Tuesday, October 23, 2018

INTRODUCTION TO CLINICAL RESEARCH - pharmacovigilance-material


INTRODUCTION TO CLINICAL RESEARCH

Clinical trials have revolutionised the way disease is prevented, detected or treated and early death avoided. They continue to be an expanding area of research. They are central to the work of pharmaceutical companies, which cannot make a claim about a new drug or medical device until there is sufficient evidence on its efficacy. Trials originating from the academic or public sector are more common because they also evaluate existing therapies in different ways or interventions that do not involve a commercial product. Many health care professionals are expected to conduct their own trials or to participate in trials by recruiting subjects. They should have a sufficient understanding of the scientific and administrative aspects, including an awareness of the regulations and guidelines associated with clinical trials, which are now more stringent in many countries, making it more difficult to set up and run trials.
Early construction of a Clinical Trial:
James Lind, a Scottish naval physician, has conducted the first clinical trial. During a sea voyage in 1747, he chose 12 sailors with similarly severe cases of scurvy and examined six treatments, each given to two sailors. They were cider, diluted sulphuric acid, vinegar, seawater, a mixture of several foods including nutmeg and garlic, and oranges and lemons. They were made to live in the same part of the ship and with the same basic diet. Lind felt it was important to standardise their living conditions to ensure that any change in their disease is unlikely to be due to other factors. After about a week, both sailors given fruit had almost completely recovered, compared to little or no improvement in the other sailors. This dramatic effect led Lind to conclude that eating fruit was essential to cure scurvy, without knowing that it was specifically due to vitamin C. The results of his trial were supported by observations made by other seamen and physicians.
Lind had little doubt about the value of fruit. Two important features of his trial were: a comparison between two or more interventions and an attempt to ensure that the subjects had similar characteristics.  The requirement for these two features has not changed and it is an indication that how important they are in conducting good trials that aim to provide reliable answers.
Fundamental concepts:
There are two distinct study designs used in health research: observational and experimental. Observational studies do not intentionally involve intervening in the way individuals live their lives or how they are treated. However, clinical trials are specifically designed to intervene and then evaluate some health-related outcome with one or more of the following:
·          to diagnose or detect disease
·          to treat an existing disorder
·          to prevent disease or early death
·          to change behavior, habits or other lifestyle factors
Some trials evaluate new drugs or medical devices that will later require a licence (or marketing authorisation) for human use from a regulatory authority, if a benefit is shown. This allows the treatment to be marketed and routinely available to the public.
Other trials are based on therapies that are already licensed, but will be used in different ways, such as a different disease group or in combination with other treatments. An intervention could be a single treatment or therapy namely an administered substance that is injected, swallowed, inhaled or absorbed through the skin, an exposure such as radiotherapy, a surgical technique or a medical dental device. A combination of interventions can be referred to as a regimen, such as, chemotherapy plus surgery in treating cancer. Other interventions could be educational or behavioural programmes or dietary changes.
Any administered drug or micronutrient that is examined in a clinical trial with the specific purpose of treating, preventing or diagnosing disease is usually referred to as an Investigational Medicinal Product (IMP) or Investigational New Drug (IND). An IMP could be a newly developed drug or one that is already licensed for human use. Most clinical trial regulations that are part of law in several countries cover studies using an IMP and sometimes medical devices.
What Is a Clinical Study?
A clinical study involves research using human volunteers (also called participants) that is intended to add to medical knowledge. There are two main types of clinical studies: clinical trials and observational studies. Clinical Trials includes both interventional and observational studies.
Clinical Trials
In a clinical trial (also called an interventional study), participants receive specific interventions according to the research plan or protocol created by the investigators. These interventions may be medical products, such as drugs or devices; procedures; or changes to participants' behavior, for example, diet. Clinical trials may compare a new medical approach to a standard one that is already available or to a placebo that contains no active ingredients or to no intervention. Some clinical trials compare interventions that are already available to each other. When a new product or approach is being studied, it is not usually known whether it will be helpful, harmful, or no different than available alternatives (including no intervention). The investigators try to determine the safety and efficacy of the intervention by measuring certain outcomes in the participants. For example, investigators may give a drug or treatment to participants who have high blood pressure to see whether their blood pressure decreases.
Clinical trials used in drug development are sometimes described by phase. These phases are defined by the Food and Drug Administration (FDA).
Note: Some people who are not eligible to participate in a clinical trial may be able to get experimental drugs or devices outside of a clinical trial through an Expanded Access Program. See more information on expanded access from the National Library of Medicine.
Observational Studies
In an observational study, investigators assess health outcomes in groups of participants according to a protocol or research plan. Participants may receive interventions, which can include medical products, such as drugs or devices, or procedures as part of their routine medical care, but participants are not assigned to specific interventions by the investigator (as in a clinical trial). For example, investigators may observe a group of older adults to learn more about the effects of different lifestyles on cardiac health.
Who Conducts Clinical Studies?
Every clinical study is led by a principal investigator, who is often a medical doctor. Clinical studies also have a research team that may include doctors, nurses, social workers, and other health care professionals. Clinical studies can be sponsored, or funded, by pharmaceutical companies, academic medical centers, voluntary groups, and other organizations, in addition to Federal agencies such as the National Institutes of Health, U.S. Department of Defense, and U.S. Department of Veterans Affairs. Physicians, health care providers, and other individuals can also sponsor clinical research.
Where Are Clinical Studies Conducted?
Clinical studies can take place in many locations, including hospitals, universities, doctors' offices, and community clinics. The location depends on who is conducting the study.
How Long Do Clinical Studies Last?
The length of a clinical study varies, depending on what is being studied. Participants are told how long the study will last before enrolling.
Reasons for Conducting Clinical Studies
In general, clinical studies are designed to add to medical knowledge related to the treatment, diagnosis, and prevention of diseases or conditions. Some common reasons for conducting clinical studies include:
                     Evaluating one or more interventions (for example, drugs, medical devices, approaches to surgery or radiation therapy) for treating a disease, syndrome, or condition
                     Finding ways to prevent the initial development or recurrence of a disease or condition. These can include medicines, vaccines, or lifestyle changes, among other approaches.
                     Evaluating one or more interventions aimed at identifying or diagnosing a particular disease or condition
                     Examining methods for identifying a condition or risk factors for that condition
                     Exploring and measuring ways to improve the comfort and quality of life of people with a chronic illness through supportive care
Participating in Clinical Studies
A clinical study is conducted according to a research plan known as the protocol. The protocol is designed to answer specific research questions as well as safeguard the health of participants. It contains the following information:
           The reason for conducting the study
           Who may participate in the study (the eligibility criteria?)
           The number of participants needed
           The schedule of tests, procedures, or drugs and their dosages
           The length of the study
           What information will be gathered about the participants?
Who Can Participate in a Clinical Study?
Clinical studies have standards outlining who can participate, called eligibility criteria, which are listed in the protocol. Some research studies seek participants who have the illnesses or conditions that will be studied. Other studies are looking for healthy participants. And some studies are limited to a predetermined group of people who are asked by researchers to enroll.
Eligibility. The factors that allow someone to participate in a clinical study are called inclusion criteria, and the factors that disqualify someone from participating are called exclusion criteria. These are based on things such as age, gender, the type and stage of a disease, previous treatment history, and other medical conditions.
How Are Participants Protected?
Informed consent is a process in which researchers provide potential and enrolled participants with information about a clinical study. This information helps people decide whether they want to enroll, or continue to participate, in the study. The informed consent process is intended to protect participants and should provide enough information for a person to understand the risks of, potential benefits of, and alternatives to the study. In addition to the informed consent document, the process may involve recruitment materials, verbal instructions, question-and- answer sessions, and activities to measure participant understanding. In general, a person must sign an informed consent document before entering a study to show that he or she was given information on risks, potential benefits, and alternatives and understands it. Signing the document and providing consent is not a contract. Participants may withdraw from a study at any time, even if the study is not over. See Questions to Ask a health care provider or researcher about participating in a clinical study.
Institutional review boards. Each federally supported or conducted clinical study and each study of a drug, biological product, or medical device regulated by FDA must be reviewed, approved, and monitored by an institutional review board (IRB). An IRB is made up of physicians, researchers, and members of the community. Its role is to make sure that the study is ethical and the rights and welfare of participants are protected. This includes making sure that research risks are minimized and are reasonable in relation to any potential benefits, among other things. The IRB also reviews the informed consent document.
In addition to being monitored by an IRB, some clinical studies are also monitored by data monitoring committees (also called data safety and monitoring boards).
Various Federal agencies, including the Office of Human Subjects Research Protection (OHRP) and FDA, have the authority to determine whether sponsors of certain clinical studies are adequately protecting research participants.
Relationship to Usual Health Care
Typically participants continue to see their usual health care providers while enrolled in a clinical study. While most clinical studies provide participants with medical products or interventions related to the illness or condition being studied, they do not provide extended or complete health care. By having the participant's usual health care provider work with the research team, the participant can make sure that the study protocol will not conflict with other medications or treatments being received.
Considerations for Participation
Participating in a clinical study contributes to medical knowledge. The results of these studies can make a difference in the care of future patients by providing information about the benefits and risks of therapeutic, preventative, or diagnostic products or interventions.
Clinical trials provide the basis for the development and marketing of new drugs, biological products, and medical devices. Sometimes, the safety and the effectiveness of the experimental approach or use may not be fully known at the time of the trial. Some trials may provide participants with the prospect of receiving direct medical benefits, while others do not. Most trials involve some risk of harm or injury to the participant, although it may not be more than the risks related to routine medical care or disease progression. (For trials approved by IRBs, the IRB has decided that the risks of participation have been minimized and are reasonable in relation to anticipated benefits.) Many trials require participants to undergo additional procedures, tests, and assessments based on the study protocol. These will be described in the informed consent document for a particular trial. A potential participant should also discuss these issues with members of the research team and with his or her usual health care provider.
Questions to Ask
Anyone interested in participating in a clinical study should know as much as possible about the study and feel comfortable asking the research team questions about the study, the related procedures, and any expenses. The following questions might be helpful during such a discussion. Answers to some of these questions are provided in the informed consent document. Many of these questions are specific to clinical trials, but some also apply to observational studies.
                     What is being studied?
                     Why do researchers believe the intervention being tested might be effective? Why might it not be effective? Has it been tested before?
                     What are the possible interventions that I might receive during the trial?
                     How will it be determined which interventions I receive (for example, by chance)?
                     Who will know which intervention I receive during the trial? Will I know? Will members of the research team know?
                     How do the possible risks, side effects, and benefits of this trial compare with those of my current treatment?
                     What will I have to do?
                     What tests and procedures are involved?
                     How often will I have to visit the hospital or clinic?
                     Will hospitalization be required?
                     How long will the study last?
                     Who will pay for my participation?
                     Will I be reimbursed for other expenses?
                     What type of long-term follow-up care is part of this trial?
                     If I benefit from the intervention, will I be allowed to continue receiving it after the trial ends?
                     Will results of the study be provided to me?
                     Who will oversee my medical care while I am in the trial?
                     What are my options if I am injured during the study?

Pharmacovigilance Study Material - OBJECTIVES OF THE COURSE




1. To provide an opportunity for the students to learn about development of Pharmacovigilance as a science, basic terminologies used in Pharmacovigilance, global scenario of Pharmacovigilance.

2. To train students on establishing Pharmacovigilance programs in an organization, various methods that can be used to generate safety data and signal detection.

SYLLABUS

1. Introduction to clinical research and Pharmacovigilance and their importance

Clinical trial history and stages
History and development of Pharmacovigilance

2. Definitions and Basic terminologies used in Pharmacovigilance

3. ICH-GCP Guidelines and Guidelines on Good Pharmacovigilance Practices (GVP)

4. SAE Reporting Amendments to DCGI in India

5. Seriousness and Causality assessment

6. Dechallenge and Rechallenge

7. Drug dictionaries and coding in Pharmacovigilance

MedDRA and Standardized MedDRA queries
WHO drug dictionary

8. Signal detection, Risk assessment and management

Identification of new adverse drug reactions
Signal detection in pre and post marketing period
Prioritization and risk assessment
Risk management

9. Argus Safety Databse

10. Case Narratives

Regulatory perspectives of narrative writing
Case narratives from clinical trial data
Case narratives from post marketing reporting
Quality assessment of case narratives
Spontaneous Case reporting
Literature Case reporting




11. Information resources in Pharmacovigilance

Basic drug information resources
Specialized resources for ADRs
Critical evaluation of medication safety literature
CIOMS

12. Communication in Pharmacovigilance

Effective communication in Pharmacovigilance
Communication in Drug Safety Crisis management
Communicating with Regulatory Agencies, Business Partners, Healthcare facilities & Media
Dear Doctor Letters to Healthcare Professionals and e-mail etiquettes
E-mail etiquettes

13. On Job Responsibilities

14. Resume Preparation


TYPES OF CLINICAL TRIALS - pharmacovigilance-material


TYPES OF CLINICAL TRIALS
Clinical trials can be classified based on different types:
The first way of classifying clinical trials is in the way the researchers behave.
In an observational study, the investigators observe the subjects and measure their outcomes. The researchers do not actively manage the experiment. This is also called a natural experiment. An example is the Nurses' Health Study.
                     In an interventional study, the investigators give the research subjects a particular medicine or other intervention. (Usually they compare the treated subjects to subjects who receive no treatment or standard treatment.) Then the researchers measure how the subjects' health changes.
                     Second way of classifying trials is by their purpose. The U.S. National Institutes of Health (NIH) organizes trials into five (5) different types:
                     Prevention trials: look for better ways to prevent disease in people who have never had the disease or to prevent a disease from returning. These approaches may include medicines, vitamins, vaccines, minerals, or lifestyle changes.
                     Screening trials: test the best way to detect certain diseases or health conditions.
                     Diagnostic trials: conducted to find better tests or procedures for diagnosing a particular disease or condition.
                     Treatment trials: test experimental treatments, new combinations of drugs, or new approaches to surgery or radiation therapy.
                     Quality of Life trials: explore ways to improve comfort and the quality of life for individuals with a chronic illness (e.g. Supportive Care trials).
                     Genetic trials :-Determine how one’s genetic makeup can influence detection, diagnosis, prognosis, and treatment
§  Broaden understanding of causes of cancer
§  Develop targeted treatments based on the genetics of a tumor
                     Academic clinical trials: They share a valuable component of the health care system; they benefit patients and help to determine the safety and efficacy of new drugs and devices.
Typical areas of academic clinical trials are the advancement and optimization of already existing therapies. Thus academic clinical trials may for instance test how a combination of registered drugs may improve treatment outcomes or they may apply registered treatments in additional, less frequent indications. Such research questions are not a primary focus of for-profit companies and thus these trials are typically initiated by individual investigators or academic research organizations.
There are many different organizations which have an interest in academic clinical trials and facilitate or take part in their conduct. These organizations include:
                     Hospitals, universities, researchers and institutions that view trials as a source of income and prestige and receive private, charitable and governmental funding.
                     Pharmaceutical or biotech companies who view the development and commercialization of treatments as their business.
                     Regulators who wish to ensure treatments are safe and work effectively.
                     Patients and patients' organizations and associations who want faster access to advanced treatments.
Academic clinical trials are run at academic sites, such as medical schools, academic hospitals and universities and non-academic sites which may be managed by so-called Site Management Organizations (SMOs). Site management organizations are for-profit organizations which enlist and manage the physician practice sites that actually recruit and follow patients enrolled in clinical trials. In some cases, academic members participate in clinical trials act as members of SMOs.
A crossover trial also referred to as a crossover study is a clinical trial in which patients are given all of the medications to be studied or one medication and a placebo in random order. These studies are generally done on patients with chronic diseases to control their symptoms. The data are analyzed according to the original intention to treat.
A crossover study has the advantage over a simple double-blind study that the variability between patients is minimized because each patient crossing over in effect serves as their own control. One disadvantage is that long term effects cannot be tracked with this approach. Another disadvantage is that curative therapies cannot be tested after one another or before a placebo.
There are some important issues with respect to the design of cross-over studies. Two in particular may often crop up.
First is the issue of order effects, because it is possible that the order in which treatments are administered may affect the outcome. An example might be a drug with many adverse effects given first, making patients taking a second, less harmful medicine, more sensitive to any adverse effect.
Second is the issue of carry-over between treatments. In practice carry-over can be and is often dealt with by the use of a wash-out period between treatments or by making observations sufficiently later after the start of a treatment period that any carry-over effect is minimized.
A randomized controlled trial (RCT):
Randomization is a process for allocating subjects between the different trial interventions. Each subject has the same chance of being allocated to any group, which ensures similarity in characteristics between the arms. This minimizes the effect of both known and unknown confounders, and thus has a distinct advantage over observational studies in which statistical adjustments can only be made for known confounders. Although randomization is designed to produce groups with similar characteristics, there will always be small differences because of chance variation. Randomization cannot produce identical groups.
RCT is a type of scientific experiment most commonly used in testing healthcare services (such as medicine or nursing) or health technologies (such as pharmaceuticals, medical devices or surgery). According to Lachin (1998), 'RCTs are considered the most reliable form of scientific evidence in healthcare because they eliminate spurious causality and bias'. RCTs are mainly used in clinical studies, but are also employed in other sectors such as judicial, educational and social research. As their name suggests, RCTs involve the random allocation of different interventions (or treatments) to subjects. This ensures that known and unknown confounding factors are evenly distributed between treatment groups.
Sellers of medicines throughout the ages have had to convince their consumers that the medicine works. As science has progressed, public expectations have risen, and government health budgets have become ever tighter, pressure has grown for a reliable system to do this. Moreover, the public's concern for the dangers of medical interventions has spurred both legislators and administrators to provide an evidential basis for licensing or paying for new procedures and medications. In most modern health-care systems all new medicines and surgical procedures therefore have to undergo trials before being approved.
Trials are used to establish average efficacy of a treatment as well as learn about its most frequently occurring side-effects. This is meant to address the following concerns. First, effects of a treatment may be small and therefore undetectable except when studied systematically on a large population. Second, biological organisms (including humans) are complex and do not react to the same stimulus in the same way, which makes inference from single clinical reports very unreliable and generally unacceptable as scientific evidence. Third, some conditions will spontaneously go into remission, with many extant reports of miraculous cures for no discernible reason. Finally, it is well-known and has been proven that the act of administering the treatment itself may have direct, sometimes very powerful, psychological effects on the patient, which is known as the placebo effect.
Randomized trials are employed to test efficacy while avoiding these factors. Trials may be open, blind or double-blind.
Blind trials
The randomization process minimizes the potential for bias but the benefit could be greater if the trial intervention given to each subject is concealed. Subjects or researchers may have expectations associated with a particular treatment and knowing which was given can create bias. This can affect how people respond to treatment or how the researcher manages or assesses the subject. In subjects, this bias is specifically referred to as the placebo effect. Humans have a remarkable psychological ability to affect their own health status. The effect of any of these biases could result in subjects receiving the new intervention appearing to do better than those on the control treatment, but the difference is not really due to the action of the new treatment.
Single-blind trial
In a single-blind trial, the researcher knows the details of the treatment but the patient does not. Because the patient does not know which treatment is being administered (the new treatment or another treatment) there might be no placebo effect. In practice, since the researcher knows, it is possible for him to treat the patient differently or to subconsciously hint to the patient important treatment-related details, thus influencing the outcome of the study.
Double-blind trial
An experiment designed to test the effect of a treatment or substance by using groups of experimental and control subjects in which neither the subjects nor the investigators know which treatment or substance is being administered to which group. In a double-blind test of a new drug, the substance may be identified to the investigators by only a code. The purpose of a double-blind study is to eliminate the risk of prejudgment by the participants, which could distort the results. A double-blind study may be augmented by a cross-over experiment, in which experimental subjects unknowingly become control subjects, and vice versa, at some point in the study.
Triple-blind trial
Some randomized controlled trials are considered triple-blinded, although the meaning of this may vary according to the exact study design. The most common meaning is that the subject, researcher and person administering the treatment (often a pharmacist) are blinded to what is being given. Alternately, it may mean that the patient, researcher and statistician are blinded. These additional precautions are often in place with the more commonly accepted term "double blind trials", and thus the term "triple-blinded" is infrequently used. However, it connotes an additional layer of security to prevent undue influence of study results by anyone directly involved with the study.
Aspects of control in clinical trials
Traditionally the control in randomized controlled trials refers to studying a group of treated patients’ not in isolation but in comparison to other groups of patients, the control groups, who by not receiving the treatment under study, give investigators important clues to the effectiveness of the treatment, its side effects, and the parameters that modify these effects.
Other aspects of control include having other members of the research team, who will typically review the test to try to remove any factors which might skew the results. For example, it is important to have a test group which is reasonably balanced for ages and sexes of the subjects (unless this is a treatment which will never be used on a particular sex or age group). Additionally, peer review and/or review by government regulators can be seen as another source of control. These bodies examine the trial results when they are presented for publication or when the drug manufacturer applies for a license for the drug.
The importance of having a control group cannot be overstated. Merely being told that one is receiving a miraculous cure can be enough to cure a patient—even if the pill contains nothing more than sugar. Additionally, the procedure itself can produce ill effects. For example, in one study on rabbits where these subjects were receiving daily injections of a drug, it was found that they were developing cancer. If this was a result of the treatment, it would obviously be unsuitable for testing in humans. Because this result was reflected equally between the control and test groups, the source of the problem was investigated and it was shown in this case that the administration of daily injections was the cancer risk not the drug itself.
The analysis of the trial results requires knowledge of medicine, epidemiology and in particular statistics. The branch of statistics that deals specifically with biomedical research is biostatistics. Pharmaceutical firms employ groups of biostatisticians to try to make sense of the data. Likewise, regulators pay keen attention to the appropriateness of statistical methods used to analyze trial results.

Types of control groups
                     Placebo concurrent control group
                     Dose-response concurrent control group
                     Active concurrent control group
                     No treatment concurrent control group
                     Historical control
Randomization in clinical trials
There are two processes involved in randomizing patients to different interventions. First is choosing a randomization procedure to generate a random and unpredictable sequence of allocations. This may be a simple random assignment of patients to any of the groups at equal probabilities, or may be complex and adaptive. A second and more practical issue is allocation concealment, which refers to the stringent precautions taken to ensure that the group assignment of patients are not revealed to the study investigators prior to definitively allocating them to their respective groups.
Randomization procedures
There are a couple of statistical issues to consider in generating the randomization sequences.
                     Balance: since most statistical tests are most powerful when the groups being compared have equal sizes, it is desirable for the randomization procedure to generate similarly-sized groups.
                     Selection bias: depending on the amount of structure in the randomization procedure, investigators may be able to infer the next group assignment by guessing which of the groups has been assigned the least up to that point. This breaks allocation concealment (see below) and can lead to bias in the selection of patients for enrollement in the study.
                     Accidental bias: if important covariates that are related to the outcome are ignored in the statistical analysis, estimates arising from that analysis may be biased. The potential magnitude of that bias, if any, will depend on the randomization procedure.
Complete randomization
This is commonly used in which, each patient is effectively and randomly assigned to any one of the groups. It is simple and optimal in the sense of robustness against both selection and accidental biases. However, its main drawback is the possibility of imbalances between the groups. In practice, imbalance is only a concern for small sample sizes (n < 200).
Permuted block randomization
In this form of restricted randomization, blocks of k patients are created such that balance is enforced within each block. For instance, let E stand for experimental group and C for control group, then a block of k = 4 patients may be assigned to one of EECC, ECEC, ECCE, CEEC, CECE, and CCEE, with equal probabilities of 1/6 each. Note that there are equal numbers of patients assigned to the experiment and the control group in each block.
Permuted block randomization has several advantages. In addition to promoting group balance at the end of the trial, it also promotes periodic balance in the sense that sequential patients are distributed equally between groups. This is particularly important because clinical trials enroll patients sequentially, such that there may be systematic differences between patients entering at different times during the study.
Unfortunately, by enforcing within-block balance, permuted block randomization is particularly susceptible to selection bias. That is, since toward the end of each block the investigators know the group with the least assignment up to that point must be assigned proportionally more of the remainder, predicting future group assignment becomes progressively easier. The remedy for this bias is to blind investigator from group assignments and from the randomization procedure itself.
Strictly speaking, permuted block randomization should be followed by statistical analysis that takes the blocking into account. However, for small block sizes this may become infeasible. In practice it is recommended that intra-block correlation be examined as a part of the statistical analysis.
A special case of permuted block randomization is random allocation, in which the entire sample is treated as one block.
Urn randomization Designs:
Covariate-adaptive randomization
When there are a number of variables that may influence the outcome of a trial (for example, patient age, gender or previous treatments) it is desirable to ensure a balance across each of these variables. This can be done with a separate list of randomization blocks for each combination of values - although this is only feasible when the number of lists is small compared to the total number of patients. When the number of variables or possible values are large a statistical method known as Minimization can be used to minimize the imbalance within each of the factors.
Outcome-adaptive randomization
For a randomized trial in human subjects to be ethical, the investigator must believe before the trial begins that all treatments under consideration are equally desirable. At the end of the trial, one treatment may be selected as superior if a statistically significant difference was discovered. Between the beginning and end of the trial is an ethical grey zone. As patients are treated, evidence may accumulate that one treatment is superior, and yet patients are still randomized equally between all treatments until the trial ends.
Outcome-adaptive randomization is a variation on traditional randomization designed to address the ethical issue raised above. Randomization probabilities are adjusted continuously throughout the trial in response to the data. The probability of a treatment being assigned increases as the probability of that treatment being superior increases. The statistical advantages of randomization are retained, while on average more patients are assigned to superior treatments.
Allocation concealment
In practice, in taking care of individual patients, clinical investigators often find it difficult to maintain impartiality. Stories abound of investigators holding up sealed envelopes to lights or ransacking offices to determine group assignments in order to dictate the assignment of their next patient. This introduces selection bias and confounders and distorts the results of the study. Breaking allocation concealment in randomized controlled trials is much more problematic because in principle the randomization should have minimized such biases.
Some standard methods of ensuring allocation concealment include:
                     Sequentially-Numbered, Opaque, Sealed Envelopes (SNOSE)
                     Sequentially-numbered containers
                     Pharmacy controlled
                     Central randomization
Great care for allocation concealment must go into the clinical trial protocol and reported in detail in the publication. Recent studies have found that not only do most publications not report their concealment procedure most of the publications that do not report also have unclear concealment procedures in the protocols.
 Most studies start with a 'null hypothesis' which is being tested (usually along the lines of 'our new treatment x cures as many patients as existing treatment y') and an alternative hypothesis ('x cures more patients than y'). The analysis at the end will give a statistical likelihood, based on the facts of whether the null hypothesis can be safely rejected (saying that the new treatment does, in fact, result in more cures). Nevertheless this is only a statistical likelihood, so false negatives and false positives are possible. These are generally set an acceptable level (e.g., 1% chance that it was a false result). However, this risk is cumulative, so if 200 trials are done (often the case for contentious matters) about 2 will show contrary results. There is a tendency for these two to be seized on by those who need that proof for their point of view.

INTRODUCTION TO CLINICAL RESEARCH - pharmacovigilance-material

INTRODUCTION TO CLINICAL RESEARCH Clinical trials have revolutionised the way disease is prevented, detected or treated and early deat...