Medical Device Link.

Originally Published IVD Technology November/December 2004

Commentary

Olive Wolfe is president of Clinical Consultants Inc. (Ridgewood, NJ), a consulting firm specializing in clinical trials for both the IVD and pharmaceutical industries. She can be reached at clincon1@optonline.net. .

Last March, FDA released a white paper, “Innovation or Stagnation: Challenge and Opportunity on the Critical Path to New Medical Products,” to address the need to make new medical product development more predictable, efficient, and less costly. FDA defines this critical path as the process from initial product discovery to final marketed product.

The critical path initiative is an attempt to find better methods to convert the rapid growth of new technologies, such as nanotechnology, and new scientific achievements, such as the sequencing of the human genome, into new medical products that will improve the quality of healthcare and public health. The goal of the initiative is to develop new scientific and technical tools (e.g., standards, assays, computer modeling techniques, biomarkers) that improve the efficiency and effectiveness of the product development process, which will result in safer products for patients. In addition, the critical path initiative intends not only to identify obstacles along the path, but also to foster collaborations among scientists in academia, the device industry, and government agencies, particularly FDA, to create opportunities for overcoming such obstacles.

Impact on the IVD Industry

While the intent of the initiative was directed at all medical products, FDA’s Center for Devices and Radiological Health (CDRH; Rockville, MD) acknowledged that the critical path document focuses primarily on new drug development. However, CDRH notes that in the document, many constructs directed at drug development can be powerful tools to foster device development. For example, FDA’s goals of ensuring better communication with industry, improving regulatory paths, and facilitating collaborative efforts among interested stakeholders in new technologies are tools that are valuable in device development. The critical path document also calls for the creation of a toolkit to foster the transfer of new medical products from research to clinical arenas. This concept would offer a clear and direct benefit to the IVD industry. Basic and translational research should be performed with an early eye toward future marketing opportunities and clinical use. Doing so ensures bench and clinical research are performed in a cost-effective manner that will result in rapid technology transfer for new IVDs.

All three of the dimensions identified on the critical path: product safety assessment, medical utility evaluation, and industrialization, apply to drugs and medical devices, including IVDs. Although this model assumes that all medical products under the purview of FDA follow the same pathway, there are considerable differences between the road to market for drugs versus devices including IVDs. The critical path document acknowledges that “medical device development is generally more iterative, so that prototypes often build on existing models.”

For IVDs, the road to market is often shorter than for other products. While safety and efficacy issues are critical, they can be addressed in clinical studies performed in real time, and without the need for prospective data and data follow-up. In addition to a shorter development timeline, IVDs have a clear road map for the analytical and clinical data needed during premarket review.

In a speech outlining the agency’s mission for the next six months, acting FDA commissioner Lester M. Crawford reiterated that a “versatile applied science toolkit containing powerful scientific and technical methods” is being developed as part of the critical path initiative for getting treatments to patients faster. The IVD industry’s unique toolkit could be used for such a purpose by fostering the development of new IVDs that may in turn affect the development of new drugs. This is the direct result of the potential for IVDs to allow patients to receive more-directed and-personalized treatment choices. In the areas of genetic and molecular diagnostic testing, as well as testing for emerging infectious diseases and bioterrorism threat agents, IVDs have a significant influence on both patient and public health, and may affect treatment outcomes.

IVD manufacturers that have formal or informal relationships with pharmaceutical companies may be well suited to take advantage of the critical path initiative. Insights from biomarker research by IVD companies may accelerate the selection of new therapeutics, allow for streamlined development of therapeutics, assure the use of new diagnostics to support new tests, and produce a powerful synergism. Such synergism may add certainty to the development cycle for new therapeutic products, save money in clinical trials, and identify new sources of revenue. FDA’s quality system regulation (QSR) that has been in place for almost a decade provides opportunities for harmonizing device development. The QSR also allows for a system of design planning and control likely to be consistent with the tenets of the critical path initiative.

Consequently, IVD companies with a broad portfolio of medical products including both drugs and diagnostics are equipped with resources and opportunities for product development and financial success. An important corollary is the ability of companies with joint diagnostic and drug interests to make contributions to healthcare as well as improvements to the medical care system.

In addition, as with drug development, the IVD industry would benefit from FDA’s new mandate for early research assessment and planning. This mandate attempts to ensure that new technologies that are both beneficial to the public health and profitable to companies can enter the market as early as possible.

With its experience and the vast data resources accumulated over the years from past submissions, the agency is well suited to help device manufacturers fine-tune that critical path to market and benefit the public health. In the area of IVDs, FDA has made a concerted effort to collaborate with both industry and professional group partners to develop new guidances. The agency has also encouraged using the preinvestigational device evaluation (IDE) process to allow protocol reviews before IVD companies initiate their clinical studies. The pre-IDE process helps to educate not only FDA on IVDs in the pipeline but also IVD companies on data thresholds needed to support particular claims. The results are higher-quality studies with focused data sets and faster review times.

An example of the power of such collaborative work was the rapid development and evaluation of the West Nile virus (WNV) nucleic acid blood-donor-screening test. FDA, the Centers for Disease Control and Prevention (CDC; Atlanta), and the IVD industry collaborated to obtain the samples, establish standards, and develop regulatory mechanisms to make this test available to blood banks. FDA also worked concomitantly with the IVD industry to design the necessary studies for obtaining approval for the first WNV test, and to develop a timeline for making sure that review and approval could occur prior to the start of the WNV season. This collaborative partnership resulted in the timely availability of a first-of-a-kind IVD that met an emerging medical need.

However, more of this type of collaborative work is needed. Such work should be directed on not only critical issues but also more general and incremental improvements to the general public health.

IVD Critical Path Initiatives

One of the goals of the Office of In Vitro Diagnostic Device Evaluation and Safety (OIVD; Rockville, MD) is to make the total product life cycle principle a functional reality. OIVD has instituted a system for better information flow and feedback between CDRH and other FDA divisions involved in the entire regulatory process. Resources will also be shifted to postmarket assessment and the development of new methods of postmarket monitoring to produce a better picture of real-world device behavior.

If brought to fruition, such mandates should continue to improve significantly the product approval process. While the process has indeed improved, particularly with pre-IDE and premarket approval (PMA) meetings, IVD manufacturers are not taking advantage of such opportunities. Part of the reason is because roadblocks in getting IVDs to market still reside in the review process itself.

In 2003, CDRH acknowledged that improving review times was crucial. The center committed to a goal that by 2006, 80% of product approval submissions would receive an FDA decision within 320 days. This review turnaround time should increase to 90% by 2007.

CDRH has also promised to increase the development of more guidance documents, in particular, an improved guidance on PMA applications. This would significantly expedite the process of developing new assays and instruments. In developing such guidance documents, FDA should encourage and support more input from and collaboration with scientists in the IVD industry.

Another important part of FDA’s critical path initiative and a factor recognized by CDRH’s review of its submission processes is the mandate to increase its scientific staff and train scientists properly to be expert guides for the pharmaceutical and device industries. In order to attract and retain the best scientific talent, FDA has committed to implementing a continuous learning and quality systems approach to medical product reviews. Scientists will be afforded opportunities to spend some time at the agency to collaborate on developing better tools toward improved medical products.

As has been suggested for the pharmaceutical industry, FDA scientific reviewers of IVDs need to be educated on new procedures and technologies. A system should be developed for providing the necessary educational opportunities for CDRH reviewers. Forums could be set up with scientists from IVD industry research and development divisions, CDC, and FDA. CDC has always been quick to develop assays when health emergencies occur, and its scientific acumen could be shared in these forums. FDA has initiated more of these open forums, and IVD manufacturers and scientists should take advantage of them.

In an effort to make much-needed analytes more available for patients, FDA should also review the home-brew assay market. A vast majority of genetic and other tests are performed in-house, and may only serve specific areas or numbers of patients. Although this market has grown considerably, such assays are not FDA-regulated. AdvaMed (Washington, DC) suggested that FDA should recognize such new analytes that have clinical impact and have been in demand. The agency should therefore speed up the process of allowing such analytes to enter the marketplace. AdvaMed has further suggested that permission for marketing should be based on the characterization of these analytes rather than on full clinical testing.

Although the turbo 510(k) pilot program for IVDs has begun, the process should continue at a faster pace. Electronic submissions are practically mandated for the pharmaceutical industry in an effort to streamline and expedite the approval process. The same mandate should apply to the device industries for similar reasons. IVD manufacturers pride themselves on the enormous strides made in developing sophisticated software for their instruments. Such expertise could be further extended to collaborating with FDA to develop tools for electronic PMA and 510(k) submissions.

In addition to the above comments regarding the critical path initiative, AdvaMed suggested other areas that would ease the burden of product approval submissions and make new assays available for improved patient care, including the following:

• Guidelines for using banked and leftover samples without needing informed consent and investigational review board review.
• New approaches to the clinical validation of molecular diagnostic devices where warranted, such as obtaining a statistically adequate number of specimens by phenotype rather than genotype.
• Accelerated IVD reagent stability models for establishing expiration dating.
• Risk-based approaches to process validation to expedite the availability of IVDs for emergent diseases.

Other industry groups suggested that FDA should establish objectives for the government and not just for the IVD industry. There should be a critical path set of objectives for government processes that are clear and measurable. Criteria should be set to determine if and when the initiative can be regarded as successful. Other comments include providing a list of all standards, both national and international, that have been accepted or rejected. This would facilitate submissions because IVD manufacturers could find out if they comply with specific standards.

Conclusion

OIVD and the IVD industry should eventually create their own critical path opportunity list to better address the unique needs of the IVD industry. In the meantime, IVD industry scientists should wait to see whether or not their concerns will be addressed, particularly with regard to the stated mission of OIVD. While some strides have been made, there still needs to be further communication and collaboration among the concerned parties. At some point, perhaps IVD scientists should take the ball and initiate such collaborations themselves.

The full report can be accessed on the FDA Web site at www.fda.gov/oc/initiatives/criticalpath/.

Copyright ©2004 IVD Technology