More Questions, Fewer Answers
Being proactive is the best approach when dealing with the FDA.
Ask a medical device company these days about what it thinks of the U.S. Food and Drug Administration (FDA) and you run the risk of the response being highly censorable.
The clearance process for new medicaldevices is taking longer and involves more scrutiny. The agency is asking more questions, initiating additional review cycles for requests for information and asking for greater amounts of clinical data. Industry has been crying foul about a lack of transparency, predictability and sluggish review times that critics claim is having a chilling affect on new technology and medtech firms’ ability to innovate and compete in a global market.
“For example, a manufacturer performs a cleaning validation in the same manner for its modified device as it had done for the original,” explained Cynthia Nolte, principal consultant for Medical Device Consultants Inc. (MDCI), a medical device consulting company recently specializing in quality and regulatory compliance based in North Attleboro, Mass. “In the intervening time, the FDA has added additional requirements for cleaning validations that are not published in any guidance document or other communication, so the company is asked to conduct additional testing.”
There also is more sharing and overlap between review centers within the FDA. The FDA is paying increased attention to human factors in device development. The agency has hired more reviewers, some of whom are inexperienced and don’t know what to ask, or are confused themselves about some of the technological details.
“As the FDA struggles to keep pace with more complex technologies, there can be instances where FDA reviewers may not fully understand the technology and the issues surrounding the technology, and therefore—despite their best efforts—ask questions during the review of the submission that are not relevant,” said Helen Mayfield, regulatory associate with MDCI.
Especially frustrating for companies are the new rules that give them less flexibility to modify indications for use statements for submitted 510(k)s. Testing that previously was used to support a product submission is no longer acceptable for similar products.
All of these changes add up to confusion, uncertainty and frustration for medical device companies, which are confident of their science and products, and are eager to get them to market.
“There is no question that, in our recent experience, the FDA is getting harder to deal with,” said Alan Schwartz, executive vice president for mdi Consultants Inc. in Great Neck, N.Y., an FDA regulatory affairs and quality assurance consulting firm. “There are no timeframes for many issues involving FDA review of documents and, where there are time frames, the FDA doesn’t honor them or have reasons for delays. Their communication with the industry is abysmal. You can be calling the agency to get some idea of where a review presently stands, or when the FDA will get to the file, and there is no call back or return e-mails.”
Schwartz also indicated that the FDA quality system regulation (QSR) requirements for importers (particularly those who import from China) are being unfairly scrutinized, especially since the FDA has given them no guidance to follow.
“The quality of the devices coming from China is not the best and they often have too many problems,” said Schwartz.
“However, the FDA is putting pressure on the importer/distributor for the quality, not the Chinese manufacturer where it belongs, especially for Class I devices.”
Most medical device consultants and regulatory experts believe the FDA is trying to do the right thing, which is protect the end-user from harm—which should be the goal of every medical device manufacturer. However, the industry often knows more than the FDA when it comes to emerging technology and the FDA is trying to catch up by adding more examiners, training them and issuing new guidance.
Technological and scientific discussions between industry representatives and FDA reviewers are on the rise as they strive to achieve the appropriate exchange of information.
“With the fast pace of technology, it’s understandable why the FDA needs a clear and concise understanding of the new devices in the industry,” said Jim Mewborne, manager of regulatory affairs for Rhythmlink International LLC, a Columbia, S.C.-based manufacturer and distributor of biomedical devices and accessories. “For example, in the past, a question concerning sterilization could be addressed by an affirmation of compliance. Now we are required to submit a well-defined data set to confirm we have provided all parts of compliance that the client is claiming. This gives everyone involved the necessary determination of safety and efficacy for new and evolving medical devices—the FDA just needs to be more clear, consistent and efficient in conveying these requirements.”
Impact to Manufacturers
Medical device companies are frustrated about the additional time and cost for product clearance—as well as the lost market advantages that result from these delays. They are highly concerned about how the turmoil at the FDA will impact their 510(k) filings and worry that additional testing may be required.
“In fact,” said Schwartz, “this present situation with the agency is similar to what it was like in 1992-1993 when approval times for devices were so long that many companies pulled their R&D out of the U.S. and moved it to Europe. We are starting to hear this rumor again.”
Many agree the FDA’s uncertainty and inconsistency is hurting the product development pipeline and industry investment.
“It appears that this unpredictability, coupled with today’s investment climate, has especially hurt innovators with new product ideas for the marketplace,” said Christine Hansen, product marketing manager for Epicor Software Corporation, a Livermore, Calif.-based provider of enterprise resource planning software solutions for the medical device industry.
Much of this unpredictability, however, results from the ever-changing technologies used in the medical device industry and the efforts the agency must make to assure safety and efficiency in newer devices. In most cases, the intended use has not changed. Instead, the technology surrounding the old device has improved.
“The industry is then required to use a substantial equivalence concept to show the new device is similar to the old device,” said Mewborne. “In a growing number of cases, smaller devices are being put together to improve the information being provided to the surgeons and healthcare providers—substantial equivalence does not convey the improved safety and efficiency; rather it places undue burden on the industry to ‘make it’ substantially equivalent to get it to market.”
Perhaps the biggest FDA bone to pick is the 510(k) process, which has become highly restrictive and much more time-consuming. In fact, the process has gotten so unwieldy that in July a report issued by the Institute of Medicine suggested scrapping it altogether. The 510(k) process is now very strict with intended use—a response to criticisms that the FDA was potentially allowing risky devices to move into the marketplace without appropriate regulatory oversight.
“The 510(k) that used to be its own submission is now a mini premarket approval (PMA) application with reams of information,” said Schwartz. “The time to review is even longer than a PMA in some cases. The expense of regulator compliance continues to get higher, including getting products off the import alerts. The time delays and extra unexpected costs are having a hard hit on these companies.”
According to Caleb Rancourt, business intelligence specialist for Polymer Solutions Inc. in Blacksburg, Va., a provider of analytical testing and consultative support to medical device companies, the biggest problem may be the differences that exist between the 510(k) process and the traditional premarket approval process.
“The 510(k) process is cheaper and quicker than the traditional premarket approval process,” he stated. “As a result there is an indirect incentive for an organization to pursue a 510(k) submission, even though a traditional PMA submission may reduce overall risk in taking a new device to market. When a device makes it to market through the 510(k) submission process, post-market studies are not always conducted as frequently as they should be, and this is an opportunity for industry to improve.”
The FDA is trying to make the process better by issuing more guidance documents. The agency has strongly encouraged all stakeholders in the 510(k) process to provide their comments on newly issued drafts, recognizing that industry input will help shape more meaningful guidance.
“However,” noted Nolte, “not all of the FDA’s thinking is contained in current guidance documents. This is a challenge for companies who are not actively engaged with FDA, and who do not take advantage of both formal and informal opportunities to meet and speak with FDA review staff.”
What Companies Can Do
Communicate—then communicate some more. After all, the FDA wants feedback during the comment period; they know they are behind with technology advances and genuinely seek more information to improve its procedures. Giving feedback to the FDA also is an opportunity for both sides to more clearly understand each other, experts told Medical Product Outsourcing.
“If you don’t do your best to impact the process, then you can’t complain about the result,” said Nolte pointedly. “In manyinstances only a few comments are received at the public docket for a draft guidance document or proposed policy.”
Do your 510(k) homework. Know what the FDA expects. Make your application look good and include all the proper information (try to obtain FDA input prior to filing if there is any degree of uncertainty as to requirements). Develop a reputation at the FDA for delivering outstanding documents.
“Present all the evidence in a logical, sequential manner,” advised Tina Wu, regulatory associate with MDCI, an Aptiv Solutions company. “Write clear conclusions based on the data. Point out all positive and negative data and explain what it means. All data and all conclusions have one goal: to prove the safety and effectiveness of the device. All testing should be done to high scientific standards (for example, have a control, use appropriate number of samples, do side by side testing if possible, etc.). Picking out the right predicates is very important and should be done as a first step in the process.”
To gain further insight, companies also can request early meetings with the FDA—a pre-submission meeting to review an upcoming 510(k) or PMA is especially beneficial for new or complex devices; for example, it can be used to gain feedback before submitting a 510(k) or request advice on data requirements for expanding a product’s intended use.
The meetings don’t necessarily speed things up (time to get a date easily can be three months), according to Harold Kaefer, Rhythmlink’s director of engineering, but getting constructive feedback from the FDA regarding its expectations can be beneficial and hopefully makes the 510(k) process smoother and more predictable.
For example, many companies use an informal pre-IDE (investigational device exemption) process prior to an application for the purpose of gaining insight from a FDA review team and presenting their product and testing or clinical plan. The term pre-IDE actually is a misnomer, because virtually all of these meetings occur without the company submitting an IDE.
Be careful not to ask for a meeting too early in the process; it’s usually best to request the meeting after the prototype has been made and preliminary data is available. Meetings usually are about an hour in length, so keep the company introduction short and focus on your questions for the FDA.
To stay on target Wu suggests practicing for these meetings.
“We find that manufacturers are so focused on their device/product they cannot see the bigger issues being raised by the FDA,” she said. “As consultants, we are unbiased and understand the FDA’s thinking. We moderate pre-IDE meetings so attendees do not become fixated on some irrelevant detail and go off on a tangent.”
Ultimately the FDA calls the shots, so don’t fight with them; do your best to build a relationship and a reputation for thoroughness. Be unbiased in discussions with the FDA and don’t get defensive. Be open and honest.
“If the FDA says something that you do not agree with, don’t start arguing with them,” advised Wu.
“Know that the FDA cannot promise you anything. We have found it’s hard for our clients to remain unbiased and calm when speaking with the FDA, so we often are tasked with communicating with the agency. These discussions offer an excellent opportunity to gain insight into FDA’s thinking. Quite often we find that what the agency thinks today is different from the information in current guidance documents.”
Only submit an application when all known requirements have been fully addressed. If a company files prematurely it may lose credibility with the FDA due to an inadequate submission. This may result in several new rounds of questions that cannot be answered within the review period. If this happens, the company could, for example, receive an NSE (not substantially equivalent) designation during a 510(k) review process and be forced to resubmit a more complete submission with the missing information.
“The FDA has complained recently that a large amount of reviewer time is spent with companies who submit poor-quality documents,” said Wu. “These documents are poorly written and not organized in a reviewer-friendly matter. They also may be missing information. Be sure to engage strong science-minded regulatory team members who can critically write a solid 510(k).”
The key to regulatory success is bringing the right information and data together effectively and quickly—of course, with the evolving FDA regulations, there is a lot more information to be gathered, analyzed, connected and presented.
“To make sure we have the mostup-to-date information and data, we have moved from filing with an enterprise solution to a product data management system,” said Mewborne. “This is a big movement in the industry and is all about document and data management control. Our system helps our organization find and access data and documents quickly and effectively.”
Rhythmlink interviewed multiple vendors, received demos and quotes and, most importantly, visited users whoactually were using the systems the company was considering purchasing. ”We selected a high-end solution because it allowed full electronic approval process with proper validation, is user-friendly and can be integrated with our CAD software,” said Kaefer. “Part of the purchase cost included assistance in setup and configuration, as well as a significant amount of training for various levels of users (administrators, power users, regular users). We are in the early stages of implementation so far, but are very happy with its performance.”
Systems today are built using Web services and a service-oriented architecture, according to Hansen.
“This architecture is ready to meet the changes in compliance standards that may be enacted overnight and offers the controls to translate a company’s unique business rules in the system where needed,” he said.
Software management solutions include product data management, enterprise resource planning,
supply chain management and human capital management. In particular, business process management can be used on any event in the system.
“For example, a piece of inventory is moved into a status of quarantine,” said Hansen. ”Once an event happens that meets the criteria, an action can occur. Perhaps the material is put on hold, or an e-mail is sent to the supplier letting them know about the event. All of these controls can be used within
medical device businesses to effectively automate and control any process that is needed in the manufacture of medical devices. Because it is automated, it can be validated and the human approvals can be eliminated.”
Integrated product lifecycle management also is an increasingly popular way to automate and control internal workflow and ensure the necessary documentation is complete, up-to-date and meets the standards required by the FDA for acceptance. Other programs can track customer relationship management, complaint management, production management, quality performance, procurement and serial and lot traceability.
“These are all invaluable tools to ensure medical device manufacturers, as well as their supply chain partners, can comply with FDA standards,” said Hansen.
More Change to Come
One thing is certain—the regulatory environment will change. Therefore, medical device companies need to be operationally ready to respond to these changes as they happen. For example, conducting realistic internal audits (and doing your own corrective and preventative actions) will make your company “audit-ready” for when the FDA comes knocking.
“We frequently conduct internal audits of all areas of our quality system and make sure that every employee is trained to perform them,” said Rancourt. “Employees also perform internal audits in areas that fall outside of their departments to make the audits more objective. This also provides them with the opportunity to experience new aspects of our organization.”
Rhythmlink has two staff members who are certified as ISO 13485 auditors and intends to train two others.
“Self-examination is the only way for long-term effectiveness to stay ahead of changing trends and updates in standards,” said Mewborne. “This self-examination also supports the management of risk to both our customers and to our industry.”
MDI Consultants performs mock FDA audits and internal auditing for its clients. Schwartz noted the biggest surprises for clients usually are corrective and preventative actions, how to perform root cause analysis, and the requirements for design validation, risk analysis and design transfer.
“We use these audits to help companies understand the FDA’s main areas of concern,” said Schwartz. “Training auditors is critical to the success of the audit process. Auditor training effectiveness can only be determined with proper follow-up by the company to check on the auditing trails and findings, as well as any corrective actions.”
It is darned tough for medical device manufacturers to stay on top of the constantly shifting regulatory environment. For example, the FDA is increasingly sharing information between the centers; regulatory professionals need to be aware of how this may impact device submissions. Consider hiring an experienced regulatory consultant—because they work for multiple clients within the industry, they tend to have the most valuable insights on how the FDA approaches a particular device or indication. They can help with gap analysis, risk management, quality improvement and other measures to improve your working relationship with the FDA.
“These regulatory trends are increasing both the time and effort required to get new products to market,” concluded Mewborne. “Both the industry and the FDA need to work more closely together to improve the way things are done. Hiring an experienced consultant adds between $5,000 and $20,000-plus to the budget, but it’s likely worth the investment, especially for scheduling pre-IDE meetings, clarifying FDA expectations, eliminating mistakes and streamlining the 510(k) process.”
Mark Crawford is a full-time freelance business and marketing/communications writer based in Madison, Wis. Contact him at firstname.lastname@example.org.