The Logistics of Conducting Clinical Studies (MDDI archive, May 96)

Medical Device & Diagnostic Industry Magazine
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CLINICAL TRIALS

THE LOGISTICS OF CONDUCTING CLINICAL STUDIES

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:

A clear statement of the study's objectives and plans for analysis.
A clinically and statistically appropriate control group.
A clear statement of the study's design and its required procedures.
Careful identification of the target patient population(s).
A method of treatment assignment that minimizes bias, stratifies the population as necessary, and minimizes the risk to study subjects to the extent possible.
A test product that is under strict change control.
Minimization of opportunities for bias during data-collection procedures.
A well-defined, reliable assessment of subject response.
Absolute data integrity.
Use of appropriate, predetermined statistical analyses.

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:

Device studies tend to involve relatively few subjects compared to drug studies, but each of the subjects might require more lengthy follow-up.
Devices are often used as part of a complex therapeutic procedure.
Many times the success of the procedure depends on factors other than the device, such as a surgeon's skill and the extent of the surgical procedure.
The more proficient the clinician, the better the results, because highly skilled clinicians perform procedures with greater competency and consistency. This performance tends to provide the sponsor with higher-quality data regarding the device's capabilities in the target population.

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.

SPONSOR OBLIGATIONS

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.

INVESTIGATOR OBLIGATIONS

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.

MANAGING THE STUDY POPULATION

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.

Chief among these conditions is a situation in which the study data demonstrate a safety problem with the investigational device or control. Similarly, if there is clear evidence of differential effectiveness of the device or the control, then the study could be stopped (although a decision for early termination based on findings of effectiveness favoring the investigational product should be taken very cautiously, since final analysis may modify preliminary conclusions and leave the sponsor with an inadequate sample size to support FDA approval). These stopping rules are best implemented in conjunction with an independent data and safety monitoring board, consisting of clinical specialists, an ethicist, and a biostatistician, none of whom has any other involvement in the study. As a practical matter, the long-term follow-up required to assess many medical devices limits the usefulness of stopping rules unless recruitment is a very slow process.

Experienced management of the study population and a commitment to the well-being of the study subjects are the keys to a successful clinical study. Inexperienced management can cost a fortune in time, money, and unwarranted risk to study subjects. The logistics involved in managing a study appear simple, yet they involve juggling a variety of concepts:

Managing the study-subject selection process closely.
Minimizing the subjects' burden as much as possible to increase likelihood of compliance.
Considering a run-in period to evaluate and inform potential study subjects in order to increase the odds of enrolling only those who will complete the study.
Ensuring that all subjects have provided true informed consent.
Using control groups carefully so that subjects are under a minimum burden and minimum risks.
Maintaining concern for the subjects' rights, safety, and well-being throughout the study.

Some of these concepts are in conflict, such as minimizing subject exposure to unnecessary procedures and investigational devices while ensuring enrollment and completion of enough subjects to guarantee adequate sample size; yet a balance must be found. Logistics in and of themselves provide assistance in obtaining that balance and bring economies to clinical studies; they are a tool that facilitates awareness and management of a study's myriad details.

STUDY MONITOR OBLIGATIONS

The overall goal of study monitoring is to ensure that the subjects' and investigators' experiences with the device and the study data are accurately captured and documented. Proper data collection leads to responsible decision making regarding the device's safety, effectiveness, and parameters of use. Accurate, well-documented data can also expedite the regulatory review process and enhance a product's approvability, thereby saving the sponsor time and money. An additional requirement of study monitoring is to ensure that the investigators' records include appropriate study documentation.

The study requirements are dictated by the protocol and its attachments: the report of prior investigation and case report forms (CRFs) including the adverse device effect reporting form. Monitoring efforts begin with monitor participation in the principal investigator selection process by conducting site qualification visits to ensure the adequacy of a site's facilities for dealing with a proposed study's demands and constraints. The monitor trains and informs the on-site staff as to the study's specific procedures and requirements. Such training increases the likelihood of compliance with the study's protocol and helps ensure both the safety of study subjects and the quality of the data. When preparing the on-site staff for the study, some of the logistical aspects focused on by the monitor include:

Procedures specific to the study.
The importance of adhering to product accountability procedures.
An explanation of the protocol and its requirements.
The need for signed informed consent forms prior to any procedures being conducted.
A full explanation of investigator and on-site staff obligations.

Monitoring Tasks. Throughout the course of a clinical study, certain monitoring tasks must be performed according to a schedule set forth in the protocol. Those typically performed on an ongoing basis include: review for deviations from the protocol; comparison of product accountability documentation against the inventory or device-use log; review of informed consent documents; comparison of completed CRFs against source documents for accuracy; check of subject source records for confirmation of subject eligibility; review of subject source records for complete adverse device effect reporting; resolution of data questions and errors; and review of study documentation for adequacy and completeness.

After every clinical monitoring visit during the conduct of a study, a report of that visit is written and all findings are documented. These reports are sent to a senior member of the project team for review and to the sponsor. Often, they are sent to the investigator as well. Noncompliance with the protocol that is not immediately addressed and corrected by the site can require termination of the investigator's participation in the study and the prompt return of all unused devices. If an investigator is removed from participation in a study, he or she receives no more devices, but must still complete subject follow-up. The regulations discussing this situation are in 21 CFR 812.46.

Monitoring Frequency. The frequency of monitoring visits suggested by FDA is a minimum of one visit per site per year. Frequency of monitoring visits may also be specified in the protocol or the investigational plan included in the IDE application. In actual practice, monitoring frequency is determined by a number of factors, such as subject volume at the site, the frequency of subject visits, the complexity of the protocol, and the type of device.

Although an initial schedule of monitoring visits may be established, site problems or confusion can cause it to be adjusted. Several events can warn a sponsor that there are difficulties at a site. Sometimes this warning becomes evident in phone calls that indicate on-site-staff confusion; other times indicators can be late receipt of CRFs, poorly completed CRFs, or enrollment of ineligible subjects. For a site with rapid enrollment of subjects and weekly visits by them, monitoring visits can be as frequent as every four to six weeks. Assurance that procedures are being followed and that the subjects' well-being remains the study's top priority requires significant logistical skill. More frequent or more complex procedures require greater vigilance and attention to details.

Case Report Forms. Data management has three main goals, all of which include completeness and accuracy. They are (1) that the database reflects subject experience as reported on the CRFs received, (2) that data discrepancies are identified and resolved so there is consistency between the subjects' experiences and the CRFs received, and (3) that there is documentation for each data point so that its source is clearly the clinical site. Each data point is subject to review by FDA and must be traceable to records at the site. The monitor's inspection of practices, procedures, and documentation plays an important role in ensuring that the database consists of accurately collected and reported data, and that thorough documentation is available for each subject's data.

Once the CRFs are completed, they should be sent to the sponsor and entered into the database as quickly as possible. When this is done, other aspects of the study benefit from access to these data, such as the generation of study management reports and support of the monitoring process by quick identification of data errors. These data errors are identified by computer review of the data file, which results in a computer-generated report. Monitors can use such reports to resolve site-specific questions by comparing them with subject charts and hard-copy documentation of data changes.

Data questions must be thoroughly resolved with full documentation of how the resolution was effected, including original value, corrected value, date of change, person authorizing the change, and reason for the change. All changes must be documented in hard copy; an electronic audit trail is not required, but assists greatly in an FDA inspection (e.g., facilitates the location of a correction) and may well be required when electronic PMAs become mandatory (consistent with the current requirement for electronic new drug applications [NDAs] and computer-assisted new drug applications [CANDAs]). Any changes on hard-copy CRFs, either by site staff or by sponsor staff based on documentation from the sites, should be made by crossing out the incorrect value (while leaving it legible), entering the correct value, and dating and initialing the change. White-out correction fluid should never be used since it obscures the original entry and may give the impression that something is being covered up.

Protocol Alterations. Any protocol can require changes or supplements during the course of a clinical study, and almost any aspect of a protocol may need modification. Specific procedures are followed when a protocol is altered in order to ensure subjects' safety and to protect study validity. Modifying a protocol is a fairly straightforward, although tightly regulated procedure. First, the required change is determined by consulting with clinical specialists. Once the appropriate change is agreed upon, the protocol change is submitted to FDA in an IDE supplement. If the proposed change affects the rights, safety, or welfare of study subjects (e.g., adding invasive procedures, adding visits to the doctor, drawing additional blood samples), the sponsor must await FDA and IRB approval before it can be implemented.

Alteration of a protocol informs the IRB and FDA that events have not transpired quite as anticipated; it also provides an opportunity to review pertinent safety and clinical utility issues. An IDE supplement states the requested change and the reason for it. Three instances in which protocols must be modified are:

Poor study enrollment as a result of overly restrictive eligibility requirements.
Imprecise definition of protocol or procedure requirements, resulting in poor compliance with CRF completion.
Improper capture of critical end point data due to improper CRF content design.

When poor study enrollment occurs as a result of eligibility requirements that are too restrictive, a single criterion can usually be identified as the problem. If that occurs, identification of the target population and claims that focus on that criterion can be discussed to determine if the criterion can be relaxed. Poor definition of requirements can lead to a study that does not answer the relevant questions. This type of problem must be identified as early as possible through monitoring or data review. Once identified, it must be corrected immediately.

Possible Study Complications. The protocol should also explicitly define any complications that may occur during the study. The investigational plan or the report of prior investigations in the IDE should define all anticipated adverse device effects (e.g., events that the subject is at risk of experiencing as a result of the condition being treated regardless of treatment, use of the device, surgical complications, etc.). They should be summarized and sent to FDA in periodic reports.

Thorough, careful monitoring is essential to the logistics of a clinical study. The complex web of intersecting obligations and required communication must be anticipated and prepared for. Applying logistics to the monitor's obligations allows early identification of enrollment difficulties, thus saving time, effort, and money. Improper procedures and documentation can be detected early in the study, thereby allowing for quick responses to any potential threat to the study's subjects, saving the sponsor time and money, and sparing the subjects possible risk. Unanticipated adverse device effects can be recognized and dealt with more quickly, thus protecting the subjects and preventing the sponsor from spending unnecessary time and money on a product. The monitor acts as an early warning system of potential problems with data collection and documentation, and provides further protection of the study subjects.

CONTROLLING COSTS

The cost of a clinical study is a significant part of the total cost of bringing a device to market. Only a manufacturer with resources adequate to support such a long-term project should embark on this expensive endeavor. The most important thing to remember about controlling the costs of a clinical study is to do everything right the first time, since such costs increase manyfold if problems are not found until it is time to submit the results to FDA. Nevertheless, there are ways to do everything right and minimize costs in each phase of a clinical study: planning, implementation, monitoring, data management, and data analysis. Logistics are the key to cost control.

Planning. Planning is intended to identify the relevant details. Focus on one goal at a time, and design the study to meet it. Everyone involved in a clinical trial wants to get as much out of it as possible: marketing approval in the United States, marketing approval in Europe and Japan, experience and acceptance by the premier physicians, marketing strategies, and cost-effectiveness data to support third-party reimbursement. However, trying to design and carry out studies to meet all of these goals at once may be unrealistic or impossible and can result in costly delays.

Another way to save money at the planning stage of a clinical study is to involve FDA reviewers in the process as early as possible. PreIDEsubmission meetings provide an opportunity to obtain guidance from FDA staff and to learn their concerns in advance of the study's final design. This should speed up the IDE review process, and, if the device manufacturer can keep FDA involved, the marketing approval process. However, the manufacturer that requests guidance from FDA must be prepared to accept it. If it is not so prepared, it should just submit its application, wait for the response, and negotiate with FDA if it is dissatisfied with the agency response.

Implementation. If the sponsor's goal is to complete the study as soon as possible, then it is important to choose clinical investigators who have the time, resources, interest, and subject population to meet its needs. It is also important to choose investigators who have the experience necessary to place the clinical benefit of the device into perspective relevant to other new and existing alternative medical technologies. As discussed earlier, those experts with the biggest reputations and the most publications may also be studying many other devices. This could result in a sponsor's sharing subject populations with its competitors, which could slow down the rate of the study's subject accrual, or else in the study's being tainted because the investigator decides to use more than one investigational device on a study subject.

Another point to consider is the number of sites to include in the clinical study, especially one that requires long-term follow-up. A sponsor should choose enough sites so that if one or two of them drop out, it still has enough to satisfy its needs. However, a sponsor should not take on more sites than it can reasonably manage (and monitor), or it may find itself with a study that is very successful in clinical terms but has inadequate documentation for regulatory approval.

Monitoring. Adequate monitoring of a clinical investigation is expensive, but the cost of inadequate monitoring is astronomical. Documentation showing the following is absolutely essential:

Only those subjects who met the enrollment criteria were accepted.
All candidates who met the enrollment criteria were accepted
as subjects.
Signed informed consent was obtained from all subjects.
IRB approval and FDA approval were obtained.
There were no undocumented deviations from the protocol.
All data were accurately and completely reported and recorded.

Despite the universal applicability of these requirements to all studies, one may realize significant savings by adapting the procedures for obtaining this documentation to the specific study. Without disregarding the regulations and other requirements, customizing procedures can significantly decrease the expense of a clinical study and the time period in which it will be completed.

Data Management. Documentation and verification of data accuracy are the keys to successful data management. Being able to document when data were entered, checked, and revised is necessary. Communication between data management and monitoring personnel is critical to a study. However, as with monitoring, one may be able to save or reduce costs significantly by adapting the procedures for data documentation and verification to the specific study. For large studies, automated and verified data management software may be the least expensive way to accomplish these goals. On the other hand, for feasibility studies or other small clinical investigations, especially those for which the subject accrual rate is low, it may be much more cost-effective to accomplish these goals by less sophisticated procedures.

Data Analysis. It is important to analyze and present data in a manner that is consistent with the overall strategy of the clinical trial. This seems obvious, but it is not uncommon to see a manufacturer react to something that was discovered in the clinical study and to analyze and present the unanticipated data in a new way without addressing why they are not consistent with the original strategy, or without presenting a new strategy. The analysis and presentation should be direct, simple, and complete (i.e., don't evade the difficult issues; it is generally best to address them directly). It is commonplace to see a manufacturer try to broaden the indications for the device, even though the data supporting some of the broader indications are weak. This can be successful, but more often than not the application becomes as weak as the weakest argument, and the manufacturer may lose time in the approval process by not making the strongest case and limiting the request for approval to that case. Remember, one can always supplement an approved marketing application for additional indications, but only if there is an approved application already in existence to supplement. Veering from the direct and simple approach may cost much in reanalysis, resubmissions, and time. Time is very expensive, whereas the actual cost of any additional analysis or submission, while expensive, is usually small in comparison to the cost of lost sales (for existing manufacturers) or, for new ones, of maintaining the company while the analysis is being performed or the additional submission is being prepared.

There are minimum costs associated with clinical studies of medical devices. These costs are associated with meeting FDA requirements and documenting compliance with them. However, one can minimize the costs associated with planning, implementing, and monitoring the study, with managing and analyzing the data, and with presenting the results. This is accomplished via logistics based on a thorough strategic plan. Logistics enable one to tailor the process for each of these tasks to the specific purpose of the study, its size and duration, and the accrual rate of the subjects.

CONCLUSION

Clinical studies are about details--veritable mountains of details--all of which are crucial, and all of which must be observed. In order to conduct a clinical study in the necessarily conscientious and meticulous manner, there must be planning, attention to detail, proper documentation, and close management--in other words, logistics.

In order to make proper use of logistics, there must be a certain foundation. The main components of that foundation are knowledge, commitment, accuracy, and documentation. Knowledge of ethical, scientific, and regulatory obligations provides a framework for logistics. Commitment to these obligations and principles helps ensure responsible study management and protection of study subjects. Accuracy and documentation come from knowledge and commitment. All these facets of a clinical study are combined in one unit. Logistics allow clinical researchers to explore and map the multifaceted nature of a clinical study, gaining new insight without losing sight of their responsibility to the study subjects and those who will ultimately benefit from these labors, the patients.

Frank L. Hurley is chairman and chief scientific officer at BRI International (Arlington, VA), and David L. West is senior technical adviser at Medical Technology Consultants, BRI International (Rockville, MD).

REFERENCE

1. Mohan K, and Sargent HE, "Clinical Trials, An Introduction," Med Dev Diag Indust, 18(1):114119, 1996.

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