or health conditions. diagnostic trials are conducted to find better tests or procedures for diagnosing a particular disease or condition. treatment trials test experimental drugs, new combinations of drugs, or new approaches to surgery or radiation therapy. quality of life trials (supportive care trials) evaluate how to improve comfort and quality of care for people with a chronic illness. genetic trials are conducted to assess the prediction accuracy of genetic disorders making a person more or less likely to develop a disease. epidemiological trials have the goal of identifying the general causes, patterns or control of diseases in large numbers of people. compassionate use trials or expanded access trials provide partially tested, unapproved therapeutics to a small number of patients who have no other realistic options. usually, this involves a disease for which no effective therapy has been approved, or a patient who has already failed all standard treatments and whose health is too compromised to 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. fixed trials consider existing data only during the trial's design, do not modify the trial after it begins, and do not assess the results until the study is completed. adaptive clinical trials use existing data to design the trial, and then use interim results to modify the trial as it proceeds. modifications include dosage, sample size, drug undergoing trial, patient selection criteria and "cocktail" mix. adaptive trials often employ a bayesian experimental design to assess the trial's progress. in some cases, trials have become an ongoing process that regularly adds and drops therapies and patient groups as more information is gained. the aim is to more quickly identify drugs that have a therapeutic effect and to zero in on patient populations for whom the drug is appropriate. clinical trials are conducted typically in four phases, with each phase using different numbers of subjects and having a different purpose to construct focus on identifying a specific effect. phases main article: phases of clinical research clinical trials involving new drugs are commonly classified into five phases. each phase of the drug approval process is treated as a separate clinical trial. the drug development process will normally proceed through phases i–iv over many years, frequently involving a decade or longer. 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 trials are performed after the newly approved drug, diagnostic or device is marketed, providing assessment about risks, benefits, or best uses. phaseaimnotes phase 0pharmacodynamics and pharmacokinetics in humansphase 0 trials are optional first-in-human trials. single subtherapeutic doses of the study drug or treatment are given to a small number of subjects (typically 10 to 15) to gather preliminary data on the agent's pharmacodynamics (what the drug does to the body) and pharmacokinetics (what the body does to the drugs). for a test drug, the trial documents the absorption, distribution, metabolization, and clearance (excretion) of the drug, and the drug's interactions within the body, to confirm that these appear to be as expected. phase iscreening for safetyoften are first-in-person trials. testing within a small group of people (typically 20–80) to evaluate safety, determine safe dosage ranges, and identify side effects. phase iiestablishing the preliminary efficacy of the drug in a "treatment group", usually against a placebo control groupphase iia is specifically designed to assess dosing requirements (how much drug should be given), while a phase iib trial is designed to determine efficacy, and studies how well the drug works at the prescribed dose(s), establishing a therapeutic dose range. phase iiifinal confirmation of safety and efficacytesting with large groups of people (typically 1,000–3,000) to confirm its efficacy, evaluate its effectiveness, monitor side effects, compare it to commonly used treatments, and collect information that will allow it to be used safely. phase ivsafety studies during salespostmarketing studies delineate risks, benefits, and optimal use. as such, they are ongoing during the drug's lifetime of active medical use. trial design main article: clinical study design a fundamental distinction in evidence-based practice is between observational studies and randomized controlled trials. types of observational studies in epidemiology, such as the cohort study and the case-control study, provide less compelling evidence than the randomized controlled trial. in observational studies, the investigators retrospectively assess associations between the treatments given to participants and their health status, with potential for considerable errors in design and interpretation. a randomized controlled trial can provide compelling evidence that the study treatment causes an effect on human health. currently, some phase ii and most phase iii drug trials are designed as randomized, double-blind, and placebo-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 a subject receives. this intent is to prevent researchers from treating the two groups differently. a form of double-blind study called a "double-dummy" design allows additional insurance against bias. in this kind of study, all patients are given both placebo and active doses in alternating periods. placebo-controlled: the use of a placebo (fake treatment) allows the researchers to isolate the effect of the study treatment from the placebo effect. clinical studies having small numbers of subjects may be "sponsored" by single researchers or a small group of researchers, and are designed to test simple questions or feasibility to expand the research for a more comprehensive randomized controlled trial. active control studies in many cases, giving a placebo to a person suffering from a disease may be unethical. to address this, it has become a common practice to conduct "active comparator" (also known as "active control") trials. in trials with an active control group, subjects are given either the experimental treatment or a previously approved treatment with known effectiveness. master protocol in such studies, multiple experimental treatments are tested in a single trial. genetic testing enables researchers to group patients according to their genetic profile, deliver drugs based on that profile to that group and compare the results. multiple companies can participate, each bringing a different drug. the first such approach targets squamous cell cancer, which includes varying genetic disruptions from patient to patient. amgen, astrazeneca and pfizer are involved, the first time they have worked together in a late-stage trial. patients whose genomic profiles do not match any of the trial drugs receive a drug designed to stimulate the immune system to attack cancer. clinical trial protocol main article: clinical trial protocol a clinical trial protocol is a document used to define and manage the trial. it is prepared by a panel of experts. all study investigators are expected to strictly observe the protocol. the protocol describes the scientific rationale, objective(s), design, methodology, statistical considerations and organization of the planned trial. details of the trial are provided in documents referenced in the protocol, such as an investigator's brochure. the protocol contains a precise study plan to assure safety and health of the trial subjects and to provide an exact template for trial conduct by investigators. this allows data to be combined across all investigators/sites. the protocol also informs the study administrators (often a contract research organization). the format and content of clinical trial protocols sponsored by pharmaceutical, biotechnology or medical device companies in the united states, european union, or japan have 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. journals such as trials, encourage investigators to publish their protocols. informed consent example of informed consent document from the paramount trial clinical trials recruit study subjects to sign a document representing their "informed consent". the document includes details such as its purpose, duration, required procedures, risks, potential benefits, key contacts and institutional requirements. the participant then decides whether to sign the document. the document is not a contract, as the participant can withdraw at any time without penalty. informed consent is a legal process in which a recruit is instructed about key facts before deciding whether to participate. researchers explain the details of the study in terms the subject can understand. the information is presented in the subject's native language. generally, children cannot autonomously provide informed consent, but depending on their age and other factors, may be required to provide informed assent. statistical power in any clinical trial, the number of subjects, also called the sample size, has a large impact on the ability to reliably detect and measure the effects of the intervention. this ability is described as its "power", which must be calculated before initiating a study to figure out if the study is worth its costs. in general, a larger sample size increases the statistical power, also the cost. the statistical power estimates the ability of a trial to detect a difference of a particular size (or larger) between the treatment and control groups. for example, a trial of a lipid-lowering drug versus placebo with 100 patients in each group might have a power of 0.90 to detect a difference between placebo and trial groups receiving dosage of 10 mg/dl or more, but only 0.70 to detect a difference of 6 mg/dl. placebo groups main article: placebo-controlled studies merely giving a treatment can have nonspecific effects. these are controlled for by the inclusion of patients who receive only a placebo. subjects are assigned randomly without informing them to which group they belonged. many trials are doubled-blinded so that researchers do not know to which group a subject is assigned. assigning a subject 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 provides guidelines on this issue. duration timeline of various approval tracks and research phases in the us 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, six 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 eight 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 such as 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. a clinical trial might also include an extended post-study follow-up period from months to years for people who have participated in the trial, a so-called "extension phase", which aims to identify long-term impact of the treatment. 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