6.1. Introduction

Device developers, policy-makers and regulators all share a desire to see safe, effective diagnostic devices on the market. However, the rapid technological innovation that characterizes this industry is outpacing current regulatory frameworks. Reforms are under way in both the United States and the EU, with regulators on both sides of the Atlantic seeking to reduce bureaucratic roadblocks to developers while still ensuring patient safety.

This chapter provides a comparative overview of the regulatory pathways that developers embark on to gain access to the United States and European markets. Much like the reimbursement process, the regulatory processes in the EU and United States are littered with quirks, foibles and inconsistencies that increase uncertainties, creating hurdles to bringing new devices to market. This chapter provides no silver bullet solutions, but rather provides description of the changing regulatory landscape and the current challenges faced by diagnostic developers. Greater transparency in the process, harmonization between regulators, and more open lines of communication with developers about evidence requirements are needed to help bring truly innovative devices to the market.

6.2. History of medical device regulation

Regulation came relatively late to the medical device world and was largely stimulated by a number of public health scares in the 1960s and 1970s. Those that led the way in regulatory strengthening in the 1970s were notably Australia, Canada, the EU countries, Japan and the United States, which together account for close to 85% of the device market share today.¹ In the United States, 1976 saw a regulatory overhaul which covered “food, drugs and cosmetics (and medical devices)”. In Europe, too, the regulatory environment became more stringent, although mainly to enhance the cohesion of a single internal European market. Beginning in 1990, the EU introduced in all its Member States an approach to medical device regulation based on mandatory “essential requirements” of safety, performance, and quality.² In the United States, the early 2000s saw an increase in data requirements in response to the increasing number of tests with more specific intended use (as opposed to broad tools) and requirements surrounding analytic performance have increased in complexity due to adverse events and other pitfalls.

6.3. Evolving needs for medical device regulation

Over the last 50 years the technical advances in diagnostic development (supply side) have been rapid, leading to a bolus in availability and variety of IVD devices based on an increasingly diverse array of underlying technologies across the disease spectrum. When the 1988 CLIA guidelines were issued there were seven “waived” tests compared to hundreds today. Additionally, on the demand side we have not only seen an increase in the prevalence of many diseases for which diagnostic tools are available, notably cardiovascular, oncological and infectious diseases, but also an increase in outpatient care and shorter inpatient stays make them an increasingly valuable addition to the physician’s toolbox. Additionally, as the underlying technologies become more sophisticated (yet simple in presentation and use) the tests are increasingly moving out of the laboratory and are available to a broader number of less specialized health care professionals, for whom the more limited diagnostic knowledge facilitates both a greater use of, and at the same time greater dependence on, the information these tools provide to aid clinical decision-making. Increasingly, diagnostics are no longer about a single test for a single disease but a single sample being used to measure multiple parameters and provide a cumulative risk score. Additionally, anecdotal evidence also suggests that financial incentives (through reimbursement policy) favour physicians using a greater number of more sophisticated tests particularly in the United States. This additionally raises questions about the point at which a physician’s office should be considered (for regulatory purposes) a laboratory (and therefore requiring regulatory oversight), a challenge which has recently been acknowledged by CMS.^a Given this context and the relatively short time period, the challenge faced by regulators of this small but very dynamic health technology sector is to safeguard patient safety while remaining sufficiently nimble regarding the needs of developers.

6.4. Overview of regulatory processes for market entry in Europe and the United States

In comparison to Europe, and indeed most of the rest of the world, where a relatively “light touch” approach is favoured, the United States adopts a more holistic or “health system” approach to the regulation of IVD devices, which are often quoted as being the most highly regulated medical devices on the United States market and perhaps also globally. However, when looking beyond history and ideology, we actually see greater similarities between the United States and EU than we might expect, notably that stringency in regulation has been increasing the world over for a number of decades, and this is a trend that is also foreseen to increase in the medical device field. Another similarity is the challenge that regulatory agencies the world over have in adapting and updating their systems in a timely manner in response to an evolving external environment (i.e. health systems) and a small, dynamic, sector (i.e. rapid technological evolution). Global harmonization efforts have been active in the IVD space since 1992 and, while the approach to risk was largely based on the Canadian model, it was the Europeans who were initially more responsive and engaged with these efforts than the United States (which has recently been empowered for deeper participation in these forums). The 2013 announcement of the opening of bilateral trade deal^a negotiations will likely give fresh impetus to these long-standing efforts to streamline and globalize the regulatory dialogue, and to remove more peripheral administrative barriers in areas such as general controls (i.e. labelling and post-market surveillance).

Both the United States and EU are in the process of, or have recently completed, a period of regulatory reform in the area. In the United States a number of recent reforms became effective in 2012 and address issues in the areas of: Resourcing (the FDA Safety and Innovation Act [FDASIA Part II]/Medical Device User Fee Amendments [MDUFA]), Regulatory Improvements (FDASIA Part VI) and Registration and Device Listing (CFR21-807). The MODDERN (Modernizing Our Drug and Diagnostics Evaluation and Regulatory Network) Cures Act has been referred to committee. With bipartisan support the senate version of the bill is expected to be introduced in the second half of 2013. In the EU, reform to the Medical Device Directives has been a longer time coming as it has been nearly a decade since the In Vitro Diagnostic Medical Devices Directive (IVDD) came into effect and it has not been revised in this time; as a result reform is expected to have a more revolutionary impact when it is signed into law^b when IVD devices are likely to become directly regulated for the first time. The nature of and response to these reforms again reveal some common focus areas in current regulatory evolution and indicate some shared challenges to be resolved moving forward. As regulation becomes more stringent in the EU, stakeholders have raised concerns regarding the effective resourcing of the agencies to manage review times. While in the United States “time to market” (particularly for high-risk devices) is longer than in the EU, reflecting their more robust approach, “time to patient” tends to be similar due to the longer duration of reimbursement decisions in the EU than the United States. Developing effective communication pathways between regulator and developer is also a long-standing issue where we see improvements but also a need for ongoing attention. These areas have significant possibilities to affect the efficiency of regulatory processes. Some of the main technical challenges are also priorities on both sides of the Atlantic. For example:

• How should “investigational” devices be regulated so as to acknowledge their pivotal role in development innovation, while preventing regulations from undermining commercial incentives in the market?
• How is device “novelty” translated into a risk classification and therefore regulatory stringency?
• What is the minimum level of clinical evidence required to ensure safety and efficacy? Can performance ever really be determined without testing occurring in the same environment where the device is intended to be used?

Regarding the latter, the United States currently has far more stringent – but clear – requirements; the EU, however, seems also to be moving in the direction of both greater clarity and stringency. Although both the United States and EU regulatory systems are perceived by developers as being less than perfect, with further room for improvement and efficiency gains, it seems the remaining challenges no longer present a significant barrier to market access for the developers of innovative new POC diagnostics for bacterial infections.

6.5. United States current regulatory structures/frameworks

6.5.1. Framework/oversight

The United States DHHS has overall responsibility for ensuring safe and efficacious medical interventions are available in the United States market. The responsibility for IVD devices is shared between the CMS and the FDA (see Fig. 6.1). This shared responsibility is because two pathways oversee IVD regulation in the United States. The location where the test is performed is regulated through CMS via the CLIA regulations, while market entry of the device is regulated by the FDA.

Fig. 6.1

DHHS organizational chart showing medical device regulatory oversight in the United States (adapted from, , , , ).

CLIA (Public Law 100-578) was first instituted in 1967 to establish quality standards for laboratory^a testing, where CMS reimbursement was being sought and was to ensure the accuracy, reliability and timeliness of patient test results regardless of where the test was performed, at the time CDC performed the categorizations (for CMS). The 1998 CLIA regulations were expanded to include all laboratories in response to the concerns about laboratory testing errors.⁸ At the same time the FDA became responsible for complexity categorization⁹ (for which CMS pays FDA). While overseen by the CMS, CLIA is implemented through the Division of Laboratory Services, within the Survey and Certification Group, under the Office of Clinical Standards and Quality; CLIA is user-fee funded.¹⁰

In addition to being subject to the CLIA regulations, IVD devices are additionally subject to pre-market and post-market controls as defined by the FDA’s Office of In Vitro Diagnostics and Radiological Health^b at the Center for Devices and Radiological Health. The Center also has the responsibility for regulating firms that manufacture, repackage, re-label and/or import medical devices sold in the United States.¹¹

6.5.2. Broad approach and classification

For POC devices that obtain a CLIA-waiver, CLIA regulation of laboratories and FDA regulation of tests are complementary for diagnostic testing. While the trials required for the submissions and separate applications generally occur in parallel, the FDA prefers that reviews occur simultaneously (concomitant review is perceived as too risky), with CLIA review following after the initial FDA decision. Developers prefer to reduce the time lag between the two processes as much as possible. IVD tests are perceived to be the most highly regulated diagnostics in the United States.¹²

Taking the FDA pathway first, all medical devices, of whatever class, require general controls to obtain FDA clearance to market. In addition, IVD devices are subject to pre-market and post-market controls. At present, as the level of technological advancement (underlying the diagnosis) increases, so too does the complexity of the device, and therefore the stringency of the regulatory pathway for approval.

For IVD devices, the FDA takes risks of a new technology into account (particularly if there is no predicate and is therefore “novel”) but focuses predominantly on the risk of the information provided (established through an “intended use” statement). In the United States, the FDA has established classifications for approximately 1700 different generic types of devices and grouped them into 16 medical specialties referred to as panels. Each of these generic types is assigned to one of three regulatory classes (Class I–III) based on the level of control necessary to assure the safety and effectiveness of the device (see Table 6.1). “A device should be placed in the lowest class whose level of control will provide reasonable assurance of safety and effectiveness.” Class I devices are subject only to general controls, with “special controls” being required in addition for Class II devices, Class III devices require general controls plus PMA.

Table 6.1

FDA regulatory classes for IVD devices.

CLIA categorizations are differentiated on the basis of complexity, mainly with regard to the technical competence required by the user (number of technical steps, system maintenance and troubleshooting requiring more qualified staff, level of automation). Categorization is determined for each laboratory test system, assay and examination by assigning scores of 1, 2 or 3 for each of seven criteria associated with appropriate usage.¹³ Currently, a POC diagnostic that would provide timely results – about a bacterial infection – at patients’ bedside, is most likely to receive a CLIA-waiver. Because this status assumes least competence from the user, this is the hardest and most challenging (compared to CLIA moderate and high complexity) for manufacturers to meet; that is, more data is required to prove simplicity of use (see Table 6.2).

Table 6.2

Relative proportions of CLIA designated laboratories.

As the subsequent regulatory pathways can vary in duration and costs by a factor of >2 and 200 respectively, this initial classification decision can be crucial for developers. However the FDA itself acknowledges that classification is “not always intuitive” and that “reasonable people may disagree on the appropriate class”.¹⁴ Reclassification (up and down) can occur but, until recently, has been uncommon and administratively complex.

Overall, the vast majority of microbial non-molecular medical devices are approved through the PMA (510k) route of the FDA first and then, most likely, a CLIA moderate certification by CMS (Table 6.3). This requires studies to confirm performance of the product (510k) and analytical studies, that is, comparison studies performed at the testing site (CLIA). The likelihood of the FDA assigning a microbial molecular POC device to Class I is a far more remote possibility and, indeed, the best developers of microbial molecular POC devices can hope for at present is a Class II designation. In fact, most (74%)^a Class I products are exempt from the FDA’s pre-market review. Furthermore, while many non-molecular antimicrobial IVD devices have been CLIA-waived, to date no molecular test has yet received a CLIA waiver, although anecdotal evidence suggests this is not far off.^b Most still fall under the “high complexity” categorization: developers are being encouraged to pursue “moderate” complexity categorization to expand the size of their possible, eventual market.

Table 6.3

Complementarity of the United States system for regulating IVD devices.

6.5.3. General controls

General controls (Fig. 6.2) occur at three levels: those aimed at the facility where the device is manufactured, those pertaining specifically to the device and those governing any clinical trials required for device approval. As regards the former, the intention is that the devices must be manufactured under a recognized quality assurance programme. The key requirements are¹⁶ “establishment registration” and establishing certificated and ongoing compliance with the FDA’s Quality System Regulations (QSR) which replaced, but largely mirror, Good Manufacturing Practices standards.^a As QSR is specific for the United States market, global developers may also choose to also obtain ISO (ISO 13485) certification – the globally acknowledged equivalent. While not harmonized with QSR, ISO has some specific procedures, but in general the requirements are overlapping. Additionally, as ISO issues certification documents, this can be helpful for manufacturers wanting to demonstrate compliance. As could have been anticipated, mutual recognition of ISO 13485 is the top of the list of items industry is pushing for as part of the Transatlantic Trade and Investment Partnership (TTIP).

Fig. 6.2

General controls.

Regarding the device itself, general controls state that the device must be suitable for its intended use, be adequately packaged, properly labelled, and have FDA Medical Device Listing. In addition, post-market surveillance and record keeping systems known as Medical Device Reporting must be in place.¹⁷ General controls are one area that saw fairly extensive revisions in the latest FDASIA.

Additionally where clinical trials are required, Good Laboratory Practices and an Investigations Device Exemption (IDE) will be required. Some products are also exempted from some of the general controls mentioned above, for example general purpose reagents.

6.5.4. 510(k) regulatory pathway

A 510(k) is a pre-marketing submission made to the FDA to demonstrate that the device to be marketed is as safe and effective, that is, substantially equivalent, to a legally marketed device that is not subject to PMA. Pre-market notification/review of a 510(k) is the least stringent of the two main FDA regulatory pathways for IVD medical devices and the majority of devices approved under this system are Class II products which require additional study and control (Fig. 6.3).¹⁸

Fig. 6.3

510(k) pathway.

PMA (Fig. 6.4) is the most stringent type of device marketing application required by the FDA prior to receiving approval for market. It is predominantly for Class III medical devices where there is no substantially equivalent product to compare to, or if the device is a type of product that FDA considers too high a risk to down-classify and for which special controls alone are insufficient to ensure safety and effectiveness. Unlike pre-market notification, PMA is to be based on a determination by the FDA that the PMA contains sufficient valid scientific evidence that provides reasonable assurance that the device is safe and effective for its intended use or uses.¹⁹ The FDA has established methods of early collaboration with the sponsor allowing PMA devices to be brought to market expediently; that is, modular and streamlined product development protocols.

Fig. 6.4

Pre-market approval.

6.6. EU current regulatory structures/framework

6.6.2. Broad approach and classification

The EU regulatory system for medical devices is seen to be a “tools-based pathway” as opposed to the more holistic “systems” approach of the United States system. The focus is primarily on ensuring the safety of the test. Any IVD medical device manufacturer wishing to place a product on the market or put the product into service must first classify the IVD medical device in accordance with certain predefined risk categories contained in the IVDD (Class A–D; Fig. 6.5). Having determined the category for the IVD medical device, the manufacturer must ensure that the device meets the essential requirements of the IVDD by following the appropriate conformity assessment procedure(s) for that device, seeking NBs’ input if appropriate. A core component of proposed reforms to the current IVDD is that this current “list-based” approach should be replaced with a risk-based approach, as recommended by the Global Harmonization Task Force (GHTF). It is widely accepted that the current list (Annex II List B) lacks intellectual coherence in its assessment of risk and this is largely due to how it was developed by Member States. A move to a list based on a coherent assessment of risk would provide greater flexibility to respond to emerging health threats and diseases more rapidly, although there remain question marks as to how the new rules will be applied and implemented across Europe.

Fig. 6.5

Categorization of medical devices according to the EC’s IVDD, . Ind – individual; PH – public health

Registration of the manufacturer and device on the market is mandatory prior to market launch and serves to inform the relevant national medical device regulators which medical devices are being marketed in their jurisdiction. This process, while not onerous, will be streamlined when EUDAMED – the European Database on Medical Devices – comes into full operation (part of this will involve transitioning the current registration and coding system to the Global Medical Devices Nomenclature System).²⁹ Owing to the coming into force of the EC decision concerning the implementation of the European databank EUDAMED, the Medicines and Healthcare products Regulatory Agency (MHRA) no longer accepts these notifications nor will it acknowledge notifications submitted under the legislation quoted.

This decision mandates each Member State to forward to the European databank certain medical devices information collected in each country where the manufacturer or the authorized representative is located. Therefore the implementation of EUDAMED, the transitional provision in Article 12 of IVDD 98/79/EC which obliges IVD manufacturers to give notification to every Member State concerned by the placing on the market of IVD devices, ceases to apply.

6.7. Reform under way in the United States

Recent regulatory reforms surrounding medical devices affect three main areas of regulation: Reimbursement (MODDERN Cures Act), Resourcing (FDASIA Part II/MDUFA), Regulatory Improvements (FDASIA Part VI) and Registration and Device Listing (CFR21-807). We provide an overview of the latter three in this section, which were part of the same Congressional Bill: the FDA Safety and Innovation Act (FDASIA)³⁴ signed into law July 2012 and effective from the fiscal year 2013, which begins on 1 October 2012.^a The Bill passed with bipartisan support and one interviewee, following the signing, said that “Congress on both sides of the aisle seems intent on further FDA reform, including the Device Centre.”³⁵ FDASIA includes 11 titles, including the fifth reauthorization of the Prescription Drug User Fee Act (PDUFA V), first enacted in 1992, the first iteration of the Generating Antibiotic Incentives Now Act (FDASIA VIII), as well as the third reauthorization of the Medical Device User Fee Amendments of 2012 (MDUFA III). The MODDERN Cures Act, which predominantly focused on further discovery and innovation in diagnostics, more timely access for those in need by streamlining the inclusion of new diagnostics in Medicare, and ensuring appropriate reimbursement for diagnostic tests, is discussed in Chapter 5.

As regards FDASIA, MDUFA was first enacted in 2002 in order to:

provide the FDA with the resources necessary to better review medical devices, to enact needed regulatory reforms so that medical device manufacturers can bring their safe and effective devices to market earlier, and to ensure that reprocessed medical devices are as safe and effective as original devices.

The challenges of sufficient regulatory resourcing – more broadly than medical devices – continues with the FDA commissioner stating in 2010: “the FDA’s resources are outstripped by our responsibilities … there is a continuing need for expansion of investment”.³⁶

MDUFA III is the result of more than a year of public input, negotiations with industry representatives, and discussions, and will automatically end in five years (October 2017). MDUFA is seen as having made significant progress towards meeting some of its objectives, such as expanding its review capabilities and expertise, defining and meeting a number of its performance goals, expanding the availability of innovative (expedited) review processes, developing electronic tracking systems etc. The latest boost to funding is seen as a significant step in mobilizing the necessary resources to facilitate manufacturers getting products to market sooner. User fees are expected to more than double from US$ 277 million in 2008–2012 to US$ 609 million in 2013–2017, the equivalent of 200 new full-time staff involved in device approvals by 2017.³⁷ Despite this triumph, some consternation has been expressed that the user fee framework under MDUFA has created uncertainty for industry and the FDA regarding the annual increase in fees and the amount of funds that would be collected by the agency in any given year (Fig. 6.6).³⁸ This was recently compounded when the new fees being paid by developers to the agency were sequestered making US$ 2.9 million (in fiscal year 2013) of medical device user fees unavailable for use by the FDA – a situation that has now been rectified. Additionally, some manufacturers have short-term concerns about the impact on “review consistency” of a rapid influx of new regulatory reviewers.

Fig. 6.6

Impact of MDUFA reforms on FDA fee revenues for medical devices. Note: FY – fiscal year

Thirty-three provisions were included in the Medical Device Regulatory Improvements part of the Bill (FDASIA Part VI), with the most significant highlighted in Table 6.4. It seems that manufacturers perceive the Bill as increasing overall regulation.³⁹ However, it also provides some advantages to industry, such as changes in the accepted data standards (the FDA can now only request the “minimum necessary”) and shorter time commitments from the FDA, particularly during the appeals process, will particularly assist SMEs. The fact that the agency is now able to use data from outside the United States for approvals will reduce the information requirements for global manufacturers and increase the FDA’s ability to change the risk classification of a device (where it now has more autonomy). The re-introduction of a third-party review process^a and the more efficient granting of De Novo classification help expedite some previously cumbersome parts of the process, the latter particularly for truly innovative devices.

Table 6.4

A selection of the 33 provisions, signed into law in July 2012, in the FDASIA relating to medical device regulatory improvements.

Finally, on 1 August 2012 the FDA published the revised version of Part 807 to reflect the statutory amendments to the device registration and listing provisions of the Federal Food, Drug, and Cosmetic Act (FDC Act) and accommodate new requirements of the Public Health Security and Bioterrorism Preparedness and Response Act of 2002 (Bioterrorism Act) and the FDA Amendments Act of 2007. Essentially these provisions make electronic submission mandatory,^a raise the fees and remove previous fee exceptions. They also facilitate collection of additional registration and listing information from foreign establishments and initial importers, and attempt to improve the quality of registration and listing information available to the FDA.

6.8. Reforms under way in Europe

Some experts suggest that the regulatory changes currently under way in the EU are “far more significant” than those under way in the United States. The EU IVDD (98/79/EC), written in 1998, came into full force in 2003 and has not been substantially amended since its adoption.⁴⁷ In 2008, the EC held a public consultation concerning the recasting of the medical devices directives. This started a process that will lead to a fundamental revision of the existing directives in order to simplify and strengthen the current framework.⁴⁸ This public consultation was complemented in 2010 by a similar consultation regarding the technical aspects of the revision of the IVDD; this is also undergoing a “fundamental revision” to keep pace with technological advancements and keep IVDD “fit for purpose”.⁴⁹ The consultation invited comments from a broad range of stakeholders on 19 questions and comments received through the public consultation highlight that more than 10 years of implementation have revealed weaknesses in the IVDD. These issues were raised as part of a review initiated following widespread acknowledgement that scientific and technological evolutions, as well as new business trends in the IVD field – for example, the emergence of companies offering IVD testing as a service – were ineffectively handled in the IVDD. Other concerns have been raised⁵⁰ around weaknesses related to implementation of the Medical Device Directives, such as challenges in the exchange of information (EU database), the long process to conclude on interpretations/borderlines and the 27 Member States having their respective and at times differing views on implementation.

On 26 September 2012, the EC published the long-awaited proposed regulation (not a Directive),^a which covers medical devices in the broader sense (93/42/EEC) and – for the first time – specific regulation for IVD devices (to replace 98/79/EC). The regulation must receive approval from both the European Parliament and European Council before becoming final. The key areas of discussion prior to its release had focused on: the need to revise the current device classification system which was seen as inadequate; whether or not to include specific requirements for POCTs (which previously had been done only indirectly); the need to clarify the requirements regarding clinical evidence; and the handling of in-house tests and companion diagnostics. The published proposed regulation does include all these issues and was broadly welcomed by the European industry association (EDMA). The key areas of proposed change include:

• stronger supervision of NBs;
• more powers and obligations for assessment bodies to oversee manufacturers;
• clearer rights and responsibilities of manufacturers including more stringent clinical evidence requirements and an increase in the classification;
• harmonization of Member State authorities’ approach to regulation and improvements to the exchange and coordination of information, especially in the pre-market phase;
• better supply chain traceability of devices.

One additional area of concern is the implications of the likely absence of a “Grandfather clause”, whereby companies will be required to review their current products (those already approved and on the market) for compliance with any new classification system. This initial bolus in submissions on enactment of the legislation raises questions as to whether the national systems and NBs have the resources to absorb this initial work without significant supply disruptions for existing or – even more importantly – innovative new products needing licensure at the same time. The responses to the public consultation on all of these issues are briefly summarized in Table 6.5, which also includes a focus on developer responses.

Table 6.5

Summary of the response to the public consultation of the IVDD revisions.

The commenting period ended in September 2010 and a summary of the results was published in February 2011. The EC had 12^a “Medical Device working groups”⁵² tasked with exploring various issues in greater depth and facilitating pan-European dialogue, and a proposed regulation was published by the EC (at the same time as an impact assessment) in September 2012. The regulation has been approved by both the European Parliament and the European Council before becoming EU law. However a number of Members of the European Parliament have proposed revisions to the regulation, most notably in April 2013 Dagmar Roth-Behrendt called for medical devices marketed in the EU to be subject to a pre-market assessment system in which high-risk devices would need to undergo a full review – as in the United States, while devices of lesser risk would undergo an expedited assessment procedure overseen by NBs. Lack of agreement on what the final proposal should look like, plus the fact that the recast of the Medical Devices, Implantable Medical Devices and IVD Directives will be occurring in parallel means 2014 will be the earliest point at which agreement will be reached.^a There is likely to be a minimum of a three-year transition period to the new legislation, therefore implementation may not now occur until 2017–2018.

6.9. Industry stakeholder involvement in European regulatory reforms

As part of the ongoing efforts to update the IVDD, a consultation with key stakeholders was held in June 2010 on the proposed revisions to Directive 98/79/EC on In Vitro Diagnostic Medical Devices. Among others, IVD manufacturers have had an opportunity to express their views, particularly on a number of critical or potentially contentious aspects of the proposed legislative changes. Both the reforms and, more specifically, IVD manufacturers’ response to the public consultation, have been addressed in section 6.7. An assessment as to whether or not industry input into the process will have shaped the outcome will need to be revisited once the changes to IVDD have been finalized, and thus an analysis of the effectiveness of this communication pathway, and regulator flexibility to industry demands, will be saved until such time as the evidence is available.

6.10. Evaluation of communication pathways between regulator and industry

In the past there have been frustrations from both developers and the regulator regarding communication deficiencies that have added to review times and exacerbated tensions. Additionally a number of recent studies continue to criticize regulatory agencies for limited transparency.⁵³ However, it seems things are slowly changing, especially in the United States, with a number of developers citing an improved “flexibility” on the side of the FDA and willingness/openness to interact with those making submissions and to engage in public meetings.⁵⁴ In June 2009, the FDA launched its “transparency initiative”.⁵⁵ This had three phases, which started in January 2010 with the launch of a web-based resource for public access called “FDA basics”. Phases 2 and 3 in – in May 2010 and January 2011 respectively – were the release of two transparency reports, the first for the public and the second for regulated industry. Most recently, in January 2012, the FDA released a new report⁵⁶ presenting eight initiatives adopted by the Commissioner to explore avenues for making FDA’s compliance and enforcement data more accessible and user-friendly (this followed a two-year period of development that included a public consultation). The eight initiatives include items such as the exploration of different ways to: improve data quality, facilitate more timely data disclosure by expediting data entry, expedite inspection review and classification, update the data more frequently, explore tools that may facilitate more expedient error reporting, and better integrate presentation (including through mobile apps) of its compliance and enforcement data, etc.

Aside from more administrative commitments of the FDA, however, recent regulatory reforms highlight how the FDA is making great strides in improving the communication during the core processes and dealings with industry. This is best illustrated through the expedited regulatory pathways and some of the newer more flexible regulatory pathways (see section 6.5.5 on Exceptions). The FDA comments that “a PMA will be assessed against the MDUFMA II expedited performance goals without a pre-filing meeting, however FDA strongly recommends to industry to have such a meeting”.⁵⁷ In order to reap a benefit from the expedited review process, the commitment on behalf of the applicant to resolve all scientific and regulatory issues should match that of the FDA. It will only be through effective communication (i.e. interactive review) and a total commitment to fulfilling all regulatory and scientific requirements that the FDA and the applicant can speed market authorization for safe and effective products. Also, the newer pathway processes, such as the Pre-De Novo, pre-SUB^a product development protocols, modular and streamlined PMAs are all underlain by an earlier, more flexible and interactive communication between the developer and regulator (see section 6.5.5 Exceptions). Here the FDA states that establishing a solid working relationship with the FDA during development can facilitate the pre-market submission review and set expectations with regard to data requirements for the submission.

In order to facilitate dialogue and approval, particularly for innovative devices, the FDA has established a “pre-submission” (pre-SUB) process, whereby manufacturers of particularly cutting-edge technology (which may include many molecular diagnostics) are invited to submit to an informal pre-SUB process to open dialogue on appropriate analytical or clinical protocols and discussing requirements for the appropriate regulatory pathway. This is entirely voluntary for device manufacturers, although arguably FDA familiarity with the product may facilitate speed of approval once the relevant formal FDA approval is sought. In reality, however, this mechanism applies to all FDA applications rather than being restricted to particularly innovative devices, with the majority of applicants taking advantage of pre-submission communication to facilitate the approval process once the formal application has been submitted.

One such example of a positive and open communication process between the FDA and industry is the current application by Curetis for their Unyvero platform. Curetis’ Unyvero platform is a rapid molecular diagnostic that has the capability to extract DNA from a range of microorganisms, including bacteria and fungi. It is the first platform to market in Europe which can handle detection of both bacteria and fungi from any native clinical samples, including many antibiotic resistance markers, and is currently going through a trial aimed at the FDA approval process, with Curetis announcing the launch of United States multi-site clinical trials in December 2012. Given the innovative nature of the platform, the regulatory pathway in the United States was unchartered, and while the product is still in the early stages of the approval process with United States clinical trials having begun in late 2012, to date it provides a strong positive example of the flexible, interactive communication between regulator and developer outlined above. Throughout the process thus far, Curetis has indicated there has been a genuine partnership between manufacturer and regulator regarding forming an appropriate regulatory pathway for the product, including evidence expectations and trial design. While the outcome of the application is yet to be determined, feedback from Curetis thus far is that there has been demonstrable effort from the regulator to actively engage with the manufacturer to ensure the process is product-appropriate.

More generally, the FDA appears to have been making efforts to bring closer coordination between their drug and diagnostic arms, which is potentially supportive for co-development candidates: they now hold joint meetings between their drug side (Center for Drug Evaluation and Research, Center for Biologics Evaluation and Research), and diagnostics side (Center for Devices and Radiological Health).⁵⁸ Industry feedback about the FDA approach in this regard has been positive: a recent comment piece by the College of American Pathologists regarding co-development more generally cited Dr Walk (Ventana) as saying “The FDA’s been very good about working with industry, both diagnostics and pharma”, and Dr Hampton (Senior Director, oncology biomarker development and companion diagnostics, Genentech): “They’re genuinely interested in enabling the use of diagnostics to identify patients who will or won’t gain benefit from drugs. There’s no question about that.”⁵⁹

6.11. FDA flexibility in antibiotic approval/trial design which may influence uptake of diagnostics

6.12. Flexibility in clinical trial requirements for antibiotic development

The challenges of enrolling patients in antibiotic trials have been well documented elsewhere in the literature (see 2010 European Observatory book Policies and incentives for promoting innovation in antibiotic research), with strict regulations on patient enrolment attracting much criticism from industry, who argue that antibiotic trials for critical indications are exceptionally difficult, hampering R&D in infectious disease at a time when new antimicrobial therapies are needed. Signals from the FDA indicate some agreement with this view, most notably comments from Janet Woodcock, Director of the Center for Drug Evaluation and Research at the FDA, regarding a “reboot” for antibiotic trials, at a presentation in May 2012 to the Brookings Institution.⁶¹ Reportedly Dr Woodcock mentioned a number of areas up for discussion in regard to trial design, such as pathogen- rather than indication-specific studies (which may facilitate greater partnering with diagnostic firms, given their scientific objective tends to be pathogen identification). The use of Bayesian methods was also mentioned,⁶² a topic which has most prominently been championed by John Rex of Astrazeneca. This could involve using Bayesian statistical methods to inform how non-trial data, for example from natural history studies, could be incorporated into trial design, such as in the calculation of non-inferiority margins or non-inferiority analysis, although there are a number of issues with such approaches, not least that the strength of the prior evidence is critical. Discussions at the conference indicated that areas of priority for potential trial flexibility would be targeted at areas of unmet clinical need, and that ideally labelling would limit the usage of such approvals to restricted patient populations.

A further change which key antibiotic stakeholders have indicated is under discussion at the FDA is the potential for new regulations regarding the enrolment of patients in clinical trials: changes discussed may enable the enrolment of patients who are culture negative if they fit a number of other criteria, including positive diagnosis from a PCR diagnostic. This should significantly support the role of PCR diagnostics in trial settings.

6.13. Regulatory comparison United States/EU

When comparing the United States with the EU system of IVD device regulation, an active debate continues – on both sides of the Atlantic – around the robustness, advantages and disadvantages of both systems. As discussed earlier in this chapter the United States system, specifically for IVD devices, is characterized by a dual regulatory system that is not just about the device itself but also takes into account the environment in which the testing is performed,^a previous devices that have gone before, the intended use, etc. This creates a more holistic or “health system” approach to regulation but also attracts accusations of being “complex” and “cumbersome” for developers to navigate compared the “light-touch”, single or “tools-based” or self-certification pathway presently favoured by the EU, which allows the manufacturer to self-declare compliance with the IVDD and notify respective countries of their intention to market. Conversely, the EU system’s harshest critics tend to be the public health community, who voice concerns for patients on the grounds that it potentially allows “ineffective” devices onto the market and, due to the absence of post-market surveillance,^a the downstream impacts on patients are largely unknown. While ongoing reforms limit meaningful comparison of the two regulatory systems, important fundamental differences can be highlighted, including in the areas of IVD device regulation that remain the most contentious, or challenging, on both sides of the Atlantic.

For example, the issue of how to regulate research use only (RUO) or “for investigational use only (IUO)” products (products that a manufacturer provides to laboratories to do research/investigation). Frequently RUO instruments and reagents are used in LDTs. This can create a situation whereby rapid development and innovation maybe stifled if these tests “leak” onto the commercial market, either providing a “back door” route to market or undercutting those regulated more stringently through commercial regulatory pathways. In the EU these tests are referred to as “in-house” tests whereas in the United States they are LDTs or “home-brews”. We have seen that this is perhaps the single most pressing issue to be addressed in the United States market but also that this was the area that received most responses from the public consultation in the EU. While in both regions the issue of LDT definition, terminology and scope are similar, in the United States the current focus seems to be as much around the reality of how and who should enforce the existing provisions whereby in the EU, despite a guidance document being issued in February 2004 to clarify its situation,⁶³ the question remains one of the need to clarify or limit the scope of these exemptions. While the device industry (through AdvaMed) is strongly in favour of the FDA regulating the LDTs, there remains significant opposition from many of the (larger) laboratory associations (notably the American Clinical Laboratory Association), which favour^b keeping these provisions, citing the need (in patients’ interest) for a rapid route to market in certain circumstances. The “un-level” playing field this creates in the United States between different sections of the same industry is seen as a significant market distortion, negatively impacting the current incentives to IVD development and exacerbating a perceived laboratory monopoly.

“Optimum source and quantity” of clinical evidence in order to determine safety and performance is another area to highlight. The EU focus is “clinical evaluation” (assessment and analysis of clinical data),^c while the United States focuses on assessing safety and performance, and accepting only clinical data (from a variety of settings). In the EU data can also be accepted from broader, non-clinical sources and include post-market data but United States data requirements are seen as much more stringent and resource intensive than those currently required in the EU, where there is currently seen to be “little emphasis on clinical evidence – the focus is on analytical performance”.⁶⁴ However this was a key area of debate in the IVDD review, and it seems the EU is likely to increase the requirements of clinical evidence when the legislation is enacted. The EU discussions focused on three components: clinical evidence, clinical validity and clinical utility. Despite developer concerns over the “radical” implications for IVD manufacturers, 90% of respondents agreed with the need of the Directive to provide “more detailed requirements regarding what clinical evidence is required and how to demonstrate it, while making these specific for different device classes”. Most respondents felt that current requirements were insufficient and that the clinical validity of the test must be demonstrated in the same conditions than those in which the test will be used (i.e. manufacturer needs to demonstrate the same level of clinical sensitivity or specificity as the test performed in a clinical laboratory). As the EU increases its stringency in this area, it is also possible that the United States will soften a little (at least informally) its requirements, having the overall effect of some level of convergence between the two regions. In the past, regulatory authorities would not approve devices that were inferior to the performance of predicate devices. Signs are beginning to show of a convergence towards an understanding that, while POC devices may have comparatively inferior performance, they can prove beneficial through significantly increasing access to testing.

Finally, the third area of note is that of risk-based device classification and how risk is determined and categorization occurs. As outlined earlier, the class designation decision directly determines the stringency of the regulatory pathway to be pursued by the developer and therefore has significant implications for the speed and cost of getting that product to market. However, we have also seen how the designation decision itself is not always straightforward, as acknowledged directly by the regulatory agencies themselves. The commonality between the two systems here is in the shared challenge of finding the optimum (or at least a satisfactory) approach to the issue of class reassignment in the situation of designation disputes. The principal distinction between the two systems is in how the classes are determined in the first place: in the United States they have classes I –III and in the EU also a fourth (Class A–D), with regulatory controls increasing as the class number rises. Both systems currently utilize a categorization based on risk, but the method for defining risk differs.^a In the EU it is widely acknowledged that the classes listed in Fig. 6.5 do not resemble an intellectually coherent list based on risk assessment, while in the United States the three main areas used to define risk (underlying technology, intended use and possibility for misuse) inevitably introduce a component of interpretation or subjectivity. As we have seen, in the EU there appears to be broad, cross-stakeholder, support for moving^a to a pure “risk-based” categorization – in line with International Harmonization proposals. However, developers again highlighted the significance of the impact of such a move, particularly in terms of additional costs (especially for Class C products) and advocated for a sufficient “transition time”. More timely access to market, better protection of public health and more robustness to technological progress were also cited as advantages.

As the FDA takes pains to point out, the reality of what its more robust system means in terms of impact on developers and ultimately patients is less than is often cited or claimed by developers. Although focusing more on high-risk devices a 2012 study in the New England Journal of Medicine concluded that although “time to market is quicker in the EU”, “time to patient” remains faster in the United States once reimbursement decisions are factored in (see Fig. 6.7).⁶⁵

Fig. 6.7

Comparison of time to market in PMA and reimbursement processes between the United States and the EU.

6.14. Harmonization of the diagnostics regulatory pathway in the United States and EU

The importance of global regulatory harmonization in the field of medical devices has long been acknowledged. The growing importance of this need was formally acknowledged with the inception in 1992 of the GHTF, whose founding member countries were: United States, United Kingdom, Japan, Australia and Canada. It was convened from a voluntary group of representatives from national medical device regulatory authorities and the regulated industry and had a rotating Chairmanship. Their work to develop and promote a GHTF medical device regulatory model was built on interlinking guidance documents and was accomplished through five Study Groups and various Ad Hoc Working Groups under the oversight of the GHTF Steering Committee. GHTF handed over in February 2011 to the International Medical Device Regulators Forum (IMDRF), whose mandate is the “strategic acceleration of medical device regulatory convergence”. Officially instituted in March 2011, the new forum has a similar structure and mandate to the GHTF but has a broader country membership (including emerging economy^a regulatory authorities and the possibility to invite “official observers” such as WHO). Its Management Committee now excludes industry^b in order that regulators can truly work on converging internal practices and procedures. During the first meeting of the IMDRF in March 2012 priority areas for moving forward were identified (remaining current as of July 2013) and are summarized in Table 6.6; these demonstrate some overlap with the previous GHTF working groups.

Table 6.6

Priorities of the new international forum (IMDRF) for facilitating global regulatory harmonization for medical devices.

The efforts made in the two decades since GTHF was founded are likely to receive new impetus with the announcement in 2013 of the TTIP whose negotiations are already under way. AdvaMed in the United States made “harmonization” one of seven items on its wish list^a and in April 2013 industry representatives^b from the EU and United States met with the US–EU High Level Regulatory Cooperation Forum to announce its “enthusiastic support” for the TTIP while highlighting four areas that it would be looking for the scope to encompass: (1) mutual recognition of ISO 13485, (2) a single audit process, (3) harmonized format for product registration submission and (4) a common product tracing system using a single UDI process with interoperable databases. These four areas demonstrate significant overlap with the ongoing five focus area of IMDRF efforts (see Table 6.6).

Previously, WHO has also played a pivotal role in the quest for global harmonization of medical devices. These activities were initiated in the early 2000s with two publications,^c including WHO’s 2001 report: A model regulatory programme for medical devices: An international guide. The focus of this document was to provide a framework to assist Member States in establishing regulations for medical devices, which has greater relevance for countries yet to enshrine regulatory pathways, rather than to directly influence the regulatory process in key markets such as Europe and the United States. More recently, WHO’s activities have supported harmonization through the hosting of the First Global Forum on Medical Devices, held in Bangkok in September 2010. At the Bangkok meeting it was reported that approximately 30% of countries have a developed framework for regulation of medical devices, approximately 30% of countries only have partial regulation of medical devices, and the remaining countries are either developing a framework or proceeding without any current regulation. WHO has largely encouraged the use of mutual recognition as a key tool in its harmonization objective.

Beyond mutual recognition, a number of other mechanisms are in use supporting harmonization between countries, such as the signing of Memorandums of Understanding on manufacturing protocols such as Good Manufacturing Practices, or similarly Good Laboratory Practices, upon which the OECD has issued guidelines. The EU, for example, has signed Mutual Acceptance Agreements in the area of Good Laboratory Practices with Israel, Switzerland and Japan. More broadly, the liberalization of trade policy can facilitate acceptance of standards from other countries, with recent EU free trade negotiations with Japan actively supported by the key diagnostics industry body, the EDMA.⁶⁸ While an in-depth analysis of industrial policy and trade protectionism in key diagnostic markets is beyond the scope of this study, one SME diagnostic manufacturer did indicate that, in their opinion, the FDA approval process was sometimes used as a barrier to entry for foreign firms, and a more detailed analysis of approval time-lines for foreign versus domestic firms in the United States may be of future interest.

At a regional level, one key player also contributing to the device regulatory harmonization movement is the Asia-Pacific Economic Cooperation (APEC) Harmonization Center launched in Seoul, Korea in June 2009. This grew out of the APEC Life Sciences Innovation Forum (LSIF), founded in 2002, which has since grown to become APEC’s leading initiative on health and health sciences innovation. As part of the Center, an LSIF Regulatory Harmonization Steering Committee (RHSC) was created to advance the harmonization agenda. During the first IMDRF meeting in March 2012, the RHSC was invited to become an affiliate organization due to the similarity and complementarity of its mandates.

Outside of these global and regional initiatives and forums, individual national regulatory authorities continue to be active in the dialogue. For example the FDA’s Center for Devices and Radiological Health has stated that it intends to release a position paper in on global harmonization. Further, as part of the July 2012 FDASIA regulatory revisions, the FDA has now been freed to greater participation through two new legislative provisions. The first is its new ability to “enter into arrangements with nations regarding methods and approaches to harmonizing regulatory requirements for activities, including inspections and common international labelling symbols”, where previously its role was limited to harmonizing Good Manufacturing Practices, that is, the agency may now use data from outside of the United States for device approvals, further reducing the information requirements for global manufacturers.⁶⁹ Although the FDA allowing the incorporation of international symbols in device labelling has been easier and more widespread in IVD devices than other devices, the rapid pace of acceptance here is seen as particularly advantageous to global harmonization efforts. The second is a subtle expansion of the FDA’s ability to “Participate in International Fora”, which now includes the ability to also provide guidance to organizations running them and involving the United States public.

6.15. Industry perspectives on harmonization

While the diagnostic manufacturers participating in this study indicated that having to face a number of differing regulatory regimes did add to the costs of getting their products to market, it was clear that harmonization in and of itself was not desirable if it meant convergence towards an FDA approach, as the costs involved in this would be significant for industry versus what are viewed as less stringent regimes in other key markets such as Europe. Further, there appeared to be little sense from industry players that the FDA would be willing to soften its stance to levels similar to those seen in Europe. Many manufacturers indicated a belief that the United States would always forge its own path rather than compromise its position, with one commentator noting that the FDA considered the EU system to be an “honour system” that goes against their philosophy of needing bureaucratic oversight of the regulatory process.

6.16. Stakeholder perception of overall regulatory processes for diagnostics