Medical Device Link.

Originally Published MX September/October 2003

BUSINESS PLANNING & TECHNOLOGY DEVELOPMENT

An early-stage company can save time and money if it develops a suitable program.

Cynthia Fink and Beth Silverstein

Managers of medical device firms must realize that having an effective clinical research program in place from the beginning is vital. Executives of early-stage medical technology companies know that investors concentrate on funding later-stage companies with viable products to offer. However, small medtech companies in a hurry to meet milestones imposed by investors, or under other business pressures, all too often rush to get a device into clinical study without fully understanding what data are needed for marketing approval. As a result, time to market may be extended as the company revises clinical study protocols, adds investigational sites, considers adding new research end points, increases the sample size, performs more statistical analyses, or undertakes further studies.

To develop a complete clinical research program can be a daunting prospect for an early-stage medical product company of limited staff and resources. A medtech clinical research program typically involves the personnel, procedures, and technology necessary to manage studies in humans, including both pilot studies to investigate the technology and pivotal studies to evaluate product safety and effectiveness. Common program activities include the design and management of clinical studies, enrollment of study subjects, management of clinical investigators, study monitoring, maintenance of regulatory documentation, and data management and analysis. 

Medical device manufacturers often have fewer products to research clinically than pharmaceutical manufacturers, and those products generally require smaller quantities of clinical data (fewer studies or fewer patients participating in them) in order to obtain approval to market. Still, the basic procedures for clinical study of any regulated healthcare product are universal and must be conducted in compliance with good clinical practices (GCPs) and ethical standards.

A small medtech company needs to develop and implement a clinical research program that smartly and efficiently carries new products into the last stages of development and to market. Company leaders can employ several strategies to maximize the success of such a program. Regardless of the nature of the company or its products, they will:

• Take time to determine the current need for and expectations from any clinical studies.
• Be realistic about their ability to implement and manage necessary clinical data–related activities.
• Know when to seek help and from whom to get it.
• Maximize existing company resources.
• Think ahead to potential future clinical study needs.

Some points for consideration discussed in this article are obvious, but they are worth mentioning because they are so commonly overlooked. A few pertain to the early stages of a clinical research program, while others are applicable to the overall enterprise. All share the common themes of planning ahead, keeping expectations realistic, and communicating frequently and effectively.

Program Start-Up

Important first steps for executives developing a company’s clinical research program are to establish clearly how the program serves business goals and to lay out program expectations in terms of short- and long-term goals. In addition, they should settle on the objectives and goals of the clinical effort and outline the steps necessary to move product development forward expeditiously.

Business Goals and Program Expectations. Many early-stage medtech companies operate with the goal of advancing a new product’s development enough to attract the interest of another company in purchasing or in-licensing the product or in acquiring the company itself. In such cases, a comprehensive, in-house clinical research capability probably does not need to be developed. However, if the company intends to market the product, or to seek additional indications for a product, management must develop a functional area within the organization to oversee all clinical study efforts.

Without an understanding of the company’s business goals, appropriate expectations for the clinical research program cannot be conceived. Senior corporate managers should decide early on what type of infrastructure will be needed to support the company’s clinical study activities, if any. Among the factors they should consider are the company’s plans for staff growth, the number and skills of personnel, the number of products under development and to be developed, and possible expansion of core competencies. A vision of the product pipeline over the next several years is imperative. Once the company’s future direction is clearly established and understood by all, corporate executives will be ready to develop a clinical program customized to meet the unique demands of the organization (see sidebar, page 35).

The volume of products in development and related data to be managed will determine clinical trial procedural requirements, the number of program personnel, and the amount of technical support needed to maintain the study procedures. Too often, small companies underestimate the level of effort involved in managing a clinical study. Staff and technological resources are consequently overtaxed, resulting in delay in completing a clinical study. This can be true even when contract research organizations (CROs) are used to carry out studies, or some aspects of them; the effort required to effectively manage contractors can just as easily be underestimated.

Also helpful is an early appreciation of the intended outcome of the clinical effort with respect to product marketing. Senior regulatory and clinical study managers, in setting up the research program, should take into account:

• Desired label claims for the 
product, including indications.
• Uses of clinical study data to support U.S. and multinational marketing approval submissions.
• Potential benefit of the device in different patient populations.
• The potential need for bridging or comparability data to fulfill regulatory requirements.
• The potential need for postmarket clinical studies.

Marketing designs, along with the clinical study steps needed to support them, will affect research program resource requirements.

Company Capabilities. Small medtech companies often try to do it all themselves in order to keep expenses in check. But the small medical device company that has adequate in-house clinical research capabilities in terms of experience or manpower is rare. Staff members are likely to be called upon to oversee clinical research efforts in areas that are beyond their expertise. For example, a regulatory affairs professional may be asked to design a clinical protocol or an information technology manager may be asked to design a clinical data management database. Not surprisingly, such job stretching can result in costly and time-consuming mistakes.

Clinical study design, management, and analysis are specialized fields requiring their practitioners to understand and implement GCPs. Individuals involved in clinical studies must also be familiar with the ever-changing guidance surrounding electronic records and electronic signatures. Senior corporate managers need to recognize that submitting high-quality study data to a regulatory agency maximizes the likelihood of marketing approval, and must therefore make appropriate adjustments in staffing and resources.

Outsourcing

Once the clinical management team has assessed the company’s clinical capabilities, its next task is to determine what outside assistance may be needed and what form that assistance should take. The clinical program may encompass design of the clinical protocol; identification of investigators; study management; collection, management, and analysis of the data; and preparation of the clinical study report in a form appropriate for regulatory submission. Many types of vendor companies provide a broad spectrum of services to support clinical research programs. These include CROs, regulatory consulting firms, statistical support firms, data management companies, and providers of study supply replenishment, distribution, and packaging. The management team should consider whether the company requires assistance managing some or all of the functions involved in a study (see sidebar).

Clinical study managers need to be realistic about the company’s clinical trial requirements and whether the company can meet them in a timely fashion with existing staff, expertise, and infrastructure. Among the issues to consider is the company culture and how it drives timelines, priorities, and data management requirements. Program leaders should also take into account CRO responsiveness, the manner in which clinical data will be collected, the potential volume and flow of data for all clinical development projects, and the qualified technical and managerial resources available in-house, not to mention general corporate economic drivers.

It is crucial that support services be used wisely. Just as with in-house staff, outsourced companies must have expertise sufficient to the job. If the medtech company is relying on a statistician to design a clinical study, that consultant should demonstrate proficiency in accommodating the regulatory and GCP requirements pertinent to the product under development. Corporate managers should hire consultants in different areas of expertise who can work with the company effectively in developing a clinical study approach that ensures that study objectives are realized. Cost savings can be achieved when experienced contractors handle certain necessary tasks while the company concentrates its own resources on other aspects of the clinical research program.

Even if the medtech company intends ultimately to establish a department to handle many aspects of clinical trial management, outsourcing may be necessary at the beginning or at key transitional points in its growth history. Using contract services can also be a good way to determine which aspects of clinical trial management should become core competencies of the company and which may remain as contracted services as the company grows. The key to success with outsourcing is to establish in-house personnel who can carefully prequalify outsourced companies and manage relationships with outside service providers during the course of the clinical program.

Program Coordination

Clinical, regulatory, and business activities relating to clinical studies should be linked through coordinated plans. Just as it is critical that a clinical program be designed in the context of the company’s particular business considerations, the program cannot be well designed without planning for the effect of regulatory review on the process.

Determining the Study Size. One key factor affecting the cost and duration of a clinical study, for example, is the number of study subjects, which is typically determined statistically and depends upon the hypothesis to be tested. Regulatory professionals can review the regulatory history of similar devices to obtain information on study sample size. Regulatory executives should then determine whether the marketing of a sufficiently similar device was approved recently by the regulatory agency and, if so, take note of the nature of the clinical data provided in support of the submission, the number of patients included in the clinical study, and the identifiable end points. Subsequently, they should look for the most efficient way to generate and provide data that will adequately support claims of product safety and effectiveness in the eyes of the regulators.

Keeping Long-Term Objectives in Mind. Creative business strategies can promote clinical research program goals. For example, some U.S. companies find it prudent to set up a clinical study in another country where costs may be lower. Another strategy is to examine the safety and effectiveness of the device for an alternative indication with relatively low costs of patient follow-up first, and then conduct a study for the primary indication. 

It is not uncommon for medical device companies to market products initially outside of the United States, in countries with less-stringent regulatory and clinical requirements, before seeking domestic market approval. Before deciding to conduct clinical trials abroad, however, company executives have to consider whether the study data will ultimately be used to support a U.S. regulatory submission. If so, it is imperative that the data be collected following GCP guidelines, that the patient population be comparable to the proposed target U.S. patient group, and that the clinical practice and medical care characteristic of the trial be comparable to that available in the United States. Time and money will be wasted if the data obtained for an overseas submission cannot be used to help bring the product to the U.S. market.

Figure 1. A typical example of a clinical study project plan in the form of a Gantt chart, showing the general activities to be completed by in-house or outsourced personnel. The ID number identifies the item by its line in the full chart of general and specific scheduled tasks (Click to enlarge).

In order to avoid funding a clinical study that may not support U.S. regulatory approval, clinical research program managers must ensure that the clinical development plan for the device incorporates the objectives, milestones, and assumptions identified in the regulatory and business plans for it, and also must obtain FDA concurrence that the regulatory plan is appropriate. To do this, they must decide where the product is likely going to be marketed at first and over the long term, and what other indications or patient populations will be investigated in the future. They also should consider the need for pilot studies and their intended purpose.

Using a Project Plan. Some small companies take a seat-of-the-pants approach to clinical research project management and do not prepare a formal project plan. However, the best way to ensure that the clinical effort progresses smoothly is to develop a written clinical study project plan that details the activities necessary to complete the study. This would preferably take the form of a Gantt chart or detailed task list that itemizes activities and the dates or time periods for which they are scheduled (see Figures 1 and 2). Contributions made by outside companies such as contract service providers or project partners should, of course, be included.

Senior company leaders should designate a project manager who will be responsible for its execution. Although this manager’s job will be to keep the project on course, any strategy will require frequent reevaluations, and sometimes redirection. Recognizing that, executives should set realistic goals. They should issue clear and detailed expectations based on reasonable assumptions, timelines, and projections; for example, likely FDA review times should be incorporated into the timeline. Continual revisitation of the clinical study project plan enables necessary reevaluation and redirection to be anticipated and stakeholders to be provided with periodic updates of project progress.

FDA Can Help

Early consultation with regulators regarding the design and expected outcome of a clinical trial is a wise investment of time and resources. FDA’s Center for Devices and Radiological Health (CDRH), for example, endeavors to assist small medtech companies inexperienced in the regulatory process by providing on-line services and a willingness to answer questions as they arise.¹

Presubmission meetings with FDA help to define the type and extent of clinical data required and to ensure that FDA concerns are addressed.² A company can come away from such a meeting with a better understanding of the agency’s expectations regarding the scope and size of studies necessary to demonstrate safety and effectiveness, as well as with some useful level of up-front agreement on a study design that enhances the likelihood of eventual FDA approval. Key to avoiding any surprises later on is to include both agency statisticians and project clinicians in these communications. The interactions enable the company to establish a rapport with key FDA personnel while obtaining valuable guidance on the direction of the clinical program.

Figure 2. A detailed breakout of the project plan sections in the example (Figure 1) that are concerned with performing the pivotal study (Click to enlarge).

As the scope and design of the pivotal clinical trial are being planned, company regulatory professionals should consult readily available sources of information and assistance, such as FDA guidance documents applicable to the type of device under study or the disease it treats (see sidebar). The suggestions regarding clinical data outlined in these agency documents are represented as guidance rather than requirements, but FDA reviewers tend to rely upon them. A clinical trial sponsor failing to take them seriously or trying to circumvent them may only be delaying the product’s approval. In this matter, decision makers should avoid being penny-wise and pound-foolish.

Examination of the regulatory and clinical trials approaches used by companies that have already had similar products approved can be valuable, as noted previously. The summary of safety and effectiveness (SSE) or the 510(k) summary for related approved products may provide insight into viable study designs and serve to guide the selection, measurement, and analysis of clinical end points. They certainly provide examples of clinical trial strategies that were successful in supporting product approval (though past approvals are no guarantee of success in a present case). Such documents are often readily available on the CDRH Web site (see aforementioned sidebar).

In addition, it is prudent to search the published scientific literature for articles describing clinical studies of similar products that may have been used to support regulatory approval. Such articles often provide information not available in the SSE, such as the study objective, sample size determination, measurement of end points, and secondary end points.

Another valuable source of information and guidance is the pool of healthcare practitioners who are familiar with the therapeutic area for which the product is intended and with clinical research practices. These medical experts can provide useful advice regarding clinical trial protocols, particularly if they have participated in clinical studies of related products. They also may be available to act as principal investigators when the clinical program reaches that stage.

The Well-Run Clinical Study

The ultimate goal of a clinical research program is to foster clinical studies that will provide the most objective and efficient evaluation of the safety and effectiveness of the medical devices for their application claims. But within the enormously challenging enterprise of developing safe, effective medical technology, company leaders can underestimate the logistics and resources necessary for carrying out the clinical trial successfully.

Maximizing Data Value. A well-designed pivotal-trial protocol exhibits a delicate balance: it involves as simple a process as possible that is yet able to generate data sufficient to prove that the product is safe and effective and therefore meets all regulatory requirements. The study hypotheses and corresponding end points should directly support the proposed intended use of the product, and outcome measures should be objective, easily quantifiable, and easily obtained. 

Outcome determinants should, whenever possible, be validated clinical end points rather than surrogate measures. Clinical program managers can look to principal investigators, regulatory guidance documents, summaries of similar device approvals, and relevant scientific literature to obtain assistance. By applying organizational principles gleaned from the designs of other clinical studies that were regulatory successes, they can save considerable time and resources on their own projects.

A pilot, or feasibility, study can be extremely valuable as a tool to help design a well-targeted pivotal study that is very likely to be successful. The pilot study is a dry run to illuminate and resolve many scientific, clinical, and logistical issues that will be faced during the pivotal clinical trial. It is a device for working out the timing of protocol-driven clinical testing and other events. A pilot study can make possible more-accurate determinations of the appropriate sample size, patient population, and scope of the pivotal study by providing data to support these decisions. Information acquired through a pilot program elevates clinical managers above reliance on educated guesswork and comparative study of the scientific literature.

Minimizing Study Complexity. The principle of parsimony should be applied to the study protocol. Limiting data collection to only that information necessary to demonstrate the safety and effectiveness of the product minimizes costs and can streamline the approval process. The proposed product label claim will dictate the study end points. While it may also be prudent to include data to support the acquisition of insurance reimbursement codes and to support marketing efforts, the protocol should not be cluttered with too many objectives. The pivotal trial should not be turned into an academic research study because, if for no other reason, ethics oblige the sponsor to analyze all trial data obtained. Nothing will slow enrollment more quickly than a protocol that is logistically difficult to carry out or involves tricky data collection.

Communicating with Investigational Sites. Maintenance of good relationships with qualified, experienced clinical study sites, and specifically with the principal investigators and research coordinators, is essential for a smoothly run, successful pivotal trial. Effective communication allows the company to identify problems early and make corrections in midstream. For example, executives from the trial sponsor should arrange periodic meetings or teleconferences with representatives of all the clinical sites in order to facilitate sharing of ideas and insights that can optimize the quality of data collected at every site over the course of the study. This will enable any problems to be caught and corrected early and prevent the collection of data that are inconsistent, not usable, or acquired in a way different from that intended.

For all practical purposes, the quality of the data generated at the sites is only as good as the research coordinators; consequently, their importance to study success should not be underestimated. Executives of the device manufacturing company should regard the research coordinators’ attitudes and input as important indicators of how well patient recruitment and data collection are progressing. These project linchpins are intimately familiar with the kinds of issues that inevitably arise with every new study protocol and can be a resource for solving problems that emerge along the way.

Keeping on Track. The clinical study has been well planned and has gotten under way; the next requirement of the clinical research program is that it ensure the study meets the company’s scientific, business, and regulatory objectives and is consistent with its product development plan.

Regardless of the extent of its active participation in the clinical study process, it is crucial that the small medtech company identify an in-house staff member to maintain vigilant regular communication with both internal staff and external contractors contributing to the clinical research effort. Unless authority is formally transferred, the manufacturer is the sponsor of the clinical study. Its leaders are responsible for meeting regulatory requirements—and to investors for ensuring that the clinical effort under way will support the company’s business strategy.

Conclusion

The clinical research program should contribute to the achievement of company goals for moving products through development and obtaining market approvals. A critical mistake a growing early-stage medical device company can make is to rush its clinical development program so as to compromise the quality and utility of the data obtained. The best way for responsible managers to ensure that that doesn’t happen is to recognize and then maximize the company’s existing clinical strengths in a systematic fashion. 

References

1. Small Business Guide to FDA, [on-line] (Rockville, MD: FDA, Office of Regulatory Affairs, 2001 [cited 4 July 2003]); available from Internet: http://www.fda.gov/ora/fed_state/Small_ Business/sb_guide/default.htm.   
2. Early Collaboration Meetings Under the FDA Modernization Act (FDAMA); Final Guidance for Industry and for CDRH Staff, [on-line] (Rockville, MD: FDA, Center for Devices and Radiological Health, 2001 [cited 4 July 2003]); available from Internet: http://www.fda.gov/cdrh/ ode/guidance/310.pdf. 

Cynthia Fink is managing consultant and Beth Silverstein is director at SciLucent LLC (Herndon, VA).

Copyright ©2003 MX