Originally Published MDDI November 2002

FIRST PERSON

Steven W. Mayo, founder and CEO of the Austin, Texas–based contract research organization Emissary Inc., explains how device companies can make clinical trials an asset rather than a liability.

Unlike the pharmaceutical industry, which has long been dominated by global giants, the medical device industry is characterized by a large share of small, privately funded companies. Because Congress and FDA recognized this fact when devising the 1976 amendments to the FD&C Act, the regulatory burdens imposed on these companies have been comparatively manageable.

Since the passage of the amendments, however, regulatory, societal, and macroeconomic changes have helped put medical device clinical research under a microscope. Developing and launching a new medical device has become much harder over the last quarter-century, and it's not going to get any easier.

Now more than ever, the medical device industry is the target of ever increasing FDA and public scrutiny. So far, most of the media attention has centered on postapproval activities such as manufacturing changes, quality control, and medical device reporting requirements, but clinical research is under scrutiny as well. A complex process like medical research makes fertile ground for all kinds of so-called investigative news reports. For instance, a recent three-part exposé about implantable devices published in Newhouse newspapers around the nation began with the statement that 98% of the medical devices cleared by FDA last year did not undergo clinical testing. Of course, the authors didn't mention that this figure included all FDA-regulated devices, including Class I devices like rubber gloves and scalpels. The reader was left to infer inaccurately that most high-risk devices had not been tested.

In an era of ever increasing scrutiny, manufacturers would do well to examine their current practices in conducting clinical trials. A good place to start would be the following five common pitfalls I have seen during my two decades of involvement in clinical research. Taking action to avoid these mistakes can help ensure that a company is ready for this increased scrutiny.

PITFALL #1: BLURRING LINES BETWEEN SALES AND RESEARCH

Given their knowledge of the capabilities and patient populations of their current and potential customers, it makes sense for the field sales force to help find potential clinical research sites. However, its involvement should generally not extend to contacting, qualifying, and selecting clinical investigators.

Proper selection of clinical investigators is perhaps the single most important factor in the success of a clinical trial. Therefore, the goal of the clinical research associate, or CRA, is to choose investigators with the necessary experience for the trial, a sufficiently large target patient population, and a commitment and motivation to steadily and rapidly enroll patients in the study. Finding the right investigators is a delicate balancing act requiring specialized knowledge, years of experience, and a pinch of intuition.

The CRA seeks to build a level of enthusiasm and perhaps even a spirit of competitiveness among the contenders, so that the physicians will be eager to participate in the study. At the same time, a CRA must play hardball. If potential investigators are slow to respond, are often unavailable, or don't have the required facility, staff, equipment, or patient population, they should be dropped from consideration.

Certainly, it may be desirable in a multicenter trial to keep a few key physicians who don't meet these standards, perhaps because of the prestige of the institution or the physician's experience in that particular therapeutic area. But this decision must be made with the knowledge that patient recruitment, ease of data collection, and even data quality could be adversely affected.

By contrast with a CRA, a sales associate may have difficulty making such decisions objectively. A salesperson's goal, after all, is to generate current or future sales of the product. By definition, this creates an immediate conflict of interest. Given that it is a violation of FDA regulations to market an investigational medical product, it is critical to maintain a clean separation between informing physicians about a potential clinical trial and actually selling them on the product.

The promise of participation in a clinical trial is too often used in the medical device industry as a sales inducement to a key account, or even just as a way to get more face time with a hard-to-reach prescriber. In such cases, the outcome is rarely good. If the physician is not selected, the sales associate may well be discredited. Worse yet, if the site is not appropriate, the trial may be jeopardized.

Participating as a clinical investigator requires a lot of time and effort, and study budgets generally do not compensate the investigator commensurate with this level of effort. A good CRA will spend many hours ensuring that the potential investigator understands the significant commitment he or she is making, and will discuss with all the support staff their respective roles as well. Typically, a sales associate lacks knowledge of all the regulatory and contractual requirements of a study, and rarely knows much about protocol and data requirements. What happens if, after being encouraged to participate in the trial by an eager yet uninformed sales associate, some important customers discover that the trial isn't as rewarding as they expected?

The lesson: Don't allow sales and marketing considerations to drive investigator selection. It will only undermine the clinical trial.

PITFALL #2: USING UNDERQUALIFIED CLINICAL RESEARCH STAFF

In the pharmaceutical industry, the typical CRA began his or her career as a clinical study coordinator. In the medical device industry, by contrast, the typical CRA previously worked in the company's sales support or manufacturing departments.

As with a drug trial, monitoring a medical device trial demands the CRA have an understanding of the therapeutic area. But a device trial also requires that the CRA have in-depth knowledge of the specific device under investigation.

As a new medical device moves from engineering and manufacturing to clinical development, personnel are often shifted from these areas to the clinical department, to take advantage of their knowledge of the device. But device expertise alone is not an adequate substitute for knowledge of and experience with the clinical research process. In the current environment of intense scrutiny of the device industry, it is desirable to have highly experienced CRAs monitoring clinical trials.

A CRA needs to do much more than read the regulations or attend a class or two. It takes at least a year of intensive classroom and on-the-job training just to acquire the working knowledge necessary for the job. Developing the more highly refined visceral skills, such as that gut feeling about the suitability of a potential investigator, takes many more years in the trenches.

Expertise is required in all the other clinical research areas as well, such as regulatory affairs. Just keeping up with all the legislative and FDA changes can be difficult. Still more difficult is developing the ability to foresee what the regulatory climate will be once the trial is over and it is time to make the premarket approval submission.

One way to acquire the needed expertise, especially for smaller medical device companies that may not have the experts on staff, is to employ outside consultants in selected areas or to outsource some or all of the trial to a contract research organization (CRO). In either case, the cost and quality of the services provided become prime considerations.

Individual consultants may be ideal for isolated activities such as a statistical or regulatory project, or designing a case report form. It is relatively easy to find very experienced and knowledgeable consultants in these fields and to obtain suitable references on the specific individuals who will conduct these tasks. Control of costs is a relatively simple matter of monitoring the number of hours billed each week.

At other times, it may be better to partner with a CRO. A clinical research staff member for a device company may do everything from writing the study protocol, monitoring sites, keying the data, and writing the final report to providing product training and even working the trade show booth. The staff at a CRO tend to be more focused on specific activities, such as monitoring or medical writing. Such specialization allows the development of more in-depth expertise and tends to result in greater efficiency. When the full cost of building and sustaining internal clinical research capability is considered, it may even be less expensive to outsource the entire project.

The lesson: Make sure the members of your clinical research staff—in-house or not—have the right experience, and lots of it. They're your first defense against clinical trial mishaps.

PITFALL #3: UNDERESTIMATING THE BENEFIT OF TECHNOLOGY

New clinical research technologies such as electronic data capture (EDC) increase accountability, improve decision making, and aid regulatory compliance. Studies show that under the traditional paper-based approach it costs as much as $100 to generate a single data-entry query, send it back to the investigator, revalidate the corrected data against the source document, re-enter the data into the database, and rerun the edit programs. Multiply this by an average of one to three queries on each of the 10 to 100 case-form pages required for each of the dozens to hundreds of patients in a typical clinical trial, and the value of EDC's ability to collect and clean data via the Internet becomes readily apparent. Combined with the potential to shave weeks off the time required to lock the clinical trial database and the ability to analyze the results in near real time, it is clear that EDC is becoming a important tool.

Acceptance of EDC by clinical investigators is growing rapidly. A majority now express a preference for non–paper-based trials. Implementation costs have fallen with the near ubiquity of the Internet.

Most vendors now offer their software as a hosted service, eliminating the need to install and maintain software internally. Many CROs have aligned themselves with an EDC vendor to reduce implementation costs. Several have incorporated EDC and related technologies throughout their operations. A few are even attempting to expand EDC into a more expansive clinical research platform, combining data collection with tools to speed investigator and patient recruitment as well as regulatory reporting. The completely paperless clinical trial could soon become a reality.

The lesson: Use the Web to help make the clinical trial process faster, cheaper, and more efficient.

PITFALL #4: OMITTING QUALIFIED ADVISORS

A well-designed clinical trial requires the fusion of therapeutic expertise, fundamental scientific principles, statistical procedures, nursing input, clear scientific writing, and regulatory experience. A clinical protocol that anticipates all the issues related to patient screening, data requirements, and statistical analysis is essential. It's generally not possible to find one person with expertise in all relevant areas. It takes a team. Be sure to include representative CRAs, study coordinators, investigators, data managers, statisticians, device technical experts, regulatory experts, and yes, even the marketing staff, on this team.

The lesson: Use a team approach to ensure that you have a variety of experts supporting the clinical trial.

PITFALL #5: OVERLOOKING GCP COMPLIANCE

Medical device trials are required to meet the same standard of quality that drug clinical trials must meet. Proper consent procedures with detailed procedure descriptions and risk-benefit discussions are critical. There must also be well-written SOPs and a quality assurance function to ensure they are followed. All computerized systems, including data entry, must comply with 21 CFR Part 11 and have audit trails and validation and design documentation. All data recorded in the case report form must be supported by the investigators' medical records. The investigators' patient management software is probably not compliant with FDA regulations, so the patient data must be printed and signed, and it must then be monitored by a qualified CRA.

The lesson: Remember to ensure good clinical practice compliance, not just for regulatory reasons, but to reduce the company's risk from potential adverse publicity or patient lawsuits.

CONCLUSION

I can attest from personal experience that nothing is more exciting than witnessing a small start-up company develop a novel idea into a useful new medical device, take it through clinical trials, and then obtain FDA approval for marketing. As the regulatory environment becomes more intense, this process will become more challenging. But with careful and informed management, clinical trials can help ensure that the product development process remains successful and rewarding to everyone involved—investors, patients, and society as a whole.

Copyright ©2002 Medical Device & Diagnostic Industry