The Regulatory Path
Written by John Randle
Most new technologies and products will require regulatory scrutiny and approval prior to marketing. These requirements vary widely depending on the nature of the technology/product and their intended medical use, as well as the regulatory precedent set by existing market-related technologies/products. Therefore, as you progress on your product development plan, you should create an outline of the regulatory plan that will enable marketing approval of your technology/product.
For USA-based companies developing technologies and products in the health sciences, the Food and Drug Administration (FDA) will typically be the regulatory gatekeeper. Determine which FDA division is likely to have oversight for development and approval by visiting the FDA website (www.fda.gov) and finding the documents entitled “Guidance for Industry: …” that outline these requirements. Much can be learned from these documents, but as their titles suggest, they only provide “guidance” at best. Therefore, direct consultation with the appropriate FDA Division is an essential step to ensure the smoothest possible design and conduct of a development plan that will lead to approval.
FDA regulations provide formal opportunities for FDA-sponsored interactions at each stage of development, as outlined in guidance documents by each FDA Center. Once a sponsor establishes a working relationship with the FDA Division members, it will often be possible to garner additional informal correspondence for ad-hoc feedback on development issues. For products with potential for international reach, it is often advisable to seek early advice from the European Medicines Agency or member country agency, as well as from selected regulatory authorities around the world.
For medical devices, investigators can inform themselves by consulting the FDA Center for Devices and Radiological Health (CDRH), specifically the Office of Device Evaluation (ODE). The first step is to determine the “class” of your device. The FDA has established three class levels (I, II, III) based on the level of control necessary to provide reasonable assurance of safety and effectiveness. As device class increases from Class I through Class III, the regulatory controls also increase. Most Class I devices are exempt from premarket submission, yet class I devices that are not exempt also require premarket notification known as a 510k. All class II devices require a 510k. Class III devices need to go through the premarket application (PMA) process. New device types may also need to go through the PMA process unless the safety profile and technology are reasonably well understood in which case the “De Novo” process can be used.
To determine the class of your device you need its regulation number. The regulation number can be found through the FDA classification database or through the FDA device panel to which your device belongs. The regulation number will provide a description of devices covered and the class. Based on the class, you now know what regulatory pathway applies.
For in vitro diagnostics, the same process is followed as for devices with the exception that Clinical Laboratory Improvement Amendments (CLIA) regulations also apply. Radiation-emitting imaging systems (e.g. CT) are regulated as radiation-emitting electronic products under the Radiation Control for Health and Safety Act and as medical devices. Investigators can inform themselves by consulting guidance from the FDA CDRH, specifically the Office of In Vitro Diagnostics and Radiological Health (OIR). Sponsors must submit a 510(k) Premarket Notification prior to commercialization. New diagnostics meeting certain criteria may be eligible for a Special or Abbreviated 510(k), allowing a streamlined review process.
Sponsors should identify a Predicate Device(s) with which the new diagnostic will be compared to demonstrate “substantial equivalence”. If applicable, early in development a determination of Non-Significant Risk should be obtained from a competent Institutional Review Board, enabling issuance of an Investigational Device Exemption. Prior to the conduct of pivotal development work and studies, sponsors should also submit a 510(k) Pre-submission Review to solicit feedback from FDA on the adequacy of the development plan and address any other questions.
For therapeutic drug products, investigators can inform themselves by consulting FDA Center for Drug/Biologics Evaluation and Research (CDER & CBER) guidances on their disease area and therapeutic type (e.g. small molecule, biological, cell or gene therapy), as well as regulatory precedent and risks with relevant marketed products (e.g. package insert, Summary Basis of Approval). An Investigational New Drug (IND) application must be filed/approved prior to initiating clinical trials, supported by data from a range of preclinical studies and documentation supporting the manufacture of the drug. Sponsors should generally undertake a Pre-IND consultation with the appropriate FDA Division prior to, or early in the conduct of the IND-enabling studies, to gain FDA’s agreement on the early development plan, including both the preclinical and initial clinical studies. Thereafter, regular FDA consultation and a development plan designed to address FDA’s requirements and concerns will help smooth the development process towards a New Drug Application and marketing approval.
Regulated environments and agencies are typically a long way from the experience of academic investigators. Although motivated investigators can go a long way towards understanding and implementing regulatory requirements for their projects, investment in a regulatory specialist for advice early in their development planning process may well pay off in streamlined development and more efficient use of resources.