THE LOGISTICS OF CONDUCTING CLINICAL STUDIES

Medical Device & Diagnostic Industry Magazine
MDDI Article Index

Frank L. Hurley and David L. West

Clinical studies are driven by details. From the selection of clinically significant end points to the analysis of the final patient data, sponsors of clinical trials are awash in a sea of details that must be handled accurately and properly if the overall investigational findings are to be sound. For this reason it is essential that trial sponsors pay close attention to logistics, which is the art of managing the details of such undertakings.

As discussed in a previous installment of this series, careful and thorough planning is the crucial first step in the successful conduct and completion of a clinical study. Such planning helps to identify the myriad details that will become part of the study, and enables the study sponsor to plan strategies for managing those details. In turn, planned management of such details--logistical planning--can enable trial sponsors to save considerable time, resources, and money.

Clinical studies are inherently expensive in terms of time, resources, and money. An inadequately planned study might be more quickly initiated and completed than a well-planned one, but the cost of that haste can be enormous--and not just in financial terms. It is important to remember that the most significant costs of all can be paid by the subjects enrolled in the study, from inconvenience and discomfort, to pain and even death. Keeping this in mind, it becomes evident that logistics are paramount when human lives and quality of life are at risk. Although a hastily planned study might cost many millions of dollars less than a well-planned, carefully executed, and meticulously documented study, that financial saving pales next to the possible human cost.

Clinical studies represent a major investment for product success. An adequate, well-controlled clinical study is essential to timely regulatory approval of a device and the advertising claims that may subsequently be made for it. In today's competitive economic climate, efficient, experienced management of a study is not an option--it is a necessity. The fundamental principles of adequate, well-controlled studies are universal and some are actually specified by regulation; they include:

Following these principles enhances proper management of the study and its population. It also increases the study's validity.

Although this article focuses on the logistics and management of studies for Class III devices, the points apply equally to studies in support of 510(k)s. Aspects of clinical studies that are unique to devices include the following:

In designing an investigational plan and clinical study, it is important to remember that regulatory reviewers rarely test the device itself. Rather, their review must be based on the sponsor's documentation of the design, validation, and preclinical and clinical testing of the device. Inadequate documentation, evidence, or details about how the device was designed and tested can significantly affect the ultimate quality of the premarket approval (PMA) submission and result in extensive delays of the PMA until the detailed information is provided. In fact, documentation can often make more of a difference in the speed of an investigational device's approval than the relative quality of the device itself.

This article addresses the logistics involved in the major aspects of a clinical investigation: sponsor obligations, investigator obligations, managing the subject population, study monitor obligations, and controlling costs.

In planning the logistics of a clinical study for an investigational device, the sponsor should maintain focus on its own ethical, scientific, and regulatory obligations. This allows the sponsor to balance these obligations against what might appear to be competing factors in the conduct of a clinical study: the ever-present constraints of time, money, and other resources.

Ethical and scientific obligations recognized in most industrialized countries are embodied in the Declaration of Helsinki, which has been discussed in the lead article of this series.¹ That article also described the Belmont Report which, together with the Declaration of Helsinki, has greatly influenced the codification of statutory and regulatory obligations for conducting clinical studies in the United States. The authors will not repeat here what has already been written about the Declaration of Helsinki or the Belmont Report, but it is instructive to highlight some of the fundamental issues that have become manifest in the regulations governing clinical studies for medical devices in the United States.

Patients as Subjects. Foremost among the sponsor's obligations is to recognize that each study subject is first and foremost a patient whose rights, safety, and welfare must always be ensured. Accordingly, a sponsor should have comprehensive knowledge of the technologies embodied in the device being studied and an appreciation of the factors affecting its safety and effectiveness. Before clinical studies are designed or initiated, the sponsor should assemble or generate information that defines, to whatever extent is practical, the device's performance characteristics. The sponsor should have sufficient knowledge of the device and the medical condition in which it is used to reasonably predict the nature and magnitude of risks posed by it as well as its expected clinical benefit. Risks that might be posed by a device must be minimized through its design, or safeguards must be incorporated into the study protocol.

The knowledge of the device's potential risks and anticipated benefits, together with a study protocol that is scientifically valid, must lead to the conclusion that the potential risks to study subjects are outweighed by the anticipated benefits to them or the importance of the knowledge to be gained from the study. To ensure that the benefits outweigh the risks, the study protocol must be followed in a disciplined and well-documented manner. Otherwise, safeguards incorporated into the protocol to protect study subjects might be subverted, leading to unwarranted risks. In addition, the validity of the study might be undermined, jeopardizing the accuracy of conclusions drawn from its data.

Informed Consent. All study subjects must be fully informed of the study's potential risks and benefits and must freely provide written consent before participating in the study. This requirement is essential to ensuring that the subjects' rights, safety, and welfare are protected. That the sponsor and investigators of any clinical study should recognize and take seriously their role in informed consent matters is underscored by the fact that there exists an entire body of regulations on the subject, namely Title 21 of the Code of Federal Regulations (CFR), part 50, Protection of Human Subjects (commonly referred to as the informed consent regulations). The Declaration of Helsinki also contains a provision requiring informed consent. A study sponsor has the obligation to understand FDA regulations and to follow them faithfully.

Adverse Effects. Among the sponsor's many other obligations is the reporting of adverse device effects. Regulations governing this are provided in 21 CFR 812.150(a)(1) and (b)(1). They state that the sponsor is obligated to review a report of a serious complication in order to determine if the event was "anticipated." Typically, anticipated adverse events are those identified in the protocol, and they are, to a certain extent, considered acceptable--in the sense that the benefit of the device outweighs the risk of the anticipated adverse event. An unanticipated adverse device effect must be evaluated by the sponsor to determine whether the event poses an unreasonable risk to other subjects. If so, the study must be terminated as soon as possible but in any event within 5 business days of that decision and within 15 business days of the sponsor's receipt of notification of the event from the site. An unanticipated adverse device effect must be reported to FDA, participating investigators, and all institutional review boards (IRBs) as soon as possible, but no later than 10 business days after the sponsor's receipt of notification of the event.

IRBs. Clinical studies for product approval always require approval of the protocol and relevant forms by the hospital's IRB or a regional IRB. Throughout the course of the study, regularly scheduled contact should be maintained, and documented communications should be provided to the IRB by the principal investigator. To ensure complete compliance with this aspect of study documentation, the study monitor must periodically review the documentation held in the investigator's files and records. If proper documentation is not present, the monitor must advise the sponsor of this fact. The sponsor should oversee the investigation to ensure that the IRB is properly informed by the investigator of such things as unanticipated adverse events and annual reports. Failure to track and ensure proper documentation and to communicate it to the IRB could result in the study's early termination or its being determined invalid or without scientific merit.

Oversight. Ultimately, the sponsor is responsible for all aspects of a clinical study. Although a sponsor may assign some of these responsibilities to other parties, it remains responsible for ensuring that these parties remain in strict compliance with the relevant regulations. Specific responsibilities of sponsors are provided in the investigational device exemption (IDE) regulations at 21 CFR 812, subpart C (812.40­812.46). These responsibilities include: selecting qualified investigators; providing the investigators with the information necessary to conduct the investigation properly; ensuring IRB review and approval of the study in accordance with the IRB regulations (21 CFR 56); submitting an IDE application to FDA and receiving approval (for significant-risk device studies); ensuring proper monitoring of the investigation; ensuring that the investigators obtain informed consent from subjects; ensuring that all reviewing IRBs and FDA are promptly informed of any significant new information concerning the investigation; and maintaining accountability of the device's distribution and return--the device may be shipped only to qualified investigators who are participating in the study. The operational logistics of conducting a study, discussed in detail below, should be planned with the sponsor's obligations clearly in focus and with constant attention to the safety of the study subjects.

The investigators' careful, thoughtful commitment to a study and attention to all aspects of fulfilling their obligations are of critical importance to a study's value and ultimate success. Therefore, the selection and oversight of the investigators are important considerations when designing and executing a clinical study. Ensuring that these obligations are properly met--that the investigators perform the expected and required tasks completely, accurately, and in a timely fashion--is the responsibility of the investigators, the clinical monitor, and, ultimately, the sponsor. Careful planning and consideration of the details--in other words, logistics--assist the investigators in fulfilling these obligations. For more specific information on investigator responsibilities see 21 CFR 812, subpart E.

Investigator Responsibilities. Each investigator's first responsibility is ensuring the safety of the subjects. Others typically include: following the protocol, which entails the complete, accurate, and timely reporting and recording of the necessary data regarding the investigational device; and following the specific procedures contained within the protocol. A prospective investigator's previous clinical research record should be carefully examined to verify his or her past commitment to these responsibilities.

By making a commitment to the sponsor, the investigator assumes the responsibility for ensuring proper conduct at the sites under his or her authority in compliance with the signed agreement, the investigational plan, the protocol, and applicable FDA or other governmental regulations. This responsibility includes: protection of the rights, safety, and welfare of subjects under the investigator's care; timely and accurate communications with and reporting to the IRB, sponsor, medical monitor, and FDA; accurate maintenance of records; and control of the device or devices under investigation. The investigator's responsibilities also include ensuring that signed informed consent is obtained in accordance with 21 CFR 50, subpart B before any study procedures are begun. Additionally, he or she is responsible for maintaining the records and reports specified under 21 CFR 812, subpart G.

An important aspect of an investigator's obligations is the requirement that he or she maintain appropriate and scheduled communication with the study sponsor, monitor, and applicable IRB. Again, skill at planning and attention to detail are important tools in complying with these requirements. Complete, accurate, and timely reports must be provided by the investigator according to governmental regulations 21 CFR 812.150(c)(1) through (7) at protocol-specific time periods. The investigator should establish an open, professional dialogue with the IRB and keep it informed of the study's progress as it develops. Failure to provide the required reports and other information to the IRB and the sponsor can jeopardize the entire investigation. Here the monitor and sponsor share responsibility since they both have the obligation to verify the investigator's fulfillment of these requirements. If an investigator is repeatedly noncompliant, his or her participation in the study should be terminated immediately.

Selecting an Investigator. An investigator's performance is of major importance to the successful execution and report of a clinical study. Should the investigator fail to fulfill his or her responsibilities, no amount of planning and details would establish the study's usefulness and validity. The first step in the selection process is to develop and carefully review the list of potential investigators. Many times this is easy because, in the device industry, manufacturers usually work closely with physicians and know those who are prominent in their field of study. From that information, a list is created of the recognized authorities in that particular specialty. However, if there are difficulties locating potential investigators, a variety of methods can be used, including: querying a company's investigator database, attending annual meetings and conferences in the relevant medical specialty, contacting acquaintances and associates in that specialty, and performing an on-line database search of the recent scientific literature in that field.

After identifying potential investigators, one must determine which candidates are most qualified and best suited to participate in the study. The study sponsor is responsible for selecting investigators "qualified by training and experience" to conduct a study investigating the device according to the protocol's specifications, the relevant governmental regulations, and the conditions detailed in the investigator agreement. Some other regulatory requirements include the responsibility of ensuring that each prospective investigator has read the agreement, understands all of his or her responsibilities, and conscientiously and sincerely agrees in writing to carry them out.

An investigator must not only be trained in his or her field, but should also have experience and knowledge about the type of device and its intended use in order to appropriately assess and properly record the measured or observed results. Familiarity with the types of procedures involved in the protocol minimizes the learning curve for compliant study execution and promotes efficiency and high-quality care of the study subjects. It is also important that an investigator understand the often complicated logistics involved in directing research at a clinical site within the constraints of the protocol and governmental regulations. He or she should be clearly familiar with the targeted study population and have easy access to a sufficient number of appropriate candidates for the study. Understanding what sort of clinical course is anticipated and being able to recognize clinical subtleties in a subject's status or treatment response is another valuable asset.

The patient population at the investigational site and their willingness and availability to participate in a study should be confirmed. Patient availability is often influenced by the willingness of the investigator and his or her staff to randomly assign patients to an alternative, unfamiliar, and experimental treatment. It is critical that the investigator and participating staff be completely neutral on this matter because bias either way can compromise the integrity of data from the investigational site. The investigator's amount of available time to execute and supervise his or her staff in the execution of the study's requirements must be closely and realistically examined and assessed. The qualifications and availability of the site's staff should be reviewed, with an understanding of the intended means of study implementation at that site.

Selection of a qualified investigator for a clinical study is a major factor in determining its successful conduct and outcome. Finding a pool of potential candidates and carefully examining their qualifications and attributes must be done with full awareness of the potentially disastrous, and at a minimum draining, consequences of an inadequate choice. Although there is a significant amount of redundancy in the regulations governing investigator, sponsor, and monitor responsibilities, the investigator has the primary obligation for conducting a study in the specified manner. This responsibility should be given to, and its fulfillment expected from, an investigator who is capable of handling the logistics of the study, one who is genuinely interested in and committed to the investigation. Therefore, it is essential that both the investigator and sponsor fully understand what is required and expected of them, and sincerely agree and commit to complete and timely execution of the study.

Fame Not Always the Best Fortune. It is widely accepted that one of the factors most likely to influence an investigational device's performance is the investigator's skill and experience. A sponsor wants a highly skilled, experienced investigator to ensure that there will be a minimum probability that an investigator's lack of skill will cause unnecessary failures of the device. However, renowned investigators, although skilled in both performance and promotion, frequently do not meet the previously specified criteria regarding commitment and availability. The eminent world figure often has so many other demands on his or her time and attention that he or she may not give sufficient attention to detail or an appropriately high priority to careful and thorough management of a study.

The best candidate for investigator of a clinical study is often a less highly acclaimed individual who, nonetheless, is seasoned and highly skilled. This type of investigator possesses high-quality surgical or clinical skills and, due to greater availability and commitment to a study, is able to oversee and conduct the research in a superior fashion. Such a typically skilled and experienced clinician in the relevant specialty also represents a more genuine test of the eventual clinical performance to be expected in a device's widespread use after approval. An investigator with these qualities typically pays more attention to a protocol's details and is generally more faithful to the protocol. In contrast, the preeminent figures in a specialty are tempted to make unilateral decisions that can lead to protocol violations.

Selection of study subjects must be a closely managed process to avoid unnecessary subject exposure to investigational products and study procedures, and to avoid collecting data that cannot be used because the subjects are not representative of the intended patient population. Thorough planning and careful consideration of proper inclusion and exclusion criteria at study start-up can avoid protocol violations. Requirements for subject age, disease duration and status, concomitant conditions that may or may not be included, concomitant medications that are or are not allowed, and so on, are the types of criteria that should be clearly specified in the protocol and adhered to by the investigators. Preparation of specific procedures to enhance selection of only those subjects with a high probability of protocol-compliant study completion is also valuable.

Easing the Burden on Study Subjects. Study subjects who must be excluded from analysis as protocol violators are costly from both a financial and a study resources perspective, but, more significantly, they may undermine the credibility of the study as adequate and well controlled. Additionally, given the expectations for 85% complete follow-up, sponsors must recognize that including a single subject who is unlikely to complete follow-up requires the addition of 10 more subjects who actually will complete the protocol. In order to increase the probability of subject completion, protocols should, within the constraints of the study's objectives, minimize the subject burden and length of follow-up as much as possible. When demonstration of a device's effectiveness requires burdensome procedures for the subject, consideration should be given to the possibility of multiple studies so that complex evaluations or requirements for randomization can be met first in small studies with greater support of subjects by study staff to compensate for the increased subject burden. Then larger, simple studies with less burden on subjects can be conducted to broaden the base of knowledge about the safety of the product or differential effects in population subgroups.

Some studies include a "run-in" evaluation period both to educate subjects about the protocol requirements and to evaluate their ability to comply with them. Telling subjects precisely what will be expected of them helps ensure that they will be committed to completing the study. Obviously the run-in must occur before exposure to the investigational device. The subjects' education and the investigator's evaluation of the subjects increase the likelihood that a subject will successfully complete the study according to the protocol. In addition, a study protocol should be defined to allow subjects to successfully complete it even though they do not complete the full follow-up period. For example, subjects who discontinue treatment due to an adverse event or lack of effectiveness should be defined as having reached a study end point and, therefore, should be considered as completed subjects for the protocol rather than as lost to follow-up.

Informed Consent. True informed consent includes not only consent to being exposed to the investigational device but also consent to the procedures and requirements of the study. A fully informed subject will understand his or her responsibilities vis-a-vis compliance with protocol-defined treatments or concurrent therapy and the follow-up visit schedule. Of course, any subject has the absolute right to drop out of any study for any reason at any time without prejudice to his or her ongoing health care. Nevertheless, an informed subject will be in a better position to fulfill the study contract and to comply with its protocol.

Some institutions and sponsors have used videos as part of the informed consent procedure to ensure standardized, consistent communication about the device as well as fulfillment of the requirements of the study protocol. The investigator, study coordinator, and other local institution representatives or subject advocates are available to elaborate on the basic information and to answer questions from potential subjects. Concern for the rights and well-being of the individual subjects is the most important principle underlying a well-controlled clinical study. There can be no faith in research if there is no confidence that it was conducted in an atmosphere of absolute protection of the individual subject's rights. This is a severe constraint on the logistics of managing clinical studies; however, anyone not willing to accommodate the logistical challenges caused by protection of subjects should not be involved in human research.

Control Groups. Although control groups are necessary for these types of studies, their use should be carefully calculated to minimum requirements (e.g., to demonstrate efficacy in a small, comparative study rather than in a large, controlled one). Scientifically, the most credible control group is a concurrent randomized control that is subject either to no treatment, to conservative therapy, or to alternative treatment.

The choice of a proper control is critical because it has a dramatic effect on the study's ultimate sample size. Often the subjects' condition requires a minimum of an active control; occasionally, the only ethical controls are historical ones. For example, studies involving prosthetic heart valves can be conducted using objective performance criteria (OPC) as the control data. These data are a metanalysis of the existing literature identifying adverse effects and their rate of occurrence. Using these data, a sponsor can evaluate heart valves, and FDA has indicated it will accept such data.

If conservative therapy or no treatment is used as a control, the subjects should be offered a safety net of active treatment after passage of the minimum time necessary to document for each subject that conservative therapy has not been effective (i.e., the subject is judged to be a treatment failure for protocol purposes and then switched or crossed over to active treatment as part of a follow-on protocol). Although some might consider conservative therapies equivalent to a placebo assignment, there are many instances in which they prove much more successful than anticipated. A good example is the surprising success of conservative therapy in clinical studies of nonhealing ulcers. The unexpected success of the control treatment resulted in a sample size being too small to demonstrate the statistical significance of the improvement associated with the use of the investigational device.

Minimizing Subject Risk. At each stage of investigation, there must be a constant effort to minimize the risk to the subjects. Thus, studies should be designed to expose a minimum number of subjects to the as-yet-not-quantified risks of investigational products as well as to the risks of protocol-mandated evaluation procedures. The research program should be designed to require complex or high-risk evaluation procedures in the minimum population subset necessary. In addition, the sponsor should consider the possibility of safety- or effectiveness-driven stopping rules for the clinical study. That is, predefined conditions or procedures should be established specifying under what conditions the study will be stopped early.