Trial design

Main article: Clinical study design

A fundamental distinction in evidence-based practice is between observational studies and randomized controlled trials.^[33] 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.^[33] 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.^[34]
A randomized controlled trial can provide compelling evidence that the study treatment causes an effect on human health.^[33]
Currently, some phase 2 and most phase 3 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.^[35]

Active comparator studies

Of note, during the last 10 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 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 importing (importing a patented compound for sale in a country outside the patenting agency's sphere of influence).^{[citation needed]}

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.^[36]

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^[37] issued by the International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH).^[38] Regulatory authorities in Canada and Australia also follow ICH guidelines. Journals such as Trials, encourage investigators to publish their protocols.

Design features

Informed consent

Example of informed consent document from the PARAMOUNT trial

Clinical trials recruit study subjects to sign a document representing their "informed consent".^[39] The document includes details such as its purpose, duration, required procedures, risks, potential benefits, key contacts and institutional requirements.^[40] 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.