Timothy M. Pawlik and Julie A. Sosa (eds.)Success in Academic SurgerySuccess in Academic Surgery: Clinical Trials201410.1007/978-1-4471-4679-7_10
© Springer-Verlag London 2014
10. Device Versus Drug Clinical Trials: Similarities and Important Differences
Department of Surgery, Medical College of Wisconsin, Milwaukee, WI, USA
T. Clark Gamblin (Corresponding author)
William S. Ragalie
The regulatory requirements for investigational drugs and devices are complex, and the clinical investigator must have a working knowledge of these requirements as mandated by the Food and Drug Administration in order to effectively bring a product to market. Preclinical laboratory data must support an application in order to test the drug or device in humans. A clinical trial focused to gain approval then proceeds through defined phases of clinical testing. Data from the clinical investigations must be used in the various application documents required to legally market a new drug or device. The differences between the drug and device approval process include classifications based on risk, different application documents, and different checkpoints in the investigational and approval process.
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The approval processes in the United States for new drugs and devices intended to treat a medical condition share similarities; however, they routinely take different regulatory routes. The approval process mandated by the US Food and Drug Administration is a substantial part of this process. The academic investigator should have a general understanding of the steps required to bring a new drug or device to market. In an era where academic investigators often work closely in collaboration with industry in the development of drugs or devices, a working knowledge and fluency with the required regulatory steps will facilitate a successful team and provide valuable medical insights to the process.
In the United States, the authority to grant market approval to drugs and devices is vested in the Food and Drug Administration (FDA). Formed in 1906, the FDA is an agency of the US Department of Health and Human Services of the federal government. Approval of a new drug or device is based on the results of clinical investigation, often randomized controlled trials (RCT). RCTs are a relatively recent tool, being developed over the last century. In the 1930s concern over researchers’ bias led statisticians R.A. Fisher and A.B. Hill to write texts on ideal design of clinical trials. The passage of the Food, Drug, and Cosmetic Act in 1938 enabled the FDA to grant approval based on demonstration of safety and efficacy through RCTs.
10.1.1 Overview of Randomized Controlled Trials
A randomized controlled trial proceeds through several defined steps, described below.
Phase 0—A drug is given to a small number of human subjects to determine whether it behaves in humans as expected from preclinical studies. Gathering safety and efficacy data is not a goal of a phase 0 trial. Phase 0 trials are not necessary prior to beginning a phase 1 trial, but they have the ability to rapidly develop a drug by quickly establishing its behavior in humans.
Phase 1—A drug is tested in a small number of volunteer subjects, who are usually healthy, though some phase 1 trials are run with diseased patients. The purpose of phase 1 is to gather data on safety as well as dosing. Note that devices need not pass through a phase 1 trial because it would be unethical to implant devices in healthy subjects, and such a trial would not provide clinically useful information.
Phase 2—A drug or device is tested on a larger group of subjects with the disease in question. This is compared against the standard of care. Further data on safety as well as data on efficacy of the intervention are gathered.
Phase 3—This phase of investigation involves a very large number of subjects, from several hundred to several thousand. Data continue to be gathered on safety and efficacy, as well as minor adverse effects. Investigators use results of phase 3 trials in applying for market approval of the drug or device.
Phase 4—Postmarketing surveillance. This phase gathers data on safety and minor adverse events as the newly approved product is consumed in the market.
10.2 Steps Specific to the Clinical Trial of a Drug
10.2.1 Step 1: Investigational New Device (IND) Application
Clinical trials for drugs are evaluated by the largest of the FDA’s five divisions, the Center for Drug Evaluation and Research (CDER). Once an investigator has obtained initial data from laboratory studies, an Investigational New Drug (IND) application is filed with the FDA. The investigator may begin the proposed clinical trial 30 days after submission of the IND. This 30 day period permits the FDA an interval in which they may mandate a clinical hold if they deem it necessary. There are two main legal ramifications of an approved IND application. It allows the investigator an exemption to the federal law requiring that a drug must be market-approved before it can be transported across state lines. In addition, it allows the drug to legally be tested in humans.
There are two categories of INDs. A “research” or investigator-initiated IND is submitted by an individual physician or investigator. An IND is categorized as “commercial” when it is submitted by a corporate entity or by one of the institutes of the National Institutes of Health (NIH).
An IND can be considered as one of three types when it is filed:
Investigational IND. This is the most commonly filed IND by academic investigators when the investigator initiates, conducts, and supervises the administration of the investigational drug.
Emergency IND. This filing allows the FDA to approve the investigational drug in cases where normal review timelines would be too long for the patients in question. This includes an after-hours emergency contact line and may be used in cases for compassionate care.
Treatment IND. This filing is used by investigators for drugs showing initial promise in clinical trials for the treatment of immediately life-threatening conditions before a final FDA review.
The CDER provides resources and guidance documents to help the researcher prior to IND submission. These include the Pre-Investigational New Drug Application Consultation Program. An index of resources provided by the FDA and their respective contact information are included at the end of the chapter.
10.2.1.1 Information Required of the IND
Certain information in three critical areas must be addressed by the investigator in the IND application:
Toxicology and pharmacology studies. The investigator’s preclinical laboratory data must demonstrate the safety of the drug and explicitly state that the experimental drug will not expose trial subjects to unnecessary risk. If the drug has been approved for use outside the United States, data from other countries can be included as part of the application.
Investigator information and clinical protocols. The investigator is required to state the intention to adhere to IND regulations, institutional review board (IRB) oversight, and to obtain informed consent from all study subjects. The investigator also states the qualifications of the physicians overseeing the drug’s administration.
Manufacturing information. Basic information about the physical process of creating the drug is provided. An attestation to the ability to manufacture a consistent product must describe the internal quality control, as well as ability to provide adequate quantities of the drug.
10.2.2 Step 2: New Drug Application (NDA)
The approved IND application allows the investigator to conduct and complete the proposed trial. More lengthy trials will need to include a predetermined interim analysis as well as to assess safety and efficacy. The data gathered in the investigational phase is submitted as part of the New Drug Application (NDA) to the FDA. Provided the FDA grants approval of a NDA application, commercial use is then pursued. The NDA must contain the following information:
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