type of study is relatively cheap.

Cohort Studies:

These are the best method for determining the incidence and natural history of a condition. The studies may be prospective or retrospective and sometimes two cohorts are compared. A cohort is a group of people who have something in common and who remain part of a group over an extended time .The subjects in cohort studies are selected by some defining characteristics suspected of being a precursor to or risk factor for a disease.

Historical cohort studies:

This is a cohort studies in which the result can be analyzed by using information collected in the past and kept in records or files. This approach to a study is possible if the records on follow-up are complete and adequately detailed .This type of study is also called as retrospective cohort study.   

A prospective cohort study is a research effort that follows over time groups of individuals who are similar in some respects (e.g., all are working adults) but differ on certain other characteristics. Given the individual differences that exist in a sample (e.g., some people smoke, others do not), all the individuals in the sample are followed over time. The incidence rates for the disease under study are ascertained in key subgroups.

Advantages and Disadvantages

The use of cohorts is often mandatory as a randomized controlled trial may be unethical; for example, you cannot deliberately expose people to cigarette smoke or asbestos. Thus research on risk factors relies heavily on cohort studies. As cohort studies measure potential causes before the outcome has occurred the study can demonstrate that these “causes” preceded the outcome, thereby avoiding the debate as to which is cause and which is effect.

A further advantage is that a single study can examine various outcome variables. For example, cohort studies of smokers can simultaneously look at deaths from lung, cardiovascular, and cerebrovascular disease. This contrasts with case-control studies as they assess only one outcome variable (that is, whatever outcome the cases have entered the study with).Cohorts permit calculation of the effect of each variable on the probability of developing the outcome of interest (relative risk). However, where a certain outcome is rare then a prospective cohort study is inefficient. Another problem with prospective cohort studies is the loss of some subjects to follow up. This can significantly affect the outcome

Retrospective studies are much cheaper as the data have already been collected. One advantage of such a study design is the lack of bias because the outcome of current interest was not the original reason for the data to be collected Retrospective cohorts also suffer the disadvantage that people with the outcome of interest are more likely to remember certain antecedents, or exaggerate or minimize what they now consider to be risk factors (recall bias).

Where two cohorts are compared one will have been exposed to the agent of interest and one will not. The major disadvantage is the inability to control for all other factors that might differ between the two groups. These factors are known as confounding variables.

The only way to eliminate all possibility of a confounding variable is via a prospective randomized controlled study. In this type of study each type of exposure is assigned by chance and so confounding variables should be present in equal numbers in both groups.

Blinding:

This is the basic tool to prevent conscious as well as subconscious bias in research.

Single Blinding:

In a single blind experiment, the subjects do not know whether they are so-called "test" subjects or members of an experimental control

Double Blinded Trials:

Double-blind describes an especially stringent way of conducting an experiment in an attempt to eliminate subjective bias on the part of both experimental subjects and the experimenters. Also held to achieve a higher standard of scientific rigor. In a double-blind experiment, neither the individuals nor the researchers know who belongs to the control group and the experimental group. Performing an experiment in double-blind fashion is a way to lessen the influence of the prejudices and unintentional physical cues on the results

Triple-blind" trials

Triple-blind trials are double-blind trials in which the statistician interpreting the results also does not know which intervention has been given. Sometimes triple-blind is used to mean that multiple investigators are all blinded to the protocol (such as the clinician giving the treatment and a radiologist or pathologist who interprets the results.)

                                           Open-label trial

In this type of clinical trial in which both the researchers and participants know which treatment is being administered. Open-label trials may be appropriate for comparing two very similar treatments to determine which is most effective.

Open-label trials may be appropriate for comparing two very similar treatments to determine which is most effective. An open-label trial may be unavoidable under some circumstances, such as comparing the effectiveness of a medication to intensive physical therapy sessions.An open-label trial may still be randomized. Open-label trials may also be uncontrolled, with all participants receiving the same treatment.

Reference:

1.Wikipedia.

EXPERIMENTAL CLINICAL STUDY DESIGN

Clinical study design is the formulation of trials and experiments in medical and epidemiological research, sometimes known as clinical trials. A plan for carrying out or accomplishing something (especially a scientific experiment).

Experimental Study Design

1.Experimental Studies-Experimental Studies are generally easier to identify than observational studies in the medical literature.Experimental studies in medicine that involve humans are called as clinical trials ,because their purpose is to draw conclusions about a particular procedure or  treatment

Experimental studies differ from observational studies described /reported rather than simply to observe, the exposure of interest. There are many different approaches used in experimental studies, from very tightly controlled laboratory experiments to large scale community intervention. Experimental studies either focus on assessing change at the level of the individual or the group. The most important aspect of experimental studies, no matter what study group is used., is to ensure that the allocation of the study group to the different treatments/ interventions / exposures under investigation is done randomly. The development of the research protocol will then focus primarily on how to measure the effect of an exposure on an outcome with consideration of the effects of other factors (potential confounders as well as factors related to the efficacy of the delivery of the intervention)

Historical introduction

Lind and Louis are two notable workers who used experimentation to attempt objectively to assess the effect of a treatment on a disease. In 1753, Lind described an experiment in which 12 sailors with scurvy were put on the same standardized diets, and then allocated to one of six treatment groups for 14 days. Those receiving oranges and lemons were much improved after six days. His study must be considered one of the first controlled clinical trials. In 1834, Louis articulated further guidance to follow regarding study design. The number of  subjects required to show benefit of one treatment over another; (sample size).The need to observe disease progress accurately in treated and controlled groups; (end point).The need to define precisely disease state before the experiment;(inclusion criteria) and the importance of observing deviations from intended treatments.The first randomized controlled trials were undertaken until the later 1940s by the Medical Research Council. These were trials of streptomycin in the treatment of pulmonary tuberculosis (1948).These were trials of antihistamines for the treatment of the common cold (1950 double-blind, placebo-controlled trial.

In 1950, Cochran and Cox published an important textbook on experimental designs.This book was clearly and simply described the major statistical consideration relevant for experimental studies. Bradford-Hill was also an important force in making the design of clinical trials more rigorous. (Principles of medical statistics) .In 1959, Truelove summarized the current thinking on experimental design where he clearly described the essential elements of a therapeutic trial as follows:

1. The trial should be planned so that decisive answers can be given to one or more important questions (internal validity)

2. Patients should be selected for inclusion in the trial before it is known into which group they will go. After admission to the trial, patients should be allocated at random to one or other treatment group.

3. Systematic and pertinent observations should be made on patients so that relevant data are available for analysis at the conclusion of the trial.

4. When possible, trials should be so arranged that neither the physician nor the patient knows which treatment is being used - the so-called double- blind system. 

In broad terms there are two major types of experimental study. Those where the unit of measurement and exposure is:

    1. The individual.

    2. The population

Individual-based experimental studies are sometimes sub-divided on the basis of the level of the outcome as clinical trials (or therapeutic, secondary, or tertiary prevention trials), and field trials (primary prevention trials) where the subjects do not have any defined level of outcome which may be classified as disease.In addition, a third group of individual-based studies are called intervention studies, where the individuals who have the outcome of interest above a certain level at baseline are excluded. (in a trial of vitamin A supplementation children with xerophthalmia are excluded).

Experimental studies in whole populations (communities) are usually referred to as community trials or community intervention studies. Community trials focuses on mass education campaigns aimed at changing people’s knowledge and attitudes. Community intervention studies, the exposure is usually given to subjects (for example, by vector control to reduce malaria, pit latrines for clean water), or to reduce work load and/or to increase disposable income. These community intervention studies have also been characterized as:

 (1) Explicitly nutritional

(a) Nutrition oriented food programs (b) feeding programs (c) Weaning foods (d) fortification (e) nutrition education;

(2) Implicitly nutritional

(a) Health related, e.g. immunization, sanitation (b) Economic, e.g. income generation or substitution; (c) labor-saving, e.g. cereal mills;

(3) Integrated

 Combinations of (1) and (2) above. 

General considerations in experimental studies

There are a number of general principles that are relevant to all experimental studies.

(1)selection of the study population;

(2)allocation of treatment regimes;

(3)length of observation;

(4)observer effects;

(5)participant effects;

(6)compliance;

(7)ascertainment of exposure and     outcome;

(8)statistical power;

(9)analysis and interpretation. 

Selection of study population

The issues of internal and external validity aim to design a study so that it is free from bias and internally valid. For short-term, tightly controlled metabolic studies, compliance and loss to follow-up are less likely to be a problem. In a larger, less tightly controlled intervention trial which requires a longer follow-up to assess the desired effect, poor compliance and loss to follow-up may be crucial. In clinical trials, volunteers are usually recruited who are not necessarily representative of the general population; here the main concern is to demonstrate whether a change in exposure leads to a change in an outcome (effectiveness). In community intervention studies, the aim is to assess whether the intervention works at a practical level (efficacy), and some notion of the representation of the study sample is important in order to be able to generalize the results. For clinical trials where a therapeutic agent or procedure is to be tested, consideration may need to be given as to admission criteria.

These criteria may include certain demands for exclusion   and inclusion, and may primarily be intended for pragmatic and ethical purposes.

The restriction of subjects to be included in the study may also relate to the underlying hypothesis being tested; for example, the effect of changing the exposure may differ at different levels of the exposure and the researcher may only be interested in the effects in those with either a high or low intake.In a clinical trial the investigator may want to specif suitable clinical indications for treatment.

Allocation of treatment regimes

Random assignment implies that individuals or communities are allocated randomly to each study group and that allocation of subjects to a group is independent of the allocation of other subjects. In a community trial randomization occurs at the level of the community, subjects within a community are not randomly assigned to treatment or control group. However, for practical reasons the two largest community trials in the US did not fully randomly allocate towns, and this may undermine the confidence with which the results of these studies are judged. The purpose of randomization is to ensure that differences between treatment and control groups or towns/populations in potential confounders and levels of other important variables arise by chance alone. The random allocation of subjects to groups also ensures that neither the observers nor the individual participating in the study can influence, by way of personal judgment or prejudice, which is allocated to receive which treatment. Where the study sample is small and a factor is known to be an important determinant of the outcome, it is common to block on that factor to ensure that differences between treatment groups for levels of that factor do not occur by chance. For example, subjects are often blocked on age and gender to ensure that groups are balanced for these factors. For large trials, it is not usually necessary to block, as it is possible in the analysis to consider the treatment-outcome effect in subcategories of the factor of interest. While the effect of these blocking factors could be considered in the analysis, if the experiment is small and the chance variation large, it may be difficult to adjust for these effects in the analysis. Some studies make use of historical controls as a comparison group. For example, a new treatment may have been developed to the extent that it is considered unethical to withhold it from any subjects. It may be very difficult using historical controls to ensure that conditions other than the treatment of interest are comparable for the treatment and control periods. It is also possible to use exclusion criteria and matching to take account of the effects of other factors. If, for example, smokers behave differently from non-smokers and this difference is believed to influence the way treatment affects outcome.

Length of observation

An experiment should be just long enough to allow the effect of exposure change to result in the hypothesized change in outcome. In deciding on the length of the study the investigator must have an idea as to the mechanism of action of the proposed treatment and thereby some idea as to how long it should take to affect the various steps in the pathway (whether related to change in knowledge, attitudes, or behavior). The outcome of interest will affect the length of observation. For example, catecholamine or glucose metabolism, the study may only last a few hours.  For studies of diet and serum cholesterol or blood pressure the study may need to last weeks. For endpoints such as death the length of observation will need to be longer, perhaps many years. For short-term clinical trials, it may be important to consider whether the short-term changes being assessed are representative of what may occur when the diet is adopted over a longer period of time.

For longer-term studies, the effects of secular trends in the underlying rates of the outcome measure being studied need to be considered. If the treatment (or lack of treatment in the control group) appears to be resulting in an increased rate of disease, it may also be advisable to stop the trial. Where it may be considered likely that either of the above situations could occur, there should be clearly defined stopping rules incorporated into the study design.

Observer effects

It is desirable that both the observer and the participants are blinded as to the participants’ treatment group. Prior to the commencement of the study, all personnel involved in the study must be carefully trained to ensure uniformity in the administration of the protocol. The instruments, be they for measuring height, weight, or blood pressure; biochemical assay methods; dietary questionnaires; or any other source of ascertainment of information about the study, subjects must be carefully piloted to ensure that they measure what was intended and also that they measure it in a way that gives reliable information.

In a multi-centre trial, it may not be possible for the same observer to make all the measurements. If different observers are involved, careful consideration needs to be given as to the effect this may have on the consistency of results between centre’s.

If this type of problem can be thought of in the design stage, it may be better to consider an observer-independent means of measuring the variable of interest.

If this is not possible, it will be necessary to have a standardized comparison of the differences between observers which should occur in the training/pilot phase of the study.

It is important that a subset of subjects in each community have repeat measures taken by an observer from another centre. For example, if blood or urine or other tissue samples are being collected they should be analyzed in one center or at least in centres with identical analytical and standardization procedures. When any measurements are being made or data are being collected by interview, the observer should be blind as to the treatment or intervention group of that subject. This will ensure that any effect of the observer on the measurement will be random. A clear and standardized research protocol and procedures manual, there should be strict quality control procedures throughout. It is important to have a measure of the size of the likely intra-observer variation. The aim is to standardize the conditions under which the experiment is conducted so that the response of the participant to the intervention can be attributed to the treatment. To be a participant in the trial a person must be recruited and give free and informed consent to participate. They should be aware of the general nature of the research and aware of what they will be expected to do, and have done to them. The provision of adequate information about the study for the participants is important to improve subject compliance. The exact detail given to the participants needs to be balanced with the requirement that as far as possible the subjects be blinded as to the treatment allocation. For example, one drug is given compared to another or to a placebo. For dietary interventions this is much more difficult and it is likely that the subject will know the treatment group. This may affect their response to the treatment.

In community trials, subjects will probably not be asked if they agree to being involved in the study, and may not even know that they are in a study. Here the researcher must be sure that the treatment is ethical and not likely to harm the members of the community. The way a subject passes through the research protocol should be carefully standardized. Any violation of the protocol should be noted. For example, if a subject is scheduled to have their blood pressure measured in the morning, they should always have their blood pressure measured at the same time. In practice this is not always possible and when it does not occur it should be noted. Subjects should be given clear and consistent instructions for the completion of dietary records and questionnaires. If they are to provide urine or blood samples, they should be given clear, written instructions about what they need to do, for example, whether to fast the night before or, for a urine sample, how long the urine collection is for and when it is to stop and start. It is still important to measure these potentially important variables. These variables need to be measured with sufficient precision for their effect to be properly considered. As mentioned repeatedly elsewhere, measurement error in potential confounders is just as important as in the exposure and outcome measures. The way information is collected needs to take account of the within-subject variability. Just as repeat measures give an idea of observer effects, they also give an indication of subject variability.

In a clinical trial the aim is to characterize the individual, and measurements need to be precise enough to achieve this. The prime concern must be the internal validity that all aspects about subject participation in the study are comparable and that deviation from this ideal can be documented. In a community trial, participants may not even know they are participating in a study; if they do, then the same issues as mentioned for clinical trials need to be considered.

Compliance

They respect to participant effects relates to compliance. Deviation from the protocol needs to be documented in all subjects, not just those on the treatment. It may be that a comparison or control group alters their behavior so as to make them more like the treatment group in their exposure status. Perhaps more commonly, participants will forget or deliberately fail to take drugs, or, if they have been placed on a dietary regime, they may occasionally 'break-out' and deviate from the protocol. Measurement of compliance is essential in any clinical (dietary) trial. The study must be designed so that all variables of importance can be measured during the trial with sufficient precision to give a sensitive and specific (valid) indication of the level of each variable.

Where possible, an independent measure of compliance should be used. For example, measuring changes in the levels of fatty acids in serum, red blood cells, or a fat biopsy enables the researcher to assess the compliance with dietary advice to alter fat intake.

If a dietary intervention aims to increase fiber intake, it may be possible to include in the fiber diet a marker which can subsequently be measured in fecal samples. The level in the fecal sample may give an indication of the amount of fiber supplement eaten. From our experience it is helpful to tell participants that we are checking their compliance by taking blood or urine samples.

It may be more difficult to measure individual compliance in a community trial, but by random sampling of subjects within each study community, it should be possible to measure at least whether subjects are aware of the community intervention and whether it has had any effect on their knowledge, attitudes, behavior, or levels of some outcome variables. The efficiency of the treatment as measured by changes in community rates of disease may be adequate. Not measuring change in levels of the exposure which was supposed to be changed in the study may lead to a false impression of the effect of the exposure on the outcome (either positive or negative).The use of a run-in or familiarization period may improve compliance. It gives the subjects time to adjust to the rigors of the study protocol. However, the diet being fed during this period should not have any effect on the outcome measure. In theory it should be similar to the subject's usual diet.

If the trial is for a therapeutic agent, the run-in period should only use a placebo or usual care treatment. The run-in period should be before randomization, so that any drop-outs which occur during this period do not affect the internal validity of the study. There are situations where it may not be possible or appropriate to have a run-in period. For example, where the experiment is assessing the effect of treatment following an acute event.

Ascertainment of exposure and outcome

The aim of an experiment is to assess the effect of a defined change in exposure on the outcome of interest. To assess whether the change in exposure has affected the outcome requires that some measure of each can be obtained to confirm the changes. For studies where subjects are given advice as to how to change their diet, a measure of compliance with this advice is required; this will usually require an accurate assessment of an individual’s intake. Irrespective of the measures require to assess exposure and outcome ,the protocol should be administered in the same way in all subjects or groups included; it is not acceptable to use different measures of exposure and outcome in intervention and control groups.

Ascertainment of exposure

If diet is measured poorly, it may be impossible to detect the desired change in exposure which the study has sought, and the study may wrongly conclude that the subject's diet did not change significantly as a result of the intervention. Studies aimed at achieving dietary change by giving people dietary advice, but without measuring diet, and where the advice has not lead to statistically significant change in the outcome measure, are open to the criticism that the reason the advice did not lead to change in the outcome measure was because the advice did not achieve the desired change in diet (as well as concerns about statistical power and length of follow-up).For studies aiming to change people's behavior by changing people's knowledge, there is a need to consider the complex series of steps involved in going from knowledge to attitudes to behavior. Intervention studies seeking to change behaviors by dietary advice have measured psychological factors related to the subjects' readiness to change (transtheoretical models of behavior in general, and in relation to change in fat intake) and taken this into account when exploring the outcome measure. Because of the limitations of assessing dietary intakes by subject-based recording methods, alternative methods of assessing intake have been sought.

There is little point in precisely measuring, for example, a blood or urinary constituent that is not involved in or affected by the exposure of interest. Potentially important confounding factors should also be measured during the study; the effects of measurement error or misclassification need to be considered when selecting the method for measuring the confounding factor.

Ascertainment of outcomes

Outcomes in experimental studies are measured in the same way as in a cohort study. The outcome measures may be routinely collected data sources (death certificates or hospital activity / medical records), may be collected by the participants themselves (by completion of a questionnaire), or may be collected by investigator (by personal interviewer or medical examination).The outcome of the study is dependent on the completeness and validity of the information obtained.

Where routinely collected data are to be used to measure outcome, it must be possible to ascertain for all subjects whether they have died or been admitted to hospital. It may be relatively simple to determine vital status and obtain a death certificate where there is a central registry of deaths. It may be much more difficult to obtain complete hospital admission data in the absence of a suitable computerized system. If the investigator finds that a subject has died or had an event of interest (in a hospital or elsewhere), they are then reliant upon the accurate ascertainment, (usually by some other person) of the cause of death or clinical details related to the hospital admission. Where general practitioner’s records are to be used, the investigator must also be assured that subjects only attend that practice and that if an illness occurs they go to the same practitioner. The more subjects and information lost to follow-up, the more likely that a biased result will occur.

Where outcome measures are obtained either by self-report or observer measurement, it is essential that information is obtained in the same way for all subjects. Any under-ascertainment of outcome will effect the validity of the study. Observer blindness will reduce the risk of ascertainment bias and will also ensure at follow-up procedures to obtain outcome will not influenced differentially in treatment groups. It is also essential that the measurement of outcome is precise enough to categorize subjects correctly. The is no substitute, in designing an experiment with accurate ascertainment of outcome, to having a clear understanding of the biological process under investigation and potential errors associated with  the outcome measure.

Statistical power /sample size

To estimate the statistical power for clinical trials, the investigator needs to be able to estimate the likely random errors in the measurements being used and the number of events or changes in an outcome measure to be expected. The investigator also needs to specify the acceptable level of statistical significance and confidence. The statistic power of community trials relates to the number of communities, not the number of individuals, in each group. The power of community trials can be increased by matching intervention and control centres, stratifying on a baseline variable which is strongly related to the outcome, and also by increasing the number of times a community is observed.

Analysis and interpretation

This will ensure both that there are sufficient subjects available in subjects of the sample and that the data are collected in a way that is appropriate for the required analysis. In general, the correct estimate of the effect of the intervention will be the difference in the change from baseline in the intervention compared with the control group, irrespective of the exposure or outcome measure. The statistical significance can be expressed using the 95% confidence interval around the mean difference. In clinical trials, with data collected at the level of the individual, the change from baseline can be measured for each subject and the average change assessed for all subjects. For community trial, the analysis will be of the change in the population incidence or mortality.

Where measuring the outcome of interest (e.g.blood pressure) may itself influence the measurement, and may therefore be considered as an intervention in its own right, some researchers have argued that it is not appropriate to make this measurement at baseline. In this situation, the analysis simply measures the difference between groups in the outcome at the end of the study, and assumes that because of randomization baseline differences will not affect the final differences seen. There are two major approaches to the consideration of the subjects in the analysis of the data for clinical trials.  One view is that once subjects have been randomly allocated to treatment groups they should be included in the analysis irrespective of whether their compliance was good or bad or whether they dropped out or not. This is sometimes referred to as analyzing on an ‘intention to treat’ basis. Excluding subjects who have ‘measured’ compliance below a certain level is arbitrary and may give optimistically positive results.

A second view would argue that if the aim of the study was simply to demonstrate that a treatment can effect an outcome, then it may be acceptable to use a restricted subset (on the basis of compliance) of the data. If this approach is taken, consideration must be given to the effect that breaking the balanced group allocation may have on any comparisons. It may be that those who comply sufficiently well to included are either different in other important characteristics from those not adequately complying and/or the distribution of those characteristics may be different   in treatment and control groups. This latter question is more relevant to public health issues, where the investigator wants to know  whether the treatment works in the community. For more detailed consideration on statistical analysis readers are referred to other texts. 

Classification Of Experimental Studies

Parallel Trials

Most common design used in clinical trials .Some subjects are assigned to a treatment group and some other are assigned to control group with all the subjects following the same schedule and activities.

Controlled  trials

Controlled trials are studies in which the experimental drug or procedure is compared with another drug or procedure, some times a placebo & some times the previously accepted treatment.

Uncontrolled trials are studies in which the investigators experience with the experimental drug or procedure is described, but the treatment is not compared with another treatment . Studies with control are much more easier & valuable than those without controls to detect whether the difference is due to the experimental treatment or to some other factor.

Randomized controlled Trials

The Randomized controlled trial is the epitome of all research designs  because it provides the strongest evidence for concluding causation

Non Randomized Clinical Trials

A clinical trial in which the participants are not assigned by chance to different treatment groups.Participants may choose which group they want to be in, or they may be assigned to the groups by the researchers.

Sequential Controls

Sequential- in regular succession without gaps, having a systematic arrangement; especially having elements succeeding in order according to rule)

Self-controlled: The type of study uses patients as their own controls.

Example, the study by sauter and colleagues (2002) involved patients who underwent cholecystectomy.

Follow-up occurred 1 & 3 month after cholecystectomy to detect changes such as abdominal pain, flatulance,and dyspepsia(Dyspepsia is a pain or an uncomfortable feeling in the upper middle part of your stomach).

Studies with self-controls are vulnerable to the well known Hawthorne effect described by Roethlisberger & colleagues (1946),in which people change their behavior and some times improve simply because  they receive special attention by being in a study and not because of the study intervention

Cross -over Study: This design uses two groups of patients ,one group is assigned to the experimental treatment, second group is assigned to the placebo or control treatment.After a time the experimental treatment & placebo are withdrawn from both groups for a washout period.During the wash out period, the patients receive no treatment. The groups are then given the alternative treatment i.e.., the first group now receives the placebo,& the second group receives the experimental treatment.   

 Trials with external controls

The third method for controlling experiments is to use controls external to the study. Some times the result of another investigators research is used as an comparison.On other occasions the controls are patients the investigator has previously treated in another manner called Historical controls. 

HISTORY OF CLINICAL TRIAL

Going down the memory lane of clinical trials is interesting and useful in understanding the present scenario. Progresses of science and technology have all contributed to refining and redefining the whole process of clinical trial.

BACKGROUND

Earliest recorded Clinical trial is documented in the Old Testament. In BC 605-562, King Nebuchadnezzar II carried out the first clinical trial. Strict diet of meat and wine was changed to bread and water. Found that those who consumed bread and water were better nourished and resplendent than others.

CLINICAL TRIALS TIMELINE

In 1537,first Clinical Trial of novel therapy conducted unintentionally. By the Royal surgeon Ambroise Parè treated open wounds with a new mixture (oil of rose, turpentine and egg yolk).Observed that the wounds treated with traditional formula were swollen and extremely painful, while that treated with the experimental mixture was not painful. In 1600 Seafarers who were setting out to East Indies made a chance discovery.Found out that addition of sour oranges and lemons to their diet  improves general health and saves life.

                                                            

FIRST CONTROLLED CLINICAL TRIAL

In 1747,147 years after the discovery made by seafarers, James Lind proves the effectiveness of lemon juice in preventing scurvy.Experiment is known as the first controlled Clinical Trial;a trial with a parallel control group that is given an alternative treatment.

EMERGENCE OF PLACEBO

In 19^th Century,Trials utilizing placebo emerged(1863).A placebo is any intentionally non-effective medical treatment,especially an inactive or inert substance.It is often given to control groups in Clinical Trials to compare the results with those of the experimental drug.Placebo in Latin means “ I will please”.

PROOF OF SAFETY

In 1938, about 107 people died after taking Exilir sulfanilamide used DEG as solvent. The US Food, Drug and Cosmetics Act came into action and enforced the need for manufacturers to demonstrate safety.

INTRODUCTION OF MULTICENTRE STUDIES

In 1944, Studies were conducted at different sites using the same protocol. This allows the results to be pooled, so that greater numbers give increased statistical power.

NUREMBERG CODE OF 1947

The Nuremberg Code is a set of research ethics principles for human experimentation set as a result of the Subsequent Nuremberg Trials at the end of the Second World War.Developed as a result of German prisoner research trial.Established 10 points for the safety and protection of clinical trial participants.

1. The voluntary consent of the human subject is absolutely essential.

2. The experiment should be such as to yield fruitful results for the good of society, unprocurable by other methods or means of study, and not random and unnecessary in nature.

3. The experiment should be so designed and based on the results of animal experimentation and knowledge of the natural history of the disease or other problem under study that the anticipated results justify the performance of the experiment. 

4. The experiment should be so conducted as to avoid all unnecessary physical and mental suffering and injury.

5. No experiment should be conducted where there is a prior reason to believe that death or disabling injury will occur; except, perhaps, in those experiments where the experimental physicians also serve as subjects.

6. The degree of risk to be taken should never exceed that determined by the humanitarian importance of the problem to be solved by the experiment.

7. Proper preparations should be made and adequate facilities provided to protect the experimental subject against even remote possibilities of injury, disability or death.

8. The experiment should be conducted only by scientifically qualified persons. The highest degree of skill and care should be required through all stages of the experiment of those who conduct or engage in the experiment.

9. During the course of the experiment the human subject should be at liberty to bring the experiment to an end if he has reached the physical or mental state where continuation of the experiment seems to him to be impossible.

10. During the course of the experiment the scientist in charge must be prepared to terminate the experiment at any stage, if he has probable cause to believe, in the exercise of the good faith, superior skill and careful judgment required of him, that a continuation of the experiment is likely to result in injury, disability, or death to the experimental subject.

Outcome of Nuremberg Code

23 German scientist taken to court, 7 acquitted,9imprisoned,7given death sentence.

FIRST RANDOMIZED CONTROLLED CLINICAL TRIAL

In 1948, trials utilizing randomization developed. Idea of randomization was introduced in 1923.Randomization is a process by which subjects in a clinical trial are randomly assigned to receive one of the treatments offered. Trial was conducted to study the effect of streptomycin in TB patients. Patients were randomly divided into 2 separate groups of equal size. One group received streptomycin and the other received placebo.

THALIDOMIDE DISASTER 1961

Thalidomide was introduced as a sedative drug in the late 1950s. In 1961, it was withdrawn due to teratogenicity and neuropathy. Thalidomide was sold in a number of countries across the world from 1957 until 1961 when it was withdrawn from the market after being found to be a cause of birth defects in what has been called "one of the biggest medical tragedies of modern times.

PROOF OF EFFICACY

Kefauver-Harris Drug Amendment (1962) in USA.Action taken after thalidomide disaster.It introduced a "proof-of-efficacy" requirement, which was not present before. In addition, the Amendment required drug advertising to disclose accurate information about side effects and efficacy of treatments.The law was signed by President John F. Kennedy on October 10, 1962.

DECLARATION OF HELSINKI

Until the ICH GCP guidelines were adopted in 1996, the Declaration of Helsinki was the worldwide statement of ethical principles providing guidance to physicians and other subjects in medical research involving human subjects.

 

The principles in the declaration specifically address physicians. Non-physician clinical research professionals completing this module are encouraged to consider the applicability of each principle to their own research role and to the responsibilities they will assume. To fully comply with ICH GCP guidelines, you must have a clear knowledge of and be able to apply the principles in the Declaration of Helsinki.

Developed by World Medical Association in 1964.12 ethical principles (now serves as principles of ICH-GCP).Serves as a statement of ethical codes to provide direction for physicians and other participants in medical research involving human subjects. First adopted in Helsinki, in June 1964.Subsequently amended in the years 1975,1983,1989,1996,2000, 2001 and 2008.

TUSKEGEE SYPHILIS EXPERIMENT

The Tuskegee syphilis experiment was an infamous clinical study conducted between 1932 and 1972 in Tuskegee, Alabama by the U.S. Public Health Service to study the natural progression of untreated syphilis in poor, rural black men who thought they were receiving free health care from the U.S. government.By 1947, penicillin had become the standard treatment for syphilis. Instead, the Tuskegee scientists continued the study without treating any participants and withholding penicillin and information about it from the patients.The Tuskegee Syphilis Study, cited as "arguably the most infamous biomedical research study in U.S. history, led to the 1979 Belmont Report

BELMONT REPORT-1979

US Congress appointed a commission to identify the basic ethic principles that should underline the conduct of biomedical research.

Sets forth 3 ethical principles:

          Respect for persons: protecting the autonomy of all people and treating them with courtesy and respect and allowing for informed consent. Researchers must be truthful and conduct no deception;

     Beneficence: The philosophy of "Do no harm" while maximizing benefits for the research project and minimizing risks to the research subjects;
Justice: ensuring reasonable, non-exploitative, and well-considered procedures are administered fairly the fair distribution of costs and benefits to potential research participants and equally

                                                                                                          

GCP RECOMMENDATIONS

In 1986,Pioneered in European community.Individual countries such as Great Britain, France,Germany and the Scandinavian countries issued Good Clinical Practice recommendations.Discussions between Europe,Japan and US.1988-US Food and Drug Administration (FDA).Has broader responsibility and authority regarding the approval of new drugs.Regulation is Code of Federal Regulations (CFR).

TOWARDS HARMONIZATION

ICH born in Brussels in April 1990.Goal is to decrease country-to-country difference in guidelines for the conduct of clinical research.Topics included are: Safety(S),Quality(Q),Efficacy(E) and Multidisciplinary(M).Among these,E6 deals with the guidelines for Good Clinical Practice(GCP).European Union (EU) Directive or Clinical Trial Directive.Regulatory body-European Medicines Agency (EMEA).The Clinical Trials Directive (Officially Directive 2001/20/EC of 4 April 2001, of the European Parliament issued to implementation of good clinical practice in the conduct of clinical trials on medicinal products for human use) is a European Union directive.Aimed at facilitating the internal market in medicinal products within the European Union, while at the same time maintaining an appropriate level of protection for public health. It seeks to simplify and harmonize the administrative provisions governing clinical trials in the European Community, by establishing a clear, transparent procedure.

CONCLUSION

Since 1945,the ethical impact of CTs has become increasingly important, resulting in strict regulation of medical experiments on human subjects.CTs have thus evolved into a standard procedure, focusing on patient safety and requiring consent from all participants. There is always a need for balance between medical progress and patient safety, and the regulation of CTs helps to ensure that this balance is acceptable.

Reference:
1.http://www.sjph.net.sd
2http://en.wikipedia.org/wiki/Nuremberg_Code.
3.http://www.ccr.med.keio.ac.jp