Staying Ahead of the Curve

It’s an ever-changing regulatory world—not only with the U.S. Food and Drug Administration (FDA), but around the globe. Major international regulatory agencies continue to transition toward global standardization. Countries are improving their regulatory systems and revising regulations (for example, Japan is thinking about modifying the Pharmaceutical Affairs Law to include separate medical device regulations). In another development, Health Canada has adopted the Summary Technical Document (STED) format for Class III and Class IV medical device license applications and suggests that applicants follow the STED guidelines issued by the Global Harmonization Task Force.

The FDA continues to push for patient-centered product development. FDA reviewers are requiring user input (human factors) into product design in order to ensure that the finished device is safe and effective. The FDA also has expanded the degree and extent of testing required—especially for high-risk devices—to improve safety and reduce the number of dangerous use errors.

“We are seeing increased requirements for testing, not only for FDA submissions, but also in the European Union,” said Sherry P. Parker, director of regulatory and technical for medical devices for WuXi AppTec, a contract non-clinical medical device research and testing firm in St. Paul, Minn. “This includes more complete biocompatibility panels, chemical characterization of the finished product and risk assessments.”

One of the strongest trends is the need for risk analyses to gain regulatory approvals. This also involves 60601-1 safety testing, software standards and the increasing requirements for risk-based usability testing, which directly impact European submissions and indirectly impact U.S. submissions.

“The paradigm, particularly for 510(k) devices, has been changed from more simple equivalence testing and assurance that the design meets the customer inputs, to a more forward-looking perspective, taking into account all the potential risks, including a larger focus on the impact of the user/patient on the longer-term safety of the medical device,” said Grant Palmer, vice president of quality and regulatory for the Aubrey Group, an Irvine, Calif.-based consulting firm that specializes in design and development, contract manufacturing, and quality systems. “Testing these additional aspects does add to the short-term costs with additional resources; however, I believe that in the longer term there will be savings to medical device companies in terms of fewer user-error complaints/complications resulting in an enhanced user experience.”

Parker also noted the emphasis is now on testing the final finished device—testing components and/or materials is no longer adequate for demonstrating biocompatibility. The FDA also is requiring more genotoxicity testing for more products, including almost all devices in contact with circulating blood. It also is likely that any non-FDA certified color additives will require additional chemical characterization and/or biocompatibility testing.

“Chemical characterization is not a standardized test and goes beyond United States Pharmacopeial Convention (USP 661),” said Parker. “USP 661 is not specific and quantitative for individual leachable chemicals. Chemical characterization is different for every product and the approach is based on the formulation, process aids/additives and the fact it may be done differently based on the nature and duration of body contact. For example, more aggressive, sometimes exhaustive extraction conditions are expected for permanent implant devices. Performing a standard ISO 10993-12 extraction may not be sufficient to obtain maximum extractables for a risk assessment of a permanent implant device.”

The FDA also recently revised the establishment registration and device listing regulations (21 CFR §807) to require contract manufacturers and sterilizers to register their establishments and list the devices they manufacture or sterilize for other companies.

“As part of this process they need to include their customers’ 510(k) numbers and proprietary names of the products,” said Barbara Atzenhoefer Stegmeier, senior principal consultant for NAMSA, a Minneapolis, Minn.-based provider of regulatory, quality system testing and post-market services.

The FDA also is evaluating safety assurance cases as a tool for streamlining the review process for certain medical devices. According to the FDA, an assurance case is a “formal method for demonstrating the validity of a claim by providing a convincing argument together with supporting evidence. It is a way to structure arguments to help ensure that top-level claims are credible and supported. In an assurance case, many arguments, with their supporting evidence, may be grouped under one top level claim.” For a complex case, there may be a network of arguments and sub-claims. At present, assurance cases only are required for infusion pumps.

The interpretation and expansion of current rules seems to be a trend with the FDA. For example, the Unique Device Identification (UDI) proposal rule that went out in July this year for a 120-day review “has the potential to impact 100 percent of a company’s (and its OEM customers’) labeling and artwork,” commented Daniel McCoy, director of engineering and regulatory affairs for Rhythmlink International, a Columbia, S.C.-based manufacturer of medical devices for intra-operative neuromonitoring, electroencephalography and continuous EEG monitoring. “In some instances, with the additional barcoding required, packaging size may also have to change.”

Many medical device companies have noticed over the last year that, rather than accepting predicate and/or paper adoption of existing materials on new or special 510(k)s, the FDA is being very specific regarding biocompatibility requirements. The FDA has indicated the testing needs to be performed on a finished final device rather than using components and/or predicate device data. Biocompatibility testing can take up to six to 12 weeks based on the medical device, which adds that amount of time to the product delivery date.

“While neither of these situations are new, the current interpretation on biocompatibility and the new rule proposal on UDIs illustrate what is meant by ‘interpretation and expansion’ of current rules,” said McCoy. “For example, the UDI barcoding requirement on all medical devices is an expansion of current labeling into a new technology format that will reduce medical errors and simplify the integration of device-use information into data systems.”

On the international front, more countries are harmonizing their regulations around European Union and ISO standards, rather than following FDA standards. In September the European Commission published new draft regulations for medical devices and in-vitro diagnostics. These proposed changes will result in significantly greater pre-market and post-market controls of devices as more countries adopt regulatory requirements for medical devices.

“What’s refreshing is that many countries are adopting regulatory processes based on the Global Harmonization Task Force guidance documents,” said Stegmeier. “If more countries take this approach, eventually we will see greater consistency in international medical device registration and product approval processes.”

Stegmeier also pointed out that it’s important for contract manufacturers to understand that in most countries the “manufacturer” is defined as the organization that places the product on the market under its trade name. “This means that the onus for obtaining and maintaining international regulatory approvals lies primarily with the contract manufacturer’s customer—not the contract manufacturer,” she added.

Validation and Quality by Design
Cynthia Rancourt, director of business operations at Polymer Solutions, a Blacksburg, Va.-based testing laboratory that provides chemical analysis, physical testing, research and development services and litigation services, attended a senior-level breakout session titled, “Most Critical Challenges Facing Analytical Scientists” during the recent ninth annual IV Validation Conference in Philadelphia, Pa. Analytical scientists and senior quality managers used this forum as a place to discuss the regulatory topics that create daily challenges to completing laboratory testing work.

“I was amazed that large companies and small companies were experiencing the same challenges related to regulatory demands, regulatory changes and business constraints related to the economy,” said Rancourt. “There are challenges to moving products through their life cycle where time is money and businesses have reduced their workforces due to the economy, but they still expect results in the same timeframes.”

Key discussions involved:

• Knowledge management with limited resources (including time constraints). “Attendees related that their document management systems had very poor search functions for locating previous work that could expedite and help with present work,” said Rancourt. “Oddly enough there were four different systems mentioned, each with the same complaint.”
• Ensuring method quality with tight timelines—methods must be validated according to the International Conference on Harmonization’s (ICH) Q2 (R1) Validation of Analytical Methods.
• How quality by design (QbD) is being used for analytical method development across the industry, including successes and pitfalls. “One company used the QbD approach to develop a method for testing a product,” said Rancourt. “They took a case and retrospectively applied QbD principles to it as a pilot study and used this approach as a teaching tool for developing methods—very impressive.”
• Bridging/equivalency studies to replace dated technologies with more modern techniques. “If the new method improves accuracy, how do we rationalize that against historical data?” said Rancourt.
• Determining phase-appropriate validation of methods. This applies to the determination of when it is appropriate to use reduced validation for different phases, and at what level of reduction.

“Balancing the need for rapid completion of validation or transfer activities and the needs to be compliant with regulatory expectations was the most common challenge mentioned and potentially the most impactful,” said Rancourt. “Validation of methods and processes takes time, especially with new products or processes. If a company has to add a new way to approach validation through QbD, there will be a learning curve that may take additional time initially. Those outside the quality department may have difficulty understanding the quality timelines for validation. And at the same time the regulatory authorities will expect validations according to the new QbD approach. Currently, QbD is suggested, but it will become the expectation of the FDA since it is official guidance through ICH Q8, ICH Q9, and ICH Q10. The bottom line is QbD is good science and good science can’t be rushed.”

Working With the FDA
How well things are going with the FDA depends on who you’re talking to and what products they make. Overall, it seems that the majority of premarket submissions are reviewed in a fairly timely manner, considering that requests for more detailed information from the FDA always should be expected.

“The FDA is asking more specific questions about test methods (including well-established compendial methods),” said Parker. “This may be due to the recent addition of new reviewers. With the release of a draft pre-submission guidance, encouraging more and frequent communication with FDA during the submission process and timely FDA responses to our questions, it is obvious to me that efforts have been made to improve communication overall.”

According to Palmer, the FDA also has grown more visible at industry and medical community conferences and improved its approachability. As part of its communication efforts, the agency has released an abundance of guidance documents related to 510(k), investigational device exemptions (IDE) and post-market processes. The agency also is encouraging medical device companies to take advantage of pre-submission meetings to make sure everyone understands the submission requirements, especially for new, innovative products that don’t have a scientific or user history behind them. This is a good way to minimize or eliminate misunderstandings and avoid surprises down the road (such as more testing) that could require resubmission.

Although these are steps in the right direction, communication with the FDA still can be an issue that leads to delays and confusion.

“Although the FDA has dedicated significant resources to the development or revision of guidance documents with the intent of providing more transparency and consistency, it is unclear how well this is being communicated to the FDA reviewers,” said Stegmeier. “We are still experiencing differences between the divisions and between reviewers within the same division in regards to the amount and type of data to be included in a submission. The inconsistencies make decision making extremely difficult.”

Alan P. Schwartz, executive vice president of MDI Consultants in Great Neck, N.Y., a FDA regulatory affairs and compliance consulting company, agrees it is more difficult to get timely answers from the FDA these days.

“The FDA appears to be in a state of flux,” said Schwartz. “Things seem to be taking longer. There does not seem to be enough transparency. It appears that many of the more experienced reviewers have taken retirement or left the agency, which now has a new group of reviewers that has yet to get up to speed in dealing with the industry.”

Overall, McCoy has been pleased with Rhythmlink’s dealings with the FDA.

“Our FDA reviewers have been helpful regarding our 2012 submittals to date and very complete on any additional information requests,” he said. “Developing a relationship with our reviewer up front as a partner enables us to clarify any comments, or requests for additional information, to exactly what the agency feels is required for safety and efficacy of the product.”

Palmer is optimistic about the FDA’s efforts to connect with the medical device industry.

“From my perspective, they have worked hard to establish a new norm,” said Palmer. “In discussions with reviewers, they are moving to a more interactive process, more informal and real-time review and questions. These changes do improve the transparency of the process and make the relationship more collaborative. The process for non-PMA devices still needs to change, with more focus on risk-based development.”

Speeding Things Up
Companies struggle with reviewer changes during the course of the submission process, which results in very different FDA expectations and sometimes more testing is required. The review is by nature subjective, so there are differences in opinion among different reviewers (often based on experience or expertise). Sometimes the review process takes too long—particularly with IDEs and pre-market approval applications (PMAs), which usually involve more than one reviewer.

“One thing companies can do better is engage the FDA earlier in the pre-submission process,” advised Parker. “Things have gotten more complicated and regulatory requirements are increasing. Getting agency feedback on a biocompatibility testing strategy, for example, or an expensive and lengthy sub-chronic or chronic toxicity study protocol before testing is complete, will make the whole process smoother.”

OEMs can take more care in selecting appropriate materials and chemically characterize these materials early in the development process. Sometimes a certificate of analysis, material safety data sheets or other data sheets for a material do not give accurate information and may not include manufacturing process residuals.

“Some materials that are labeled ‘DEHP-free’ may contain other phthalates,” said Parker. “Early efforts to qualify and select suppliers who provide sufficiently detailed chemical information on their materials and good quality control will save headaches later and avoid costly surprises.”

Back-and-forth submittals, extended review times for each stage and requests for additional information typically slow down time to market. Reading the existing regulations in detail for compliance, and working with the FDA through pre-IDE to identify critical information that is required, help to streamline the submittal process.

“The biggest change Rhythmlink has made over the last year is to have more frequent and data-specific communications with the FDA before our submittals,” said McCoy. “Using pre-IDE e-mail and teleconferences have strengthened our relationship with our reviewers and allowed us to define more robust test protocols and data analysis. We typically interact under pre-IDE guidance for more difficult and complicated new devices, whether or not we actually submit under an IDE application or standard 510(k).”

Ultimately, the best way to maximize the chances of a speedy clearance or approval is to apply solid, rigorous scientific principles when collecting data/evidence to support the safety and effectiveness of your device for a submission to market the product. There are no shortcuts to good science.

“It is the job of the person who is writing the submission to make it as easy as possible for the reviewer to do their job,” said Stegmeier, who also pointed out the writer should keep the following in mind when preparing submissions:

• Make sure all of the necessary information is provided; FDA will be screening submissions and rejecting those that do not contain all of the necessary information;
• Provide a clear description of the product, including illustrations and photographs—this can go a long way in helping the reviewer understand the product;
• Provide well-written summaries of the testing that you did to show the product met the design specifications; and
• Clearly describe the similarities and differences between your product and the predicate product if the device will be submitted under the 510(k) process and why the differences do not pose any additional risks to the patient.

The Challenge of New Technology
Changing technology has a large impact on the medical device approval process. New materials and methods push the 510(k) process, where the newer items make the traditional substantial equivalence argument more challenging. “New technology is great and needs to come to market, but one cannot blanket-claim that because it appears safe for one therapeutic area, that it is safe for all,” said Palmer. “Scaling, application and potential complications all do need to be taken into account.”

The FDA cannot keep up with the rapid evolution of material science, electronics and smaller and more complex medical devices—this is a big reason why FDA offices are extremely backlogged.

“Their system just cannot handle the amount of scrutiny and oversight with the rapidly advancing technologies and increased global harmonization of regulated quality systems,” said Rancourt.

One thing companies can do better is understand that, besides being a simple demonstration of performance, the regulatory submission also is a story with a particular audience. “The story needs to set the framework for the device and explain where the device is compliant and how the compliance is achieved,” said Palmer. “This begins with the specification and risk documents and traces forward through bench, in-vivo and human testing.”

Scientific justification for decisions absolutely is essential, especially for new products or technologies that don’t have years of accumulated performance data behind them. Risk analysis also can be used to support scientific justification.

“There are very few standards or benchmarks when it comes to developing a new product or method,” said Rancourt. “This is why knowledge management was a major issue at the conference. If companies can find previous knowledge in-house from former projects, this will save them time and money in finding scientific justifications. There is no sense in reinventing the wheel. Second to previous knowledge is risk: taking the time to think through and document the risks can provide the scientific justification, or point to the data or change needed to mitigate the risks.”

Quality risk management—the systematic process for the assessment, control, communication and review of risks to quality across the product life cycle—also is essential. Risk management can be a proactive approach for identifying and controlling potential quality issues during development and manufacturing and facilitating more informed (risk-based) decisions. It also will maintain consistent quality through the product life cycle (happier customers). ICH Q9 OEMs can streamline the product design and subsequent approval process by establishing an internal quality system that is compliant with ISO 13485 and the FDA’s Quality System Regulation. If needed, OEMs can file and maintain a Device Master File with the FDA that holds the technical information for a manufacturer’s product, which can be referenced by the submitter of the 510(k)/PMA.

Whether your product is a complex new technology or a variation on an existing design, Stegmeier indicates there are several key things OEMs can do to make the process go more smoothly:

• Put effort into determining and documenting the design requirements—make sure you consider the pertinent standards, guidance documents and regulatory requirements when developing these mandates;
• Prepare well-written design verification and validation test protocols and reports; and
• Prepare a summary document, if the customer is handling the device submission, that describes the product and the testing performed using the Global Harmonization Task Force’s document “Summary Technical Documentation for Demonstrating Conformity to the Essential Principles of Safety and Performance of Medical Devices” as a guide.

“Follow your design control process from the beginning of the product design,” concluded Stegmeier.
“If used as intended, a good design control system will help you bring the right product to market faster and less expensively.”

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Mark Crawford is a full-time freelance business and marketing/communications writer based in Madison, Wis. He can be reached at [email protected].