Originally Published MDDI May 2001
A systematic approach that views the clinical research department as an integral part of the development team can enhance the likelihood of success in the creation of new products.
Nancy J. Stark
Many medical device companies use a project management approach for product development. The project team, comprising a team leader (or project manager) and representatives from various departments, is responsible for planning and implementing the project. When the project is to develop a new device or enhance an existing one, the clinical research department can play an active, contributory role.
The product development cycle can be divided into five phases: concept, prototype, prepilot, pilot, and production. This paradigm is similar to the standard project management model consisting of project definition, project planning, project tracking and maintenance, and project closeout.
The elements of design control—plan, input, review, output, verification, validation, transfer, changes, and history file—are embedded over specific phases of the product development cycle and help characterize the phases. Figure 1 shows the relationship of the product development cycle, design control elements, and clinical research activities.
|Figure 1. Schematic overview of clinical research in the product development cycle.|
Clinical trials most often occur during the last four phases of product development, depending on the purpose of the trial. Typically, the way one names a trial—for example, pilot, feasibility, manufacturing, pivotal, postmarket surveillance—reflects the phase in the product development cycle in which the trial is taking place. Device companies that are owned by drug companies, or those whose management previously worked in the pharmaceutical industry, often use a different nomenclature for trials—generally phase I, phase II, phase III, and phase IV. Regardless of the nomenclature, the role of clinical research is separate and distinct in each of the five product development phases.
The first step in standard project management models is the concept phase, in which a project team is appointed to design the new device in accordance with design control requirements. The design control steps are to create the project control plan and to obtain design input.
Project team members meet to identify the design requirements of the product, including requirements for product configuration, formulation, processing and manufacture, packaging, labeling, performance, storage, handling, distribution, regulatory status, bench and animal testing, and human clinical trials. This process is called design input. The team also develops a project control plan describing in general terms who will do what by when. The concept phase of product development culminates when a general plan for building, testing, and manufacturing the product is completed.
Clinical Research Activities. The clinical research representative to the team acts as a consultant during the concept phase, providing input for development of claims and advising as to claims that may be necessary, claims that may be difficult to substantiate, or claims that should be avoided. (A claim is an assertion of truth about a product, especially about its safety, efficacy, performance, or regulatory status.) The representative's primary work product is a clinical development plan—that is, a group of one or more clinical trials that are necessary to substantiate the claims for the product.1
PROTOTYPE (FEASIBILITY) PHASE
During the prototype phase—called the feasibility phase by some companies— various departments will begin evaluating the feasibility of the concept. The manufacturing group will look at production issues, whereas the marketing department may conduct focus panels to evaluate design concepts. If test outcomes are unsuccessful, the prototype is redesigned. If test outcomes are successful, the product design is frozen, signifying the culmination of the prototype phase. Hereafter, all design changes are captured through design change control.
Clinical Research Activities. Preclinical tests for safety, efficacy, or performance in in vitro and animal systems are initiated during the prototype phase. These include biocompatibility tests designed to ensure biological safety of the materials and animal efficacy tests designed to evaluate effectiveness of the design in nonhuman systems. In some companies, these tests are coordinated by the clinical research group; in other firms, preclinical testing is assigned to a different department.
Clinical trials in the prototype phase may include pilot studies to aid in design definition. For example, an algorithm might be loaded into a personal computer, measurements from the subject fed into the computer, and a computed result evaluated for its accuracy in representing a physiological event, with the goal of defining the algorithm. Similarly, various configurations of a device might be evaluated in ill subjects to finalize a design, or anatomical measurements taken from a group of subjects to establish size ranges.
One issue for clinical trials of prototype devices is the extent to which the sponsors must comply with good manufacturing practices. In the United States, regulations declare that investigational devices "are exempt...from good manufacturing practice requirements . . . except for the requirements found in Section 820.30 [Design Controls]..."2 FDA recognizes that prototype devices are unlikely to meet all the requirements of design controls—a prototype device will not be verified and validated. The preamble to the quality system regulations specifies that "the use of prototypes in clinical studies is acceptable. When prototype devices are used on humans, they must be verified as safe to the maximum extent feasible. Final design validation, however, cannot be done on prototypes because the actual devices produced and distributed are seldom the same as the research and development prototypes. The final verification and validation, therefore, must include the testing of actual production devices under actual- or simulated-use conditions."3
In preparation for any clinical trial, the clinical research team will work with the regulatory department to determine the trial's regulatory status. Is the device under investigation also a drug or cosmetic, requiring compliance with additional regulations? Is the trial exempt from the investigational device exemption (IDE) regulation or an approved IDE needed for the trial? Will the trial be multinational, requiring compliance with regulations from other countries?
Clinical research personnel will also work with the project team to develop a risk analysis. It should be noted that the risk analysis developed for the device is much broader than the risk analysis needed for a clinical trial, which focuses on the medical risks to the subject. The latter also includes any risks that may be study-specific—for example, risks associated with experimental procedures that may be used during the trial, but are not part of the device itself.
PREPILOT (DEVELOPMENT) PHASE
In the prepilot phase—sometimes called the development phase—the manufacturing department works to develop the production process, while other departments develop the processes necessary to carry out functions such as packaging, distribution, or marketing. In design control language, this is the phase of design verification—the period of testing and proving the design features of the device. The design is changed if study outcomes are unfavorable, and design changes are captured through the design change control system. The prepilot phase culminates when the manufacturing process has been finalized.
Clinical Research Activities. During the prepilot phase, prototype devices may be evaluated in humans to verify claims that cannot be tested on the benchtop or in animals. Human studies in healthy volunteers may be conducted with dermal-contact devices to verify safety claims regarding nonirritating or hypoallergenic properties. Feasibility studies in ill human subjects may be conducted to develop hypotheses or obtain data for sample-size calculations. Manufacturing studies may be conducted to optimize formulations to verify claims of reagent sensitivity and specificity for IVD tests, for example, or to evaluate manufacturing processes to verify the integrity of a heat seal in actual use.4
Additional activities of the clinical research team during the prepilot phase include assisting with regulatory applications for clinical trials and beginning execution of the clinical development plan for design verification.
PILOT (SCALE-UP) PHASE
Pilot plants are small manufacturing sites in which processes or techniques planned for full-scale production are tested in advance. Scale-up refers to the activity of moving from limited production to full production, and typically takes place during the pilot phase of product development. The pilot or scale-up phase is that in which design and process verification are completed and transferred into device specifications. The pilot phase culminates when the manufacturing process is confirmed and transfer to production facilities begins.
Clinical Research Activities. A clinical trial is simply one more tool in the product developer's test arsenal for verifying or validating a design. This view of a clinical trial fully integrates clinical research into the product development cycle, and is made clear in the preamble to the quality system regulation: "Clinical evaluation is an important aspect of the design verification and validation process during the design and development of the device."5 Pivotal studies—conducted to substantiate claims of safety, efficacy, or performance—are conducted during the pilot phase to verify processes and design. The trials are called pivotal because the success or failure of marketing applications can depend on the outcome of these studies.
Some companies assign the important activity of reviewing label copy to the clinical research group. The purpose of the review is to identify claims for the device and ensure that there are adequate in vitro, animal, or human clinical data to substantiate them.
The design is changed if test outcomes are unfavorable, and changes are captured through the design change control system. The device may proceed to regulatory submission and commercialization if the test outcomes are favorable.
PRODUCTION (COMMERCIALIZATION) PHASE
Production or commercialization is the final phase of product development—the phase in which the fully approved product is made available for marketing. Validation takes place in the very late stages of the pilot phase or the very early stages of the production phase, since validation testing is performed on initial production units.
Clinical Research Activities. Postmarket surveillance studies and marketing studies are typically performed during the production phase. Postmarket surveillance studies are usually required by FDA in exchange for early introduction of a device. The studies are designed to assess the incidence of patient complications.
Marketing studies is a catch-all phrase referring to the many reasons for conducting clinical studies after device commercialization. Some of these reasons are to generate publicity about the device, to introduce the device into a hospital, to gain additional experience with a device, or to verify design changes subsequent to commercialization.
During the production phase the clinical research group also handles medical complaints, supports regulatory submissions, prepares publications and presentations, and assists with customer preference evaluations.
An outdated and unfortunate view of the clinical research department sees it merely as the company's watchdog—reviewing the work of others and passing judgment on its validity or value. A new, more productive view considers the department as a full stakeholder in the product development team. With its unique skill set and access to both medical professionals and human subjects, the clinical research department can bring opportunities for design testing and customer feedback that are vital to a successful product development effort.
|Clinical Development Plan—A grouping of one or more clinical trials that, taken together, substantiate the claims, intended use, and regulatory requirements of a device.
Pilot Study—Small-scale study often conducted in healthy human volunteers to aid in concept definition, especially for dermal-contact devices.
Human Safety Study—Study conducted in healthy human volunteers to assess irritation or sensitization potential of materials, especially for dermal-contact devices.
Feasibility Study—Small-scale study conducted in ill subjects to develop hypotheses, obtain data for sample-size calculations, or investigate other early development issues.
Manufacturing Study—Study conducted in ill subjects or with specimens to optimize formulations or investigate manufacturing processes.
Pivotal Study—Study conducted in ill subjects to determine safety, efficacy, or performance of a medical device. The study is given this name because the success or failure of a marketing application can depend on the outcome of the trial.
|Postmarket Surveillance Study—Study of all persons in whom a device is used after the device is commercialized, usually to investigate the occurrence of rare adverse events or complications. Data are reported as number of adverse events per number of devices used. Comparable to drug phase IV study.
Phase I Study—A drug term referring to safety studies in humans to determine maximum safe dose. Usually performed in healthy volunteers, with a typical sample size of ~30 subjects.
Phase II Study—A drug term referring to the first studies in ill humans to investigate safety and efficacy. Typical sample size is ~300 subjects.
Phase III Study—A drug term referring to studies in ill humans to verify efficacy. Typical sample size is ~1000 to 3000 subjects. Comparable to a pivotal study.
Phase IV Study—A drug term referring to a postmarket study.
1.NJ Stark, "Claims," Chap. 3 in Project Management for Clinical Trials (Chicago: Clinical Design Group, 1999), 47–62.
2.21 CFR, Part 812.1, "Investigational Device Exemptions, Scope."
3.61 FR: 52619–52620, October 7, 1996.
4.The names device companies use to describe these studies—pilot, safety, feasibility, manufacturing—vary widely and the actual name is unimportant. The studies are characterized by a small sample size and a specific objective where the data are used to guide subsequent product development decisions.
5.61 FR: 52618, October 7, 1996.
Nancy J. Stark is president of Clinical Design Group Inc., a Chicago-based contract research organization serving the device and diagnostics industry.
Copyright © 2001 Medical Device & Diagnostic Industry