The Research Process of Clinical Reviews
By Jack Haddad, DPM
1. What is a clinical review?
A clinical review is a research study designed to test the safety and efficacy of a medical device, synthetic drug, nutraceutical, herb, or vitamin/mineral on human subjects. The research is designed by a protocol methodology that when repeated, should yield fairly the same results. A protocol is a study plan on which all clinical reviews are based. The plan is carefully designed to safeguard the health of the participants as well as answer specific research questions. A protocol describes what types of people may participate in the review; the schedule of tests, procedures, medications, and dosages; and the length of the study. While in a clinical review, participants following a protocol are seen regularly by the research staff to monitor their health and to determine the safety and effectiveness of their treatment.
The clinical review team includes doctors and nurses as well as social workers and other health care professionals. They check the health of the participant at the beginning of the review, give specific instructions for participating in the review, monitor the participant carefully during the review, and stay in touch after the review is completed.
2. What are the different types of clinical reviews?
A. Treatment reviews test experimental treatments of medical devices, synthetic drugs, nutraceuticals, herbs, or vitamins/minerals.
B. Prevention reviews 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, vaccines, vitamins, minerals, or lifestyle changes.
C. Diagnostic reviews are conducted to find better tests or procedures for diagnosing a particular disease or condition.
D. Screening reviews test the best way to detect certain diseases or health conditions.
E. Quality of Life reviews (or Supportive Care trials) explore ways to improve comfort and the quality of life for individuals with a chronic illness.
3. What are the phases of clinical reviews?
Each phase is designed to determine specific information about the potential new product or treatment such as its risks, safety and effectiveness compared to standard therapy. The hope is that the new therapy will be an improvement over the previous standard therapy.
A. Phase I reviews. This phase is probably the most important step in the development of a new drug or therapy. These reviews usually involve a small number of patients (20-80) where researchers test a new product or treatment for the first time to evaluate its safety, determine a safe dosage range, and identify side effects. The primary goals of this phase are to determine the product's activity in humans, the maximum tolerated dose of the treatment, the manner in which the product works in the body, the toxic side effects related to different doses and whether toxic side effects are reversible. Upon completion of phase I reviews, the information that has been gathered is used to begin phase II reviews.
B. Phase II reviews. Once the information is gathered and analyzed from phase I reviews, phase II reviews are designed to determine the effectiveness of the treatment in a specific patient population at the dose and schedules determined in phase I. These reviews usually require a slightly higher number of patients (100-300)than phase I reviews. This number may increase depending on the number of responses as the phase II review progresses. Products or therapies that are shown to be active in phase II reviews may become standard treatment or be further evaluated for effectiveness in phase III reviews.
C. Phase III reviews. Phase III reviews compare a new product or therapy with a standard therapy in a randomized and controlled manner in order to determine proof of effectiveness. Phase III reviews require a large number of patients (1000-3000) to measure the statistical validity of the results because patient age, sex, race, and other unknown factors could affect the results. To obtain an adequate number of patients, several physicians (investigators) from different institutions typically participate in phase III clinical reviews.
D. Phase IV reviews. Once the product or treatment becomes part of standard therapy, the manufacturer may elect to initiate phase IV reviews. This phase includes continued evaluation of the treatment effectiveness and monitoring of side effects as well as implementing studies to evaluate usefulness in different types of patients.
4. Who sponsors clinical reviews?
Clinical reviews are sponsored or funded by a variety of organizations or individuals such as physicians, medical institutions, foundations, voluntary groups, and pharmaceutical companies, in addition to federal agencies such as the National Institutes of Health (NIH), the Department of Defense (DOD), and the Department of Veteran's Affairs (VA). Reviews can take place in a variety of locations, such as hospitals, universities, doctors' offices, or community clinics/labs.
5. Who can participate in a clinical review?
All clinical reviews have guidelines about who can participate. Using inclusion/exclusion criteria is an important principle of medical research that helps to produce reliable results. The factors that allow someone to participate in a clinical review are called "e;inclusion criteria"e; and those that disallow someone from participating are called "e;exclusion criteria"e;. These criteria are based on such factors as age, gender, the type and stage of a disease, previous treatment history, and other medical conditions. Before joining a clinical review, a participant must qualify for the study. Some research studies seek participants with illnesses or conditions to be studied in the clinical review, while others need healthy participants. It is important to note that inclusion and exclusion criteria are not used to reject people personally. Instead, the criteria are used to identify appropriate participants and keep them safe. The criteria help ensure that researchers will be able to answer the questions they plan to study.
To help someone decide whether or not to participate, the doctors and nurses involved in the review explain the details of the study. If the participant's native language is not English, translation assistance can be provided. Then the research team provides an informed consent document that includes details about the study, such as its purpose, duration, required procedures, and key contacts. Risks and potential benefits are explained in the informed consent document. The participant then decides whether or not to sign the document. Informed consent is not a contract, and the participant may withdraw from the review at any time.
6. How are clinical reviews conducted?
Clinical reviews use written protocols to define the purpose, design and conduct of a specific study. All of the research centers participating in a particular study use the same research protocol. The protocol is written by the sponsor of the study and explains what the review will do, how it will be conducted, where it will be conducted, who may participate and how and when the participants will be evaluated. In order to protect patients participating in clinical reviews, the sponsor reviews the protocol for safety and appropriateness and then the protocol must undergo a second neutral review by an Institutional Review Board (IRB). The Institutional Review Board is responsible for overseeing any clinical reviews that are performed in the specific healthcare institution where the clinical review is offered/conducted. An Institutional Review Board includes physicians, healthcare providers and individuals not involved in healthcare, including the clergy or ordinary citizens/consumers. Institutional Review Board members do not have any personal interest in the results of the review and, therefore, can ensure that the study is conducted fairly and safely. Committee members serving on Institutional Review Boards address the following questions in reviewing protocols:
Does this protocol have scientific value?
Does the protocol have scientific validity?
Does the study have a valid scientific design and yet pose an inappropriate risk for subjects?
Are risks to subjects minimized?
Are the risks to subjects reasonable in relation to anticipated benefits, if any, to subjects and the importance of the knowledge that may reasonably be expected to result?
Is the selection of subjects equitable?
Are additional safeguards in place for subjects likely to be vulnerable to coercion or undue influence?
Will informed consent be obtained from research subjects or their legally authorized representatives?
Is there adequate provision for monitoring the data collected to ensure the safety of subjects?
Are there adequate provisions to protect the privacy of subjects and to maintain the confidentiality of data?
The Institutional Review Board also reviews all informed consent documents to make sure that they provide clear and complete information for those evaluating the merits of enrolling in a specific clinical review.
Clinical reviews evaluating treatments may be offered in large university hospitals, local community hospitals and/or physician practices. The location where a clinical review is conducted depends on the specific resources required to conduct the review, the number of patients needed for enrollment in the review to answer the question and the individual or institution's interest in performing clinical reviews in general.
7. What are the safeguards of clinical reviews?
Both standard care and clinical reviews have risks, side effects and benefits that vary depending on the individual. However, there are rigorous guidelines in place to protect the well-being and safety of clinical review participants. The physician and research nurse conducting the study will explain any known or anticipated risks ahead of time. Once a patient's eligibility for a specific review is established, the research nurse will explain the informed consent process. Informed consent is one of the patient's most important rights in the research process, as it outlines the purpose of the study, the exact treatments that will be administered, all possible side effects, and the patient's right to withdraw from the study at any point. Signing the consent form acknowledges that the review was explained and is understood. Also, clinical review participants are constantly monitored to identify any changes in their condition.
8. What is the cost of a clinical review?
There are two types of costs associated with a review:
Patient care costs
Patient care costs: These are costs associated with providing medical goods and services to each patient. Usual care costs include doctor visits, hospital stays, clinical laboratory tests, x-rays, and any other medical costs that occur regardless of whether a patient is participating in a clinical trial or receiving standard treatment. These costs are usually covered by a third-party health plan, such as Medicare or private insurance.
Research costs: Research costs are costs that are associated with clinical review participation, such as data collection and management, research physician and nurse time, analysis of results, and tests performed purely for research purposes. Such costs are usually covered by the sponsoring organization, such as a pharmaceutical company. The sponsor and the participant's health plan need to resolve coverage of these costs for particular reviews. Be sure to consult with your physician about the financial aspects of any review you are evaluating.
Health insurance companies and managed care companies decide which health care services they will pay for by developing coverage policies regarding the specific services. In general, the most important factor determining whether something is covered is a health plan's judgment as to whether the service is established or investigational. Health plans usually designate a service as established if there is a certain amount of scientific data to show that it is safe and effective. If the health plan does not think that such data exists in sufficient quantity, the plan may label the service as investigational.
Health care services delivered within the setting of a clinical review are very often categorized as investigational and are not covered. This is because the health plan thinks that the major reason to perform the clinical review is that there is not enough data to establish the safety and effectiveness of the service being studied. Thus, for some health plans, any mention of the fact that the patient is involved in a clinical review results in a denial of payment.
Health plans may define specific criteria that a review must meet before extending coverage. Some plans, especially smaller ones, will not cover any costs associated with a clinical review, while other, larger managed care plans have recently announced at least partial coverage of costs associated with clinical research. Policies vary widely, but in most cases the best strategy is to have a doctor initiate discussions with the health plans.