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Clinical trial

Clinical trial

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Encyclopedia
Clinical trials are a set of procedures in medical research and drug development
Drug development
Drug development is a blanket term used to define the process of bringing a new drug to the market once a lead compound has been identified through the process of drug discovery...

 that are conducted to allow safety (or more specifically, information about adverse drug reaction
Adverse drug reaction
An adverse drug reaction is an expression that describes harm associated with the use of given medications at a normal dosage. ADRs may occur following a single dose or prolonged administration of a drug or result from the combination of two or more drugs...

s and adverse effects of other treatments) and efficacy
Efficacy
Efficacy is the capacity to produce an effect. It has different specific meanings in different fields. In medicine, it is the ability of an intervention or drug to reproduce a desired effect in expert hands and under ideal circumstances.- Healthcare :...

 data to be collected for health interventions (e.g., drugs, diagnostics, devices, therapy protocols). These trials can take place only after satisfactory information has been gathered on the quality of the non-clinic
Clinic
A clinic is a health care facility that is primarily devoted to the care of outpatients...

al safety, and Health Authority/Ethics Committee
Institutional review board
An institutional review board , also known as an independent ethics committee or ethical review board , is a committee that has been formally designated to approve, monitor, and review biomedical and behavioral research involving humans with the aim to protect the rights and welfare of the...

 approval is granted in the country where the trial is taking place.

Depending on the type of product and the stage of its development, investigators enroll healthy volunteers and/or patients into small pilot studies initially, followed by larger scale studies in patients that often compare the new product with the currently prescribed treatment. As positive safety and efficacy data are gathered, the number of patients is typically increased. Clinical trials can vary in size from a single center in one country to multicenter trials in multiple countries.

Due to the sizable cost a full series of clinical trials may incur, the burden of paying for all the necessary people and services is usually borne by the sponsor who may be a governmental organization, a pharmaceutical, or biotechnology
Biotechnology
Biotechnology is a field of applied biology that involves the use of living organisms and bioprocesses in engineering, technology, medicine and other fields requiring bioproducts. Biotechnology also utilizes these products for manufacturing purpose...

 company. Since the diversity of roles may exceed resources of the sponsor, often a clinical trial is managed by an outsourced partner such as a contract research organization
Contract research organization
A contract research organization, also called a clinical research organization, is a service organization that provides support to the pharmaceutical and biotechnology industries in the form of outsourced pharmaceutical research services...

 or a clinical trials unit in the academic sector.

Overview


Clinical trials often involve patients with specific health conditions who then benefit from receiving otherwise unavailable treatments. In early phases, participants are healthy volunteers who receive financial incentives for their inconvenience. During dosing periods, study subjects typically remain on site at the unit for durations of anything from 1 to 30 nights, occasionally longer, although this is not always required.

In planning a clinical trial, the sponsor or investigator first identifies the medication or device to be tested. Usually, one or more pilot experiments are conducted to gain insights for design of the clinical trial to follow. In medical jargon, effectiveness
Effectiveness
Effectiveness is the capability of producing a desired result. When something is deemed effective, it means it has an intended or expected outcome, or produces a deep, vivid impression.-Etymology:...

 is how well a treatment works in practice and efficacy is how well it works in a clinical trial. In the U.S., the elderly comprise only 14% of the population but they consume over one-third of drugs. Despite this, they are often excluded from trials because their more frequent health issues and drug use produce unreliable data. Women, children, and people with unrelated medical conditions are also frequently excluded.

In coordination with a panel of expert investigators (usually physicians well known for their publications and clinic
Clinic
A clinic is a health care facility that is primarily devoted to the care of outpatients...

al experience), the sponsor decides what to compare the new agent with (one or more existing treatments or a placebo), and what kind of patients might benefit from the medication or device. If the sponsor cannot obtain enough patients with this specific disease or condition at one location, then investigators at other locations who can obtain the same kind of patients to receive the treatment would be recruited into the study.

During the clinical trial, the investigators: recruit patients with the predetermined characteristics, administer the treatment(s), and collect data on the patients' health for a defined time period. These patients are volunteers and they are not paid for participating in clinical trials. These data include measurements like vital signs
Vital signs
Vital signs are measures of various physiological statistics, often taken by health professionals, in order to assess the most basic body functions. Vital signs are an essential part of a case presentation. The act of taking vital signs normally entails recording body temperature, pulse rate ,...

, concentration of the study drug in the blood, and whether the patient's health improves or not. The researchers send the data to the trial sponsor who then analyzes the pooled data using statistical tests
Statistical hypothesis testing
A statistical hypothesis test is a method of making decisions using data, whether from a controlled experiment or an observational study . In statistics, a result is called statistically significant if it is unlikely to have occurred by chance alone, according to a pre-determined threshold...

.

Some examples of what a clinical trial may be designed to do:
  • Assess the safety and effectiveness of a new medication or device on a specific kind of patient (e.g., patients who have been diagnosed with Alzheimer's disease
    Alzheimer's disease
    Alzheimer's disease also known in medical literature as Alzheimer disease is the most common form of dementia. There is no cure for the disease, which worsens as it progresses, and eventually leads to death...

    )
  • Assess the safety and effectiveness of a different dose of a medication than is commonly used (e.g., 10 mg dose instead of 5 mg dose)
  • Assess the safety and effectiveness of an already marketed medication or device for a new indication, i.e. a disease for which the drug is not specifically approved
  • Assess whether the new medication or device is more effective for the patient's condition than the already used, standard medication or device ("the gold standard" or "standard therapy")
  • Compare the effectiveness in patients with a specific disease of two or more already approved or common interventions for that disease (e.g., Device A vs. Device B, Therapy A vs. Therapy B)

Note that while most clinical trials compare two medications or devices, some trials compare three or four medications, doses of medications, or devices against each other.

Except for very small trials limited to a single location, the clinical trial design and objectives are written into a document called a clinical trial protocol
Clinical trial protocol
A clinical trial protocol is a document that describes the objective, design, methodology, statistical considerations, and organization of a clinical trial...

. The protocol is the 'operating manual' for the clinical trial and ensures that researchers in different locations all perform the trial in the same way on patients with the same characteristics. (This uniformity is designed to allow the data to be pooled.) A protocol is always used in multicenter trials.

Because the clinical trial is designed to test hypotheses
Hypothesis
A hypothesis is a proposed explanation for a phenomenon. The term derives from the Greek, ὑποτιθέναι – hypotithenai meaning "to put under" or "to suppose". For a hypothesis to be put forward as a scientific hypothesis, the scientific method requires that one can test it...

 and rigorously monitor and assess what happens, clinical trials can be seen as the application of the scientific method
Scientific method
Scientific method refers to a body of techniques for investigating phenomena, acquiring new knowledge, or correcting and integrating previous knowledge. To be termed scientific, a method of inquiry must be based on gathering empirical and measurable evidence subject to specific principles of...

, and specifically the experiment
Experiment
An experiment is a methodical procedure carried out with the goal of verifying, falsifying, or establishing the validity of a hypothesis. Experiments vary greatly in their goal and scale, but always rely on repeatable procedure and logical analysis of the results...

al step, to understanding human or animal biology.

The most commonly performed clinical trials evaluate new drugs
Medication
A pharmaceutical drug, also referred to as medicine, medication or medicament, can be loosely defined as any chemical substance intended for use in the medical diagnosis, cure, treatment, or prevention of disease.- Classification :...

, medical devices (like a new catheter
Catheter
In medicine, a catheter is a tube that can be inserted into a body cavity, duct, or vessel. Catheters thereby allow drainage, administration of fluids or gases, or access by surgical instruments. The process of inserting a catheter is catheterization...

), biologics
Biologics
A biologic is a medicinal product such as a vaccine, blood or blood component, allergenic, somatic cell, gene therapy, tissue, recombinant therapeutic protein, or living cells that are used as therapeutics to treat diseases...

, psychological therapies, or other interventions. Clinical trials may be required before the national regulatory authority approves marketing of the drug or device, or a new dose of the drug, for use on patients.

History


The history of clinical trials before 1750 is brief.

The concepts behind clinical trials, however, are ancient. The Book of Daniel
Book of Daniel
The Book of Daniel is a book in the Hebrew Bible. The book tells of how Daniel, and his Judean companions, were inducted into Babylon during Jewish exile, and how their positions elevated in the court of Nebuchadnezzar. The court tales span events that occur during the reigns of Nebuchadnezzar,...

 verses 12 through 15, for instance, describes a planned experiment with both baseline and follow-up observations of two groups who either partook of, or did not partake of, "the King's meat" over a trial period of ten days. Persian physician
Ancient Iranian Medicine
The practice and study of medicine in Persia has a long and prolific history. The Iranian academic centers like Jundishapur University were a breeding ground for the union among great scientists from different civilizations...

 and philosopher, Avicenna
Avicenna
Abū ʿAlī al-Ḥusayn ibn ʿAbd Allāh ibn Sīnā , commonly known as Ibn Sīnā or by his Latinized name Avicenna, was a Persian polymath, who wrote almost 450 treatises on a wide range of subjects, of which around 240 have survived...

, gave such inquiries a more formal structure. In The Canon of Medicine
The Canon of Medicine
The Canon of Medicine is an encyclopedia of Galenic medicine in five books compiled by Ibn Sīnā and completed in 1025. It presents a clear and organized summary of all the medical knowledge of the time...

in 1025 AD, he laid down rules for the experiment
Experiment
An experiment is a methodical procedure carried out with the goal of verifying, falsifying, or establishing the validity of a hypothesis. Experiments vary greatly in their goal and scale, but always rely on repeatable procedure and logical analysis of the results...

al use and testing of drugs
Drug test
A drug test is a technical analysis of a biological specimen – for example urine, hair, blood, sweat, or oral fluid / saliva – to determine the presence or absence of specified parent drugs or their metabolites...

 and wrote a precise guide for practical experimentation in the process of discovering and proving the effectiveness of medical drug
Drug
A drug, broadly speaking, is any substance that, when absorbed into the body of a living organism, alters normal bodily function. There is no single, precise definition, as there are different meanings in drug control law, government regulations, medicine, and colloquial usage.In pharmacology, a...

s and substances
Chemical substance
In chemistry, a chemical substance is a form of matter that has constant chemical composition and characteristic properties. It cannot be separated into components by physical separation methods, i.e. without breaking chemical bonds. They can be solids, liquids or gases.Chemical substances are...

. He laid out the following rules and principles for testing the effectiveness of new drugs and medication
Medication
A pharmaceutical drug, also referred to as medicine, medication or medicament, can be loosely defined as any chemical substance intended for use in the medical diagnosis, cure, treatment, or prevention of disease.- Classification :...

s:
  1. The drug must be free from any extraneous accidental quality.
  2. It must be used on a simple, not a composite, disease.
  3. The drug must be tested with two contrary types of diseases, because sometimes a drug cures one disease by its essential qualities and another by its accidental ones.
  4. The quality of the drug must correspond to the strength of the disease. For example, there are some drugs whose heat is less than the coldness of certain diseases, so that they would have no effect on them.
  5. The time of action must be observed, so that essence and accident are not confused.
  6. The effect of the drug must be seen to occur constantly or in many cases, for if this did not happen, it was an accidental effect.
  7. The experimentation must be done with the human body, for testing a drug on a lion or a horse might not prove anything about its effect on man.


One of the most famous clinical trials was James Lind
James Lind
James Lind FRSE FRCPE was a Scottish physician. He was a pioneer of naval hygiene in the Royal Navy. By conducting the first ever clinical trial, he developed the theory that citrus fruits cured scurvy...

's demonstration in 1747 that citrus fruits cure scurvy
Scurvy
Scurvy is a disease resulting from a deficiency of vitamin C, which is required for the synthesis of collagen in humans. The chemical name for vitamin C, ascorbic acid, is derived from the Latin name of scurvy, scorbutus, which also provides the adjective scorbutic...

. He compared the effects of various different acidic substances, ranging from vinegar to cider, on groups of afflicted sailors, and found that the group who were given oranges and lemons had largely recovered from scurvy after 6 days.

Frederick Akbar Mahomed
Frederick Akbar Mahomed
Frederick Henry Horatio Akbar Mahomed was an internationally known British physician from Brighton, England, in the late 19th century.-Family:...

 (d. 1884), who worked at Guy's Hospital
Guy's Hospital
Guy's Hospital is a large NHS hospital in the borough of Southwark in south east London, England. It is administratively a part of Guy's and St Thomas' NHS Foundation Trust. It is a large teaching hospital and is home to the King's College London School of Medicine...

 in London
London
London is the capital city of :England and the :United Kingdom, the largest metropolitan area in the United Kingdom, and the largest urban zone in the European Union by most measures. Located on the River Thames, London has been a major settlement for two millennia, its history going back to its...

, made substantial contributions to the process of clinical trials during his detailed clinical studies, where "he separated chronic nephritis
Nephritis
Nephritis is inflammation of the nephrons in the kidneys. The word "nephritis" was imported from Latin, which took it from Greek: νεφρίτιδα. The word comes from the Greek νεφρός - nephro- meaning "of the kidney" and -itis meaning "inflammation"....

 with secondary hypertension
Secondary hypertension
Secondary hypertension is a type of hypertension which by definition is caused by an identifiable underlying secondary cause. It is much less common than the other type, called essential hypertension, affecting only 5% of hypertensive patients. It has many different causes including endocrine...

 from what we now term essential hypertension
Hypertension
Hypertension or high blood pressure is a cardiac chronic medical condition in which the systemic arterial blood pressure is elevated. What that means is that the heart is having to work harder than it should to pump the blood around the body. Blood pressure involves two measurements, systolic and...

." He also founded "the Collective Investigation Record for the British Medical Association
British Medical Association
The British Medical Association is the professional association and registered trade union for doctors in the United Kingdom. The association does not regulate or certify doctors, a responsibility which lies with the General Medical Council. The association’s headquarters are located in BMA House,...

; this organization collected data from physicians practicing outside the hospital setting and was the precursor of modern collaborative clinical trials."

Types


One way of classifying clinical trials is by the way the researchers behave.
  • In an observational study
    Observational study
    In epidemiology and statistics, an observational study draws inferences about the possible effect of a treatment on subjects, where the assignment of subjects into a treated group versus a control group is outside the control of the investigator...

    , the investigators observe the subjects and measure their outcomes. The researchers do not actively manage the study. An example is the Nurses' Health Study
    Nurses' Health Study
    The Nurses Health Study, established in 1976 by Dr. Frank Speizer, and the Nurses' Health Study II, established in 1989 by Dr. Walter Willett, are the most definitive long-term epidemiological studies conducted to date on older women's health. The study has followed 121,700 female registered...

    .
  • 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.


Another way of classifying trials is by their purpose. The U.S. National Institutes of Health
National Institutes of Health
The National Institutes of Health are an agency of the United States Department of Health and Human Services and are the primary agency of the United States government responsible for biomedical and health-related research. Its science and engineering counterpart is the National Science Foundation...

 (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 (a.k.a. Supportive Care trials).
  • Compassionate use trials or expanded access
    Expanded access
    Expanded access refers to the use of an investigational drug outside of a clinical trial by patients with serious or life-threatening conditions who do not meet the enrollment criteria for the clinical trial in progress...

    : provide partially tested, unapproved therapeutics prior to a small number of patients that have no other realistic options. Usually, this involves a disease for which no effective therapy exists, or a patient that has already attempted and failed all other standard treatments and whose health is so poor that he does not qualify for participation in randomized clinical trials. Usually, case by case approval must be granted by both the FDA and the pharmaceutical company for such exceptions.

Design



A fundamental distinction in evidence-based medicine
Evidence-based medicine
Evidence-based medicine or evidence-based practice aims to apply the best available evidence gained from the scientific method to clinical decision making. It seeks to assess the strength of evidence of the risks and benefits of treatments and diagnostic tests...

 is between observational studies and randomized controlled trials. Types of observational studies in epidemiology
Epidemiology
Epidemiology is the study of health-event, health-characteristic, or health-determinant patterns in a population. It is the cornerstone method of public health research, and helps inform policy decisions and evidence-based medicine by identifying risk factors for disease and targets for preventive...

 such as the cohort study
Cohort study
A cohort study or panel study is a form of longitudinal study used in medicine, social science, actuarial science, and ecology. It is an analysis of risk factors and follows a group of people who do not have the disease, and uses correlations to determine the absolute risk of subject contraction...

 and the case-control study provide less compelling evidence than the randomized controlled trial. In observational studies, the investigators only observe associations (correlations) between the treatments experienced by participants and their health status or diseases.

A randomized controlled trial is the study design that can provide the most compelling evidence that the study treatment causes the expected effect on human health.

Currently, some Phase II and most Phase III drug trials are designed as randomized, double blind, and placebo
Placebo
A placebo is a simulated or otherwise medically ineffectual treatment for a disease or other medical condition intended to deceive the recipient...

-controlled.
  • Randomized: Each study subject is randomly assigned to receive either the study treatment or a placebo.
  • Blind: The subjects involved in the study do not know which study treatment they receive. If the study is double-blind, the researchers also do not know which treatment is being given to any given subject. This 'blinding' is to prevent biases, since if a physician knew which patient was getting the study treatment and which patient was getting the placebo, he/she might be tempted to give the (presumably helpful) study drug to a patient who could more easily benefit from it. In addition, a physician might give extra care to only the patients who receive the placebos to compensate for their ineffectiveness. A form of double-blind study called a "double-dummy" design allows additional insurance against bias or placebo effect. In this kind of study, all patients are given both placebo and active doses in alternating periods of time during the study.
  • Placebo-controlled: The use of a placebo (fake treatment) allows the researchers to isolate the effect of the study treatment.


Although the term "clinical trials" is most commonly associated with the large, randomized studies typical of Phase III, many clinical trials are small. They may be "sponsored" by single physicians or a small group of physicians, and are designed to test simple questions. In the field of rare diseases sometimes the number of patients might be the limiting factor for a clinical trial. Other clinical trials require large numbers of participants (who may be followed over long periods of time), and the trial sponsor is a private company, a government health agency, or an academic research body such as a university.

Active comparator studies


Of note, during the last ten years or so it has become a common practice to conduct "active comparator" studies (also known as "active control" trials). In other words, when a treatment exists that is clearly better than doing nothing for the subject (i.e. giving them the placebo), the alternate treatment would be a standard-of-care therapy. The study would compare the 'test' treatment to standard-of-care therapy.

A growing trend in the pharmacology field involves the use of third-party contractors to obtain the required comparator compounds. Such third parties provide expertise in the logistics of obtaining, storing, and shipping the comparators. As an advantage to the manufacturer of the comparator compounds, a well-established comparator sourcing agency can alleviate the problem of parallel import
Parallel import
A parallel import is a non-counterfeit product imported from another country without the permission of the intellectual property owner. Parallel imports are often referred to as grey product, and are implicated in issues of international trade, and intellectual property.The practice of parallel...

ing (importing a patented compound for sale in a country outside the patenting agency's sphere of influence).

Clinical trial protocol


A clinical trial protocol
Clinical trial protocol
A clinical trial protocol is a document that describes the objective, design, methodology, statistical considerations, and organization of a clinical trial...

 is a document used to gain confirmation of the trial design by a panel of experts and adherence by all study investigators, even if conducted in various countries.

The protocol describes the scientific rationale, objective(s), design, methodology, statistical considerations, and organization of the planned trial. Details of the trial are also provided in other documents referenced in the protocol such as an Investigator's Brochure
Investigator's brochure
In drug development, the Investigator's Brochure is a comprehensive document summarizing the body of information about an investigational product obtained during a drug trial. The IB is a document of critical importance throughout the drug development process and is updated with new information...

.

The protocol contains a precise study plan for executing the clinical trial, not only to assure safety and health of the trial subjects, but also to provide an exact template for trial conduct by investigators at multiple locations (in a "multicenter" trial) to perform the study in exactly the same way. This harmonization allows data to be combined collectively as though all investigators (referred to as "sites") were working closely together. The protocol also gives the study administrators (often a contract research organization
Contract research organization
A contract research organization, also called a clinical research organization, is a service organization that provides support to the pharmaceutical and biotechnology industries in the form of outsourced pharmaceutical research services...

 or CRO) as well as the site team of physicians, nurses and clinic administrators a common reference document for site responsibilities during the trial.

The format and content of clinical trial protocols sponsored by pharmaceutical, biotechnology or medical device companies in the United States, European Union, or Japan has been standardized to follow Good Clinical Practice guidance issued by the International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH). Regulatory authorities in Canada and Australia also follow ICH guidelines. Some journals, e.g. Trials
Trials (journal)
Trials is an open access, peer reviewed online journal regarding performance and outcomes of randomized controlled trials. The journal is published by BioMed Central whose editors in chief are Doug Altman Curt Furberg, Jeremy Grimshaw, and Peter Rothwell...

, encourage trialists to publish their protocols in the journal.

Informed consent


An essential component of initiating a clinical trial is to recruit study subjects following procedures using a signed document called "informed consent
Informed consent
Informed consent is a phrase often used in law to indicate that the consent a person gives meets certain minimum standards. As a literal matter, in the absence of fraud, it is redundant. An informed consent can be said to have been given based upon a clear appreciation and understanding of the...

".. Generally, children participating in clinical trial cannot automonously provide informed consent, but depending on their age and other factors may be required to provide informed assent
Informed assent
The term informed assent describes the process whereby minors may agree to participate in clinical trials. It is similar to the process of informed consent in adults, however there remains some overlap between the terms.- Background :...

.

Informed consent is a legally-defined process of a person being told about key facts involved in a clinical trial before deciding whether or not to participate. To fully describe participation to a candidate subject, the doctors and nurses involved in the trial explain the details of the study using terms the person will understand. Foreign language translation is provided if the participant's native language is not the same as the study protocol.

The research team provides an informed consent document that includes trial details, such as its purpose, duration, required procedures, risks, potential benefits and key contacts. The participant then decides whether or not to sign the document in agreement. Informed consent is not an immutable contract, as the participant can withdraw at any time without penalty.

Statistical power


The number of patients enrolled in a study has a large bearing on the ability of the study to reliably detect the size of the effect of the study intervention. This is described as the "power
Statistical power
The power of a statistical test is the probability that the test will reject the null hypothesis when the null hypothesis is actually false . The power is in general a function of the possible distributions, often determined by a parameter, under the alternative hypothesis...

" of the trial. The larger the sample size or number of participants in the trial, the greater the statistical power.

However, in designing a clinical trial, this consideration must be balanced with the fact that more patients make for a more expensive trial. The power of a trial is not a single, unique value; it estimates the ability of a trial to detect a difference of a particular size (or larger) between the treated (tested drug/device) and control (placebo or standard treatment) groups. By example, a trial of a lipid-lowering drug versus placebo with 100 patients in each group might have a power of .90 to detect a difference between patients receiving study drug and patients receiving placebo of 10 mg/dL or more, but only have a power of .70 to detect a difference of 5 mg/dL.

Placebo groups


Merely giving a treatment can have nonspecific effects, and these are controlled for by the inclusion of a placebo group. Subjects in the treatment and placebo groups are assigned randomly
Randomized controlled trial
A randomized controlled trial is a type of scientific experiment - a form of clinical trial - most commonly used in testing the safety and efficacy or effectiveness of healthcare services or health technologies A randomized controlled trial (RCT) is a type of scientific experiment - a form of...

 and blinded as to which group they belong. Since researchers can behave differently to subjects given treatments or placebos, trials are also doubled-blinded so that the researchers do not know to which group a subject is assigned.

Assigning a person to a placebo group can pose an ethical problem if it violates his or her right to receive the best available treatment. The Declaration of Helsinki
Declaration of Helsinki
The Declaration of Helsinki is a set of ethical principles regarding human experimentation developed for the medical community by the World Medical Association . It is widely regarded as the cornerstone document of human research ethics...

 provides guidelines on this issue.

Phases


Clinical trials involving new drugs are commonly classified into four phases. Each phase of the drug approval process is treated as a separate clinical trial. The drug-development process will normally proceed through all four phases over many years. If the drug successfully passes through Phases I, II, and III, it will usually be approved by the national regulatory authority for use in the general population. Phase IV are 'post-approval' studies.

Before pharmaceutical companies start clinical trials on a drug, they conduct extensive pre-clinical studies
Pre-clinical development
In drug development, pre-clinical development is a stage of research that begins before clinical trials can begin, and during which important feasibility, iterative testing and drug safety data is collected....

.

Pre-clinical studies


It involves in vitro
In vitro
In vitro refers to studies in experimental biology that are conducted using components of an organism that have been isolated from their usual biological context in order to permit a more detailed or more convenient analysis than can be done with whole organisms. Colloquially, these experiments...

 (test tube or cell culture) and in vivo
In vivo
In vivo is experimentation using a whole, living organism as opposed to a partial or dead organism, or an in vitro controlled environment. Animal testing and clinical trials are two forms of in vivo research...

 (animal) experiments using wide-ranging doses of the study drug to obtain preliminary efficacy
Efficacy
Efficacy is the capacity to produce an effect. It has different specific meanings in different fields. In medicine, it is the ability of an intervention or drug to reproduce a desired effect in expert hands and under ideal circumstances.- Healthcare :...

, toxicity
Toxicity
Toxicity is the degree to which a substance can damage a living or non-living organisms. Toxicity can refer to the effect on a whole organism, such as an animal, bacterium, or plant, as well as the effect on a substructure of the organism, such as a cell or an organ , such as the liver...

 and pharmacokinetic information. Such tests assist pharmaceutical companies to decide whether a drug candidate has scientific merit for further development as an investigational new drug
Investigational New Drug
The United States Food and Drug Administration's Investigational New Drug program is the means by which a pharmaceutical company obtains permission to ship an experimental drug across state lines before a marketing application for the drug has been approved...

.

Phase 0


Phase 0 is a recent designation for exploratory, first-in-human trials conducted in accordance with the United States Food and Drug Administration's (FDA) 2006 Guidance on Exploratory Investigational New Drug
Investigational New Drug
The United States Food and Drug Administration's Investigational New Drug program is the means by which a pharmaceutical company obtains permission to ship an experimental drug across state lines before a marketing application for the drug has been approved...

 (IND) Studies. Phase 0 trials are also known as human microdosing
Microdosing
Microdosing is a technique for studying the behaviour of drugs in humans through the administration of doses so low they are unlikely to produce whole-body effects, but high enough to allow the cellular response to be studied...

 studies and are designed to speed up the development of promising drugs or imaging agent
Imaging agent
Imaging agents are chemicals designed to allow clinicians to determine whether a mass is benign or malignant and locate metastatic cancer sites in the body....

s by establishing very early on whether the drug or agent behaves in human subjects as was expected from preclinical studies. Distinctive features of Phase 0 trials include the administration of single subtherapeutic doses of the study drug to a small number of subjects (10 to 15) to gather preliminary data on the agent's pharmacodynamics
Pharmacodynamics
Pharmacodynamics is the study of the biochemical and physiological effects of drugs on the body or on microorganisms or parasites within or on the body and the mechanisms of drug action and the relationship between drug concentration and effect...

 (what the drug does to the body) and pharmacokinetics
Pharmacokinetics
Pharmacokinetics, sometimes abbreviated as PK, is a branch of pharmacology dedicated to the determination of the fate of substances administered externally to a living organism...

 (what the body does to the drugs).

A Phase 0 study gives no data on safety or efficacy, being by definition a dose too low to cause any therapeutic effect. Drug development companies carry out Phase 0 studies to rank drug candidates in order to decide which has the best pharmacokinetic parameters in humans to take forward into further development. They enable go/no-go decisions to be based on relevant human models instead of relying on sometimes inconsistent animal data.

Phase I


Phase I trials are the first stage of testing in human subjects. Normally, a small group of 20-100 healthy volunteers will be recruited. This phase is designed to assess the safety (pharmacovigilance
Pharmacovigilance
Pharmacovigilance is the pharmacological science relating to the detection, assessment, understanding and prevention of adverse effects, particularly long term and short term side effects of medicines...

), tolerability, pharmacokinetics
Pharmacokinetics
Pharmacokinetics, sometimes abbreviated as PK, is a branch of pharmacology dedicated to the determination of the fate of substances administered externally to a living organism...

, and pharmacodynamics
Pharmacodynamics
Pharmacodynamics is the study of the biochemical and physiological effects of drugs on the body or on microorganisms or parasites within or on the body and the mechanisms of drug action and the relationship between drug concentration and effect...

 of a drug. These trials are often conducted in a clinical trial clinic, where the subject can be observed by full-time staff. These clinical trial clinics are often run by contract research organisations (CRO) who conduct these studies on behalf of pharmaceutical companies or other research investigators. The subject who receives the drug is usually observed until several half-lives
Biological half-life
The biological half-life or elimination half-life of a substance is the time it takes for a substance to lose half of its pharmacologic, physiologic, or radiologic activity, as per the MeSH definition...

 of the drug have passed. Phase I trials also normally include dose-ranging, also called dose escalation studies, so that the best and safest dose can be found and to discover the point at which a compound is too poisonous to administer. The tested range of doses will usually be a fraction of the dose that caused harm in animal testing
Animal testing
Animal testing, also known as animal experimentation, animal research, and in vivo testing, is the use of non-human animals in experiments. Worldwide it is estimated that the number of vertebrate animals—from zebrafish to non-human primates—ranges from the tens of millions to more than 100 million...

. Phase I trials most often include healthy volunteers. However, there are some circumstances when real patients are used, such as patients who have terminal
Terminal illness
Terminal illness is a medical term popularized in the 20th century to describe a disease that cannot be cured or adequately treated and that is reasonably expected to result in the death of the patient within a short period of time. This term is more commonly used for progressive diseases such as...

 cancer or HIV
HIV
Human immunodeficiency virus is a lentivirus that causes acquired immunodeficiency syndrome , a condition in humans in which progressive failure of the immune system allows life-threatening opportunistic infections and cancers to thrive...

 and lack other treatment options.
Volunteers are paid an inconvenience fee for their time spent in the volunteer centre. Pay depends on length of participation.

There are different kinds of Phase I trial:

SAD: Single Ascending Dose studies are those in which small groups of subjects are given a single dose of the drug while they are observed and tested for a period of time. If they do not exhibit any adverse
Adverse event
An adverse event is any adverse change in health or side effect that occurs in a person who participates in a clinical trial while the patient is receiving the treatment or within a previously specified period of time after the treatment has been completed.AEs in patients participating in...

 side effects, and the pharmacokinetic data is roughly in line with predicted safe values, the dose is escalated, and a new group of subjects is then given a higher dose. This is continued until pre-calculated pharmacokinetic safety levels are reached, or intolerable side effects start showing up (at which point the drug is said to have reached the Maximum tolerated dose (MTD)).

MAD: Multiple Ascending Dose studies are conducted to better understand the pharmacokinetics & pharmacodynamics of multiple doses of the drug. In these studies, a group of patients receives multiple low doses of the drug, while samples (of blood, and other fluids) are collected at various time points and analyzed to acquire information on how the drug is processed within the body. The dose is subsequently escalated for further groups, up to a predetermined level.

Food effect: A short trial designed to investigate any differences in absorption of the drug by the body, caused by eating before the drug is given. These studies are usually run as a crossover study
Crossover study
A crossover study is a longitudinal study in which subjects receive a sequence of different treatments . While crossover studies can be observational studies, many important crossover studies are controlled experiments, which are discussed in this article...

, with volunteers being given two identical doses of the drug while fasted, and after being fed.

Phase II


Once the initial safety of the study drug has been confirmed in Phase I trials, Phase II trials are performed on larger groups (100-300) and are designed to assess how well the drug works, as well as to continue Phase I safety assessments in a larger group of volunteers and patients. When the development process for a new drug fails, this usually occurs during Phase II trials when the drug is discovered not to work as planned, or to have toxic effects.

Phase II studies are sometimes divided into Phase IIA and Phase IIB.
  • Phase IIA is specifically designed to assess dosing requirements (how much drug should be given).
  • Phase IIB is specifically designed to study efficacy (how well the drug works at the prescribed dose(s)).


Some trials combine Phase I and Phase II, and test both efficacy and toxicity.

Trial design: Some Phase II trials are designed as case series
Case series
A case series is a medical research descriptive study that tracks patients with a known exposure given similar treatment or examines their medical records for exposure and outcome. It can be retrospective or prospective and usually involves a smaller number of patients than more powerful...

, demonstrating a drug's safety and activity in a selected group of patients. Other Phase II trials are designed as randomized clinical trials, where some patients receive the drug/device and others receive placebo/standard treatment. Randomized Phase II trials have far fewer patients than randomized Phase III trials.

Phase III


Phase III studies are randomized controlled multicenter trial
Multicenter trial
A multicenter research trial is a clinical trial conducted at more than one medical center or clinic. Most large clinical trials, particularly Phase III trials, are conducted at several clinical research centers...

s on large patient groups (300–3,000 or more depending upon the disease/medical condition studied) and are aimed at being the definitive assessment of how effective the drug is, in comparison with current 'gold standard' treatment. Because of their size and comparatively long duration, Phase III trials are the most expensive, time-consuming and difficult trials to design and run, especially in therapies for chronic
Chronic (medicine)
A chronic disease is a disease or other human health condition that is persistent or long-lasting in nature. The term chronic is usually applied when the course of the disease lasts for more than three months. Common chronic diseases include asthma, cancer, diabetes and HIV/AIDS.In medicine, the...

 medical conditions.

It is common practice that certain Phase III trials will continue while the regulatory submission is pending at the appropriate regulatory agency. This allows patients to continue to receive possibly lifesaving drugs until the drug can be obtained by purchase. Other reasons for performing trials at this stage include attempts by the sponsor at "label expansion" (to show the drug works for additional types of patients/diseases beyond the original use for which the drug was approved for marketing), to obtain additional safety data, or to support marketing claims for the drug. Studies in this phase are by some companies categorised as "Phase IIIB studies."

While not required in all cases, it is typically expected that there be at least two successful Phase III trials, demonstrating a drug's safety and efficacy, in order to obtain approval from the appropriate regulatory agencies such as FDA (USA), or the EMA
European Medicines Agency
The European Medicines Agency is a European agency for the evaluation of medicinal products. From 1995 to 2004, the European Medicines Agency was known as European Agency for the Evaluation of Medicinal Products.Roughly parallel to the U.S...

 (European Union), for example.

Once a drug has proved satisfactory after Phase III trials, the trial results are usually combined into a large document containing a comprehensive description of the methods and results of human and animal studies, manufacturing procedures, formulation details, and shelf life. This collection of information makes up the "regulatory submission" that is provided for review to the appropriate regulatory authorities in different countries. They will review the submission, and, it is hoped, give the sponsor approval to market the drug.

Most drugs undergoing Phase III clinical trials can be marketed under FDA norms with proper recommendations and guidelines, but in case of any adverse effects being reported anywhere, the drugs need to be recalled immediately from the market. While most pharmaceutical companies refrain from this practice, it is not abnormal to see many drugs undergoing Phase III clinical trials in the market.

Phase IV


Phase IV trial is also known as Postmarketing surveillance
Postmarketing surveillance
Postmarketing surveillance is the practice of monitoring the safety of a pharmaceutical drug or device after it has been released on the market and is an important part of the science of pharmacovigilance...

 Trial. Phase IV trials involve the safety surveillance (pharmacovigilance
Pharmacovigilance
Pharmacovigilance is the pharmacological science relating to the detection, assessment, understanding and prevention of adverse effects, particularly long term and short term side effects of medicines...

) and ongoing technical support of a drug after it receives permission to be sold. Phase IV studies may be required by regulatory authorities or may be undertaken by the sponsoring company for competitive (finding a new market for the drug) or other reasons (for example, the drug may not have been tested for interactions with other drugs, or on certain population groups such as pregnant women, who are unlikely to subject themselves to trials). The safety surveillance is designed to detect any rare or long-term adverse effects over a much larger patient population and longer time period than was possible during the Phase I-III clinical trials. Harmful effects discovered by Phase IV trials may result in a drug being no longer sold, or restricted to certain uses: recent examples involve cerivastatin
Cerivastatin
Cerivastatin is a synthetic member of the class of statins used to lower cholesterol and prevent cardiovascular disease. It was marketed by the pharmaceutical company Bayer A.G. in the late 1990s, competing with Pfizer's highly successful atorvastatin...

 (brand names Baycol and Lipobay), troglitazone
Troglitazone
Troglitazone is an anti-diabetic and antiinflammatory drug, and a member of the drug class of the thiazolidinediones. It was developed by Daiichi Sankyo Co.. In the United States, it was introduced and manufactured by Parke-Davis in the late 1990s, but turned out to be associated with an...

 (Rezulin) and rofecoxib
Rofecoxib
Rofecoxib is a nonsteroidal anti-inflammatory drug that has now been withdrawn over safety concerns. It was marketed by Merck & Co. to treat osteoarthritis, acute pain conditions, and dysmenorrhoea...

 (Vioxx).

Phase V


Phase V is a growing term used in the literature of translational research
Translational research
Translational research is a way of thinking about and conducting scientific research to make the results of research applicable to the population under study and is practised in the natural and biological, behavioural, and social sciences...

 to refer to comparative effectiveness research and community-based research; it is used to signify the integration of a new clinical treatment into widespread public health practice. http://www.asha.org/academic/questions/PhasesClinicalResearch/

Length


Clinical trials are only a small part of the research that goes into developing a new treatment. Potential drugs, for example, first have to be discovered, purified, characterized, and tested in labs (in cell and animal studies) before ever undergoing clinical trials. In all, about 1,000 potential drugs are tested before just one reaches the point of being tested in a clinical trial. For example, a new cancer drug has, on average, 6 years of research behind it before it even makes it to clinical trials. But the major holdup in making new cancer drugs available is the time it takes to complete clinical trials themselves. On average, about 8 years pass from the time a cancer drug enters clinical trials until it receives approval from regulatory agencies for sale to the public. Drugs for other diseases have similar timelines.

Some reasons a clinical trial might last several years:
  • For chronic conditions like cancer, it takes months, if not years, to see if a cancer treatment has an effect on a patient.
  • For drugs that are not expected to have a strong effect (meaning a large number of patients must be recruited to observe any effect), recruiting enough patients to test the drug's effectiveness (i.e., getting statistical power) can take several years.
  • Only certain people who have the target disease condition are eligible to take part in each clinical trial. Researchers who treat these particular patients must participate in the trial. Then they must identify the desirable patients and obtain consent from them or their families to take part in the trial.


The biggest barrier to completing studies is the shortage of people who take part. All drug and many device trials target a subset of the population, meaning not everyone can participate. Some drug trials require patients to have unusual combinations of disease characteristics. It is a challenge to find the appropriate patients and obtain their consent, especially when they may receive no direct benefit (because they are not paid, the study drug is not yet proven to work, or the patient may receive a placebo). In the case of cancer patients, fewer than 5% of adults with cancer will participate in drug trials. According to the Pharmaceutical Research and Manufacturers of America (PhRMA), about 400 cancer medicines were being tested in clinical trials in 2005. Not all of these will prove to be useful, but those that are may be delayed in getting approved because the number of participants is so low.

For clinical trials involving a seasonal indication (such as airborne allergies
Aeroallergen
An Aeroallergen is any airborne substance, such as pollen or spores, which triggers an allergic reaction.-Pollens:...

, Seasonal Affective Disorder
Seasonal affective disorder
Seasonal affective disorder , also known as winter depression, winter blues, summer depression, summer blues, or seasonal depression, is a mood disorder in which people who have normal mental health throughout most of the year experience depressive symptoms in the winter or summer, spring or autumn...

, influenza
Influenza
Influenza, commonly referred to as the flu, is an infectious disease caused by RNA viruses of the family Orthomyxoviridae , that affects birds and mammals...

, and others), the study can only be done during a limited part of the year (such as Spring for pollen allergies), when the drug can be tested. This can be an additional complication on the length of the study, yet proper planning and the use of trial sites in the southern as well as northern hemispheres allows for year-round trials can reduce the length of the studies.

Clinical trials that do not involve a new drug usually have a much shorter duration. (Exceptions are epidemiological studies like the Nurses' Health Study
Nurses' Health Study
The Nurses Health Study, established in 1976 by Dr. Frank Speizer, and the Nurses' Health Study II, established in 1989 by Dr. Walter Willett, are the most definitive long-term epidemiological studies conducted to date on older women's health. The study has followed 121,700 female registered...

.)

Administration


Clinical trials designed by a local investigator and (in the U.S.) federally funded clinical trials are almost always administered by the researcher who designed the study and applied for the grant. Small-scale device studies may be administered by the sponsoring company. Clinical trials of new drugs are usually administered by a contract research organization
Contract research organization
A contract research organization, also called a clinical research organization, is a service organization that provides support to the pharmaceutical and biotechnology industries in the form of outsourced pharmaceutical research services...

 (CRO) hired by the sponsoring company. The sponsor provides the drug and medical oversight. A CRO is a company that is contracted to perform all the administrative work on a clinical trial. For Phase II, III and IV the CRO recruits participating researchers, trains them, provides them with supplies, coordinates study administration and data collection, sets up meetings, monitors the sites for compliance with the clinical protocol, and ensures that the sponsor receives data from every site. Specialist site management organization
Site management organization
A Site Management Organization is an organization that provides clinical trial related services to a contract research organization , a pharmaceutical company, a biotechnology company, a medical device company or a clinical site...

s can also be hired to coordinate with the CRO to ensure rapid IRB/IEC approval and faster site initiation and patient recruitment. Phase I clinical trials of new medicines are often conducted in an specialist clinical trial clinic, with dedicated pharmacologists, where the subject can be observed by full-time staff. These clinics are often run by a CRO who specialises in these studies.

At a participating site, one or more research assistants (often nurses) do most of the work in conducting the clinical trial. The research assistant's job can include some or all of the following: providing the local Institutional Review Board
Institutional review board
An institutional review board , also known as an independent ethics committee or ethical review board , is a committee that has been formally designated to approve, monitor, and review biomedical and behavioral research involving humans with the aim to protect the rights and welfare of the...

 (IRB) with the documentation necessary to obtain its permission to conduct the study, assisting with study start-up, identifying eligible patients, obtaining consent from them or their families, administering study treatment(s), collecting and statistically analyzing data, maintaining and updating data files during followup, and communicating with the IRB, as well as the sponsor and CRO.

Ethical conduct


Clinical trials are closely supervised by appropriate regulatory authorities. All studies that involve a medical or therapeutic intervention on patients must be approved by a supervising ethics committee before permission is granted to run the trial. The local ethics committee has discretion on how it will supervise noninterventional studies (observational studies or those using already collected data). In the U.S., this body is called the Institutional Review Board
Institutional review board
An institutional review board , also known as an independent ethics committee or ethical review board , is a committee that has been formally designated to approve, monitor, and review biomedical and behavioral research involving humans with the aim to protect the rights and welfare of the...

 (IRB). Most IRBs are located at the local investigator's hospital or institution, but some sponsors allow the use of a central (independent/for profit) IRB for investigators who work at smaller institutions.

To be ethical, researchers must obtain the full and informed consent
Informed consent
Informed consent is a phrase often used in law to indicate that the consent a person gives meets certain minimum standards. As a literal matter, in the absence of fraud, it is redundant. An informed consent can be said to have been given based upon a clear appreciation and understanding of the...

 of participating human subjects. (One of the IRB's main functions is ensuring that potential patients are adequately informed about the clinical trial.) If the patient is unable to consent for him/herself, researchers can seek consent from the patient's legally authorized representative. In California
California
California is a state located on the West Coast of the United States. It is by far the most populous U.S. state, and the third-largest by land area...

, the state has prioritized the individuals who can serve as the legally authorized representative.

In some U.S. locations, the local IRB must certify researchers and their staff before they can conduct clinical trials. They must understand the federal patient privacy (HIPAA) law and good clinical practice. International Conference of Harmonisation Guidelines for Good Clinical Practice
Good clinical practice
Good Clinical Practice is an international quality standard that is provided by International Conference on Harmonisation , an international body that defines standards, which governments can transpose into regulations for clinical trials involving human subjects.Good Clinical Practice guidelines...

 (ICH GCP) is a set of standards used internationally for the conduct of clinical trials. The guidelines aim to ensure that the "rights, safety and well being of trial subjects are protected".

The notion of informed consent
Informed consent
Informed consent is a phrase often used in law to indicate that the consent a person gives meets certain minimum standards. As a literal matter, in the absence of fraud, it is redundant. An informed consent can be said to have been given based upon a clear appreciation and understanding of the...

 of participating human subjects exists in many countries all over the world, but its precise definition may still vary.

Informed consent is clearly a necessary condition for ethical conduct but does not ensure ethical conduct. The final objective is to serve the community of patients or future patients in a best-possible and most responsible way. However, it may be hard to turn this objective into a well-defined quantified objective function. In some cases this can be done, however, as for instance for questions of when to stop sequential treatments (see Odds algorithm
Odds algorithm
The odds-algorithm is a mathematical method for computing optimalstrategies for a class of problems that belong to the domain of optimal stopping problems. Their solution follows from the odds-strategy, and the importance of the...

), and then quantified methods may play an important role.

Additional ethical concerns are present when conducting clinical trials on children
Ethical problems using children in clinical trials
In health care, a clinical trial is a comparison test of a medication or other medical treatment , versus a placebo , other medications or devices, or the standard medical treatment for a patient's condition....

 (pediatrics
Pediatrics
Pediatrics or paediatrics is the branch of medicine that deals with the medical care of infants, children, and adolescents. A medical practitioner who specializes in this area is known as a pediatrician or paediatrician...

).

Safety


Responsibility for the safety of the subjects in a clinical trial is shared between the sponsor, the local site investigators (if different from the sponsor), the various IRBs that supervise the study, and (in some cases, if the study involves a marketable drug or device) the regulatory agency for the country where the drug or device will be sold.

For safety reasons, many clinical trials of drugs are designed to exclude women of childbearing age, pregnant women, and/or women who become pregnant during the study. In some cases the male partners of these women are also excluded or required to take birth control measures.

Sponsor

  • Throughout the clinical trial, the sponsor is responsible for accurately informing the local site investigators of the true historical safety record of the drug, device or other medical treatments to be tested, and of any potential interactions of the study treatment(s) with already approved medical treatments. This allows the local investigators to make an informed judgment on whether to participate in the study or not.
  • The sponsor is responsible for monitoring the results of the study as they come in from the various sites, as the trial proceeds. In larger clinical trials, a sponsor will use the services of a Data Monitoring Committee (DMC, known in the U.S. as a Data Safety Monitoring Board). This is an independent group of clinicians and statisticians. The DMC meets periodically to review the unblinded data that the sponsor has received so far. The DMC has the power to recommend termination of the study based on their review, for example if the study treatment is causing more deaths than the standard treatment, or seems to be causing unexpected and study-related serious adverse event
    Adverse event
    An adverse event is any adverse change in health or side effect that occurs in a person who participates in a clinical trial while the patient is receiving the treatment or within a previously specified period of time after the treatment has been completed.AEs in patients participating in...

    s.
  • The sponsor is responsible for collecting adverse event
    Adverse event
    An adverse event is any adverse change in health or side effect that occurs in a person who participates in a clinical trial while the patient is receiving the treatment or within a previously specified period of time after the treatment has been completed.AEs in patients participating in...

     reports from all site investigators in the study, and for informing all the investigators of the sponsor's judgment as to whether these adverse events were related or not related to the study treatment. This is an area where sponsors can slant their judgment to favor the study treatment.
  • The sponsor and the local site investigators are jointly responsible for writing a site-specific informed consent
    Informed consent
    Informed consent is a phrase often used in law to indicate that the consent a person gives meets certain minimum standards. As a literal matter, in the absence of fraud, it is redundant. An informed consent can be said to have been given based upon a clear appreciation and understanding of the...

     that accurately informs the potential subjects of the true risks and potential benefits of participating in the study, while at the same time presenting the material as briefly as possible and in ordinary language. FDA regulations and ICH guidelines both require that "the information that is given to the subject or the representative shall be in language understandable to the subject or the representative." If the participant's native language is not English, the sponsor must translate the informed consent into the language of the participant.

Local site investigators

  • A physician's first duty
    Hippocratic Oath
    The Hippocratic Oath is an oath historically taken by physicians and other healthcare professionals swearing to practice medicine ethically. It is widely believed to have been written by Hippocrates, often regarded as the father of western medicine, or by one of his students. The oath is written in...

     is to his/her patients, and if a physician investigator believes that the study treatment may be harming subjects in the study, the investigator can stop participating at any time. On the other hand, investigators often have a financial interest in recruiting subjects, and can act unethically in order to obtain and maintain their participation.
  • The local investigators are responsible for conducting the study according to the study protocol, and supervising the study staff throughout the duration of the study.
  • The local investigator or his/her study staff are responsible for ensuring that potential subjects in the study understand the risks and potential benefits of participating in the study; in other words, that they (or their legally authorized representatives) give truly informed consent
    Informed consent
    Informed consent is a phrase often used in law to indicate that the consent a person gives meets certain minimum standards. As a literal matter, in the absence of fraud, it is redundant. An informed consent can be said to have been given based upon a clear appreciation and understanding of the...

    .
  • The local investigators are responsible for reviewing all adverse event reports sent by the sponsor. (These adverse event reports contain the opinion of both the investigator at the site where the adverse event occurred, and the sponsor, regarding the relationship of the adverse event to the study treatments). The local investigators are responsible for making an independent judgment of these reports, and promptly informing the local IRB of all serious and study-treatment-related adverse events.
  • When a local investigator is the sponsor, there may not be formal adverse event reports, but study staff at all locations are responsible for informing the coordinating investigator of anything unexpected.
  • The local investigator is responsible for being truthful to the local IRB in all communications relating to the study.

IRBs


Approval by an IRB, or ethics board, is necessary before all but the most informal medical research can begin.
  • In commercial clinical trials, the study protocol is not approved by an IRB before the sponsor recruits sites to conduct the trial. However, the study protocol and procedures have been tailored to fit generic IRB submission requirements. In this case, and where there is no independent sponsor, each local site investigator submits the study protocol, the consent(s), the data collection forms, and supporting documentation to the local IRB. Universities and most hospitals have in-house IRBs. Other researchers (such as in walk-in clinics) use independent IRBs.
  • The IRB scrutinizes the study for both medical safety and protection of the patients involved in the study, before it allows the researcher to begin the study. It may require changes in study procedures or in the explanations given to the patient. A required yearly "continuing review" report from the investigator updates the IRB on the progress of the study and any new safety information related to the study.

Regulatory agencies

  • If a clinical trial concerns a new regulated drug or medical device (or an existing drug for a new purpose), the appropriate regulatory agency for each country where the sponsor wishes to sell the drug or device is supposed to review all study data before allowing the drug/device to proceed to the next phase, or to be marketed. However, if the sponsor withholds negative data, or misrepresents data it has acquired from clinical trials, the regulatory agency may make the wrong decision.
  • In the U.S., the FDA can audit
    Audit
    The general definition of an audit is an evaluation of a person, organization, system, process, enterprise, project or product. The term most commonly refers to audits in accounting, but similar concepts also exist in project management, quality management, and energy conservation.- Accounting...

     the files of local site investigators after they have finished participating in a study, to see if they were correctly following study procedures. This audit may be random, or for cause (because the investigator is suspected of fraudulent data). Avoiding an audit is an incentive for investigators to follow study procedures.


Different countries have different regulatory requirements and enforcement abilities. "An estimated 40 percent of all clinical trials now take place in Asia, Eastern Europe, central and south America. "There is no compulsory registration system for clinical trials in these countries and many do not follow European directives in their operations", says Dr. Jacob Sijtsma of the Netherlands-based WEMOS, an advocacy health organisation tracking clinical trials in developing countries."

Beginning in the 1980s, harmonization of clinical trial protocols was shown as feasible across countries of the European Union. At the same time, coordination between Europe, Japan and the United States led to a joint regulatory-industry initiative on international harmonization named after 1990 as the International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH)
Currently, most clinical trial programs follow ICH guidelines, aimed at "ensuring that good quality, safe and effective medicines are developed and registered in the most efficient and cost-effective manner. These activities are pursued in the interest of the consumer and public health, to prevent unnecessary duplication of clinical trials in humans and to minimize the use of animal testing without compromising the regulatory obligations of safety and effectiveness."

Sponsor


The cost of a study depends on many factors, especially the number of sites that are conducting the study, the number of patients required, and whether the study treatment is already approved for medical use. Clinical trials follow a standardized process.

The costs to a pharmaceutical company of administering a Phase III or IV clinical trial may include, among others:
  • manufacturing the drug(s)/device(s) tested
  • staff salaries for the designers and administrators of the trial
  • payments to the contract research organization, the site management organization (if used) and any outside consultants
  • payments to local researchers (and their staffs) for their time and effort in recruiting patients and collecting data for the sponsor
  • study materials and shipping
  • communication with the local researchers, including onsite monitoring by the CRO before and (in some cases) multiple times during the study
  • one or more investigator training meetings
  • costs incurred by the local researchers such as pharmacy fees, IRB fees and postage.
  • any payments to patients enrolled in the trial (all payments are strictly overseen by the IRBs to ensure that patients do not feel coerced to take part in the trial by overly attractive payments)

These costs are incurred over several years.

In the U.S. there is a 50% tax credit
Tax credit
A tax credit is a sum deducted from the total amount a taxpayer owes to the state. A tax credit may be granted for various types of taxes, such as an income tax, property tax, or VAT. It may be granted in recognition of taxes already paid, as a subsidy, or to encourage investment or other behaviors...

 for sponsors of certain clinical trials.

National health agencies such as the U.S. National Institutes of Health
National Institutes of Health
The National Institutes of Health are an agency of the United States Department of Health and Human Services and are the primary agency of the United States government responsible for biomedical and health-related research. Its science and engineering counterpart is the National Science Foundation...

 offer grants to investigators who design clinical trials that attempt to answer research questions that interest the agency. In these cases, the investigator who writes the grant and administers the study acts as the sponsor, and coordinates data collection from any other sites. These other sites may or may not be paid for participating in the study, depending on the amount of the grant and the amount of effort expected from them.

Clinical trials are traditionally expensive and difficult to undertake. Using internet resources can, in some cases, reduce the economic burden.

Investigators


Many clinical trials do not involve any money. However, when the sponsor is a private company or a national health agency, investigators are almost always paid to participate. These amounts can be small, just covering a partial salary for research assistants and the cost of any supplies (usually the case with national health agency studies), or be substantial and include 'overhead' that allows the investigator to pay the research staff during times in between clinical trials.

Subjects


In Phase I drug trials, participants are paid because they give up their time (sometimes away from their homes) and are exposed to unknown risks, without the expectation of any benefit. In most other trials, however, subjects are not paid, in order to ensure that their motivation for participating is the hope of getting better or contributing to medical knowledge, without their judgment being skewed by financial considerations. However, they are often given small payments for study-related expenses like travel or as compensation for their time in providing follow-up information about their health after they are discharged from medical care.

Participating in a clinical trial


Phase 0 and Phase I drug trials seek healthy volunteers. Most other clinical trials seek patients who have a specific disease or medical condition. There is general consensus that the diversity observed in society should be reflected in clinical trials through the appropriate inclusion of ethnic minority populations.

Locating trials


Depending on the kind of participants required, sponsors of clinical trials use various recruitment strategies, including patient databases, newspaper and radio advertisements, flyers, posters in places the patients might go (such as doctor's offices), and personal recruitment of patients by investigators.

Volunteers with specific conditions or diseases have additional online resources to help them locate clinical trials. For example, people with Parkinson's disease can use PDtrials
PDtrials
PDtrials is an initiative to increase education and awareness about Parkinson's disease clinical research. The initiative is led by the Parkinson's Disease Foundation, and involves a collaboration between a number of Parkinson's organizations in the U.S...

 to find up-to-date information on Parkinson's disease
Parkinson's disease
Parkinson's disease is a degenerative disorder of the central nervous system...

 trials currently enrolling participants in the U.S. and Canada, and search for specific Parkinson's clinical trials using criteria such as location, trial type, and symptom. Other disease-specific services exist for volunteers to find trials related to their condition. Volunteers may search directly on ClinicalTrials.gov
ClinicalTrials.gov
ClinicalTrials.gov is a registry of clinical trials. It is run by the United States National Library of Medicine at the National Institutes of Health, and is the largest clinical trials database, currently holding registrations from over 93,000 trials from more than 170 countries in the...

 to locate trials using a registry run by the U.S. National Institutes of Health and National Library of Medicine.

However, many clinical trials will not accept participants who contact them directly to volunteer as it is believed this may bias the characteristics of the population being studied. Such trials typically recruit via networks of medical professionals who ask their individual patients to consider enrollment.

Steps for volunteers


Before participating in a clinical trial, interested volunteers should speak with their doctors, family members, and others who have participated in trials in the past. After locating a trial, volunteers will often have the opportunity to speak or e-mail the clinical trial coordinator for more information and to answer any questions. After receiving consent from their doctors, volunteers then arrange an appointment for a screening visit with the trial coordinator.

All volunteers being considered for a trial are required to undertake a medical screen. There are different requirements for different trials, but typically volunteers will have the following tests in a medical laboratory
Medical laboratory
A medical laboratory or clinical laboratory is a laboratory where tests are done on clinical specimens in order to get information about the health of a patient as pertaining to the diagnosis, treatment, and prevention of disease.-Departments:...

:
  • Measurement of the electrical activity of the heart (ECG)
  • Measurement of blood pressure, heart rate and temperature
  • Blood sampling
  • Urine sampling
  • Weight and height measurement
  • Drugs abuse testing
  • Pregnancy testing (females only)

Information technology


The last decade has seen a proliferation of information technology use in the planning and conduct of clinical trials. Clinical trial management systems
Clinical Trial Management System
A Clinical Trial Management System, also known as CTMS, is a customizable software system used by the biotechnology and pharmaceutical industries to manage the large amounts of data involved with the operation of a clinical trial...

 (CTMS) are often used by research sponsors or CROs to help plan and manage the operational aspects of a clinical trial, particularly with respect to investigational sites. Web-based electronic data capture
Electronic Data Capture
An Electronic Data Capture system is a computerized system designedfor the collection of clinical data in electronic format for use mainly in human clinical trials.Typically, EDC systems provide:* a graphical user interface component for data entry...

 (EDC) and clinical data management system
Clinical data management system
A clinical data management system or CDMS is a tool used in clinical research to manage the data of a clinical trial. The clinical trial data gathered at the investigator site in the case report form are stored in the CDMS...

s (CDMS) are used in a majority of clinical trials to collect case report data from sites, manage its quality and prepare it for analysis. Interactive voice response
Interactive voice response
Interactive voice response is a technology that allows a computer to interact with humans through the use of voice and DTMF keypad inputs....

 systems (IVRS) are used by sites to register the enrollment of patients using a phone and to allocate patients to a particular treatment arm (although phones are being increasingly replaced with web-based (IWRS) tools which are sometimes part of the EDC system). Patient-reported outcome
Patient-reported outcome
A patient-reported outcome or PRO is a questionnaire used in a clinical trial or a clinical setting, where the responses are collected directly from the patient.-Overview:...

 measures are being increasingly collected using hand-held, sometimes wireless ePRO (or eDiary) devices. Statistical software is used to analyze the collected data and prepare it for regulatory submission. Access to many of these applications are increasingly aggregated in web-based clinical trial portals
Clinical Trial Portal
A clinical trial portal is a web portal or enterprise portal that primarily serves sponsors and investigators in a clinical trial...

.

Controversy


In 2001, the editors of 12 major journals issued a joint editorial, published in each journal, on the control over clinical trials exerted by sponsors, particularly targeting the use of contracts which allow sponsors to review the studies prior to publication and withhold publication. They strengthened editorial restrictions to counter the effect. The editorial noted that contract research organization
Contract research organization
A contract research organization, also called a clinical research organization, is a service organization that provides support to the pharmaceutical and biotechnology industries in the form of outsourced pharmaceutical research services...

s had, by 2000, received 60% of the grants from pharmaceutical companies in the U.S. Researchers may be restricted from contributing to the trial design, accessing the raw data, and interpreting the results.

Seeding trial
Seeding trial
A seeding trial or marketing trial is a form of marketing, conducted in the name of research, designed to target product sampling towards selected consumers...

s are particularly controversial.

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