Clinical trials are fundamental to the development of innovative, investigational products such as drugs or high-risk (and some medium-risk) medical devices.* Many products are found to be safe and effective in bench testing, in vitro testing or animal studies, but fail to demonstrate the same effect in humans.1,2 These investigational products must be proven safe and effective in a clinical study in humans before use in the general population.
Clinical trials: Drug development
Drug development is often complex, time-consuming and resource-intensive. It requires particular attention to ensure the appropriateness of the clinical trial being conducted for the drug or biologic.
Adequate and well-controlled clinical studies
Clinical studies that support regulatory submissions are expected to be adequate and well-controlled. The clinical study reports should provide sufficient details of the study design, conduct and analysis to determine whether there is substantial evidence to support the claims of effectiveness of the investigational product.
The US Code of Federal Regulations, Title 21, Part 314.126 describes the characteristics of such a study:3
- Study objective and analysis method: Document this in the clinical study protocol and report.
- Study design: Design with a valid comparison to a control (for example, placebo, dose-comparison, active, no treatment, or historical controls) to provide a quantitative assessment of the product’s effect. The clinical study design, including treatment duration, whether treatments are parallel, sequential or crossover, and whether the sample size is predetermined or based upon interim analysis should be included in the protocol and the report.
- Subject selection method: Use a method that provides adequate assurance that the subjects have the disease or condition being studied, or evidence of susceptibility and exposure to the condition against which prophylaxis is directed.
- Patient assignment method: Use a method to assign patients to treatment and control groups that minimizes bias and assures group comparability regarding pertinent variables such as age, sex, severity of disease, duration of disease, and use of therapy other than the investigational product. Assignment is normally by randomization, with or without stratification, in a concurrently controlled clinical study.
- Minimize bias: Take adequate measures (for example, blinding) to minimize bias on or by subjects, observers and data analysts.
- Assessment method of subject’s response: Use a method that is well-defined and reliable. In the clinical trial protocol and report, include the variables measured, the observation methods and the criteria used to assess response.
- Product effect analysis: In the clinical trial protocol and report, include the results and analytic methods, as well as any statistical methods. The analysis should include information such as the comparability of test and control groups regarding pertinent variables and the effects of any interim data analyses performed.
Uncontrolled or partially controlled clinical studies
Uncontrolled or partially controlled clinical studies3 are generally not acceptable as the sole basis for approval of claims of effectiveness. Such studies that are carefully conducted and documented may provide corroborative support of well-controlled studies regarding efficacy, and may yield valuable data regarding the safety of the test product.
Isolated case reports, random experience and reports lacking the details that permit scientific evaluation are not generally considered.
Clinical trials: Medical devices
For medical devices, frequent innovations in the design and use (for example, minor modifications that enhance safety, reliability, patient comfort, or ease of use) are common and often do not require prior regulatory approval. Bench and/or animal testing is often sufficient to validate the suitability of a design change.4
In cases when a clinical trial is required (for example, for high-risk or some medium-risk devices), evidence can come from sources other than well-controlled clinical studies, when justified. Such sources may include:
- Partially controlled clinical studies
- Clinical studies and objective trials without matched controls
- Well-documented case histories conducted by qualified experts
- Reports of significant human experience with a marketed device
The reason for these varied sources of evidence is that the design of medical-device clinical trials may present some special challenges that do not arise with drug trials. These are outlined below.
Challenges in designing clinical trials for medical devices
- Devices are primarily used by healthcare professionals: The clinical outcomes of a medical device’s safety and effectiveness are a function of the user’s skill paired with the device-patient interaction. Having training in the use of the medical device is a key part of its clinical performance.
- Inability to blind the user/patient: Medical devices are often designed differently and this can introduce bias into the assessment of the clinical performance if the clinical investigator is jointly responsible for treatment and assessment of performance. Thus, whenever possible, blinded evaluators are preferred to clinical investigators for the assessment of efficacy.
- Limitation in comparative trial design (for example, an implanted device): Comparative clinical trials may be precluded due to ethical considerations. The use of historical controls in the trial or patients as their own controls (pre- and post-surgery) may be required to evaluate outcomes.
Often, the process for regulatory clearance or approval for medical devices is more flexible than it is for drug development.
In drug development, the replication of clinical findings (that is, more than one clinical trial) is required. However, for medical devices, sometimes a single pivotal clinical trial can suffice because the mechanism of action is a result of product design and can be substantially verified by in vitro performance testing.5
*Certain lower-risk medical devices (for example, class I or most 510[k] devices) do not require a clinical study.
The information presented in these articles is intended to outline the general processes, principles and concepts of the healthcare product development lifecycle. Since regulatory requirements are ever-changing, it is current only as of the date of publication and not intended to provide detailed instructions for product development. Every healthcare product is unique and therefore so is its associated product development lifecycle. Specific advice should be sought from a qualified healthcare or other appropriate professional.
Published: October 17, 2012
- Canada trials. (2008, April 26.) What is clinical research? Retrieved July 13, 2012, from http://www.canadatrials.com/AboutClinicalResearch.php.
- People for the Ethical Treatment of Animals. (n.d.). Animal Experiments: Overview. Retrieved September 24, 2012, from http://www.peta.org/issues/animals-used-for-experimentation/animal-experiments-overview.aspx.
- United States Code. Title 21, Part 314.126, Adequate and well-controlled studies.
- Becker, K.M. (2006). Clinical trials in development and marketing of medical devices. In Becker, K.M., Whyte, J.J. (Eds.) Clinical evaluation of medical devices. Principles and case studies. (2nd ed.). Totowa: Humana Press.
- U.S. Department of Health and Human Services. (1995, August 1). Statement Regarding the Demonstrations of Effectiveness of Human Drug Products and Devices. Docket No. 95N-0230. Retrieved September 26, 2012, from US Federal Register Online via the Government Printing Office: http://www.gpo.gov/fdsys/pkg/FR-1995-08-01/html/95-18877.htm.