Introduction
A regulatory/reimbursement product plan should be created simultaneously, early in the product development cycle, with the concept of developing ongoing evidence to support appropriate device use. If each is treated separately and implemented linearly rather than collectively, significant market access delays and restrictions can be anticipated. Outlining clinical study protocols with regulatory agencies and payers is necessary to demonstrate whether the product is not only safe and effective but also reasonable and necessary, providing value to the health care system. An evidence development strategy sensitive to the needs of regulators, payers, and providers—when successfully implemented—allows patients faster access to life-saving technologies. This chapter provides global historical content impacting our current regulatory/reimbursement environment and defines the necessary course to patient access. The case study of mechanical circulatory support provides many elements of a successful regulatory/reimbursement evidence-based strategy.
History of medical device regulations
Within the realm of US Medical Device Regulation and Reimbursement, medical devices went largely uncontrolled from a regulatory standpoint until the late 1930s, when Congress enacted the Federal Food, Drug, and Cosmetic Act of 1938. This established the Food and Drug Administration (FDA) as a separate law enforcement agency to regulate mainly drugs but also medical devices and required they be proven safe before they could be marketed. Until 1938, medical devices were developed and marketed in an unregulated way, including eyeglasses (1752), the stethoscope (1815), the x-ray machine (1895), the electrocardiogram device (1903), and the world’s first cardiac pacemaker (1936). In the early 1950s came the first use of a mechanical heart manufactured by General Motors, and by the late 1960s, the world saw its first heart-lung bypass machine and mechanical artificial heart. Developments in medical devices and surgical procedures led to the first heart transplant (1967), performed by a South African surgeon Dr. Christiaan Barnard. The patient, a 53-year-old man, died 18 days later, but this event started what is now regarded as one of greatest medical achievements of our time, made possible by the advancement of medical devices.
In 1966, another regulatory milestone was established under the authority of the US FDA called the Fair Packaging and Labeling Act. This act required all US foods, drugs, cosmetics, and medical devices in interstate commerce to be honestly and informatively labeled. Furthering the regulation of medical devices, the US Legislature passed the Medical Device Amendments Act of 1976 to establish a classification and control process to ensure the safety and effectiveness of medical devices. The amendments also required manufacturers of medical devices to register with the FDA, follow quality control procedures, and established premarket-approval (PMA) requirements for certain types of medical devices. It was not until the early 1990s when the next milestone relative to regulation of medical devices occurred. The US Legislature passed the Safe Medical Device Act of 1990, requiring nursing homes, hospitals, and other facilities that use medical devices to report to the FDA incidents that suggested that a medical device probably caused or contributed to the death or serious injury of a patient. The Act also required manufacturers to conduct postmarket surveillance on permanently implanted medical devices whose failure might cause serious harm or death and to establish methods for tracing and locating patients depending on such devices. It also authorized the FDA to order medical device product recalls and other actions.
In 1997, after complaints of a slow medical device approval process from medical device manufacturers, the Legislative branch enacted the Food and Drug Modernization Act to accelerate review of medical devices. The Modernization Act exempted premarket regulatory requirements for all Class I medical devices (low risk) that are not intended for critical human health. In 2002, the Legislature passed the Medical Device User Fee and Modernization Act, which mandated fees to medical device companies for evaluation or approval of medical devices. Provisions were also established for medical device manufacturing inspections by accredited third parties and new requirements emerged for single-use medical devices. Then, in 2005, the Medical Device User Fee and Stabilization Act was passed, which amended the original Medical Device User Fee and Modernization Act of 2002. This allowed the FDA to change how it uses the user fees and requires development of better regulatory systems to support effective and timely product reviews and also allowed it to enact new regulatory reforms, all aimed at bringing safe and effective devices to market sooner.
Finally, there are two additional pieces of legislation aimed at aiding in the FDA’s goals to protect and promote public health while providing timely access to safe and effective medical devices; the FDA Amendments Act of 2007 and the FDA Safety and Innovation Act of 2012. Both these legislative acts reauthorized user fees to provide resources to the FDA, aimed at timely review and approval of medical devices. These include improvements in the approval submission review process, codification of the use of interactive reviews to speed the review process, better FDA guidance development, and authorized FDA resources for improvements in reviewer training and review performance tracking.
Fig. 21.1 is a timeline of regulatory milestones from the inception of regulation through the current day.
History of Reimbursement in the United States
In 1965, the Federal Government created the Medicare program to combat the difficulties that people over 65 years had in getting private health insurance coverage. Remaining relatively static until the late 1990s, in the early 2000s, the program experienced a myriad of changes, including a name change. Previously called the Health Care Financing Administration, the Agency under the Department of Health and Human Services was renamed the Centers for Medicare and Medicaid Services (CMS). Along with this name change came several changes in Medicare benefits and the associated payment structures, which have evolved to shift away from fee for service to a more quality- and value-based payment system through legislative changes.
Throughout this evolution, Medicare has become both the most transparent and the most influential payer in the United States. The payment systems, decisions, and policies from Medicare often influence the decisions and policies of private payers and other governmental programs.
Naturally, private or commercial payers continue to provide insurance coverage, mainly for employed Americans and their families. After World War II, President Truman lobbied for universal health care coverage, but the appetite of the Federal Government to fund such an endeavor was not there and the proposal failed as it was seen by many Americans as a form of socialism. Labor unions took over the charge and campaigned for employer-sponsored health insurance, which grew steadily from the 1940s and by 1960 had grown to nearly 145 million people covered.
European Medical Device Regulations
Until the mid-1980s, each European country had its own approach to regulating medical device use. This made commercialization of medical devices within Europe very difficult for device manufacturers because each country had their own set of regulatory requirements. Some were less stringent and some were extremely complex, making it difficult for patients to access new technologies as they were developed. To remove individual country barriers within Europe, the New Approach to device regulations and the Global Approach to conformity assessments were developed. Medical devices that are granted market access using the New Approach can be recognized by the Conformité Européenne (CE) Mark. New Approach directives were harmonized across European Union (EU) member states, which allowed device manufacturers to comply with a single set of requirements to market devices within the EU. Approximately 20 New Approach directives came into force during the mid-1980s, resulting in the creation of a single European market for devices by December 1992. The Global Approach supplemented the New Approach by defining the basis for Conformity Assessment Procedures within the New Approach directive but does not give conformity assessment details; those are described in the directives themselves— The Guide to the Implementation of Directives Based on the New Approach and the Global Approach .
The EU has an open medical device regulatory system that is transparent, based on harmonized standards and spans all EU member states. Medical devices sold within the EU must meet the health and safety requirements set forth in the EU medical devices directives. These directives consolidate the EU regulatory requirements under one system, meaning that if a medical device receives CE Mark designation in one member state, it can be sold in all EU member states.
This standard-based framework has remained intact and relatively unchanged since its inception. However, in 2017, two new regulations on medical devices were adopted by the EU and entered into force in mid-2017. These two new directives will replace existing directives and will begin to be enforced after a transitional period of 3 years. These new directives contain a series of important improvements to modernize the current system, including stricter controls on high-risk medical devices, greater definition of oversight of the Notified Bodies that perform the conformity assessments, improved transparency, a tracking system for implantable medical devices, and reinforcement of rules governing clinical evidence that a medical device is safe for its intended use.
In summary, since the mid-1980s, medical devices placed on the market within the European community must bear the CE Mark indicating that the product complies with the applicable EU regulations and enables the commercialization of medical devices in 32 European countries.
Medical Device Regulations in Rest of World Markets
Countries such as Australia, Canada, Israel, Japan, New Zealand, Switzerland, South Africa, and member countries of the EU or of the European Economic Area have established a regulatory framework for approval and use of medical devices. Often, the approval process allows the leverage of experiences and regulatory approvals within other established markets such and the United States and EU. Others require specific clinical evidence within the country before regulatory approvals can be achieved. Many countries simply have not addressed the development of regulatory controls, and despite the efforts of organizations such as the World Health Organization, the International Medical Device Regulators Forum, and the Global Harmonization Task Force, a single specific set of non–country-specific standards for the regulatory control of medical devices remains elusive. However, work toward this goal continues on many fronts.
Global reimbursement
At this point in time, there is no global reimbursement pathway. Each country establishes medical coverage, creates adequate codes, and assigns a payment group for devices. However, there are country clusters with similar mechanisms in establishing reimbursement. Table 21.1 attempts to unify a noncentralized approach by country groupings.
| Cluster by Payment Type | Country | Dominant Market Access Requirements |
|---|---|---|
| Diagnostic Related Group (DRG) | Germany, Italy, Austria, Switzerland, Poland, Czech Republic | CE Mark and positive guidelines |
| Global budget | Canada, Scandinavian countries, Spain | CE Mark, hospital or regional budgets available for innovation, critical role of local providers and societies |
| Regional budget | China | NMPA (previously CFDA) approval, strong clinical claims, critical role of local providers and guidelines |
| Medicare budget | United States | FDA approval, reasonable and necessary, NCD with CED, clinical revenue during IDE trial |
| Payment categories | Japan | PMDA approval, clinical outcomes in Japanese patients, healthcare reform with focus on value underway |
| Listing with positive HTA | United States (private), France, United Kingdom, Australia (private), Belgium, Netherlands, Korea | Regulatory approval, strong clinical claims, cost-effectiveness, affordability, HTA, brand-specific lists, positive guidelines |
Regulatory pathways for mechanical circulatory support devices
Today’s mechanical circulatory support (MCS) include devices for acute temporary support, short-term support or bridge to transplant (BTT), long-term support or destination therapy (DT), and total artificial heart (TAH). For the purpose of illustrating the total product life cycle for MCS devices, we have chosen to focus on BTT and DT support devices as these are highly complex and used worldwide. The regulatory pathway to commercial approval for a MCS device is dependent largely on its intended use. Today, there are two primary intended uses for MCS devices, although this is evolving and may someday be reduced to a single intended use for advanced heart failure patients with hemodynamic compromise requiring MCS. The first is short-term MCS for advanced heart failure patients who are refractory to medical treatment and in need of hemodynamic stabilization either as BTT or for myocardial recovery, and the second is for DT where the patient’s options for either recovery or heart transplant are unlikely due to age, malignancy, or morbidity.
In the United States, MCS devices are considered Class III devices (regulatory classification) and require a PMA application from the FDA before commercialization can be granted. In the EU, MCS devices are also considered Class III medical devices and require approval of a Design Dossier from an EU Member State–appointed Notified Body before the MCS device can be commercially approved and placed onto the market. Significant preclinical design verification and validation (V&V) testing, animal testing, and data from prospective controlled human clinical evaluations are required to support the safe and effective use determination made by these regulatory bodies to gain commercial approval.
In major global markets, regulatory systems are used to establish medical device classification (Class I, II, or III) based on their function and intended use. Less critical medical devices (Class I) such as syringes, tongue depressors, and wheelchairs may be exempt or have the least burdensome premarket regulatory requirements. More complex medical devices (Class II) such as catheters and ventilators may have standards or controls that must be met to ensure their safety and effectiveness prior to PMA. The highest regulatory classification for medical devices (Class III) is reserved for those that support or sustain human life, are of substantial importance in preventing impairment of health, or present a high risk of injury or illness to patients. Medical devices in this highest regulatory classification include breast implants, knee replacements, pacemakers and, of course, MCS devices. Because of the high-risk, life-sustaining nature of these devices, the regulatory pathway to market approval is also the most comprehensive and rigorous. Most medical devices in this category require valid scientific evidence to support that they are safe and effective for their intended use. Usually, this comes from demonstrating that the medical device conforms to required standards and performing extensive, lengthy, and costly prospective controlled clinical trials.
Reimbursement pathways for mechanical circulatory support devices
Establishing reimbursement early in product development is essential for patient access. Although reimbursement is composed of coverage, coding, and payment, coverage—the conditions under which a product or service will be paid for—is the essential first step that drives ultimate access for patients and ideally is gained prior to the assignment of administrative codes or assignment into payment structures.
Before the launch of any MCS device, a comprehensive analysis of each of these reimbursement drivers is essential to market success. The primary path to payer coverage of a product, procedure, or service occurs when a product is deemed a “reasonable and necessary” medical treatment, but payers demand a further level of evidence to show effectiveness (does it work in the real world?) and efficiency (does it provide a better value?). The Advanced Medical Technology Association, an industry group representing medical technology manufacturers, has reported that CMS takes an average of 2 to 5 years to create coverage for a new product, with private insurers’ timeframes varying widely. The earlier the coverage process is initiated, the sooner reimbursement will be established. Perhaps most importantly, this 2- to 5-year anticipated timeframe for coverage can be reduced if a reimbursement plan is implemented early. When developing a reimbursement plan, the following questions should be asked and planned for accordingly:
- 1.
Where will this product fit in the larger health care arena?
- 2.
Will this product meet not only the US FDA “safe and effective” standards required for regulatory approval but also payers “reasonable and necessary” and likely “effective and efficient” requirements?
- 3.
How can the reimbursement adequately cover the cost?
Where Will It Fit?
There are three broad categories in which the technology or procedure could fit ( Table 21.2 ):
- 1.
Similar to another product already on the market (a me too device)?
- 2.
An expansion or different use of an existing technology?
- 3.
Truly new and innovative?
| Similar to Another Product | Expansion of Existing Technology | Truly New and Innovative | |
|---|---|---|---|
| Reimbursement components that must be developed | Confirm existing code and inclusion for coverage of this product | Alter coverage, coding, and payment to include this product | Create new coverage, coding, and payment structure for this product |
| Scientific evidence required | Usually FDA approval with same indications suffice for inclusion in existing coverage | Publication of controlled studies (usually one to two) | Publication of controlled studies (usually two to four) and cost-effectiveness data (publications or registry or both) data |
| Typical timeline after FDA approval | 6 months to 1 year | 1–2 years | 2–5 years |
Naturally, reimbursement is easiest to obtain with “me too” products because coverage, coding, and payment have been defined for the predicate product or products. In this case, the primary task is to ensure it fits within the structures created for the predicate product; in other words, it can be included under any existing coverage policies and is identified by using the existing technology codes, and the existing code(s) trigger appropriate payment.
“Indication expansion” of an existing technology often requires altering coverage, coding, and payment to address the new indication. Published studies supporting the proposed expanded indication and revisions of established medical policy are necessary to create additional coverage. Codes may need to be revised, including new code descriptions, which can trigger different payment rates.
If the product is a new and innovative technology, as the first MCS device was a new reimbursement structure must be constructed and implemented to address coverage, coding, and payment.
Wherever the product “fits,” a reasonable timeline for developing and implementing the reimbursement plan must be anticipated. If coverage, coding, and payment already exist for a similar product, 6 to 12 months is currently typical for getting this product positioned within the existing category. To modify existing or to obtain new administrative codes used to identify the product or service to payers—whether related to physician procedures (Current Procedural Terminology), the procedure to implant the device (International Classification of Diseases-10), or to the device itself (Healthcare Common Procedural Coding System)—the process usually takes approximately 1 to 2 years from the product’s launch. For new technologies, historically, it has taken 2 to 5 years to create national medical coverage or to substantially expand existing guidelines, and code creation follows along a similar path.
Mechanical circulatory support device total product life cycle
The Total Product Life Cycle (TPLC) is a conceptual framework for assessing any product or service. It is often used by medical device regulators in the context of a regulatory paradigm to guide the regulation of market-driven evolution of medical devices from conception, through premarket development, to widespread market use, and finally to obsolescence and replacement by subsequent generations of products. MCS devices are particularly unique in that they have one of the most challenging and potentially long lasting TPLCs of any medical device in its category. The aspects of the MCS TPLC and the regulatory and reimbursement considerations along the way are discussed in the next sections.
Design
Mechanical blood pumps are complex, electromechanical devices that must take over the workload of a weakened human heart to sustain human life for lengthy periods of time and, in many cases, for the rest of the patient’s life. Therefore, the device design is critical and must take into consideration not only ease of surgical placement, device electrical interactions, and emission effects with other medical devices but also human factors related to power, control, and situational awareness. In addition to design factors, and because the regulatory burden is so high, the requirements that must be met and documented to ultimately demonstrate preclinical and clinical safety must be taken into consideration at the earliest possible point in the design process.
Once the MCS device concept is established, prototyping begins. This is a rapid phase of iteration where the design evolves many times before the final configuration is chosen. It can be said that it is better to fail early and often in this phase because mistakes and design modifications in later stages of the TPLC become very costly and time- consuming, jeopardizing the MCS development project altogether. For planning purposes, it can be expected that this phase of the TPLC will take 1–3 years to complete. Users’ needs are of paramount importance in this phase and often involve outside expert advisory committees (clinicians, outside user communities, and patients) to help the MCS device developer meet the complex requirements associated with these medical devices. Rapid engineering feedback and design iteration are characteristics of this phase of the TPLC. Once the MCS device design is frozen, the next phase of the TPLC can begin, which is the preclinical engineering test phase.
Preclinical Testing
Preclinical testing is one of the most important and time-consuming phases of the TPLC for an MCS device. In general, MCS device developers should plan 4–5 years to complete this phase of the TPLC. A V&V master plan is first developed to define the testing requirements and the order in which they must be completed. A failure in this phase may mean an easy fix or may require a complete redesign, so this phase is one of the highest risk categories in the TPLC. Consideration must be given to material science, toxicity, biocompatibility, device characterization, limit testing, electrical safety, packaging, shelf life, software, reliability, sterilization, hazard analysis, manufacturability, human factor testing, and product quality requirements. Preclinical animal testing is also an important consideration in this phase and protocols should be developed based on prior experience, information within standards, and feedback gained from discussions with regulatory bodies. All preclinical testing should take into consideration the duration of intended use of the MCS device. In general, the longer the intended use, the longer the tests for safety and reliability should be conducted during preclinical testing.
It is usually early in this phase of the TPLC where there is the first opportunity to meet with regulators to discuss both design V&V requirements and plans for preclinical animal testing. In the United States, the MCS device developers may choose to request a presubmission meeting with the FDA to discuss and receive informal input on the preclinical testing strategy. If the developer is in the EU, they may choose to meet with their EU Member State Accredited Notified Body who will ultimately evaluate the design, perform a conformity assessment, review and approval the premarket safety and effectiveness data, and authorize the MCS device to be CE Marked, allowing commercial placement onto the EU market. There are two points in the TPLC where presubmission meetings can be useful, one is to discuss the preclinical V&V requirements, including in vivo animal testing, and the other is to review the clinical trial strategy, analysis plan, and study protocol. Since the preclinical testing depends heavily upon whether the MCS device developer has performed sufficient testing to begin human clinical trials, it makes sense that these topics are discussed with the device regulators in two separate and distinct time points within the TPLC.
Clinical Testing
The study design used to support safety and effectiveness for an MCS device should be carefully considered. A good study design developed collaboratively with study investigators is likely to produce the best possible outcomes. A poor study design can cause lack of interest, failure to complete the study, and possibly uninterpretable data, causing a loss of time and resources and rendering the MCS device unapprovable. One example of a successfully designed MCS device clinical trial is the MOMENTUM 3 study of the HeartMate 3. This was a prospective, randomized controlled trial that not only enrolled the largest number of patients of any previous MCS device study but also completed the enrollment in record time—a good example of what a collaborative effort with clinicians and regulators can mean in the execution of the clinical testing phase of the TPLC.
Efforts must be made upfront to design the trial so as to clearly demonstrate the MCS device is fit for its intended use. Other factors to be taken into consideration include study size, target patient population, duration of support, surgical considerations, statistical analysis, follow-up intervals, independent oversight committees, overall cost, and other factors that may be important for proper reimbursement once regulatory approvals are secured. In general, the clinical testing phase of the TPLC will take 3–5 years to complete. Some of the early MCS trials took twice as long to complete but less was known then compared with now, where device safety and performance characteristics are much more understood.
Sometimes, with a novel new MCS device or study design, it may be necessary to conduct a pilot study prior to beginning a pivotal trial, to better define the patient population, intended use, or appropriate outcome measures. If the MCS device is an iterative version based on historical previous devices and the intended use and patient populations are well known, a pilot phase can be incorporated into the pivotal study design.
Just as with preclinical testing, the MCS device developers should plan to meet with the appropriate regulatory bodies to gain feedback on the proposed study design prior to submitting the application to begin the formal clinical trial. In the United States, the FDA regulates medical devices. To initiate a clinical trial for a Class III high-risk, life-sustaining medical device such as an MCS device, you must first get FDA approval. The regulatory process for gaining FDA approval to begin clinical trials is known as Investigational Device Exemption (IDE). There are two categorizations for an IDE device: Category A (Experimental) or Category B (Nonexperimental/Investigational). IDE Category B allows CMS to cover both routine care items and services as well as the cost of the investigational device itself when specific criteria are met, while devices assigned to Category A are only eligible for payment of the routine services, not the device under investigation. Left ventricular assist devices (LVADs) have always been assigned Category B, and so all costs have been covered during the trials by Medicare and many commercial payers.
An IDE allows the MCS device developer to evaluate the safety and performance of the MCS device in a clinical trial environment. Once the MCS device developer has an approved IDE from the FDA, it can begin the process of gaining the necessary study site approvals so that enrollment can begin.
It is at this point the regulatory and reimbursement pathways must align. Prior to the IDE submission to the FDA, it is imperative that the CMS is engaged to determine not only if the study will be reimbursed but also if the endpoints will support the Medicare requirement that the device not only be safe and effective but also medically necessary and clinically beneficial with the Medicare population. As of January 1, 2015, sponsors requesting Medicare reimbursement during the clinical trial—which can include payment for the cost of the device—must submit a request for review and approval of IDE studies. Once CMS has approved the clinical trial and the protocol has been accepted by the FDA, enrollment can begin.
Commercial payers have specific policies regarding coverage of any clinical trial. For example, the majority of Blue Cross Blue Shield plans do not reimburse the cost of the device but will cover the routine care surrounding the procedure, but some commercial payers will reimburse for the device as well as the hospitalization. It is important to gain commercial payers input prior to initiating a clinical trial so that the payers’ concerns can be addressed prior to starting the trial, thus allowing for evidence development that can assist in creation or expansion of existing medial policies.
During an IDE study, if a need arises to implant an MCS device in a particular patient who may not qualify for the FDA-approved study, most likely due to the study’s inclusion/exclusion criteria, there are provisions within the IDE regulations that allow for compassionate use of the device. If the treating physician believes that the investigational device may be the best option and provide a benefit to the patient, this provision can be used. Compassionate use must be approved by the MCS device developer (study sponsor) and the FDA prior to use. Another important provision of the IDE regulation is the emergency use provision. The emergency use provision can be used for an MCS device in situations where it is necessary to protect the life or physical well-being of a patient in an emergency. Although prior approval for shipment or emergency use of the investigational MCS device is not required prior to implant, the emergency use case is required to be reported post hoc to the FDA, confirming that in fact it was an emergency case and that patient protection measures were not violated. This would involve assuring informed consent, institutional clearance as specified by their policies, concurrence from the institutional review board (IRB) chair, independent assessment from an uninvolved physician, and approval by the IDE study sponsor (MCS device developer).
The required contents of an IDE application and details of both compassionate and emergency use are described in detail in 21 CFR Part 812 and in FDA Guidance documents, available online from the FDA’s website.
Prior to the submission of an IDE, MCS device developers are able and encouraged to meet with the FDA in a presubmission meeting (pre-IDE meeting). There are many advantages to doing this, and while this is an optional step, it may result in the least burdensome and quickest route to beginning the study. This is a nonbinding interactive meeting where the MCS device developer gains feedback on the proposed study design and other requirements relative to supporting documentation. Once the formal IDE is submitted to the FDA for consideration, they will evaluate the proposed study and supporting documentation to ensure that they meet an appropriate level of scientific rigor and comply with regulatory requirements as previously outlined and that the results from this study will likely provide adequate safety and effectiveness data to support future regulatory approval applications.
If clinical trials are planned in other countries, the MCS device developer should seek local regulatory expertise to ensure all in-country and appropriate regulatory requirements are met. For example, in the EU, if a clinical trial is planned in several EU member states, the MCS device developer should plan to meet with an appropriate accredited Notified Body and plan to gain in-country ministry of health approval, as well as hospital ethics committee (EC) and, in some cases, regional EC approvals before initiating the study. Canada, Australia, and Japan are examples of other countries that all have well-defined regulatory pathways to gain clinical trial approvals for high-risk, life-sustaining devices, including MCS devices.
Many countries such as Japan, France, and Belgium require that local patients be enrolled in the trial to secure reimbursement. Each country has different requirements to gain reimbursement. A positive clinical trial supporting the clinical benefit to a defined population will greatly support in-country reimbursement.
While prospective randomized controlled trials are considered the gold standard design for new MCS devices, other trial designs can and have been used successfully to gain market approvals. Noncontrolled prospective study designs utilizing prespecified Objective Performance Criteria can be used if sufficient prior clinical data exist within a stable patient population. Other nonrandomized study designs can draw upon device registry data as a historical or concurrent control group, resulting in comparable outcomes that can be acceptable to regulatory agencies to support market approvals. The key to use of these alternatives is early collaboration with investigators and the appropriate regulatory bodies in the country where the clinical trial is planned to ensure that risks and benefit tradeoffs are well understood before proceeding. The goal of any prospective clinical trial should be to minimize patient risk, provide measurable benefit, allow evaluation to be completed in the shortest time possible, and produce valid scientific evidence that can be used to determine if the MCS device is safe and effective for its intended use. A well-designed study, executed properly and carefully controlled, can produce the desired results in the least burdensome way.
Another aspect of clinical trial design is planning for cost analysis of the procedure to support the value of the technology to the healthcare system. Data can be collected multiple ways, but the most common are either to collect claim-level data for each implant admission or readmission or to use big data sets, like the Medicare Limited Dataset inpatient data, or the Truven Marketscan data. With LVAD devices, a combination of claims data collected prospectively as part of the clinical trial and payer administrative claims databases was used, and all cost studies have been published.
Premarket Approval
High-risk, life-sustaining medical devices like an MCS device have the highest premarket regulatory approval requirements of any single use medical device. Most premarket regulatory reviews, regardless of country or region, can take a minimum of 6 months of substantive review time. More often, it can take somewhere between 12 and 18 months before a final market approval decision is rendered. In the United States, for an MCS device to gain commercial approval, a PMA Application must be submitted to the FDA. The PMA must contain sufficient valid scientific evidence to demonstrate reasonable assurance of safety and effectiveness when used for its intended use. The application includes information obtained from all prior studies (clinical and nonclinical) such as biocompatibility, device characterization and performance, durability, reliability, sterilization, shelf-life, and if applicable, software, electromagnetic compatibility, and electrical safety. The PMA must also include any other relevant bench or animal data, data from foreign studies, and most importantly, the final comprehensive results from the prospective studies described in the previous section (see “Clinical Testing” section).
In addition to being a time-consuming, thorough, and often interactive process, a PMA review performed by the FDA also requires the device developer to submit a user fee at the time the PMA is submitted. These fees are substantial and cover the cost of the FDA resources necessary to complete rigorous reviews. Once the FDA has completed an initial administrative review of the PMA, it is accepted for substantive review, and it can take several months before the MCS device developer will receive feedback on the progress of the review. Usually, by the third month of review, the FDA will provide the MCS device developer with a list of questions/deficiencies that must be addressed before the substantive review process can continue. Once adequate responses are submitted, the process becomes more interactive as each detail of the submission is carefully evaluated. The PMA process and regulatory requirements are in 21 CFR 814, and refer to the PMA related Guidance documents located on the FDA website.
Another option that may be an appropriate regulatory pathway to commercial use of certain MCS devices that are intended for use in a small and often underserved patient population is a humanitarian device exemption (HDE). To qualify for HDE approval by the FDA, the MCS device developer must first gain a humanitarian use device (HUD) designation. To qualify for the HUD, the MCS device must be intended to benefit patients in the treatment or diagnosis of a disease or condition that affects or is manifested in fewer than 8000 individuals per year in the United States. An HDE application is similar in both form and content to the PMA application previously described. The HDE application must provide the same level of assurance of safety as in a PMA, but the HDE is exempt from the requirements to demonstrate a reasonable assurance of effectiveness; rather, the MCS device sponsor must demonstrate that the probable benefit outweighs the probable risk. Once FDA approves the HDE application, the MCS device developer is authorized to market the HUD in the United States after obtaining IRB approval at each institution for the specific FDA-approved indication.
When FDA has completed its comprehensive review of the MCS device PMA or HDE application, it may decide to seek additional scientific review from expert advisory panels that are composed of independent external experts, familiar with the medical and surgical use of these devices and with knowledge of the disease state and patient populations, to help the FDA with important unanswered questions that must be addressed before the PMA or HDE application can be approved. Often, these expert advisory panels may help the FDA address important aspects such as which patients may benefit from the MCS device and other aspects concerning the use of the device to ensure that it is safe and effective for its intended purpose. Ultimately, the FDA carefully considers the totality of the data contained within the PMA and includes the recommendations/comments from the advisory panel in making a final decision on approvability.
Outside the United States, the regulatory approval process for MCS devices can vary greatly. In Europe, the process is well defined and similar to that in the United States. It requires data from prospective clinical trials conducted within the European community to gain authority commercially. An accredited Notified Body from an EU member state must be involved. The regulatory process involves demonstrating conformity to EU Directives (active implantable devices) and submitting a design dossier to an appointed Notified Body for review. The design dossier is similar in content to the PMA required in the United States. The overall review timeframe mirrors the FDA process and the Notified Body also has an independent scientific review committee that must review and approve the Design Dossier before they can grant the authority to affix the CE Mark to the MCS device. Once this is granted, the MCS device may be marketed within the 28 countries that comprise the EU.
Most of the Tier I countries have a similar process for the premarket evaluation of MCS devices and therefore will not be further delineated within this chapter.
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