Clinical Studies For Medical Devices
Clinical studies of medical devices and prescription drugs have been in the news lately, but exactly what is a clinical study? Clinical studies are a way for drug and device manufacturers to amass historical data on their products and their effects on human subjects which is then used to prove to the federal Food and Drug Administration (FDA) that their products are “safe and effective.” If the FDA makes such a determination, then the drug or medical device will be more freely available – in other words, patients won’t have to enter a clinical study in order to receive the drug or device.
The main players in a clinical study for a medical device are the manufacturer, which is often the sponsor of the study; the surgeon, who is called the investigator of the study; and the patients who receive the medical devices, known as the subjects or participants in the clinical study. An Institutional Review Board (IRB) exists to protect the human subjects in the study and performs some of the functions of the FDA. The IRB reviews and approves a clinical study at a particular medical facility before enrollment of subjects can begin at that site. Each of these groups is discussed in more detail below. However, before discussing those groups, some background will put clinical studies and the players in perspective.
FDA and MDA
During the administration of Franklin Delano Roosevelt, Congress passed the Food, Drug and Cosmetic Act, expanding the original Food and Drug Act of 1906. Via a 1976 amendment, Congress further empowered the FDA to regulate medical devices. (This firm frequently represents medical device manufacturers.) Not all medical devices need clinical trials to gain FDA approval.
The Medical Device Amendment of 1976 classifies medical devices into three categories based on the risk that they pose to the public. Class I devices present no unreasonable risk of illness or injury and are subject only to minimal FDA regulation via ‘general controls’. Approximately half of all medical devices are Class I and include such products as crutches and bed pans.
If a device is “potentially more harmful,” it will be classified as Class II and may be marketed without advance approval from the FDA. Class II devices are subject to ‘special controls’ established by the FDA, such as patient registries or post-market investigations of the medical device in use. Approximately 40% of all medical devices are Class II.
The final type of medical device is often the subject of clinical trials. A device will be classified as Class III if it is for use in supporting or sustaining human life or for a use which is of substantial importance in preventing impairment of human health, or presents a potentially unreasonable risk of illness or injury. Class III devices include pacemakers, heart valve replacements and breast implants.
These days Class III devices are usually subject to the FDA’s rigorous pre-market approval process (PMA). During the PMA, manufacturers must provide the FDA with ‘reasonable assurance’ that their devices are both safe and effective. Manufacturers must submit detailed information regarding the safety and efficacy of their devices, which the FDA then reviews, spending an average of 1,200 hours on each submission. Part of the detailed information that manufacturers submit to the FDA often comes from clinical trials they have sponsored.
Rather than begin the process by submitting an application, a sponsor may request a meeting with the FDA to attempt to reach an agreement regarding the investigational plan for a Class III device or any implantable device.
A device does not need PMA approval if it receives an investigational device exemption (IDE). Under an IDE, a manufacturer does not commercially market the device, but investigates the safety and effectiveness of the device via clinical studies. The purpose of the IDE is to encourage, to the extent consistent with the protection of the public health and safety, the discovery and development of useful devices intended for human use.
CFR’s and Responsibilities
The nationwide laws governing clinical trials are contained in the Code of Federal Regulations (CFR’s). The regulations include definitions which help understand how clinical trials are conducted and set forth the responsibilities of the various groups. See 21 C.F.R. § 812 et seq. “Investigational device” means a device that is the object of an investigation.
“Investigation” means a clinical investigation or research involving one or more subjects to determine the safety or effectiveness of a device. [21 C.F.R. § 812.3(h)]
“Investigator” means an individual who actually conducts a clinical investigation, i.e., under whose immediate direction the test article is administered or dispensed to a subject. An investigator, who is usually the surgeon, has numerous responsibilities in conducting the study, which include: ensuring that an investigation is conducted according to the signed agreement, the investigational plan and applicable FDA regulations; protecting the rights, safety, and welfare of subjects under the investigator’s care; controlling the devices under investigation; and ensuring that informed consent is obtained from the human subject.
“Sponsor” means a person or company who initiates the study but who does not actually conduct the investigation. That is, the investigational device is administered, dispensed, or used under the immediate direction of another individual, namely the investigator. The regulations detail that sponsors are generally responsible for selecting qualified investigators and providing them with the information they need to conduct the investigation properly; ensuring proper monitoring of the investigation; ensuring that IRB review and approval are obtained; submitting an IDE application to FDA, and ensuring that the FDA and any reviewing IRB are promptly informed of significant new information about an investigation.
“Subject” means a human who participates in an investigation and on whom an investigational device is used. A subject may be in normal health or may have a medical condition or disease. Subjects must be fully informed about the clinical study including the risks of the medical device, and must sign an informed consent document memorializing that understanding before receiving the medical product.
“Investigational Review Boards” (IRB’s) are impartial committees usually associated with hospitals which exist to protect human subjects. IRB’s review and have the authority to approve, require modifications, or disapprove all clinical investigations under an IDE.
The Study Itself
The medical device manufacturer, as the sponsor, typically designs the protocol which describes how the clinical study will be conducted. It includes an objective, inclusion and exclusion criteria for the participants, rules for the physician/investigators to follow regarding data collection and paperwork, and countless other items. The protocol is submitted to the FDA for approval.
Once the FDA approves the study, the sponsor can enlist surgeons to conduct the study on appropriate patients. The sponsor ensures that the investigators are qualified, and the investigators certify that they will conduct the study according to the protocol.
Next, the IRB must review the protocol and approve the study at a particular medical facility. IRB approval typically lasts for one year; the status of the study is reviewed annually.
Once the IRB grants its approval, an investigator approved by the sponsor may perform surgeries involving the investigational medical device at the facility approved by the IRB. The investigator will see which of his or her patients would be appropriate candidates for the product, and consult the inclusion and exclusion criteria for the clinical study.
Investigators will explain to appropriate subjects the clinical study and the risks and benefits of the subject product, which by definition has not been established as safe and effective by the FDA. If the subject wants the product, he or she must sign an informed consent document confirming his or her desire to participate in the study. Typically, a participant certifies that he or she is willing to present to the physician/investigator periodically so that the product and its safety and effectiveness can be monitored.
Investigators around the country complete data collection forms and submit them to the sponsor/manufacturer. The FDA has the right to inspect records of investigators and sponsors. Periodically the sponsor submits summaries to the FDA indicating the status of the study. After several years, the sponsor can request FDA approval of the medical device. Manufacturers seeking to obtain or maintain marketing clearance for their Class III medical devices submit PMA applications to the FDA which consist of scientific evidence and clinical study results in hopes of having their devices deemed safe and effective.