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Applying Risk Strategies to Implantable Devices
Risk evaluation and mitigation strategy (REMS) is a regulatory technique implemented by FDA to ensure that the benefits of a specific drug outweigh its associated risks. Before REMS was developed, FDA recommended that drug producers apply risk minimization action plans (RiskMAPs) to mitigate the known risk of a product while preserving its benefits. However,
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Begoña Narvaez |
FDA determined that it needed to have a better control of the information that patients were receiving from healthcare professionals and drug producers regarding the risks associated with certain drugs. With the FDA Amendments Act of 2007 (FDAAA), FDA received the authority to require any drug producer to submit a proposed REMS as part of the application for approval of a new drug product, or at any time during a product’s life cycle, if FDA becomes aware of new safety issues concerning the drug. In addition, if there is a violation, FDA can apply monetary penalties or retire the product from the market and take appropriate legal action.1 The impact of REMS on drugs and drug development has received attention in the professional press.2-4
REMS is intended to indentify, analyze, evaluate, control, and monitor the risks regarding a drug product during its entire life cycle, and to ensure that the information healthcare professionals and patients receive regarding the risks involved in the use of the product is correct and complete. It also gives the agency better postapproval control of the drug.
Some of the activities proposed in REMS include developing premarket studies, monitoring product safety, restricting product distribution, and establishing postmarket studies. The goal is to assess the known risks and identify new risks, and guarantee that promotional communications do not overwhelm the effective communication of the product risks. Although developed for drugs, this type of strategy would seem to have clear parallels with respect to a range of medical devices, including implants.
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William A. Hyman |
An Application for Risk Mitigation: Medical Implants
As in the case of drugs, FDA has been criticized for lapses in its ability to keep unsafe devices, including implantable devices, off the market, or to get them removed from the market if new and significant risk information develops. The major claim against current FDA processes is that the 510(k) premarket notification process to approve most Class II devices is inadequate, at least in some cases. Critics have cited a lack of formal clinical trials for Class II devices, even with regard to some permanent implants. This has been part of the controversy over metal-on-metal total hip replacements and their clinical performance.5 The ability to introduce certain changes in devices under the manufacturer’s self-analyzed no-510(k) rationale can lead to additional performance issues. The 510(k) process is currently under study by the Institute of Medicine on behalf of FDA.6 In addition, FDA has recently issued its proposed,and then revised, updates to the 510(k) process.7
Even the premarket approval (PMA) process for Class III devices evaluation needs to be stricter, according to some critics, in the light of the fact that various failures have occurred in devices that were approved with a PMA.8 It is argued by many that more stringent device clearance and approval processes, and more effective postmarket scrutiny and evaluation, are needed. Associated with these issues is the principle that patients should be better informed of device risks, including those of implantable devices. In addition, it is necessary to improve the interaction between FDA, implantable device manufacturers, healthcare providers who work with a given device, and patients to reduce, address, and communicate risks during its entire life cycle. FDA presented this life cycle approach in its 2010 strategic priorities.9
Current regulations regarding the information that healthcare professionals and patients should receive from a device manufacturer concerning a specific implantable device are limited. There are general labeling requirements and, for a few devices, specific regulatory guidance.10–12 However, these requirements do not address a specific and standard plan of how the information regarding the risk of implantable medical devices should be managed. FDA also has different ways to inform patients of the risks associated with implantable medical devices such as the FDA Patient Safety News and patient alerts regarding devices available on the FDA Web site.13,14 Consumer information is also a common part of new approval notices.15 However, the existence of these informative tools does not guarantee that the patient is receiving the correct information at the correct time. For that matter, they do not ensure that the patient is receiving any information at all since there is not a clear responsibility for providing the information to the patient. It also seems to be frequently overlooked that not everyone in the general public has readily available Web access, or that they would independently seek out such information.
Aside from regulatory requirements, some manufacturers of implantable medical devices have both professional and patient brochures, leaflets, manuals, online materials, and videos that contain information about their device. These items include descriptions of the proper use, risks and benefits, clinical data, as well as information on what to expect of the surgical procedure and the use of the device. Such material may also be available on company Web sites.
To improve patient safety and choice, and the quality of information in the entire process that an implantable device goes through, a consistent and more stringent method, such as REMS, should be applied as part of the clearance or premarket approval of at least higher-risk devices. However, as currently written, REMS would need some revision for it to be applied to medical devices.
Risk Requirements
At the present time REMS as mandated by FDA for drugs includes several different requirements that can be readily adopted to implantable devices. First, there should be a supporting document that includes the background of the device, the necessity to have a REMS, the explanation of how the strategy would ensure that the benefits of the device outweigh the risks, and the successes and failures of actions in mitigating the risks of concern for that product or similar products. The last item is quite important with respect to making the strategy and process relevant to the use of the device and the mitigation of its risks before adverse events occur. This document should also include a list of the goals for implementing REMS supported by specifically stated objectives. An assessment plan can determine the success of the goals or help a company evaluate whether the goals or the strategy need to be modified.1 This plan should be a component of all risk-mitigation strategies, as in ISO 14971, for example. There must be actual assessment of the effectiveness of the strategy as opposed to claiming risk mitigation without any demonstration that the mitigation has actually been achieved.16
Product Guide
The medication guide that FDA requires with the implementation of the drug REMS is similar to the device brochure that some manufacturers provide to their customers, patients, and healthcare professionals. However, the distribution of a medication guide is obligatory for some drugs. Because not all drugs (nor all implants) would necessarily require such a guide for use, FDA has clarified the circumstances in which a product guide should be submitted, as follows:
The product is one for which a guide could help prevent serious adverse effects related to the use of the product.
The product is one that has serious risks, relative to benefits, of which patients should be made aware, because information concerning the risks could affect patients’ decision to use the product.
The product is important to health, and patient adherence to directions for care or use, and observation of secondary reactions, are crucial for the interaction between the patient and the product to be effective.
The use of the word could in bullets 1 and 2 can be viewed as creating a relatively low threshold for the need to create and provide a product guide.
The product guide is one of the most important elements of REMS because it is the specific communication tool intended to inform the patient about the product they will be using and the risks this might represent. Although regulatory burden is always a concern, an advantage that exists when a regulatory organization is in charge of reviewing a product guide is that a standardized document can be developed to guarantee the information presented in it is correct, complete, and accurate, and that the patient will find it useful and easy to read.
In general, the following information should be included in a medical device product guide:
A simple explanation of the implantable medical device, describing how the device works, the maintenance it requires, and how to identify potential problems with the device, including what to expect if the device is failing or fails.
The specific actions the patient should take in case of an adverse event.
The risks and benefits for the patient associated with the use of the device, along with existing alternatives to the use of the device.
A brief description of the implantation process and its potential surgical and postsurgical complications.
A reasonably detailed description of the recovery process and period.
The reactions a patient should expect from the interaction between his or her body and the implanted medical device.
The changes the patient will need to make in their lifestyle after implantation and recovery.
A description of the types of people and situations for whom the device would not be a good choice.
Other information that would enable the patient to make an informed decision about the use of the implantable device.
Contact information for the manufacturer, and implanting physician, and other relevant physicians.
An implant card, which the patient should always carry, that informs other healthcare professionals that the patient has a specific medical device implanted.
The implant card should include contact information for the physician who implanted the device, full device identification, the date of implantation, and other relevant information.
In addition, a different product guide should be provided to the health professionals who will be responsible for implanting and managing the device.
These requirements extend beyond adequate directions for use as required in FDA regulations, including a broader interpretation of who is the user of a medical device. They also extend beyond the current reliance on the physician to adequately inform the patient in the absence of patient-specific documents or guidelines.
Communication Plan
The manufacturer’s communication plan should be a group of letters directed to healthcare professionals and directors from the hospital areas who will be interacting with the implantable medical device and the patient. The communication plan should include information that encourages the physicians and the hospital to implement REMS elements, an explanation of safety protocols, and information about serious risks related to the implantable device.
As adopted from drug REMS, such letters should include the following:
A brief description of the device and when it should be used.
A statement that emphasize to the physician the importance of distributing the product guide to the patient and encouraging the patient to review the guide and ask questions.
The known risks of the device.
The health condition that the patient must have in order to have the device implanted (indications).
The specific changes in the patient that healthcare professionals should watch for after implementing the medical device.
Instructions to the physician to encourage the patient to report signs of infection or other adverse occurrences.
Description of additional actions the physician must take in case the patient presents a case of infection or other adverse response.
The complete contact information to whom physicians must report an adverse event related to the implantable medical device.
In addition to providing the specific information indicated, these letters will help establish a functional communication channel between the manufacturer and healthcare professionals who are responsible for the implant.
Elements to Assure Safe Use (ETASU)
The elements to assure safe use are a reinforcement of the other REMS elements already discussed. As a consequence they are only required by FDA in situations in which the existing elements are not sufficient to mitigate risk.
The ETASU might include
The requirement that the healthcare professional who implants the device has particular training or is specially certified, and has adequate experience.
The certification of the healthcare setting in which the implantation procedure will take place.
Evidence that the patient understands the risks and benefits of the device through the use of appropriate consent forms.
Patient and physician agreements, or other informed consent, in which a monitoring plan is established.
The enrollment of the patient in a registry to document device outcomes, safety information, and provide data on the impact of the risk management tools with respect to ensuring compliance and outcomes.
Some elements of this list do exist within medical device regulations. However, these requirements are scattered and not uniformly identified as part of a generic risk-management strategy. For example, FDA can restrict the use of a device to appropriately trained professionals and facilities under section 520(e) of the Food, Drug and Cosmetic Act (FD&C Act) if it is determined “that such a restriction is required for the safe and effective use of the devices.” Informed consent is a general requirement for all medical care, although the degree to which it functionally occurs is open to question.
FDA can mandate monitoring plans in the form of postapproval studies as a condition of premarket approval. Public implant registries have been discussed from time to time. They are included in the Patient Protection and Affordable Care Act, wherein a National Medical Device Registry is added to the FD&C Act to “facilitate analysis of postmarket safety and outcomes data.”17 Such systems already exist in other countries (e.g. for selected devices in Australia, Canada, and the European Union). They have generated important information on actual device performance. Various private sector and proprietary registries also exist.
Implementation System
The implementation system consists of steps that the applicant, producer, or manufacturer of the REMS should take to evaluate and monitor the implementation of the strategy by healthcare providers and other professionals.
The objective of having an implementation system is to plan and organize the way the product will be managed, as well as how and when the patient receives the information necessary to make the decision about choosing the medical device.
To monitor and evaluate the implementation of the REMS with ETASUs, the applicant requires a database of practitioners and healthcare settings, along with their certification status (if appliacable). Applicants would then conduct audits to ensure compliance with the REMS.
Timetable for Submission and Assessment of the REMS
Specific dates would have to be established for future evaluation of the compliance with the REMS for each implantable medical device to ensure that the benefits of the device outweigh the risks. Furthermore, some factors, such as the size of the population that is likely to need the device, the seriousness of known potential risks that may be related to the device, and knowledge about the effectiveness of the REMS, may require additional timelines for assessments. Under a regulatory approach, this timetable would be a requirement by FDA.
The Good and the Not So Good
Having FDA further require the active management of the risks associated with an implantable medical device through the use of specific plans such as REMS could have significant benefits. For example, the access to the collected data regarding adverse events from different sources could give FDA and the medical community a better chance to take appropriate action in a timely manner. Also, making REMS a requirement could improve the coordination and communication between the manufacturer, healthcare professionals, and patients so everybody knows and understands both the risks and their respective responsibilities.
The application of REMS to implantable medical devices could increase the quality of those devices as a result of greater attention to risk. This could make an incremental improvement in patient and physician confidence, as well as in actual outcomes. In addition, if the patient has the correct information about a device it may enable wiser choices as to whether the device is appropriate for them. Better information may also improve the patient’s ability to recognize adverse events early and take the appropriate and specified action. Early intervention can make correcting problems much easier, especially if they are caught before there has been considerable secondary damage, such as wear debris, for example.5
The adverse side of REMS is the perception and reality of regulatory burden and its associated cost, especially in the absence of proven benefits. Both manufacturers and healthcare professionals may not be very happy with the implementation of REMS for devices due to the fact that it represents more office work and documentation. More importantly, it represents significant new activities, such as provider certifications and structured training. These activities increase costs without a guaranteed corresponding increase in revenue.
Device manufacturers would also face increased complexity, time, and cost requirements in launching a new product. Nevertheless, they can justify the ultimate cost of the device because they are offering a safer product with a safer application. They would benefit from the fact that implementing risk management during the development and premarket process may reduce adverse events, and the subsequent surprises that could be more costly than the early investment. This is the business case for risk management, which argues that such activities are good for the company and good for the patient, and therefore possess inherent value aside from fullfilling regulatory requirement.
Conclusion
Because the implementation of REMS for drugs is recent, the value of increased focus on risk management is still unknown. However, REMS will certainly change the strategies applied to launching new drugs and how risks are monitored postlaunch. Moreover, the way manufacturers are applying risk management should change. Internal processes, team makeup, and training must increase, and the way information is provided to healthcare professionals and patients must be better structured and better developed. REMS will also control and restrict promotion of products.
One of the challenges that FDA is facing with the implementation of REMS for devices is the same as the general problem of regulating medical devices. Because every product has specific risks, it is difficult to establish standard documents that are broad enough to be applicable to all products, yet specific enough to actually be useful. However, FDA has established a standard REMS framework that decreases the interpretative burden on manufacturers during the application of the REMS to their products, and helps FDA in evaluating submissions.
As REMS documents become known it is important that the public understands that a REMS requirement it is not a brand or product deficit. On the contrary, it is an opportunity to actively manage the communication of critical information.2 It is also crucial to ensure that the physicians do not substitute more limited and ad hoc verbal information for the written information that manufacturers will be providing.
It seems logical that a parallel system should exist for high-risk medical devices. The principles that apply to drug risk management should also apply to devices. so These are products for which safe and effective use would benefit from enhanced risk-management strategies beyond those already required under the quality system regulations and other laws. Moreover, a manufacturer need not wait for a generic or product-specific order to understand and implement at least those components of REMS that would enhance the patient’s experience with their product. As with all new strategies, adopting REMS represents a big effort at the beginning, but in the long term, the quality of medical products, could be improved, along with patient outcomes, and thus everyone will benefit.
References
Guidance for Industry Format and Content of Proposed Risk Evaluation and Mitigation Strategies (REMS), REMS Assessments, and Proposed REMS Modifications, Drug Safety, FDA (Silver Spring, MD) September 2009.
R Robinson, “Risk Evaluation and Mitigation Strategy: Take Hold,” PharmaVOICE 7, no. 3 (2009): 10–14.
“Risk Evaluation and Mitigation Strategies (REMS) Under FDAAA,” Beckloff Associates Inc. (Overland Park, KS; October 2009); available from Internet [pdf]: www.cardinalhealth.com/beckloff/documents/pdf/REMS-white-paper_final%20100509_website.pdf.
P Garces and L Jacks, “REMS and Drug Development,” Contract Pharma (January/February 2010); available from Internet: www.contractpharma.com/articles/2010/01/rems-and-drug-development.
B Meier, “Concerns Over Metal on Metal Hip Implants,” The New York Times, (March 3, 2010); available from Internet: www.nytimes.com/2010/03/04/health/04metalhip.html, accessed April 28, 2010.
“Institute of Medicine to Study Premarket Clearance Process for Medical Devices,” FDA (Silver Spring, MD): available from Internet: www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm183497.htm.
CDRH Plan of Action for 510(k) and Science, FDA (Silver Spring, MD); available from Internet: www.fda.gov/AboutFDA/CentersOffices/CDRH/CDRHReports/ucm239448.htm.
M A Garber, ”Modernizing Device Regulation,” The New England Journal of Medicine 362, no. 13 (2010): 1161–1163.
CDRH FY 2010 Strategic Priorities, FDA (Silver Spring, MD); available from Internet: www.fda.gov/AboutFDA/CentersOffices/CDRH/CDRHVisionandMission/ucm197647.htm.
Labeling-Regulatory Requirements for Medical Devices, FDA (Silver Spring, MD); available from Internet: www.fda.gov/downloads/MedicalDevices/DeviceRegulationandGuidance/GuidanceDocuments/UCM095308.pdf.
Guidance on Medical Device Patient Labeling: Final Guidance for Industry and FDA Reviewers, FDA (Silver Spring, MD); available from Internet: www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/GuidanceDocuments/ucm070782.htm.
Guidance for Industry and FDA Staff—Non-Clinical Engineering Tests and Recommended Labeling for Intravascular Stents and Associated Delivery Systems, FDA (Silver Spring, MD); available from Internet: www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/GuidanceDocuments/ucm071863.htm.
Safety News, FDA (Silver Spring, MD); available from Internet: www.fda.gov/psn.
Patient Alerts, FDA (Silver Spring, MD); available from Internet: www.fda.gov/MedicalDevices/Safety/AlertsandNotices/PatientAlerts/default.htm.
Recently-Approved, Boston Scientific—Express LD Iliac Premounted Stent System, Patient Information Guide, FDA (Silver Spring, MD); available from Internet: www.accessdata.fda.gov/cdrh_docs/pdf9/P090003c.pdf.
ISO 14971, Medical Devices—Applications of Risk Management to Medical Devices, International Organization for Standardization (Geneva); available from Internet: www.iso.org/iso/catalogue_detail.htm?csnumber=38193.
Subtitle C—National Medical Device Registry, Section 2521; available from Internet: http://docs.house.gov/rules/hr4872/111_hr4872_reported.pdf.
Begoña Narvaez is an undergraduate student of Biomedical Engineering at the Universidad Iberoamericana in Mexico City. William A. Hyman is a professor with the department of biomedical engineering at Texas A&M University.
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