REGULATORY OUTLOOK

The FDA regulatory pathway for commercializing medical devices can be a maze of mandates which, if disregarded, can slow time to market, inflate design and development costs, and even result in complete product withdrawal. Being prepared with a smart regulatory strategy and knowledge of the ins and outs of the regulatory process and requirements is critical to facilitate clearance or approval.

Too often, regulatory strategies are devised near the end of the product design and development process rather than at the start. Creating a regulatory strategy should be at the top of the list, immediately following the development of the product requirement specification. This allows manufacturers to meet launch date commitments as well as satisfy efficacy claims and validation requirements. This article discusses the four steps needed to craft a regulatory strategy as well as other considerations for getting a medical device to market.
Step by Step
One of the most challenging aspects of getting a medical device to market is knowing where to begin. What are the steps needed to gain clearance or approval? And in what order should they be taken? Before any steps can be taken toward regulatory clearance or approval, the product requirements specification document must be developed. This document defines the device function, patient population, and information required to formulate clinical claims. It also provides the foundation for a regulatory strategy. Only after this document is finalized should the following four steps—define, classify, test, and submit—be implemented.
1. Define
Medical devices are subject to the controls of the Federal Food, Drug, and Cosmetic Act (FD&C Act) and the associated regulations, which are contained in 21 CFR Parts 800–1299. General controls are the baseline requirements that apply to all medical devices regarding marketing. They include establishment registration and device listing, proper labeling, and monitoring performance for deaths, serious injuries, and device malfunctions once the products reach the market. These regulations also include Current Good Manufacturing Practice (CGMP) requirements set forth in the quality system regulation (QSR).
According to FDA's CDRH, the first step toward obtaining marketing clearance is to ensure that the product to be marketed is, in fact, a medical device according to the definition in section 201(h) of the FD&C Act. For example, the product may be a drug or biologic product that is regulated by an arm of FDA other than CDRH and for which there are different provisions in the FD&C Act. Or, a product may be a medical device that is also an electronic radiation-emitting product that must meet additional requirements. Properly defining the device, its intended use, and its indications determines the various regulations with which the device must comply.
2. Classify

The second step in navigating the device regulatory process is determining which of the three FDA classifications a device falls into; this will ultimately reveal the regulatory terrain. (See the sidebar, “Defining Medical Device Classifications.”) Classification identifies the level of regulatory control necessary to ensure the safety and effectiveness of a medical device. Most importantly, the classification of the device determines the necessary paperwork to be filed with FDA—either a premarket notification 510(k) or premarket approval (PMA) application—to obtain clearance or approval for marketing, respectively.
A 510(k) is used to demonstrate to the agency that a device is at least as safe and effective (substantially equivalent) to a legally marketed device that is not subject to premarket approval. Manufacturers must compare their device to one or more similar legally marketed devices and support their substantial equivalency claims.
Premarket approval is FDA's process of scientific and regulatory review to evaluate the safety and effectiveness of Class III medical devices. Due to the level of risk associated with Class III devices, FDA has determined that general and special controls alone are insufficient to ensure their safety and effectiveness. Therefore, these devices require a PMA application under section 515 of the FD&C Act for marketing approval. Premarket approval is the most stringent type of device marketing application required by FDA, and approval is required prior to marketing.
It should also be noted that classification may result in exemptions, because many simple devices, such as crutches, do not require either 510(k)s or PMA applications.
3. Test
All claims must be substantiated with test data or testing plans. Before submitting any application to FDA, medical device firms should determine what testing is required and ensure that the testing program is properly designed. Properly planned testing can help a manufacturer avoid a lengthy and costly delay in the review process. For some 510(k) submissions and most PMA applications, clinical performance data are required to obtain clearance or approval.
The overall market trend is to incorporate FDA-mandated as well as recognized voluntary standards. An example of a mandatory standard for medical devices is 21 CFR 898, Standard for Electrode Lead Wires and Patient Cables. Internationally recognized voluntary standards that are formally recognized by FDA include the IEC 60601 series for medical electrical equipment and the ISO 10993 series for biocompatibility testing of devices in contact with patient tissues. These standards specify test methods that yield confirmatory and validating data. It is during these testing stages that manufacturers test the requirement specifications developed at the onset of the product development process, make concept prototypes, and prove that they work.
Performance testing is an important process that can verify how well a product performs against competition. It can determine the durability of a device so that manufacturers can anticipate service and end-user issues. It also identifies a device's failure points, which are important to avoid performance-based recalls. An important consideration for any device that is in direct contact with the patient is the requirement to demonstrate that the device is biocompatible. This is especially true for long-term implanted devices that can also require long-term testing in animals.
Whatever the scope of testing involved, device makers need to prove that products meet the needs of end-users and the intended patient population.
4. Submit
Once tests and audits are complete, a written report should be drafted on the results. The report should be included in the OEM's overall submission to FDA, which is the final step. This step includes the compilation of administrative information, e.g., identification of the company sponsoring the submission, identification of the manufacturer and any sterilization contractor, applicable signed certification statements and respective FDA forms, product-specific labeling, etc. This information should be included in addition to data necessary to obtain FDA clearance or approval to market.
Ultimately, the onus falls on the device manufacturer to determine whether the goal is to get the product to market with specific claims, or to stage a rollout with limited claims (and raise capital for clinical trials to substantiate additional claims). Differences between diagnostic and screening devices provide a good example. Consider a blood test product. If the manufacturer plans to market it as a diagnostic test, it would have one set of requirements. If the manufacturer plans to promote it as a screening device to evaluate a population's risk for a given disease, a different set of requirements—including testing of a population at risk for that disease—would be required.
To facilitate a timely review of the regulatory submission, the device company must submit a well-organized document that contains all of the information the regulatory body requires. The document should be reviewer-friendly—i.e., it should make the reviewer's job easier with a detailed table of contents, a clear and concise product description, comprehensive summaries of necessary test protocols and reports, and systemic and sequential arrangement of supporting documents. Missing information and documentation related to the device software, hardware, and other components can impede final product clearance or approval, result in costly regulatory reinspection (for devices subject to premarket approval), and leave the agency with an unfavorable impression that could affect future interactions with the device company.

Failure to document design planning early in a project can also leave a medical device manufacturer scrambling to fill in the gaps as the project nears completion. It is also helpful to build a relationship with the submission reviewer. Such a rapport may encourage the reviewer to e-mail the company more frequently with minor questions, which can avoid a lengthy deficiency letter.

For those reasons, it is important to have an experienced regulatory professional prepare the FDA submission. Whether the manufacturer prepares submission documents internally or chooses to outsource these activities, it is important to work with regulatory and clinical trial professionals who are fully versed in the specific requirements of the medical device industry. Choose people who understand the needs of the company's business and who are aware of the specific regulations affecting the company's medical, diagnostic, or combination product.
Timing Is Everything
In addition to understanding the necessary steps involved in regulatory clearance or approval, manufacturers must keep regulatory concerns in mind from the beginning—as soon as product specifications are determined.
One of the most often overlooked aspects of regulatory clearance or approval is design control; clear documentation illustrating how a medical device is designed is essential. FDA indicates that all developers of Class II and III medical devices, as well as select Class I devices, are required to follow 21 CFR Part 820.30 (design controls) during development. These requirements are basic controls needed to ensure that the device being designed performs as intended when produced for commercial distribution. FDA requires this information during preapproval inspections of Class III devices as well as during routine quality system inspections for all classes of devices subject to design control.
Manufacturers must establish and maintain procedures to control the design of the device to ensure that specified design requirements are met. Design controls, according to CDRH, include establishing and maintaining plans that describe the design and development activities and also define responsibility for implementation. The plans must also identify and describe the interfaces with different groups or activities that may inform the design and development process.
Avoiding Trouble
If FDA conducts a quality system inspection and determines that the medical device has not been appropriately designed or manufactured according to the regulations, a number of things can happen. FDA will likely issue a lengthy listing of inspectional observations (also known as a Form 483). If the firm does not provide a satisfactory response, FDA can issue a warning letter to the president of the firm that will be posted on FDA's Web site and probably be picked up by the trade press.
For companies that refuse to comply with regulatory requirements, the firm can be enjoined from shipping the product. Additionally, if the product may be a danger to public health, FDA can require that the firm recall the product or criminally prosecute the firm and the responsible individuals within the firm. Any regulatory action by FDA will likely translate into exorbitant costs and delayed product launch or market re-entry, both of which could have been avoided with appropriate design controls and quality system compliance.
Don't Be Afraid of FDA
Medical device companies should engage in early communication during the design phase. In addition to contacting the agency at the start of the process, effective communication with FDA is crucial throughout the submission process. It can also help speed clearance or approval.
For example, FDA guidance documents are often revised and updated. Without early contact, the regulatory submission may be missing pertinent information. During the review process, FDA often requests clarification and additional information, and how a manufacturer responds is critical for minimizing delays. Firms must respond in a timely fashion and provide clear, concise responses that completely address the questions without extraneous information. Not completely addressing questions from the agency may result in needless and time-consuming back and forth. But OEMs must not swing too far the other way, either—providing information not specifically requested can raise new questions and require the submission of more information.
When working with the agency, be prepared. Know what the device will be, what population it will serve, its risks and benefits, and how it will function. Only after this information is gathered should any feedback be sought from FDA.
ISO 13485 Considerations
The importance of the International Organization for Standardization (ISO) is growing as many countries require companies to have a third-party-audited and -certified quality system in place before selling products. ISO 13485:2003, “Medical Devices—Quality Management Systems—Requirements for Regulatory Purposes,” is an important voluntary standard for medical device manufacturers. Although harmonization efforts are under way for ISO 13485 and 21 CFR 820, being certified to ISO 13485 does not fulfill FDA requirements.
However, there are advantages to having ISO 13485 certification. First, it aligns an organization's quality system to FDA's quality system requirements as well as to many other regulatory requirements found throughout the world. Adherence to ISO 13485 also creates a framework on which to build compliance to various regulatory and customer requirements.
Conclusion
The pathway for commercializing a medical device can be a maze of rules and requirements. As a result, OEMs should use advance planning and regulatory knowledge as the prime ingredients of a successful regulatory strategy. Manufacturers should begin with a product requirements specification document, which outlines the device function, patient population, and information required to create clinical claims.
Once this document is finalized, companies should make sure that the product to be marketed is, in fact, a medical device according to the FD&C Act. Next, manufacturers should determine which of the three FDA classifications a device falls into and substantiate the device's validity with test data or testing plans. Finally, the company should draft a written report on the testing results. This report, along with all other relevant information, should be included in the OEM's overall submission to FDA.
Shortcuts may end up costing significantly more in the long run, resulting in product liabilities, brand equity erosions, and warning letters from FDA.
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