Confidential: For Review Only - BMJ...Confidential: For Review Only story (otherwise it is probably more fitting for a specialist venue). 1) As you think about how to convey the magnitude

Confidential: For Review OnlyRegulatory Reform in an age of Blockbuster Diagnostics

Journal: BMJ

Manuscript ID BMJ-2018-047615

Article Type: Analysis

BMJ Journal: BMJ

Date Submitted by the Author: 22-Oct-2018

Complete List of Authors: Holloway, Kelly; University of Toronto Dalla Lana School of Public Health, Institute of Health Policy, Management and EvaluationMiller, Fiona; University of Toronto, Institute of Health Policy Management and EvaluationGutierrez, Alberto; NDA PartnersHogarth, Stuart; University of Cambridge, Department of Sociology

Keywords: regulation, diagnostics, genomics

https://mc.manuscriptcentral.com/bmj

BMJ

Confidential: For Review OnlyReviewer comments tableOctober 22, 2018

Dear Dr. Doshi,

Please find our revision attached. We would like to thank you and the reviewers for your comments on this paper. We have revised it significantly to address all of your questions and concerns and feel it is far stronger for your insights.

Our responses to each reviewer comment are listed in the table below. Our most substantial changes are first, that we have paid attention to making the article more engaging. We have foregrounded the Theranos story as a hook to draw the reader in and acknowledged the possible harms that could come from these regulatory loopholes. We have also pointed to the potential harms that could result from regulatory failures throughout the article.

Second, we have rewritten the paper to more clearly compare the three jurisdictions without jargon, using tables to help us with this task.

Third, we removed our discussion of transparency initiatives across jurisdictions. This was not the strongest nor most essential part of our story, and efforts to address all of the reviewers’ comments would have taken up the limited space we have to make our argument. Instead, we have addressed the most essential point about transparency, that many molecular diagnostics are not subject to statutory pre-market authorization, they are not tracked, and there is much that we do not know about their safety and efficacy.

In conclusion, we very much appreciate the reviewers’ comments and welcome further feedback.

Sincerely,

Authors.

*Action points from reviewers in red.

Reviewer Comment Our ResponsePeter DoshiWe struggled to gauge the nature and extent of the actual problem. The way the piece is written will not engage our readership, and so to make this work, we think this will require a complete rewrite based on a rethinking your approach of how you tell the

As the reviewer recommended, we have completely rewritten the article in order to be more engaging, and to clarify the problem.

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Confidential: For Review Onlystory (otherwise it is probably more fitting for a specialist venue).

1) As you think about how to convey the magnitude of the problem, it would be helpful to have statistics regarding how many devices are used, what kind of devices, how much money is spent, etc.

We have referenced an industry report on the size of the market in the introduction.

2) The situation seems like a jumble that is hard to keep straight. The EU is poor for some things, a leader in others, while the US was a leader but has fallen behind, etc… can this be made easier for the reader to keep straight?

We recognise this as a problem and have revised the article significantly to clarify the differences between the jurisdictions. Please see Tables 1 which clarifies the LDT loophole across jurisdictions and Table 3 where we have addressed the complexity of the EU’s current IVD Directive, and the new overlapping EU IVD Regulation, to take full effect in 2022.

3) The connection between molecular diagnostics and LDTs is not clear. Are all LDTs molecular diagnostics? It would be helpful to get a bit broader sense of what kind of tests fall in and out of these categories.

We have revised the paper to clarify the relationship between molecular diagnostics and LDTs (see the introduction and LDT loophole section).

Because most LDTs are not subject to pre-market authorization or tracking by statutory regulation, we do not know how many LDTs exist, or what is currently on the market. We can investigate these questions through website reviews and research in specific clinical areas. We have presented what we know of NIPT, breast cancer and HPV based on our own investigations of information published online by manufacturers.

4) We would like to see a stronger conclusion and way forward.

We have revised the conclusion to respond to this suggestion.

5) You say FDA is making summary reports of clinical and preclinical studies available for regulated products. This may not be quite

As noted above, we removed our discussion of transparency initiatives across jurisdictions. This was not the strongest nor

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Confidential: For Review Onlyright. Do you mean that FDA makes its scientific reviews available for drugs and biologics?

the most essential part of our story, and efforts to address all of the reviewers comments would have taken up the limited space we have to make our argument.

6) You say FDA issued a final rule. Wasn’t that the NIH? Alberto/Kelly, please clarify - was this an inter-agency initiative?

Removed. See above notes about transparency section.

7) The authors say that without sufficient regulation, these tests may not be safe and effective. What should safe and effective mean for a test? (We are familiar with regulatory standards for drugs … but what is safe & effective for a test?) What kind of risks do they posit? What should efficacy testing consist of? How burdensome would it be? How often does it need to be re-evaluated?

While we take this concern seriously, we have addressed the issue of risk by introducing a box on harms but we feel that a detailed discussion of the measures for safety and efficacy for diagnostic tests is outside the scope of this paper. We have also incorporated a discussion of possible harm throughout the paper.

Our impression is that the EMA is ahead of everybody including FDA on data transparency. See (link)

What is your evidence otherwise?


Reviewer 1: Peter McCullochComments:

This Analysis paper tackles what appears to be an important subject. There has been considerable international disquiet about the regulation of non-drug medical products internationally for some years. Concern has focused mostly on invasive therapeutic devices, but there are also obvious deficiencies in the systems for regulating health-related IT (apps etc) and the subject of this paper, in vitro diagnostic tests. The MS does describe the current systems of regulation and their deficiencies, but does not engage the reader because of failures of style, organisation and clarity.

We have rewritten the paper significantly to address the issues related to style, organization and clarity. We have focused on making it more engaging, using less jargon, and organising comparative material into tables.

We have developed harm as a theme throughout the paper, beginning with the Theranos story and drawing on other examples, OvaCheck and HPV. Demonstrating harm for a diagnostic test is different from demonstrating harm from drugs, but we have attempted to stay away from the complexities of measuring harm, to note

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https://www.bmj.com/content/362/bmj.k3513.full

Confidential: For Review OnlyThe style problem is one I have encountered before with experts in regulatory affairs. The habitual language used in their normal work is light years away from that required to explain clearly to the average clinician why what they are saying is important, and there is therefore a massive "lost in translation" problem - or rather a "no attempt at translation" problem. Some of the most influential articles in this area in recent years have been by investigative journalists like Deb Cohen, and when you read their work it is easy to see why. They use clear, vivid real-life examples of actual or potential harms to communicate the problem, and discuss the actual regulatory failures in simple straightforward language. The current text looks drier than left-over crispbread by comparison, but the information is in there. It just needs to be expressed in a more sympathetic fashion. A good start would be to give an example of what harm could come to a patient from a faulty in vitro diagnostic test. This is very easy to envisage for the average doctor when you talk about a heart valve, but less so when you are talking about papillomma virus tests.

The organisation problem is caused by the way in which the authors try to grapple with three main arguments (risk classification, a loophole over LDTs and transparency) in three different jurisdictions. This is challenging to do but the authors are inconsistent in the way they organise the material, which means the reader has to backtrack and check constantly to be sure they have the message correct. A summary Table might help, but so would some fairly simple rewriting. This organisation problem is compounded by a late curve-ball when, in the Conclusions section of the paper, the authors suddenly introduce a new criticism of the EU regulations around how standards

more generally that the lack of regulation for these tests makes that task challenging.

We accept the reviewer’s comment that introducing standards in the conclusion was a “late curve ball,” and have removed the discussion of standards throughout the paper. We do not feel that this detracts from our overall argument.

It is true that there is no international agreement about what constitutes a high-risk diagnostic test. We are not sure why this has not been a priority. It is a question to pursue in further research, but we feel it is outside the scope of this paper.

“What is the status of the huge number of tests recorded in the Tables as having no regulatory approval of any kind - are they on general sale?”

We hope our revision has answered this question. Yes, there are a huge number of tests recorded in the tables that have no regulatory approval, and at the time the data was gathered these tests were publicised on firm websites as marketed products. However, since no one tracks LDTs, the question of which tests are on sale is not straightforward. This would require further investigation of each company.

“The Tables and text are at odds in some places - only 11 Breast cancer tests in one column of the table but 12 in the text and when you do the arithmetic in the Table.”

We have revised the paper to address this question.

“The call for transparency is very welcome, but the Canadian initiative quoted appears to be about invasive devices, and has nothing to

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Confidential: For Review Onlyare going to be devised. This parting shot is left unresolved and unexplained.

The clarity problem is, I believe, probably due to the intimate familiarity of the authors with their subject, which leaves them largely blind to the need to explain their world to the vast majority of the clinical community who know almost nothing about it. This is subtly different to the style problem. The latter is about the manner in which the subject is discussed, whereas the former is more about the level of explanation supplied. An introductory paragraph setting out some of the basics around the three regulatory systems might be helpful here. There are however a couple of important points where even the relatively educated are left wondering. Why for example is there no international agreement around what constitutes a high risk diagnostic test? The rules for invasive devices are pretty well aligned in all jurisdictions. What is the status of the huge number of tests recorded in the Tables as having no regulatory approval of any kind - are they on general sale? The Tables and text are at odds in some places - only 11 Breast cancer tests in one column of the table but 12 in the text and when you do the arithmetic in the Table. The call for transparency is very welcome, but the Canadian initiative quoted appears to be about invasive devices, and has nothing to do with diagnostics, the transparency of whose testing is, by the end of the article, still less than transparent.

I think there is merit in the arguments made and that the topic deserves to be aired. A revised version of the article might well be suitable for BMJ readers.

do with diagnostics, the transparency of whose testing is, by the end of the article, still less than transparent.”


Reviewer 2: Jerome R Hoffman

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Confidential: For Review OnlyThe information provided in this paper is very useful, and important. Nevertheless some aspects of the situation you describe require clarification – I apologize if there is something I am missing, but the paper as written leaves me a bit confused about some key details.

The area where I am uncertain has to do with changes in current regulations – it is unclear to me which “proposed changes” have actually been implemented, such that your use of phrases like “promises to …” have uncertain meaning. Please be clearer about what changes have already been approved and are being implemented, such that any questions about their impact await only the evidence of what actually happens, versus what changes are merely proposed, such that their putative impact must remain entirely speculative at this time.

My only other large concern has to do with emphasis – I believe you could do a much better job of explaining why absence of appropriate regulation of these tests is likely to lead to substantial harm. I understand that this is not the focus of your research; still, unless you make it clear that you are not merely quibbling, and that indeed widespread inappropriate use of tests would be a true threat to the public health (as is surely the case), I suspect many readers will fail to understand why the evidence you present is truly important.

As a smaller point, I also have a question about your statement (on the first page) that “EU’s current risk classification system is uniquely inadequate …” but then add “however the EU regulation represents significant progress.” This seems to be self-contradictory, as written – please explain.

We have clarified which changes are “proposed,” particularly in the table.

On the question of emphasis, we take the reviewer’s point that we could do more to emphasise harm, or potential harm. We have done this throughout.

On the point about EU’s current risk classification system and their proposed one, we have clarified this significantly that both regulations exist simultaneously until the new one takes full effect, in both the text and in a table.

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Confidential: For Review OnlyI believe this is a very useful paper – but that it needs both to clarify some details (as noted), and that it needs to make an explicit case (in its Discussion section) for why this matters.Reviewer 3: Peter LurieThis paper presents a cross-jurisdictional comparison of diagnostic test regulation in three regions. This is an important topic, largely unappreciated by practicing physicians. However, while the authors attempt to rectify this deficit, they fail to fully acknowledge quite how unfamiliar the topic is likely to be to most readers, and lapse into jargon and assumptions of knowledge that weaken the article. In addition, the article does not provide evidence that the lack of adequate regulation has been a problem clinically. See, for example, FDA report here:, which provides a number of examples.

Page Line Comment

[To follow these comments look at the pdf of our original submission, with line numbers. The first number in each comment below is the page number, the second number is the line number. I have responded to each comment in the next column].

Title The authors need to include material on page 2 that justifies the use of the term “blockbuster.” How big are the sales? At what rate are they increasing? That would augment reader interest in the paper.

2 11 Confusing that the authors seem to be saying that the biomarkers are not in widespread use, but the tests that measure them are growing rapidly.

2 36 CE not defined (or fully explained).

The authors need to include material on page 2 that justifies the use of the term “blockbuster.” How big are the sales? At what rate are they increasing? That would augment reader interest in the paper.

Done in the first paragraph.

2 11 Confusing that the authors seem to be saying that the biomarkers are not in widespread use, but the tests that measure them are growing rapidly.

No longer in the text, but for clarification – the translation of novel biomarkers from the lab to clinical practice remains far slower than PMed enthusiasts had hoped but the molecular diagnostics market continues to grow rapidly based largely on products targeting more well-established biomarkers (especially in infectious diseases)

2 36 CE not defined (or fully explained).

Defined.

2 36-8 “however the EU regulation represents significant progress”: because the authors have not yet introduced this regulation, this is confusing.

This sentence was removed.

3 12 Need to explain what this international standard is.

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http://wayback.archive-it.org/7993/20171115144712/https:/www.fda.gov/downloads/AboutFDA/ReportsManualsForms/Reports/UCM472777.pdf

Confidential: For Review Only2 36-8 “however the EU regulation represents significant progress”: because the authors have not yet introduced this regulation, this is confusing.

3 12 Need to explain what this international standard is.

3 Table Not informative enough to stand alone; can easily integrate into text. Also, the EU seems to have about 80 “extra” tests. Have any problems arisen with them?

3 28 Need to define what a Notified Body is.

3 34 “Downclassify” needs to be explained.

3 36 What about HPV tests? That would make the authors’ case stronger.

3 38 Even if the EU strengthens its oversight, will it ever approach current (or previously proposed) US standards?

4 5 Need to explain a bit better how the two loopholes fit together. Doesn’t the LDT loophole mostly swallow the other one?

4 7 Should EU be included here? You say regulatory reform in this area is “pending”, but what does that mean? Not yet in effect? Still under debate or development in some fashion?

4 8 Suggest inserting “There” before “Firms”.

4 8 Is the reference to over-the-counter needed? Adds a new level of complexity.

We have removed mention of standards, as explained above.

3 Table Not informative enough to stand alone; can easily integrate into text. Also, the EU seems to have about 80 “extra” tests. Have any problems arisen with them?

We cut the table and embedded the figures in the text.

Regarding problems, we believe that lack of published evidence supporting their validation for use in cervical screening is a problem in itself. FDA rejected two of Roche’s early HPV tests which were both CE-marked for use in EU.

3 28 Need to define what a Notified Body is.

Done

3 34 “Downclassify” needs to be explained.

Done

3 36 What about HPV tests? That would make the authors’ case stronger.

We have added some more detail to the section on HPV tests

3 38 Even if the EU strengthens its oversight, will it ever approach current (or previously proposed) US standards?

This is a good question but we do not feel comfortable predicting the outcomes of the EU regulation. We do feel that a follow up study could evaluate risk classification by clinical area once the EU regulation has come

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Confidential: For Review Only4 10 Suggest “commercial test service to which samples are submitted for testing.”

4 10 Explain what aspects of regulation are bypassed (registration, listing, AE reporting, etc.)

4 12 Add explanation as to what these regulatory agencies are and what they do (and don’t do) with respect to regulation of LDTs.

4 7-14 Need to present data about what fraction of tests are IVDs and what fraction LDTs. (Not sure that the authors have fully explained the difference, by the way.)

5 8 CLIA not defined or explained.

5 10 It is true that this occurred after the election of Trump, but the issuance of the white paper occurred in the waning days of Obama.

5 13 How would the legislation weaken FDA regulation? Would the result be weaker than the status quo or just preclude stronger regulation?

5 31 Were they not subject to regulation anywhere? All of the tests?

5 31 The article would be considerably strengthened if the authors could point to problems that had occurred with the tests.

5 36 Is the suggestion that otherwise identical or similar tests are being regulated differently?

6 7 “self-certified in Europe with a CE mark”

into full effect, and we see the result of the proposed legislation in the US.

4 5 Need to explain a bit better how the two loopholes fit together. Doesn’t the LDT loophole mostly swallow the other one?

We have restructured the paper to emphasize the LDT loophole first and clearly indicate how the second risk classification loophole is related.

4 7 Should EU be included here? You say regulatory reform in this area is “pending”, but what does that mean? Not yet in effect? Still under debate or development in some fashion?

Our revision clarifies that there is a Directive in place which is sub-standard, and a new regulation took effect in 2017. Both exist simultaneously until the latter takes full effect (which understandably has caused some confusion). We have a table (Table 3) that helps to clarify, as well as text.

4 8 Suggest inserting “There” before “Firms”.

Done.

4 8 Is the reference to over-the-counter needed? Adds a new level of complexity.

Reworded to clarify.

4 10 Suggest “commercial test service to which samples are submitted for testing.”

Have reworded the explanation of LDTs to be:

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Confidential: For Review Only6 Table Suggest US approved and Canada approved as column titles. Would reorder to reflect order of text.

6 32 Only for higher risk devices?

6 35 But in line 30 you said Canada provides summaries too. Presumably these are summaries with different degrees of granularity, but need to explain better.

6 37 Does Health Canada treat patient-level datasets and CSRs as CCI?

6 39 I don’t’ see a reference 22 in the text, and the list of references ends at 21.

6 39-41 Not sure of the relevance of this sentence. Probably requires more detail.

8 10-12 This sentence probably not necessary, given what has just been stated.

8 15 Suggest inserting “(only to IVDs)” before the comma.

8 15-19 It would be more effective to start this section with this material, as it places the rest of the material in this section in appropriate context (suggesting how limited a fix transparency is).

8 27 “Bold new strategy” seems inordinately favorable, given the lack of clarity in the definition of “industrial scale.”

8 33 I thought you had made the case that Canada was the gold standard on transparency.

“LDTs are tests produced by a firm in their own clinical laboratory and marketed as a commercial service. LDT firms send out sample collection kits, analyse the returned samples and provide ordering customers with an interpretation of the results.”

10 Explain what aspects of regulation are bypassed (registration, listing, AE reporting, etc.)

Added the following text: “these firms bypass statutory medical device regulation that could independently assess the safety and efficacy of the tests themselves before they are sold”

4 12 Add explanation as to what these regulatory agencies are and what they do (and don’t do) with respect to regulation of LDTs.

Not sure if we can get into any more detail about this. Also see comment directly above.

4 7-14 Need to present data about what fraction of tests are IVDs and what fraction LDTs. (Not sure that the authors have fully explained the difference, by the way.)

We have compiled data on the molecular diagnostics sector in EU and N America. This data is still being checked for quality control but our figures currently suggest that in EU 57% of firms sell kits and 20% sell LDTs and 11% do both but in N America 42% sell kits and 42% sell LDTs and 7% sell both. Given that kit makers have been able to mostly self-certify in EU, then data for N America shows that when premarket review for kits is required then firms are more likely to choose to commercialise as LDTs.

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Confidential: For Review Only5 8 CLIA not defined or explained.

Removed reference to CLIA

5 10 It is true that this occurred after the election of Trump, but the issuance of the white paper occurred in the waning days of Obama.

True.

5 13 How would the legislation weaken FDA regulation? Would the result be weaker than the status quo or just preclude stronger regulation?

Since we submitted our paper the FDA responded to the Bill with a Technical Assistance paper, so we have clarified with the use of the FDAs critique.

5 31 Were they not subject to regulation anywhere? All of the tests?

WE have clarified for NIPT thus: “There are at least 86 tests on the market globally that were not subject to independent pre-market review for safety and efficacy in the US or Canada, though several firms have declared compliance with EU regulations.”

5 31 The article would be considerably strengthened if the authors could point to problems that had occurred with the tests.

We have attempted to take up this point (offered by all reviewers) by raising the issue of harm throughout the paper (also noting how it is difficult to measure for diagnostics).

5 36 Is the suggestion that otherwise identical or similar tests are being regulated differently?

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Confidential: For Review OnlyYes

6 7 “self-certified in Europe with a CE mark”

Changed so there are two refs to CE marking now, firstly under the discussion of LDT loophole: “some firms have “CE-marked” their tests, (the CE mark is the designation that states products are compliant with EU regulations).” Then under discussion of risk classification loophole “Under this system nearly all tests are classed as low-risk, allowing manufacturers to self-declare regulatory compliance with a CE mark.”

6 Table Suggest US approved and Canada approved as column titles. Would reorder to reflect order of text.

Done

The following comments are about transparency, which we have cut.

6 32 Only for higher risk devices?

N/A

6 35 But in line 30 you said Canada provides summaries too. Presumably these are summaries with different degrees of granularity, but need to explain better.

N/A

6 37 Does Health Canada treat patient-level datasets and CSRs as CCI?

N/A

6 39 I don’t’ see a reference 22 in the text, and the list of references ends at 21.

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Confidential: For Review OnlyReferences updated and fixed.

6 39-41 Not sure of the relevance of this sentence. Probably requires more detail.

I think the following are supposed to refer to page 7 instead of 8, since there is not really any text on 8, so w will respond as though they refer to the lines on page 7.

8 10-12 This sentence probably not necessary, given what has just been stated.

N/A

8 15 Suggest inserting “(only to IVDs)” before the comma.

N/A

The following comments are about transparency, which we have cut.

8 15-19 It would be more effective to start this section with this material, as it places the rest of the material in this section in appropriate context (suggesting how limited a fix transparency is).

8 27 “Bold new strategy” seems inordinately favorable, given the lack of clarity in the definition of “industrial scale.”

8 33 I thought you had made the case that Canada was the gold standard on transparency.

N/A.

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Confidential: For Review Only

1

BMJ: Analysis

Authors:

Kelly Holloway, University of Toronto, Institute of Health Policy, Management and Evaluation

Fiona Miller, University of Toronto, Institute of Health Policy, Management and Evaluation

Alberto Gutierrez, NDA Partners

Stuart Hogarth*, Department of Sociology, University of Cambridge

*Corresponding author, Email: [email protected] Address: 16 Mill Lane Cambridge CB2 1SB

Declaration of interests

We have read and understood the BMJ Group policy on declaration of interests and declare the

following interests: none.

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mailto:[email protected]


2

Regulatory Reform in an age of Blockbuster Diagnostics

An evaluation of regulatory loopholes for diagnostics in the EU, US and Canada.

Introduction:

Theranos, a US blood testing startup that was valued at $9 billion in 2015, promoted itself as the

poster child for transforming healthcare through innovation in diagnostics. The firm’s

spectacular downfall, the failure of its technology and the defrauding of its investors, has made

Theranos a poster child in another sense: the Theranos saga was a regulatory scandal with far-

reaching implications. The firm has admitted that “tens of thousands” of test results had to be

voided or revised for everything from cholesterol levels to pregnancy, with unknown

implications for patients. The scale of this scandal demonstrates the potential for harm from

unregulated diagnostics (Box 1). How was this allowed to happen? Theranos launched in the US

market with no review by the US Food and Drug Administration (FDA) to assess the safety,

efficacy or manufacturing quality of its products. Theranos profited from a gaping regulatory

loophole, developing and marketing its products as “laboratory developed tests” (LDTs) rather

than as test kits and thus evading medical device regulations.

Theranos is not alone; many firms in the molecular diagnostics sector exploit the LDT

loophole, an alarming fact given that it is the fastest growing sector of the in vitro diagnostics

(IVD) industry (1), worth $2.98 billion in global revenues in 2016, and projected to reach $6.7

billion by 2021 (2). Calls for stricter oversight of this nascent industry have been made in a

succession of high-level policy reports that have exposed multiple failings in the regulatory

frameworks for diagnostic tests in Europe and North America (3–5). How are policymakers

responding to these calls for change? Canada is characterized by inaction, with no proposal for

regulatory change. In the US longstanding efforts at comprehensive reform have faltered. In the

EU, by contrast, a weak regulatory regime is in the process of major reform. In this paper we

review policy developments in these three jurisdictions and assess their implications for the

protection of public health.

Box 1: Diagnostic Harms

Diagnostic harms: Poor quality tests can lead to both false positive or false negative results causing a variety of clinical harms and wider problems.

Patient harms

For patients the harm arising from a false positive result may include psychological anxiety and undergoing further diagnostic tests or even therapeutic interventions, either of which may carry

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3

unnecessary risks. Patients with false negative results may gain false reassurance, and delay or miss out on necessary treatment(6).

Problems for doctors

For physicians, poorly evaluated tests hamper their efforts to help patients, waste their time in unnecessary procedures and open them to the danger of accusations of malpractice and the threat of litigation.

Costs to the healthcare system

Such tests can waste resources that could have been used to deliver genuine clinical benefits, or, in the case of false positive results, may trigger unnecessary and costly additional tests or treatments(6).

The Laboratory Developed Test Loophole

There are two routes to market for diagnostics firms – kits or LDTs. Test kits are

manufactured and sold for use in laboratories, in clinics (point of care) or at home (over the

counter). LDTs are tests produced by a firm in their own clinical laboratory and marketed as a

commercial service. LDT firms send out sample collection kits, analyse the returned samples and

provide ordering customers with an interpretation of the results. There is nothing new about

LDTs - historically much diagnostic innovation has happened within hospital laboratories. What

is unprecedented is the commercial exploitation of the LDT route to market. Laboratories that

sell LDTs have to comply with the requirements of bodies that regulate the practices of a

laboratory as a whole, but typically these firms bypass statutory medical device regulation that

could independently assess the safety and efficacy of the tests themselves before they are sold. In

consequence, no public agency tracks the tests on the market.

The EU is leading efforts to close this loophole through new regulations for IVDs that

come into full effect in 2022. (See Table 1). Under the old IVD Directive, many LDTs were

exempt because they were manufactured by “health institutions.” This exemption may have been

intended to allow hospital labs to bypass statutory review, but it has been interpreted much more

generously, albeit variably by EU member states. Thus, while many firms bypass statutory

regulation of their LDTs, some firms have “CE-marked” their tests, (the CE mark is the

designation that states products are compliant with EU regulations). Under the new IVD

Regulation, health institutions will continue to be exempt, but only if certain safeguards are in

place. More importantly, the exemption will not apply when LDTs are manufactured on an

“industrial scale,” a critical caveat that has yet to be clearly defined but will likely encompass

most commercial tests.

Table 1: Regulatory Loopholes for Molecular Diagnostics

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Jurisdiction Loophole Policy Reform

European Union EU Directive (1998) (exists alongside the new regulation until 2022):

Exemption for health institutions but scope of exemption unclear and variance in interpretation across member states.

IVD Regulation (2017) (comes into full effect in 2022):

Health institution remains but commercial LDTs manufactured on “industrial scale” will be regulated as medical devices.

US FDA claims regulatory authority but only enforces on ad hoc basis

Status of reform efforts unclear, FDA guidance dropped, industry-sponsored draft legislation in Congress

Canada LDTs are not treated as medical devices

None

By contrast with the EU’s recent and decisive policy reform, the US FDA has tried and

largely failed to address the LDT loophole for more than 25 years. The agency asserted its legal

authority over LDTs in 1992, and has taken action against some of the most egregious actions of

individual firms, perhaps most famously when they shut down the health-related services of

leading consumer genetics firm 23andMe. Yet the FDA’s attempts at comprehensive policy

reform have been curtailed, battered by shifting political winds, and the resistance of clinical

laboratories (which, in the US, are typically commercial, or are major revenue streams for the

health systems with which they are affiliated) (7).1 Most recently, the FDA issued draft guidance

in 2014 proposing a significant expansion of oversight(8). This was resisted by much of the

laboratory sector, but around the time of the Theranos scandal, the FDA signaled that the

guidance would be finalized in 2016(9). However shortly after Trump was elected, the agency

dropped the plan, issuing instead an LDT Discussion Paper in 2017(10). Meanwhile, a coalition

of the leading US reference laboratories and some major IVD manufacturers have proposed a

1 FDA first Research Use Only (RUO) draft guidance 1992; ASR regulation 1997; ICH Regulation 1998; Old draft guidance for marketing RUO, IUO, 1998; IVDMIA and ASR Draft guidance 2006; Letters to industry, 2007-2010; 2010 meeting; LDT draft guidance 2014; workshop 2015; joint task force CMS/FDA, for QA; Discussion paper January 2017.

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new approach to IVD regulation. Their draft legislation would level the regulatory playing field

for kits and LDTs but at the expense of significantly weakening FDA’s regulatory power over

the IVD sector. The FDA says the draft legislation would present hurdles for collecting and

reviewing data, hampering its ability to evaluate the science behind these tests and undermining

its public health mission (11).

While both the EU and US have made efforts to close the LDT loophole, Canadian

regulators are exemplary for their passivity. A 2007 report commissioned by Health Canada

identified a range of possible responses to the LDT loophole (12), but thus far Health Canada has

not addressed this regulatory gap.

The LDT loophole means that many tests are commercialized without undergoing pre-

market review for safety and efficacy, even in cases where the intended use could have major

impact on patient welfare. The rapidly-growing market for non-invasive prenatal testing (NIPT)

exemplifies the problem. NIPT is a new form of prenatal screening to determine the risk of

certain fetal conditions using maternal blood samples, and is projected to have a market value of

$3.13 billion by 2023 (13). There are at least 86 tests on the market globally that were not subject

to independent pre-market review for safety and efficacy in the US or Canada, though several

firms have declared compliance with EU regulations.

The haphazard application of regulation is illustrated by the case of breast cancer

prognostics, which guide treatment decisions in breast cancer. The market leader in this area is

Genomic Health and its Oncotype Dx test, which has a list price of $4,620, generated $340.8

million in revenue for the firm in 2017 (14). While the tests themselves are similar, the

regulatory approach varies markedly, with some tests sold as unregulated LDTs, and others as

regulated kits (See Table 2). As the draft US legislation on LDTs indicates, levelling the playing

field between kits and LDTs may do more harm than good if it means that all tests are subject to

a lower regulatory bar for safety and efficacy. The potential inadequacy of such an approach is

exemplified by our second loophole: risk classification, a problem which, unlike LDTs, is

primarily a European one.

Table 2: Tests and regulatory approval in EU, US, CA

Total CE-Marked US

Approved

Canada

Approved

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NIPT 86 8 0 0

Breast Diagnostics

(prognostic)

11 8 2 2

Risk classification loophole

Regulatory regimes for diagnostic devices are risk-based – categories of tests classed as higher

risk are subject to greater regulatory scrutiny and stricter evidentiary standards. Higher-risk

devices are typically subject to pre-market review, but classification schemes vary across

jurisdictions, and this creates a second regulatory loophole for molecular diagnostics, particularly

in Europe.

The EU’s current risk classification system is uniquely inadequate. Under this system

nearly all tests are classed as low-risk, allowing manufacturers to self-declare regulatory

compliance with a CE mark. The OvaCheck test for ovarian cancer screening exemplifies the

problem. Even after the FDA issued a warning letter about this test in 2004, and then determined

that the test did not accurately predict or detect ovarian cancer (15), OvaCheck was CE-marked

for sale in Europe by the manufacturer in 2010 (16,17). The EU’s new regulation will close this

regulatory loophole. (See Table 3) (18). The new regulation classifies most molecular

diagnostics as high-risk, meaning they have to go through pre-market review by a Notified Body

(the regulatory authority that assesses compliance with regulations). As a result, a far broader

range of diagnostic tests, including all cancer diagnostics and all genetic tests, will be subject to

independent scrutiny before they can enter the EU market.

Yet while the EU moves to subject more tests to premarket review, the US is moving in

the opposite direction, down-classifying diagnostics that were once deemed high-risk. Under this

approach, tests for conditions such as human immunodeficiency virus (HIV) and the hepatitis

C virus (HCV) will be deemed lower-risk, and will be subject to less rigorous scrutiny before

marketing. Meanwhile, Canada has made no effort to re-think the risks posed by this changing

market.

Table 3: The EU’s Regulatory Changes for risk classification

Current Regulation New regulation

Status The EU IVD Directive,

which exists alongside the

The IVD Regulation, which

comes into full effect in 2022.

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new regulation until the latter

comes into full effect.

Risk Classification All molecular diagnostics are

low-risk and therefore not

subject to pre-market

evaluation

Most molecular diagnostics

will be high-risk and

therefore subject to pre-

market evaluation

What impact has the EU’s regulatory loophole had in practice? A clear indication of the

public health implications is provided by cervical cancer screening. Problems in screening can

lead to psychological stress and unnecessary treatment in the case of a false-positive, or a missed

cancer diagnosis in the case of a false-negative. The traditional pap smear has repeatedly been

mired in scandals of over and under-detection, not least in the USA and UK, and it took decades

to standardize cervical cytology into a reliable screening tool. Molecular tests for HPV emerged

in the 1990s as a new approach to cervical cancer screening, and in countries like the UK and the

Netherlands are poised to replace the pap smear. HPV tests are subject to pre-market review as

higher-risk tests in the US and Canada, but in the EU, the tests are classified as low-risk and

manufacturers self-certify regulatory compliance. Only 7 HPV tests have been approved by the

FDA, and only 5 have been approved by Health Canada, but eighty-seven tests are authorized for

sale in the EU. The relatively high number of HPV tests in the EU is alarming given that the

majority of HPV tests worldwide do not have adequate published evidence demonstrating they

are validated for use in screening (19). The new EU regulation could allow greater assurance

that the CE mark can be trusted as a credential of safety and efficacy.

Conclusion

It remains to be seen whether genomics will bring about a fundamental transformation in

medical practice but the molecular diagnostics sector continues to grow at a rapid pace. The

EU’s strengthened IVD regulation demonstrates the responsiveness of policymakers to these new

challenges, although there is uncertainty about how the new system will work in practice. In

contrast, Canada’s inaction is notable. The FDA’s failure to progress its proposals for enhanced

oversight of LDTs means that the world’s largest diagnostics market remains fatally bifurcated –

a medical device industry where firms can choose whether or not to be FDA-regulated is not

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good for patients, clinicians or healthcare systems. Stakeholders should be concerned about the

current industry-sponsored draft legislation circulating in the US Congress.

As the example of Theranos indicates, we must be skeptical of bold claims for the

transformative potential of new diagnostic technologies. Regulatory agencies have a critical role

to play in scrutinising the scientific data behind the corporate hype. Stakeholders must continue

to press for robust evidence and rigorous evaluation as safeguards against premature

commercialization.

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CONTRIBUTORS and SOURCES: Molecular diagnostics are the fastest growing sector of the

in vitro diagnostics industry. Yet many of these tests slip through two significant regulatory

loopholes. Kelly Holloway, PhD, Postdoctoral Fellow at the University of Toronto, Fiona A.

Miller, PhD, Professor, University of Toronto, Alberto Gutiérrez, PhD, recently retired head of

diagnostics at the FDA, and Stuart Hogarth, PhD, Lecturer, University of Cambridge, analyze

statutory product regulation for diagnostics, identify failings and report on recent efforts at

reform.

KEY MESSAGE BOX: This is a box at the end of the article containing 2-4 points summing up the main conclusions.

There are loopholes in the statutory regulation of molecular diagnostics in the EU, US

and Canada despite the increasing size and commercial significance of this sector.

This paper reviews recent regulatory reforms to remedy these loopholes.

Most molecular diagnostics are Laboratory Developed Tests, which are currently not

tracked or subject to evaluation under statutory regulation. Recent EU regulation seeks to

address this loophole. Meanwhile risk classification strategies for the molecular

diagnostics that are governed by regulators may subject too few tests to adequate

scrutiny, with contradictory tendencies in recent regulatory reforms.

WEB REFERENCE LISTSupplementary Table 1: HPV tests and regulatory approval in EU, US, CA Supplementary Table 2: Non-invasive prenatal testing (NIPT) and regulatory approval in EU, US, CASupplementary Table 3: Breast Cancer Prognosis tests and regulatory approval in EU, US, CA

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References:

1. Mark D. Hughes. Molecular Diagnostics Market Trends and Outlook [Internet]. 2013. (Enterprise Analysis Corporation). Available from: http://www.eacorp.com/images/PDFS/Molecular%20Diagnostics%20IVD%20Article%20v21%20MEK%20-%20Reprint%20FINAL.pdf

2. Technavio. Global Genomics Biomarkers Market 2017-2021 [Internet]. 2017. Available from: https://www.technavio.com/report/global-vitro-diagnostics-global-genomics-biomarkers-market-2017-2021

3. Secretary’s Advisory Committee on Genetics, Health and Society. A Roadmap for the Integration of Genetics and Genomics into Health and Society The Study Priorities of the Secretary’s Advisory Committee on Genetics, Health, and Society. 2004.

4. OECD. Genetic Testing: A Survey of Quality Assurance and Proficiency Standards. 2007 Oct.

5. Human Genetics Commission. Increasing options, informing choice: A report on preconception genetic testing and screening. London;

6. Harold Sox; Susan Stern; Douglas Owens; Herbert L. Abrams. Assessment of Diagnostic Technology in Health Care: Rationale, Methods, Problems, and Directions. National Academies; 1989. 156 p.

7. Genzen JR, Mohlman JS, Lynch JL, Squires MW, Weiss RL. Laboratory-Developed Tests: A Legislative and Regulatory Review. Clin Chem. 2017 Oct;63(10):1575–84.

8. US Food & Drug Administration. Draft Guidance for Industry, Food and Drug Administration Staff, and Clinical Laboratories Framework for Regulatory Oversight of Laboratory Developed Tests (LDTs) DRAFT GUIDANCE [Internet]. 2014. Available from: https://www.fda.gov/downloads/medicaldevices/deviceregulationandguidance/guidancedocuments/ucm416685.pdf

9. Zachary Brennan. FDA Delays Finalization of LabDeveloped Test Draft Guidance. Regulatory Focus [Internet]. 2016 Nov 18; Available from: https://www.raps.org/regulatory-focus%E2%84%A2/news-articles/2016/11/fda-delays-finalization-of-lab-developed-test-draft-guidance

10. US Food and Drug Administration. Discussion Paper on Laboratory Developed Tests (LDTs). 2017 Jan.

11. US Food & Drug Administration. FDA Technical Assistance on the Discussion Draft of the Diagnostic Accuracy and Innovation Act (DAIA). 2018.

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12. Hogarth, Stuart. The clinical application of new molecular diagnostic technologies - a review of the regulatory and policy issues. A report for Health Canada. 2007.

13. BIS Research. Global Cell Free DNA Isolation and Extraction Market Report Analysis [Internet]. [cited 2018 Oct 22]. Available from: https://bisresearch.com/industry-report/global-cell-free-dna-isolation-extraction-market-2026.html

14. Genomic Health. 2017 Annual Report and Form 10K [Internet]. 2017. Available from: http://www.annualreports.com/HostedData/AnnualReports/PDF/NASDAQ_GHDX_2017.pdf

15. US Food and Drug Administration, Office of Public Health Strategy and Analysis. The Public Health Evidence f or FDA Oversight of Laboratory Developed Tests: 20 Case Studies. 2015.

16. Annette Fribourg. Correlogic Press Releases [Internet]. http://www.correlogic.com:80/newsandevents/press-releases/20100609-ovacheck-ce-mark.php. 2010 [cited 2018 Oct 12]. Available from: https://web.archive.org/web/20101012182828/http://www.correlogic.com:80/newsandevents/press-releases/20100609-ovacheck-ce-mark.php

17. National Horizon Scanning Centre. OvaCheck in the assessment of risk of ovarian cancer [Internet]. 2010 [cited 2018 Oct 12]. Available from: http://www.io.nihr.ac.uk/wp-content/uploads/migrated/1588.88a5ae17072df84d3739022efdbacf83.pdf

18. European Parliament. Regulation (EU) 2017/746 of the European Parliament and of the Council of 5 April 2017 on in vitro diagnostic medical devices and repealing Directive 98/79/EC and Commission Decision. 2017.

19. Poljak M, Cuzick J, Kocjan BJ, Iftner T, Dillner J, Arbyn M. Nucleic Acid Tests for the Detection of Alpha Human Papillomaviruses. Vaccine. 2012 Nov 20;30:F100–6.

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Regulatory Reform BD tables

Supplementary Tables

Supplementary Table 1: HPV tests and regulatory approval in EU, US, CA *These tests were identified by Poljak et al 2012. We looked up CE mark by searching each firm’s website, then looked up US-FDA and Health Canada approval on their respective online repositories of approved tests.

TestFirm Name Location EU-CE

markUS-FDA CAN-HC

PapType HR HPV detection and genotyping Genera Biosystems Australia Yes No

No

INNO-LiPA HPV Genotyping Extra Innogenetics

Belgium Yes NoNo

Human Papilloma Virus (HPV) (Types 16 and 18) PCR Kit

Daan Diagnostics

Canada Yes No

No

Human Papilloma Virus (HPV) (Types 6 and 11) PCR Kit

Daan Diagnostics

Canada Yes No

No

High-risk Human Papilloma Virus (HR-HPV) PCR Kit

Daan Diagnostics

Canada Yes No

No

Urine-Based HPV (High and Low Risk) PCR Detection Kit

NorgenCanada No No

No

Biovue’s Sharpvue HPV detection kit

Biovue Technology

China No No

No

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14 High-risk HPV with 16/18 Genotyping Real-time PCR Kit

HybribioChina No No

No

13 High-risk HPV Real Time PCR Hybribio China No No No

HPV 16 & 18 Real Time PCR Kit Liferiver China Yes No No

HPV 6 & 11 Real Time PCR Kit Liferiver China Yes No No

Uterine Cervix Cancer of High-risk HPV Genotype Related Real Time PCR Kit Liferiver China Yes No

No

High-risk HPV 13 Genotypes Related Real-time PCR Kit Liferiver China Yes No

No

TellgenplexTM High-risk HPV Genotyping Panel Tellgen China Not known NoNo

TellgenplexTM 26 HPV Genotyping Panel Tellgen China Not known No No

Decipher HPV23genotyping DNA chip Yaneng Bioscience China Not known No

No

GenPoint™ HPV Biotinylated DNA probe (Types 16/18/31/33/35/39/45/51/52/56/58/59/68) Dako Denmark Yes No

No

Wide Spectrum HPV Biotinylated DNA Probe (Types 6/11/16/18/31/33/35/39/45/51/52) Dako Denmark Yes No

No

HPV Types 6/11; 16/18; 31/33 Biotinylated DNA Probes Dako Denmark Yes No

No

NucliSENS EasyQ® HPV Biomerieux France Yes No No

AID HPV typing kit Autoimmun Daignostika Germany Yes No

No

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AID HPV screening kit Autoimmun Daignostika Germany Yes No

No

STD kit Autoimmun Daignostika Germany Yes No

No

RealLine HPV 16/18; 52/56; 51/58; 35/45; 31/33; 6/11 (Str-format)

Bioron Diagnostics Germany Yes No

No

RealLine HPV 16/18; 52/56; 51/58; 35/45; 31/33; 6/11 (Fla-format)


No

RealLine HPV High Risk, Genotype quantitative (Str-format)


No

RealLine HPV High Risk, Genotype (Str-format); (Fla-format)


No

HPV type 3.5 LCD-Array Kit Chipron Germany No No No

HPV-2; HPV-4; HPV-7 Genekam Biotechnology Germany No No

No

HPV-6; HPV-6/11; HPV-11 Genekam Biotechnology Germany No No

No

HPV-42; HPV-43; HPV-44; HPV-45 Genekam Biotechnology Germany No No

No

HPV-16; HPV-16/18; HPV-18; HPV-31; HPV-33; HPV-35; HPV-39

Genekam Biotechnology Germany No No

No

HPV-51; HPV-56; HPV-58; HPV-59; HPV-66; HPV-68


No

Human Papilloma Virus (HPV-16) (high risk profile)


No

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Human Papilloma Virus (HPV-18) (high risk profile)


No

Human papilloma virus genotyping Genekam Biotechnology Germany No No

No

PapilloCheck® HPV-Screening Test Greiner Bio-One Germany Yes No

No

PapilloCheck® High-risk Test Greiner Bio-One Germany Yes No

No

Multiplex HPV Genotyping Kit Progen/Multimetrix Germany No No

No

ZytoFast HPV type 6/11; 16/18; 31/33 Probes ZytoVision Germany Yes No No

ZytoFast HPV type 16/18/31/33/35 Probe ZytoVision Germany No NoNo

ZytoFast HPV type 16/18/31/33/35/45/51/82 Probe ZytoVision Germany Yes No

No

ZytoFast HPV type 6/11/16/18/31/33/35 Screening Probe ZytoVision Germany No No

No

ZytoFast HPV type 6/11/16/18/31/33/35/45/51/82 Screening Probe ZytoVision Germany Yes No

No

GenoFlow HPV Array Test DiagCor Bioscience Hong Kong Yes No

No

GenoFlow HPV-HR Screening Test DiagCor Bioscience Hong Kong Yes No

No

21 HPV GenoArray Test Kit HybriBio Hong Kong Yes No No

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Full Spectrum Genital Human Papillomavirus PCR Amplification and Genotyping Kit GenoID Hungary No No

No

GenoID Real-time HPV test GenoID Hungary Yes No No

AmpliQuality HPV-type AB Analitica Italy Yes No No

AmpliQuality HPV-type HR AB Analitica Italy Yes No No

AmpliQuality HPV-type express AB Analitica Italy Yes No No

AmpliQuality HPV-type HS AB Analitica Italy Yes No No

Realquality RQ-HPV HR AB Analitica Italy Yes No No

ProDect® Chip HPV Typing kit Bcs Biotech Italy Yes No No

HPV Total & High Risk Clonit Italy Yes No No

HPV Direct-Flow Chip Kit Hospitex Diagnostics Italy

No No No

HPV High Risk Typing Sacace Italy Yes No No

HPV High Risk Screen Real-TM Sacace Italy Yes No No

HPV 16/18 Real-TM Quant Sacace Italy Yes No No

Human papillomavirus 16/18 Sacace Italy Yes No No

HPV 16/18 FEP Sacace Italy Yes No No

HPV High Risk Screen Real-TM Quant 2 x Sacace Italy Yes No No

HPV High Risk Screen Real-TM Quant Sacace Italy Yes No No

HPV High Risk Screen FEP Sacace Italy Yes No No

HPV High Risk Screen Sacace Italy Yes No No

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GeneSQUARE HPV Microarray Kurabo Industries Japan Not known No

No

GENOSEARCH-HPV31

Medical & Biological Laboratories Japan Not known No

No

PCR Human Papillomavirus Typing Set Takara Bio Japan No No No

EIA kit HPV GP HR Diassay Netherlands Yes No No

HPV SPF10 LiPA25version 1

Labo Bio-medical Products Netherlands No No

No

HPV PCR-DEIA (SPF10)


No

HPV-TS-16 and HPV-TS-18 PCR-DEIA


No

HPV-TS-31 and HPV TS-45 PCR-DEIA


No

HPV Screening (HPV6/11/16/18/31/33) PanPath Netherlands Not known No No

HPV typing: HPV 6; 11; 16; 18; 31; 33; 6/11; 16/18; 31/33 DNA probe PanPath Netherlands Not known No

No

PreTect HPV-Proofer NorChip Norway Yes No No

Human papilloma virus, HPV (18, 45, 39, 59) DNA-Technology Russia No No

No

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Human papilloma virus, HPV (16, 18) DNA-Technology Russia No No

No

Human papilloma virus, HPV (51, 26)DNA-Technology Russia No No

No


No

Human papilloma virus, HPV (16, 31, 33, 35, 35H, 58, 52, 67)

DNA-Technology Russia No No

No

Human papillomavirus high-oncogenic risk HPV (16, 31, 35), (33, 52, 58), (18, 39, 45, 59)

DNA-Technology Russia No No

No


No

AmpliSens® HPV 31/33-EPh PCR kit

Federal State Institution of Science Russia Yes No

No



No



No

AmpliSens® HPV 6/11-FRT PCR kit


No

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AmpliSens® HPV 6/11-FEP PCR kit


No

AmpliSens® HPV HCR genotype-FRT PCR kit


No

AmpliSens® HPV 16/18-FRT PCR kit


No



No

AmpliSens® HPV 16/18-FEP PCR kit


No

AmpliSens® HPV HCR screen-Eph PCR kit


No

AmpliSens® HPV HCR screen-titre-FRT PCR kit (2x;4x)


No

AmpliSens® HPV HCR screen-FEP PCR kit


No

AmpliSens® HPV HCR screen-FEP PCR kit (3x)


No

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HPVDNAChip Biomedlab South Korea Not known No No

BMT HPV Genotyping 9G Membrane Kit Biometrix Technology South Korea No No

No

BMT HPV 9G DNA Kit™ Biometrix Technology South Korea Yes No

No

AccuPower® HPV16 & 18 Real-Time PCR Kit Bioneer South Korea No NoNo

Absolute HPV HR Test BioSewoom South Korea Not known No No

REBA HPV-ID Catch by Gene South Korea No No No

GeneTrack HPV DNA Chip Genomic Tree South Korea No No No

GG HPVCHIP GoodGene South Korea No No No

HPV Liquid Beads Microarray Genotype PCR Kit Innomeditech South Korea Not known NoNo

HPV Liquid Beads Microarray Genotype Kit Innomeditech South Korea Not known NoNo

SuperFast HPV 16, 18, 6, 11 Multiplex Real-time PCR Kit

Kogenebiotech South Korea Not known No

No

SuperFast HPV 16, 18 Multiplex Real-time PCR Kit


No

SuperFast HPV 5 Low risk Multiplex Real-time PCR Kit


No

SuperFast HPV 12 Multiplex Real-time PCR Kit Kogenebiotech South Korea Not known No

No

AdvanSure HPV 16/18 real-time PCR LGLS Diagnostics South Korea No No

No

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AdvanSure HPV Screening real-time PCR LGLS Diagnostics South Korea No No

No

PANArray™ HPV Genotyping Chip PANAGENE South Korea Yes No No

HPV/STD4 ACE Screening CE Seegene South Korea Yes No No

HPV4A ACE Screening CE Seegene South Korea Yes No No

HPV-DNA Assay Kit Tofema South Korea No No No

BIOTYPAP Kit Biotools Spain No No No

Clart® HPV 2 - Papillomavirus Clinical Arrays Genomica Spain No NoNo

HPV Direct-Flow Chip Master Diagnostica Spain Yes No

No

HPV typing TM Multiplex-Fluorescent PCR Molgentix Spain

Yes No No

PapillomaStrip High Risk Operon Spain No No No

PapillomaStrip Low Risk Operon Spain No No No

f-HPV typingTM Genomed Diagnostics Switzerland Yes No

No

PGMY-CHUV low cost Test World Health Organisation Switzerland No No

No

EasyChip® HPV Blot Kit King Car Taiwan Not known No No

HPV genotyping kit PlexBio Taiwan Yes No No

Quantification of Human Papillomavirus 6; 11; 16; 18; 33; 52; 58 PrimerDesign UK No No

No

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RealTime High Risk HPV test Abbott Molecular US Yes No

Yes

AutoGenomics Infiniti® HPV Genotyping Test Autogenomics US Yes No No

AutoGenomics Infiniti® HPV-HR Quad Test Autogenomics US Yes No No

AutoGenomics Infiniti® HPV-Quad Test Autogenomics US Yes No No

BD Viper HPV Test/BD HPV-GT Assay

Becton Dickinson Diagnostics US No Yes

No

Quantivirus™ HPV E6/E7 RNA 3.0 Assay (bDNA) DiaCarta US Yes No

No

APTIMA HPV 16 18/45 GENOTYPE ASSAY Hologic (Gen-Probe) US Yes Yes

Yes

APTIMA® HPV AssayHologic (Gen-Probe) US Yes Yes

Yes

Cervista® HPV 16/18 Test Hologic US Yes Yes No

Cervista® HPV HR Test Hologic US Yes Yes No

HPV OncoTect™ Test Kit IncellDx US Yes No No

HPV OncoTestInvirion Diagnostics

USNo No

No

HPV In Situ Hybridization/Detection Kit (Types 6/11/16/18/31/33)

Maxim Biotech US No No

No

HPV In Situ Hybridization/Detection Kit (Types 6/11)


No

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No



No

HPV-1; HPV-6; HPV-11; HPV-16, HPV-18; HPV-31; HPV-33; E6 Gene Primer Set


No

MPCR Kit for Human Papillomavirus Maxim Biotech US No No

No

HPV, Mixed Type, L1 Genes Primer Set Maxim Biotech US No No

No

digene® HPV Genotyping LQ Test Qiagen US Yes No No

digene® HPV Genotyping RH Test Qiagen US Yes No No

digene® HPV Genotyping PS Test, RUO Qiagen US Yes No No

CareHPVTM Test Qiagen US Yes No No

Hybrid Capture 2 (HC2) HPV DNA Test Qiagen US Yes Yes Yes

Linear Array® HPV Genotyping Test

Roche Molecular Systems US Yes No

Yes

cobas® 4800 HPV Test

Roche Molecular Systems US Yes

Yes (for primary screening)

Yes

Amplicor HPV Test

Roche Molecular Systems US Yes No

No

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HPV MassArray (Sequenom, San Diego, CA) Sequenom US No NoNo

Human (hPV) 12 Multiplex Real-time PCR Kit USBio US No NoNo

INFORM HPV II Family 6 Probe (B) Ventana US No

INFORM HPV III Family 16 Probe (B) Ventana US No No

Biorad Dx HR-HPV Test Bio-Rad US Yes No No

Supplementary Table 2: Non-invasive prenatal testing (NIPT) and regulatory approval in EU, US, CA*We identified the following firms with a website search, and looked up CE mark by searching each firm’s website, then looked up US-FDA and Health Canada approval on their respective online repositories of approved tests.

Test Firm NameLocation

EU CE Mark US FDA Health Can

Clarigo Agilent Technologies US

YesNo

No

Non-invasive Prenatal Test

Apollo Centre for Fetal Medicine

IndiaNo

NoNo

Harmony Ariosa (Roche)US

YesNo No (Submitted

application in summer 2018)

Non-Invasive Prenatal Testing for Fetal Aneuploidy (also available with Microdeletions and with 22q11.2 Microdeletion)

ARUP

US

No

No

No

FirstVue (and FirstVue+) ATGC Diagnostics

IndiaNo

NoNo

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Babyguard BasetraChina

NoNo

No

Preseek Baylor GeneticsUS

NoNo

No

Bebeian/Bambni Test (also in plus) Berry Genomics

ChinaNo

NoNo

Nifty Pro (iGeneScreen in Australia) BGI

ChinaNo

NoNo

Bioarray non-invasive prenatal screening analysis (NIPT)

BioarraySpain

NoNo

No

CentoNIPT CentogeneGermany

YesNo

No

Tomorrow CGC GeneticsPortugal

NoNo

No

Prévu Cordlife - GenscreenSingapore

NoNo

No

Prelude CounsylUS

NoNo

No

Maternal Blood for Fetal DNA (MBFD) with Microdeletions

Dr Lal PathlabsIndia

NoNo

No

Nice EONE-DIAGNOMICS Genome Center (EDGC)Korea

YesNo

No

Ninalia (and Ninalia+) Eurofins BiomnisFrance

NoNo

No

Early Pregnancy NIPT Screen (also available in Plus)

EvolveGene (trademark of LifeGlobal Group LLC.)

USNo

NoNo

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Prendia (Start and Expert) Fasteris (with Genesupport)

SwitzerlandYes

NoNo

GeneSyte GeneaAustralia

NoNo

No

TriScreenGenesis Genetics South Africa (Next Biosciences firm)

South AfricaNo

NoNo

Tranquility Genoma Swiss Biotechnology SàrlSwitzerland

YesNo

No

Prenatal SAFE (several panels available); Genesafe (Inherited, De Novo, Complete)

Genoma Molecular Genetics Laboratory Group

Italy

No

No

No

Genomom GenomeCareKorea

NoNo

No

NIPT Basic (also available in Plus and Plus2)

Genomics Biosciences and Technology

TaiwanNo

NoNo

Generation (also available in Plus) Genomics Diagnostics

AustraliaNo

NoNo

ClariTest (also available with microdeletion panel)

Gen Path (OPKO)US

NoNo

No

Prenetix Human Stem Cells Institute - GeneticoRussia

NoNo

No

Nace (and Nace Extended 24)

IGENOMIX (formerly IVIOMICS)

SpainNo

NoNo

Verify (also available in Plus) Illumina®

USNo

No No

iGene Non Invasive Prenatal Test

Innovations Exchange Pte Ltd (INEX)

SingaporeNo

No No

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InfomaSeq; MaterniT21Plus (also available in Genome)

Integrated Genetics (now includes Sequenom)

USNo

No No

Determine 10 Lab GenomicsUS

NoNo No

Discover (available for both singleton and twin pregnancies)

Lab Solutions US

NoNo No

Babyshield - cfDNA LifeCell India

NoNo No

PrenaTest (Option 1, 2, and 3) LifeCodexx

GermanyYes

No No

Cell-Free DNA Prenatal Screen Mayo Medical Laboratories

USNo

No No

Claria MedgenomeIndia

NoNo No

MyNIPT MyGenetxUS

NoNo No

Panorama NateraUS

NoNo No

Lucina NIPT NHS West Midlands Regional Genetics LaboratoryUK

NoNo No

Trisonim Advance and Premium NIM Genetics

SpainNo

No No

Veracity NIPD GeneticsCyprus

NoNo No

NxGen Informed Prenatal Test (NIPT) NxGen MDx

USNo

No No

IONA Premaitha HealthUK

YesNo No

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Innatal™ Prenatal Screen (formerly "Verify")

ProgenityUS

NoNo No

QNatal Advanced Quest DiagnosticsUS

NoNo No

Sofiva NIPS (also available in Plus) Sofiva

TaiwanNo

No No

neoBona (also available in Advanced) Synlab Group - with Medlab

GhanaNo

No No

MyPrenatal VeritasUS

NoNo No

percept Victorian Clinical Genetics Services (VCGS)Australia

NoNo No

Sage Prenatal Screen (also available in Plus) Yourgene Bioscience

TaiwanNo

No No

safeT21express XcelomHong Kong

NoNo

No

Supplementary Table 3: Breast Cancer Prognosis tests and regulatory approval in EU, US, CA*We identified the following firms with a website search, and looked up CE mark by searching each firm’s website, then looked up US-FDA and Health Canada approval on their respective online repositories of approved tests.

Test Firm Name Location KIT/LDT EUCE mark

USFDA

Health Can

MammaPrint Agendia Netherlands LDT Yes Yes No

Blue Print Agendia Netherlands LDT No No No

MammaPrint BluePrint next-generation sequencing-based kit

Agenda Netherlands Kit Yes No No

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Test Firm Name Location KIT/LDT EUCE mark

USFDA

Health Can

MammaTyper BioNTech Germany Kit Yes No No

Breast Cancer Index BioTheranostics

US LDT No No No

Oncotype Dx Genomic Health

US LDT Yes No No

Prosigna Assay NanoString US Kit Yes Yes Yes

AdnaTestBreastCancer Select/Detect

Quiagen US Kit Yes No No

Femtelle Sekisui Germany Kit Yes No No

EndoPredict Sividon Diagnostics, acquired by Myriad

US Kit Yes No Yes

FOXC1 Onconostic Technologies, Inc.

US Kit No No No

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Confidential: For Review Only - BMJ...Confidential: For Review Only story (otherwise it is probably more fitting for a specialist venue). 1) As you think about how to convey the magnitude