Clinical trials and cancer

ALSO KNOWN AS: Clinical studies, clinical research studies, clinical investigational studies

DEFINITION: According to the US Food and Drug Administration (FDA), a clinical trial is the systematic investigation of the impact of materialssuch as investigational drugs and medical devicesor methodssuch as surgery and radiationon a disease state, conducted according to a formal trial protocol. A clinical trial's main objective is to evaluate the safety and efficacy of new materials or new methods in humans before approving these materials or methods for commercial use. Among the clinical trials that investigate methods are screening, diagnostic, and prevention trials, and palliative care trials. The FDA strictly regulates clinical trials to ensure the safety of all involved.

The trial design can be controlled or uncontrolled, randomized or nonrandomized, and nonblinded, single-blinded, or double-blinded. The term controlled in this context means that the group receiving the new treatment is compared with a control group, whose members can receive a placebo, a different dose, no therapy, standard-of-care treatment, or be historical subjects. The term randomized means that patients selected to participate in a specific trial are randomly assigned to either the treatment or the control group. The term single-blinded means that only the investigator, not the patient, knows whether the patient is in the treatment or control group. The term double-blinded means that neither the investigator nor the patient knows to which group the patient has been assigned. FDA-regulated clinical trials are prospective, meaning clinical data are collected according to a trial plan, in contrast to retrospective studies, where clinical data are retrieved from existing sources, such as medical charts. Controlled, randomized, double-masked trials have the most substantial scientific value. Starting a clinical trial has to be approved by the FDA and the institutional review board after a thorough scientific and ethical review of the mandatory regulatory documentsnamely, investigational new drug application or investigational device exemptionfor the new drug or medical device submitted by the clinical trial sponsor, which is typically a pharmaceutical or medical device company. Also, conducting, monitoring, inspecting, recording, and analyzing a clinical trial must be based on national FDA regulations and the International Conference on Harmonisation'sHarmonisation's Good Clinical Practice (ICH-GCP) guidelines to ensure proper ethical conduct of a clinical trial (such as voluntariness of participation). Participants in a clinical trial are either healthy subjectsprobandsor subjects with a specific target disease (such as breast or prostate cancer), and the clinical trial team, consisting of the principal trial investigators, the trial coordinator, and other health care professionals.

For any drug, multiple trials in three phases must be conducted. In phase I trials, typically healthy subjects are involved, and these trials mainly focus on the trial's feasibility. In addition, pharmacokinetic and pharmacodynamic data on the new drug are collected, and the maximal tolerable dose is determinedphase I trials are also called dose-finding trialsAccording to the FDA, phase I trials are usually short-term over several weeks or months and limited to 20 to 100 individuals. Phase II trials are conducted to confirm the effective dose and regimen of the investigational new drug and to provide early efficacy and safety information. These trials are usually short-termup to two yearsand include fewer than a hundred subjects with the primary target disease. Phase III trials typically include patients with the primary disease but also allow for associated conditions. These trials are usually longerone to four yearsand involve one hundred to thousands of patients, depending on the target disease.

These trials aim to determine efficacy for the primary indication (such as breast cancer), the rates of adverse eventsside effectsand, for drugs, the optimal dose. Phase IV trials, also called "postmarketing trials," are conducted according to the product label in a very large patient population after FDA approval of the new drug, medical device, or method. The goal of these trials usually is further therapy optimization.

Cancers addressed: Clinical trials are offered for patients with many kinds of cancer to evaluate new treatment options, altered treatment options, or new indications for existing cancer therapies.

Training and certification: The Food and Drug Administration regulations and Good Clinical Practice (GCP) guidelines outline the required qualifications and obligations of a clinical investigator to conduct a clinical trial.

According to these regulations and guidelines, a clinical trial's principal clinical investigator (PI) must, for example, submit a detailed curriculum vitae showing that the person is qualified by training and experience to investigate a new drug or method. The person should have at least two years of experience in conducting clinical trials. Before beginning a clinical trial, the PI is trained in detail about the latest drug or method. This training is provided by the clinical trial sponsor, which usually is a pharmaceutical company developing the drug. The training includes reviewing the clinical investigator'sinvestigator's brochure, a document prepared by the trial sponsor and containing all known relevant information on the investigational product, including preclinical, pharmacokinetic, and pharmacodynamic data in animals and humans as well as data from earlier clinical trials. The training also includes correctly reporting potential patient side effects according to the regulatory requirements. In addition, the PI has to train the trial teamtrial coordinator, coinvestigators, and otherson the investigational product, including its proper use or administration according to the trial protocol, which must be strictly followed.

Services and procedures performed: Participants in a clinical trial can benefit from being treated with an investigational new drug or method or a commercially available drug used for a new indication, mainly if standard treatments are ineffective or do not exist for the patient's disease. Patients do not have to pay for the latest treatment, and their overall health is generally more closely and thoroughly monitored than in nontrial settings. However, the new treatment is not guaranteed to work, and the patient's health may deteriorate during or after the completion of the clinical trial. Also, patients may be part of the control group and not receive the new drug.

Before patients can be included in a clinical trial, the investigator has to ensure they meet the strict inclusion criteria outlined in the clinical protocol. If a patient meets all inclusion criteria and none of the exclusion criteria, the person must be thoroughly informed about the trial, and all questions must be answered satisfactorily. The investigator has to make sure that the patient has understood all benefits and potential risks involved with the prosecution, as well as the procedures performed at each trial visit and the patient's obligation to complete the trial visits and to comply with all instructions given by the investigator. The patient must also understand the alternative treatment options. Then, suppose the patient is still willing to participate in the trial. In that case, the individual has to sign and date a patient consent form stating that participation in the clinical trial is voluntary and that the patient can withdraw at any time without compromising the standard care to which the patient is otherwise entitled. The patient consent form must have been previously approved by an institutional review board (IRB), an independent group of medical and nonmedical professionals whose goal is to ensure that the clinical trial is performed safely, with integrity, and concerning the rights of the participating subjects.

After signing the informed consent, patients will be screened to ensure they are eligible for the trial. Screening visits generally include:

• taking an anamnesis (a case history),
• performing a physical exam and lab tests, and
• documenting all medications the patient takes.

After the screening visit, eligible patients are randomly assigned to either the treatment or the control group if the trial design requires patient randomization. After performing the trial procedure, which can include, for example, taking a specific investigational new drug or undergoing a surgical procedure, the patient will be closely monitored during the subsequent, predefined follow-up visits. Depending on the protocol, the patient procedures during these visits may include another physical exam, lab tests, an electrocardiograph (ECG), filling out questionnaires, and the recording of all side effects that may have occurred since the last visit, whether they may be associated with the trial treatment or not. The clinical trial personnel document All patient data collected on case report forms.

If any severe side effects occur between trial visits, the patient must inform the trial personnel immediately seek immediate medical help, or both. The investigator's responsibility is to immediately report any severe side effectslife-threatening, lead to hospitalization, or are fatalto the trial sponsor, who will take all required actions. All patient personal data are encoded before being transferred to any third party to conceal the patients' identities.

After the completion of an individual trial, which can take weeks or years depending on the trial phase and design, the trial sponsor analyzes the trial data. The outcome of the analysis may influence the design of the next trial phase. The trial results may be published in a scientific journal. In many cases, however, studies are performed at predetermined times during a clinical trial, which may lead to continuation or discontinuation of the trial (for example, if the trial results show a significant benefit). The use of so-called open-label trials after phase III trials is relatively standard. They typically follow a double-masked, randomized, placebo-controlled trial of a new drug, and patients may be invited to enroll because this kind of trial allows the gathering of further data about the safety and tolerability of the new drug or device in long-term, day-to-day use. Treatment schedules, drug treatment, and doses are known to the investigator and the patient in these trials.

To apply for marketing approval of a new drug (or medical device) tested in clinical trials, the sponsor must prepare a new drug application (NDA) or a corresponding marketing application for the medical device for submission to the FDA. This document contains all information on preclinical and clinical trials and other knowledge about the drug or device. The FDA's standard NDA review typically takes six to ten months.

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