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BRUSSELS BEAT: There’s an EU will on UDI, but there’s no way – yet

Pharma must be consulted on companion Dx reg, EU Commission tells Parliament

INTERVIEW: Get your EU clinical evaluation report shipshape or get your products pulled

US regulatory framework for lab-developed tests gets underway

Philippines’ new AMDD regs and Indonesia goes all-e

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BRUSSELS BEAT: There’s an EU will on UDI, but there’s no way – yet

The US haS already moved ahead in imple-

menting unique device identification requirements

which help to identify medical devices through their

distribution and use. In the EU, there is also growing

demand for such a system but what is holding the au-

thorities back from moving ahead with UDI? Amanda

Maxwell reports from the European MedTech Forum to

explain the European Commission’s point of view

• • •

Unique device identification (UDI) will offer the medtech and

healthcare sectors numerous benefits in terms of traceability

of products, logistics and collecting big data to demonstrate

the value of products to healthcare providers.

This has been recognized internationally by the sector,

and has led to work aimed at developing a harmonized

guidance document at the Global Harmonization Task

Force, which is now replaced by the International Medical

Device Regulators Forum.

The value of UDI has also been widely recognized at EU

level: the European Commission’s proposed EU Medical

Device Regulation (MDR) proposes specific traceability

requirements and foresees an EU UDI system that is com-

patible with the internationally developed approach, all

of which is supported by the European Parliament and, it

seems, the Council of the European Union.

But the MDR is unlikely to be implemented before 2018 at

the very earliest. So why – given the need and desire for UDI

- can’t the EU get its act together and introduce UDI now?

That was a question on the minds of many who attended

the European MedTech Forum, held in Brussels on 15-17

October. John Parkinson, consultant expert at the UK NHS’s

Clinical Practice Research Datalink, emphasized that UDI

is urgently needed for the collection of big data which will

provide more information to payers about the real value of

different products.

Meanwhile, Mike Kreuzer, chair of the UDI group at EU medtech

trade association Eucomed, asked that since the European

Commission, Parliament and Council recognize that UDI will be

a useful enabler in the devices sector, why can’t “concerted work

between industry, member states and the Commission be put

in place now to move the whole thing forward”?

The answer was simple. While there may be a desire to move

ahead at EU level, there are legal constraints in doing so,

Sabine Lecrenier, head of the health technology and cosmet-

ics unit at the European Commission’s directorate general for

health and consumers, DG Sanco, told the meeting.

“There are currently no legal rules about traceability in the

field of medical devices so we cannot impose any in this field

at European level,” she said. ”We need to have a legal basis to

impose common rules and create a common database,” she

continued. Without this, Ms Lecrenier stressed, there can be

no EU-wide UDI system.

She acknowledged, however, that member states are free to

create their own traceability laws, but that this is “not the best

By Amanda Maxwell

2 • • •

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solution”, as traceability will be limited then to the national level.

Moreover, there is a general recognition that Europe wants to

avoid national schemes springing up that could result in dis-

crepancies and incompatibilities between member states and

with the European scheme that is yet to be developed.

This is the reason that the European Commission issued a

Recommendation on a common framework for a unique

device identification (UDI) system in the EU on 5 April 2013,

Ms Lecrenier explained.

“We adopted a Recommendation suggesting that member

states follow the international model if they want to create

national systems, as is their right,” she said. But ultimately,

she acknowledged that national schemes are not the best

way to go forward and she emphasized the need to have a

“common harmonized European system”.

The aim is to create a European UDI system which is aligned as

closely as possible to international schemes. There is a global

market for medical devices and so it would be useful to have

the same codes in the EU as in the US and China, for example,

Ms Lecrenier said. “That is what we are trying to do”.

So how soon will the European Commission be able to start

implementing UDI rules?

It is the commission’s intention to adopt implementing rules

to define all the necessary elements related to UDI as soon

as the MDR and IVD Regulation have been adopted, Ms Lec-

renier said. The commission will start with requirements for

high-risk Class III devices.

Once the rules have been adopted, however, there will also

be a transitional period to allow manufacturers time to fulfill

the new requirements.

The commission is already preparing to expand Eudamed*,

the European medical device database of which UDI will

form one part. Eudamed underpins the current medical de-

vice directives and will play an even more critical role, Clinica

notes, in the implementation of the future Regulations.

The database has to be ready for the day when the new Reg-

ulations come into force as it is a “key aspect” for the overall

functioning of the system, Ms Lecrenier noted, ensuring that

all information is duly exchanged between member states,

and providing access to relevant parts for industry too.

As well as UDI, other modules within Eudamed currently cov-

er: registration, certificates from notified bodies, vigilance

and clinical evaluation*. The commission is inviting member

states to learn from their experience with Eudamed so far – the feedback for which has been patchy, Clinica notes - as part of their preparation tasks.

Ms Lecrenier was confident that the resources and experi-ence already exist to help set up the necessary database structure within three years. She dismissed the suggestion that the fact it took over 10 years to set up the current Eu-damed, bodes ill for the newly expanded database.

“We are in a completely different situation”, she told the meeting. “There is going to be €2m per year devoted to the development of this database, and we have experience with other commission databases which we will put to good use.”

The aim will be to see if the database meets the needs of all the stakeholders, as well as to see if it is compatible with ex-isting systems. Ms Lecrenier said that the medtech industry – as one of the frequent users of the future Eudamed database – as well as member states, would be consulted.

The commission is already carrying out exploratory work to see what database structures already exist within the mem-ber states.

*The European Commission and the European Parliament have proposed that the future Eudamed system will include the electronic systems on :

• UDI

• registration of devices and economic operators;

• information on certificates;

• clinical investigations;

• vigilance ;

• market surveillance;

• the electronic system on registration of subsidiaries and subcontracting; and

• the electronic system on special notified bodies

The European Commission has proposed the first six in the list, and the European Parliament has added the last two in this list.

What is UdI?The European Commission describes Unique Device Identifica-tion (UDI) as a unique number pertaining to a medical device that enables the identification of different types of devices, and access to useful and relevant information stored in a UDI database. Due to the UDI’s specificity, it can make traceability of devices more efficient, allow easier recall of devices, fight against counterfeiting, and improve patient safety.

Medtech Intelligence@ClinicaMedTechClinica Medtech Intelligence

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Pharma must be consulted on companion Dx reg, EU Commission tells Parliament Amanda Maxwell

The European Commission has rejected Parliament’s pro-

posal that notified bodies should not be obliged to consult a

pharmaceutical authority as part of the conformity assess-

ment on companion diagnostics.

The commission has just published its responses to Parlia-

ment’s 2 April first reading amendments to the proposed IVD

Regulation. In its report, the commission says that it is vital

that the notified body consults the pharmaceutical author-

ity to ensure that companion diagnostics are suitable for the

medicinal products with which they are intended to be used.

This is just one of the Parliament’s amendments rejected by

the European Commission in the context of the proposed

IVD Regulation. In total, it rejects 81 of the Parliament’s pro-

posed amendments.

The table below reflects how the commission voted on the

European Parliament amendments, and compares with with

the commission’s voting on Parliament’s first reading amend-

ments to the proposed Medical Devices Regulation:

As with the Medical Device Regulation proposal, where the

future regulation of the highest-risk class of products provoked

the most debate, the response to the IVD Regulation is particu-

larly long-winded and complex. Nevertheless, the commission’s

response to the European Parliament’s proposals with regards

to this issue is arguably more accepting than might have been

expected, given the multiple layers of regulation proposed.

When it comes to the pre-market assessment of high-risk

IVDs, Parliament proposes to subject these products to a

case-by-case, clinically focused assessment by the Medical

Device Coordination Group (MDCG). The MDCG would be

assisted by a new committee of scientific experts called the

Assessment Committee for Medical Devices (ACMD).

The commission, on the other hand, feels that the assess-

ment should also include the summary of the preliminary

conformity assessment by the notified body – and not just

the clinical aspects.

Parliament continues to suggest that the commission

would be empowered to extend the application of the

assessment procedure to other classes of devices when

necessary for the protection of patient safety and pub-

lic health, something which the commission itself does

not comment on.

The MDCG, according to Parliament, could invoke the

novelty of the device, an adverse change of the risk-benefit

profile, or an increased rate of serious incidents to trigger the

assessment procedure. As for the commission, Parliament

says that it is also necessary to keep the existence of “signifi-

cant discrepancies in the conformity assessments carried

out by notified bodies” as one of the criteria to trigger the

assessment procedure.

The commission, as suggested by Parliament’s amendment,

could amend or supplement these criteria by delegated act.

This proposal is not addressed in particular by the commission.

Parliament suggests that the assessment procedure for

high-risk IVDs could not be triggered if Common Technical

Specifications (CTS) or harmonized standards exist. Con-

versely, the commission says that the existence of Common

Technical Specifications or harmonized standards should be

taken into account but should not prevent the procedure to

be triggered, when necessary.

Parliament’s proposed amendments on the rules for assess-

ing high-risk IVDs are lengthy, but the commission does not

address all the aspects in its report.

No. of amendments accepted directly or in

principle

No. of amendments accepted partially or subject to rewriting

No. of amendments rejected

IVD Regulation proposal 64 116 81

Medical Device Regulation proposal

85 127 131

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Regulatory issue(European Parliament amendment numbers in brackets)

European Parliament position European Commission response

Scope: in-house exemption (in particular, amendment 70)

Parliament proposes a conditional exemption from the most of the requirements of the Regulation for class D in-house tests, in particular, where the recipient patient or patient group’s specific needs cannot be met by an available CE-marked device.

Where the exemption is invoked, Commission would verify if conditions are met and if devices eligible for exemption.

The information on exempted devices would be made public

Member States would retain right to impose stricter requirements on in-house devices and regulate aspects that are not covered by the Regulation.

Commission could agree on this amendment, except on the obligation for the it to systematically verify that the exempted devices were eligible for exemption.

Counseling and informed consent in the field of genetics (in particular, amendment 271)

Parliament proposes that an IVD may only be used for a genetic test if prescribed by a medical profession, after a personal consultation and appropriate information, and if the subject of the testing has given free and informed consent.

Parliament amendment includes specific provisions regarding genetic counseling in the case of predictive and prenatal testing, as well as where a genetic condition has been diagnosed. It limits the use of devices for the determination of sex in prenatal diagnosis.

Commission could agree with the introduction of the proposed provisions relating to the use of IVDs for genetic testing, such as the information to be provided to the person concerned before using a device for the purpose of a genetic test and the provisions related to informed consent, subject to possible rewording.

Prescription requirement (in particular, amendment 268)

Parliament proposes that certain IVDs may only be supplied on a medical prescription ( i.e. class D devices, class C devices for genetic testing, class C companion diagnostics).

Direct-to-consumer advertising of devices classed as prescription would be prohibited.

By derogation, Member States may maintain or introduce national provisions allowing some class D tests to be available without a medical prescription.

Commission to be empowered to adopt delegated acts to decide that other class C tests may only be supplied on a medical prescription after consultation with stakeholders.

Commission could agree on Parliament’s proposal to introduce provisions on prescription with regard to genetic tests.

However, issues relating to advertising of devices and rules on prescription with regard to class D devices and companion diagnostics should be left to member states.

Notified bodies (in particular, amendment 147)

Parliament’s amendments aim at further strengthening the control, monitoring and functioning of Notified Bodies.

A separate designation by the EMA of Special Notified Bodies is proposed for high-risk IVDs.

Commission could support more stringent criteria for Notified Bodies which process the conformity assessment of high-risk devices.

However, the added value of EMA involvement will need to be thoroughly analyzed, in particular, where the relevant resources and financing have not been foreseen.

It is also necessary to analyze the issue of the legal basis for the involvement of EMA.

Vigilance (in particular amendment 180)

Parliament amendments aim at extending reporting by manufacturers to all incidents – serious and non-serious. Parliament additionally proposes that Periodic Safety Update Reports (PSURs) be drawn up by manufacturers

Commission will have to evaluate the implications of enlarging the scope of reporting, as there is a risk that it would render the rapid identification of serious incidents and their proper follow-up more difficult. Commission supports proposal for PSURs this proposal.

Market surveillance (in particular, amendment 185)

Parliament’s amendments propose competent authority checks may also take place at economic operators located in third countries.

Final inspection report should be made available in the electronic system on market surveillance.

Member States should draw up strategic market surveillance plans, periodically review them; Commission to make recommendations for adjustments of those plans.

Summary of the results and Commission recommendations to be accessible to the public.

Commission to provide an overview of the information received in the electronic system every six months, for the public and healthcare professionals.

Commission supports proposed amendments for reinforced market surveillance by competent authorities but does not consider necessary a systematic general reporting twice a year, as it would be too burdensome.

Ethics committees (in particular amendment 167)

Parliament’s amendments introduce new provisions to reinforce role of ethics committees in conducting clinical performance studies.

Commission could agree, provided reinforced provisions are aligned with Regulation on clinical trials on medicinal products for human use.

Minors and incapacitated (in particular, amendment 253)

Parliament amendments aim at further protecting minors and incapacitated subjects in clinical performance studies, in particular in terms of informed consent and adequate information to be provided.

As above, Commission could agree, provided provisions are aligned with the Regulation on clinical trials on medicinal products for human use.

Transitional period (in particular, amendment 202)

Parliament has proposed an amendment to cut time between adoption to full compliance from five to three years.

Commission rejects this , saying operators need sufficient time to adapt to the changes.

6 • • • Reprinted by Clinica (www.clinica.uk.co). Unauthorized photocopying prohibited.

Indeed, Parliament is also suggesting the following:

• the MDCG would have 60 days to deliver an opinion, dur-

ing which it has to consult the ACMD;

• where the Special Notified Body (SNB) concerned (and

involved in the assessment of high-risk IVDs) disagrees with

the MDCG’s opinion, it may request a re-examination;

• where the final opinion of the MDCG is favorable, the

SNB may proceed with the certification;

• where it is unfavorable, the SNB shall not (yet) deliver the

certificate for the device; and

• at the request of the manufacturer, the Commission has

to organize a hearing allowing scientific discussion and

action which it can take to address the MDCG’s concerns.

In response, the commission merely says that the outcome

of the procedure after the hearing, as foreseen by the Parlia-

ment, is not clear.

The commission says that it should be noted that a previ-

ous version of this amendment (amendment 151) was also

adopted by the Parliament, seemingly by mistake. The main

difference is that it foresees the adoption of a decision by the

commission on the basis of the MDCG opinion, which makes

the outcome of the assessment procedure more certain.

Despite a non-confrontational reaction, that is not to say

that the battle is over concerning the regulation of the high-

est risk IVDs. The position of the Council of the EU, which is

the third party in these trialogue discussions, is still un-

known, and possibly still undecided.

The following are a series of further issues on which the

commission chooses to explain its views within its report on

the European Parliament’s first reading resolution:

As with its report on the Medical Devices Regulation, the

Commission notes that there is no calendar available yet for

the adoption of the Council’s common position, and so no

need yet for a formal modified position.

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INTERVIEW: Get your EU clinical evaluation report shipshape or get your products pulledAmanda Maxwell

IT may STIll be Several yearS before the

new EU regulation for medical devices come into

full force, but if the medtech industry does not

keep up to date with current changes to clini-

cal evaluation requirements, it could well find its

products pulled from the market. Amanda Max-

well spoke with Sarah Sorrel, founder and presi-

dent of MedPass International, to find out what

manufacturers need to know to ensure they do

not fall on the wrong side of the regulators

• • •

The nature of the EU medical devices regulatory environ-

ment is changing rapidly, pushed from behind by the

European Commission’s plan of urgent actions and pulled

forward by the proposed Medical Devices Regulation. One

particular area where manufacturers need to reevaluate their

compliance is clinical data requirements.

There is no doubt that this should be on the top of manu-

facturers’ priority lists. Companies are coming under increas-

ingly intense scrutiny over compliance with clinical data

requirements: notified bodies are becoming more stringent

and coordinated market surveillance action by the compe-

tent authorities will also be leading to closer assessment of

all aspects of products that fall under the spotlight.

Here, Clinica’s Amanda Maxwell spoke with Sarah Sorrel,

president of MedPass International, a Paris-based consul-

tancy specializing in clinical data and regulatory compliance

for medical devices, and her colleagues Jeremy Tinkler, direc-

tor of regulatory consultancy and quality assurance, and

Estelle Geffard-Duchamp, director of regulatory affairs. They

explained why companies should be vigilant now to ensure

their clinical evaluation reports (CERs) are up to date.

Clinica: The 2007/47/EC revision of the Medical Devices Direc-

tive already places a heavier emphasis on the need to have

clinical investigations for most devices – especially for high-risk,

Class III products – rather than rely on literature reviews etc.

Have there been any major developments in terms of clinical

evaluation since this revision?

medPass: Two major developments have been in the fore-

ground since the 2007 revision of the Medical Devices Directive.

The first is the interpretation of equivalence, and the second is

the importance of the post-market follow-up plan.

If a device can be proven to be equivalent to one already on

the market, then this, in theory, can be an argument for not

doing clinical investigations as long as there is strong litera-

ture evidence support.

But manufacturers have been creating all kinds of invalid ar-

guments based around equivalence and literature searches

to avoid clinical investigations.

Now, the authorities and the notified bodies are determined

to stamp out abuse of the system and it is almost impossible,

especially for a Class III product, to avoid a clinical investiga-

tion, no matter how equivalent your product is.

Clinica: So how can manufacturers know where they are justi-

fied in claiming equivalence?

medPass: If it is more a product iteration - where you can

justify the original clinical data applies and risk has been miti-

gated by design - or you can prove the risk/benefit balance re-

mains favorable, then it may be possible to claim equivalence.

Otherwise some sort of clinical investigation will be required.

It is not entirely black and white, however. There may be

some aspects of a device which you can demonstrate are

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8 • • • Reprinted by Clinica (www.clinica.uk.co). Unauthorized photocopying prohibited.

equivalent, while focusing the investigations on the other

aspects. This will mean you can tailor the study design to ex-

actly what is needed and carry out the investigations more

efficiently. In other words, if you get as much leverage as you

can from the literature, you can streamline the study design

and make savings.

Ultimately the decision on whether a clinical investigation is

needed will depend on the notified body – and that decision

may vary according to the notified body you choose as it is

still not a totally level playing field.

While it will theoretically remain possible to avoid a clinical

investigation, the circumstances where this can be done will

be limited. The revision of guidance document meddev 2.7/1

should clarify many of the difficulties that manufacturers are

having in understanding where they can claim equivalence.

Clinica: Can you explain more about why post-market clinical

follow-up is so important?

medPass: Yes, it is now virtually mandatory to present a

post-market clinical follow up (PMCF) plan in the clinical

evaluation report (CER); that is unless you have an extremely

robust justification for not doing so.

You always need a post-market surveillance plan; and if you

have a strong case, it is there that you justify any decision

not to carry out post-market clinical follow up.

As the post market surveillance plan has to be presented at

the time of CE marking, manufacturers approaching recerti-

fication by the notified body must do an inventory to ensure

everything is updated to the new requirements, including

PMCF or justifying the lack of PMCF, and updating the CERs,

as necessary.

Clinica: Which manufacturers (in terms of the type of products

they manufacture) are going to have the toughest time as a

result of the proposed changes to clinical data requirements

under the revised Medical Devices Regulation? What impact

might this have on industry as a whole?

medPass: It has always been a requirement of the Medical

Devices Directive to have a clinical evaluation report for all

products regardless of class. Indeed, a robust and scientifi-

cally valid clinical evaluation report is needed for Class I

products, just as for higher risk products.

Manufacturers of high-risk devices are used to close

scrutiny of the CER; Class III products have always had go

through a design dossier process so these companies are

well aware of the demands and not at such risk of being

caught by surprise.

While it has always been theoretically possible that a notified

body might scrutinize the CER for lower-risk devices, this has

happened less [frequently] or with less intensity. Basically,

they have got off lightly in the past.

With greater demands of notified body performance, manufac-

turers of all devices can expect closer scrutiny of the CER by the

notified body, and may also see competent authority policing

activities widening. And, if a competent authority does get in-

volved in assessing the compliance of lower risk products – for

example, during spot checks or in response to vigilance cases

- it will look at the CER. Many companies don’t realize that this is

the case and are likely to be taken by surprise.

Manufacturers need to also be aware that notified bodies may

want to look at the clinical evaluation report not just during

regular audits, but during the unannounced audits, which will

occur at least once every three years. The CER and the risk man-

agement report are key evidence in terms of non-compliance.

Clinica: So how likely is it that manufacturers of medium-risk

devices are going to be found failing in this area?

medPass: The real danger is for the Class IIb devices. Some

have got through on patchy clinical data in the past, and

some based on literature. Our advice to manufacturers of

devices in Class IIb would be to be very careful and do inven-

tory of where they stand.

To give an example, one of our clients had a vigilance issue

with a Class IIb product in Germany. The German authorities

requested the CER and found it had not been updated in line

with state of the art. The company risked having its products

taken off the whole EU market.

Clinica: If you could give device manufacturers five top tips

in terms of preparing now for compliance with clinical data

requirements under the new Regulation, what would they be?

medPass : They would be

• do an inventory of all CERs and risk management reports

to make sure they are updated to the current meddev or

European standard requirements;

• prioritize Class IIb products;

• re-evaluate the need for PMCF on the basis of the risk

assessment;

• study the new meddev guidance documents as they

come out, particularly MEDDEV 2.7/1; and

• ensure that your CERs are logical, concise and focused on

the principles of clinical evaluation. ➤

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Clinica: Can you explain when the next version of the meddev

guidance documents on clinical evaluation should be available?

medPass: Three guidance documents in the meddev 2.7

group are being rapidly revised under the leadership of the

European Commission’s Clinical Investigation and Evaluation

working group in which MedPass participates. They are:

• meddev 2.7/1: Clinical evaluation: guide for manufactur-

ers and notified bodies;

• meddev 2.7/2: Guide for competent authorities in making

an assessment of clinical investigation notification; and

• meddev 2.7/3 Clinical investigations: serious adverse

event reporting.

The intention is to have the revised documents at committee

stage by November and to have them available sometime

early next year.

The hope is that the concept of equivalence will be explained

much more logically in meddev 2.7/1, given that many people

have difficulties interpreting and using the equivalence

concept. Issues are arising now because notified bodies are

being told to enforce the equivalence concept very strictly, but

the current meddev definition is unrealistically simplistic and

therefore not very helpful. You cannot have an all or nothing ap-

proach to a such a complex concept , so we are hoping we will

end up with a more useful document soon.

Clinica: Which are the preferred countries in Europe/outside

Europe for carrying out clinical investigations at present and why?

Do you think that will change under the new EU Regulations?

medPass: There is no easy answer. The answer depends on

whether you are talking about first-in-man studies, clinical

investigations for CE marking, or post-market studies, as the

regulatory situation differs in each country according to the

type of study.

The issues we would advise manufacturers to consider in

making their decision are:

• site qualification and motivation;

• patient availability;

• ethics committee and competent authority approval

timelines (sequential or parallel submissions);

• required documentation / translation;

• site contract timelines; and

• whether there are additional radiation regulations.

When using site outside the EU, ensure they comply with the

international clinical investigations standard, ISO 14155.

Clinica: Why are there issues with conducting clinical investi-

gations in Germany? ➤

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10 • • •

medPass: We would advise caution in Germany if a manu-facturer is likely to be impacted by its additional radiation regulation. In Germany, if you have a patient assessment in your protocol using ionizing radiation that is outside the standard of care, you have to apply to the Federal Office for Radiation Protection (BfS). Their approvals, in our experience, can take up to a year.

BfS will also need to look at the ethics committee opinion first, so it is not even possible to do applications to the two bodies in parallel.

Clinica: Is Germany the only country with ionizing regulations?

medPass: The point is that Germany is the only country to have an extra regulatory body checking the application regarding compliance with ionizing regulations.

In theory, the BfS, [Germany’s Federal Office for Radiation Protection], should be able to do the review in 2-4 months, but in practice they have so many dossiers they cannot predict timelines. It makes nonsense of the 60-day limit by which competent authorities should grant permission for clinical investigations for high-risk devices.

Germany was the largest market, with a lot of investigators and key adopters of new technology, but all of a sudden they are being pushed out of the game because of these new requirements.

Clinica: Can you explain the importance of the EU require-ments for post-market follow-up and why these are changing?

medPass: There’s nothing new in terms of PMCF require-ments - to manage risks you have always needed appropriate post market surveillance. It’s just that the rules are now being enforced by NBs in a way we have not generally seen before.

From a practical standpoint, you can’t get a CE marking now unless you are proposing a post-market surveil-lance plan at the same time. You normally have to have a detailed and scientifically justified PMCF plan, including statistical justification.

Typically, notified bodies now also request clinical data updates on some of the plan at certain time points after CE marking. Frequency depends on risk of the product and how much clinical data was in original submission.

Details of PMCF requirements are currently addressed in a Commission guidance document and will be included in the forthcoming Medical Device Regulation.

Clinica: Do you think that US companies who currently often use the EU as a launch pad, in terms of both clinical investiga-

tions and market entry, will become more reluctant to use

Europe in this way because the system is much slower, more

expensive? Where do you think their preferred markets will be in

future for this purpose?

medPass: It will depend on the product. If you have a de-

vice where you can get US device clearance faster, eg 510(k),

then it is unlikely a company would go for CE marking first.

On the other hand, if you have a high-risk product that

needs to go through premarket approval in the US, even if

the EU is more stringent, comparatively speaking it will still

be easier to get a CE marking first.

The other important thing to note is that the CE marking is

becoming more robust and this will offer more confidence

to users in terms of using the EU as a springboard and also

companies use European CE marking to get free sale certifi-

cates for countries outside Europe. This is a huge benefit as if

you are a US company, it will take a long time to get through

the FDA to obtain this certificate

It is worthwhile considering central and South America and

South Africa for first-in-man studies, but Europe should

remain the preferred location for pre-market studies and

market entry.

For first-in-man studies, if you have a product you know will

require several iterations before it reaches the design freeze

stage, you may want to go to South America and South Af-

rica where the patient enrolment rate is usually higher than

in Europe. (In Brazil, they have just tightened the regulations

and this is impacting the popularity of that market.)

The ethical requirements are the same in all these countries as

they all have to follow Helsinki agreement. Wherever you do

your clinical investigations, you still need to follow ISO 14155.

Clinica: What about the costs of compliance with the clinical

data requirements?

medPass : The cost of regulatory compliance is no longer

the whole story as reimbursement is becoming more impor-

tant as part of an overall clinical strategy.

For reimbursement purposes in the EU, we are moving more

towards an HTA approach where we have to demonstrate

clinical evidence.

Reimbursement studies have to be more comprehensive

than studies for CE marking purposes, more akin to stage III

studies, and of larger sample size. They may be randomized.

The real costs will come from that. For companies needing to

do reimbursement studies, these trials will cover their post-

market clinical follow up. ➤

Reprinted by Clinica (www.clinica.uk.co). Unauthorized photocopying prohibited. • • • 11

The CE marking requirements fall short of the reimburse-ment requirements. So companies that have to do a PMCF that don’t really need to do investigations for reimburse-ment purposes, do not need to go to the same level in producing evidence and can do this relatively cheaply.

Clinica: Do you think Europe has sufficient resources at

authority and Commission level to manage the proposed new

clinical data requirements?

medPass: No, the expertise of competent authorities is still patchy. But their combined efforts are achieving major improvements and there is more discussion between com-petent authorities, unofficially and in meetings, and regular conference calls.

The European Commission is organizing joint audits of noti-fied bodies and joint appraisal of clinical investigation ap-plications. The EU is moving into a more collaborative phase to ensure that the resources that are available, eg techni-cal expertise, are shared so less experienced competent authorities will learn about things and there will be a gradual increase in expertise, applied in a more equitable manner.

It is early days. A lot has already been done through this collaboration which has resulted in higher clinical evaluation demands.

Clinica: Can you give three tips on how companies should

best prepare to exploit the opportunities that are expected to

arise for multi-state investigations? And are there any potential

pitfalls in these new arrangements?

medpass: They would be:

• ensure that the quality of the investigator brochure meets the technical standards of BfArM in Germany and the UK’s MHRA, with all full reports available;

• ensure that the quality of the protocol meets the ethical expectations of France’s ANSM which has the highest standards for risk/benefit balance; and

• ensure that the protocol clearly links to the requirements of CE marking and, if it is not sufficient for CE marking on

its own, show how it will feed into a study that will meet CE marking requirements.

Clinica: Can you explain how notified bodies are preparing to take on additional clinical experts and how this will impact the relationship between manufacturers and notified bodies when it comes to technical file review, including clinical data? How can companies prepare for the new challenges?

medPass : Manufacturers should not forget that it neces-sary to give the notified body, and their clinical assessors, confidence that the clinical evaluation accurately reflects best clinical practice and leading opinion.

But things are changing among notified bodies, even among those that previously used clinical experts. There is now an expec-tation that an assessor with the relevant specialist clinical expertise will be used in most cases for the CER assessment.

It can be challenging for the notified body to manage the process and ensure that the focus remains on regulatory compliance. We have seen examples of clinical assessors causing long delays and going off at tangents. To avoid this, companies should examine carefully the notified body’s access to appropriate clinical expertise in the product area. Our recommendation is that should be one of key factors in selection of the notified body.

Many of these assessors are outside experts and can be opinionated. Not everything they say is relevant to the case they are looking at.

Key takeaway messages• It is vital to keep the CER up to date both for the pre-

market and post market phases.• The medtech industry is increasingly seeing – in this

post-PIP breast implant scandal era – more intense mar-ket surveillance by competent authorities, particularly in the context of vigilance reports.

• Competent authorities are tending more now to request CERs and companies are risking having product taken off the EU market on the action of a competent authority triggered by vigilance.

• Germany is a particular hotspot for these incidents.

Medtech Intelligence@ClinicaMedTechClinica Medtech Intelligence

Reprinted by Clinica (www.clinica.uk.co). Unauthorized photocopying prohibited.

12 • • •

US regulatory framework for lab-developed tests gets underwaySue Darcey

The US FDA followed through with its promise to officially issue its proposals to regulate laboratory-developed tests (LDTs) as soon as possible under congressional notification requirements with the posting of two draft guidances at the end of last month.

One of the documents outlines the FDA’s planned regulatory framework for LDTs and the other more specifically describes planned notification and medical device reporting require-ments for LDTs. Both were formally published in the Federal Register on 3 October.

Under the proposed regulatory framework, all laboratories making LDTs would be expected to notify the FDA about the tests and begin to submit adverse event reports soon after the guidance is finalized, followed by a nine-year transition period for additional requirements to take effect on a risk-based schedule.

The substance of the documents is no surprise, as they are virtually unchanged from proposals unveiled on 31 July. Under a provision of the FDA Safety and Innovation Act, the FDA was required to give Congress a 60-day advance notifi-cation before issuing draft guidance. Since the initial release, the House held a hearing on the topic, where laboratory groups, and some lawmakers, spoke against the FDA’s plans to expand active oversight to LDTs.

The agency has called for an unusually long 120-day com-ment period on the draft guidance documents, signaling an expectation for very active public engagement on the topic.

Notification detailsIf/when the guidance is finalized, the notification require-ment will be one of the first labs will need to mind. The FDA wants labs to notify it of all LDTs (except for forensic tests and certain tests used for transplantation testing) and provide basic information about each test. It plans to use the notification information to risk-classify LDTs, with assistance from advisory panels in some cases, to determine what re-quirements they will be subject to and when. The FDA plans

to issue a classification guidance 24 months after it finalizes

the initial guidance documents.

The FDA distinguishes between this type of notification

and its registration and listing regulations, which the

agency does not plan to enforce for LDTs in the early stages.

The distinction between notification and registration and

listing is important, and the latter requirement triggers a

registration fee for the manufacturer and also would make a

lab subject to the medical device tax. ➤

Photographee.eu/shutterstock.com

Reprinted by Clinica (www.clinica.uk.co). Unauthorized photocopying prohibited. • • • 13

LDT makers will have six months following finalization of the

guidance documents to notify the FDA of all LDTs that were

on the market at the time the framework was finalized or are

put on the market within that six-month period. For LDTs

launched after the six-month interval, labs will be expected

to notify the FDA prior to clinical use of the test. But for test

makers who fail to provide notification, the agency says it

will lift its enforcement “discretion,” and the LDT manufac-

turer will be subject to registration and listing requirements

and all that entails, including fees and the device tax.

Once a lab submits a premarket submission to the FDA for

an LDT under the risk-based timeline outlines the frame-

work, the lab would become subject to formal registration

and listing requirements for that test.

To fulfil the notice requirements, manufacturers are supposed

to provide basic information about each LDT, the FDA says in its

notification draft guidance. The data elements the FDA expects

in the notification include: laboratory name; lab contact email

address; test name; monthly test volume; intended use; clinical

use of test; analytes measured; disease or condition; patient

population; any pediatric populations; sample types, such as

serum, plasma or urine; test method; whether it modifies an

FDA cleared/approved test; and any modifications made.

Notification is expected to occur once for each LDT, but if sig-

nificant changes are made to a test, additional notification will

be required. The FDA says it will apply its registration and listing

enforcement discretion, as long as basic notification is supplied.

Additionally, the FDA intends to the make the notification

data publicly available – although it will remove any infor-

mation that may not be legally disclosed – “because FDA

believes this information will be helpful to stakeholders,

including industry, patients and physicians”, the agency says

in the draft notification guidance.

medical device reportingThe other main requirement that many LDT makers would

need to worry about soon after an LDT framework is final-

ized is adverse event reporting under the FDA’s medical

device reporting regulation.

Laboratories have already been subject to certain provisions

of the MDR regulation, but primarily as user facilities. The

new framework would subject LDT makers to the same MDR

requirements as other device firms.

In particular, this means a lab would need to submit reports

of individual adverse events no later than 30 days after the

lab becomes aware of the information from any sources, that

reasonably suggests an LDT: a) may have caused a death or

serious injury; or b) has malfunctioned, and the test would

be likely to cause or contribute to a death or serious injury

while malfunctioning.

In the case of a lab test, a malfunction could mean that the

test does not accurately or reliably diagnose a specific dis-

ease or disease condition, a situation that could lead an in-

dividual patient to forgo treatment and die or be injured by

the condition. In announcing the agency’s intent to regulate

LDTs on 31 July, both FDA commissioner Margaret Hamburg

and agency device center director Jeff Shuren said that some

LDTs on the market were inaccurate, negatively impacting

patient outcomes.

LDT makers will also have to submit reports of individual

adverse events no later than five working days after the day

that the lab becomes aware of a reportable advent requiring

remedial action to prevent an unreasonable risk of substan-

tial harm to the public.

Also, LDT manufacturers must submit supplemental reports

within one month of the day the lab receives reportable

information that was not submitted in an initial report. FDA

also goes into detail in its draft “notification” guidance about

requirements for developing, maintaining and implement-

ing written MDR procedures.

Third-party reviewers for Class II ldTsSeveral clinical lab regulatory experts wonder how the FDA

will manage, even under the agency’s nine-year phase in,

to review the 10,000 to 11,000 LDTs that could fall under its

purview under the proposed framework. In its framework

draft guidance, the agency says it intends to use third party

reviewers, for the bulk of the lab tests.

The FDA writes: “For those LDTs that present moderate

risk (ie, LDTs that fall into class II) FDA intends to work with

interested parties to expand the Agency’s third party review

program to include these types of devices. If successful, FDA

believes that most moderate-risk LDTs could be reviewed by

a third party reviewer.”

Also, the FDA said in its framework document that clinical

literature could be used to provide evidence of clinical utility

of the tests. “FDA expects [this] would reduce the need for

additional clinical studies to show clinical validity for LDTs

where the analytes/markers that are measured/assessed

have had their clinical validity established in the literature,”

the agency wrote.

Medtech Intelligence@ClinicaMedTechClinica Medtech Intelligence

Reprinted by Clinica (www.clinica.uk.co). Unauthorized photocopying prohibited.14 • • •

Philippines’ new AMDD regs and Indonesia goes all-eTina Tan

September marked the inaugural session of Clinica’s new

monthly Access All Asia forum, which provides a platform

for a core group of Asia-focused regulatory professionals

to crosscheck intelligence regarding developments in the

region, discuss specific obstacles they’re encountering and

share any tips on clearing these hurdles.

In the first session, Jack Wong, May Ng and Alexandra Baer

discussed the challenges of China’s labelling rules, the new

product registration requirements in the Philippines and

Indonesia’s new online reporting systems. Below are the

highlights of the discussion:

ChINaForeign manufacturers importing medical devices into China

continue to struggle to meet the country’s product labelling

requirements. But are bonded warehouses – buildings in which

goods can be stored without paying duty – a possible solution?

These labelling requirements, which have been introduced

as part of China’s overhaul of its medtech regulatory frame-

work, are set to come into force officially after 1 October. Ac-

cording to Dr Baer, carrying out the labelling in-house is an

onerous task that is challenging not just from the regulatory

perspective but also in terms of cost control: “You need to

calculate the quantity of goods that needs to labelled, how

many working hours it would take to do the labelling and if

the quantities are small, it is not cost effective.”

Mr Wong added that creating a label itself is already a big

project as you have to ensure you include the country’s specific

requirements: “And it is not easy to suddenly change all your la-

bels to meet new requirements.” He told the forum participants

that there are manufacturers who have found a solution by

having the labels done locally. Then they send their devices to

bonded warehouses in China, where the sticking of the labels

is carried out before the devices are passed through Chinese

customs. However, he advised that if a company does find a

bonded warehouse to do the labelling for them, to make sure it

is one of with high quality control and the right ISO certification.

PhIlIPPINeSThe Philippines recently issued for comment its proposal to

adopt new documentary requirements to register medical

devices based on the ASEAN Medical Device Directive.

There had been concerns over some aspects of the new

requirements, one being that free sales certificates (FSCs)

would no longer be accepted by the Philippines FDA for

registering a product in the country. One stakeholder had

commented on the FDA website that FSCs were the only

evidence of registration in Australia for low-risk devices

and if these were no longer accepted in the Philippines, the

manufacturer would have no other option available. Howev-

er, Ms Ng believes that with these particular device groups,

it is likely that the Philippines FDA would accept the FSCs for

registration.

She did acknowledge though that this requirement could be

more of a concern for European manufacturers, as it is not

clear whether the Philippines FDA would agree to accept the

certificate from the notified body if that notified body is not

in the same country where the legal manufacturer is based.

This issue would need to be clarified during the comment

period, she said.

Bonded warehouses could ease the burden of meeting China’s labelling requirements

➤

Reprinted by Clinica (www.clinica.uk.co). Unauthorized photocopying prohibited. • • • 15

INdoNeSIaIndonesia continues to build up its online reporting infra-

structure for the medical device industry, according to Ms

Ng. The country already has in place an online product regis-

tration system, and most recently, it has introduced two new

initiatives. The first is E-Watch, an online system for reporting

adverse events, while the other, E-Report, is an online system

for recording the importation, distribution and/or manufac-

ture of medical devices in Indonesia. With the latter, compa-

nies need to report every six months details of the products

and the lot numbers that have been sold and distributed in

Indonesia. It would be the responsibility of the appointed

Indonesian distributor – not the overseas device’s legal

manufacturer – to provide these e-reports, Ms Ng clarified.

TaIWaNDr Baer warned companies with high-risk devices of a

particular stumbling block in the Taiwanese regulatory

system that may limit the intended use of the product

in that market. For all devices where the intended use is

general in Europe, such as intradermal devices or those

that can be used in all types of joints or arteries, the

Taiwan FDA would focus solely on the available clinical

data and give approval within the parameters in which

the device has been tested. “So even if a device could be

used on all joints, but only one joint has been tested for

efficacy/safety, this would result in a narrowing down of

the [approved] intended use in Taiwan,” said Dr Baer. If

you want to expand the intended use of the device, you’d

then need to get the clinical data for that specific use.

Taiwan is not the only Asian country that works this way – Korea

and China also have this requirement. In this context, compa-

nies with limited financial resources may do well to consider

carefully what they want the key indication to be for that device

and get the clinical data required for that intended use.

ISoOn more international matters, Mr Wong attended an ISO

meeting earlier this month. He reported that the committee

overseeing the updating of ISO 13845 and ISO 9000 is aiming to

publish the revised standards for September 2015. Companies

would then have a three-year transition period. According to

Mr Wong, September would be the earliest timeline, provided

everything goes smoothly and that there are no delays with

the comments. That said, he added that his conversations with

notified bodies and regulatory experts at the meeting have led

him to believe that the amended standards will be more exact-

ing than the previous versions. “The new ISO standard will have

significant changes and demand higher requirements in safety

and validation information, so medical device manufacturers

need to be prepared and start talking to their notified bodies,”

he advised.

Jack Wong (jack.wong@terumobct.com) is director of regulatory af-

fairs, Asia-Pacific, at Terumo BCT, and is also the founder of the Asian

Regulatory Affairs Professionals Association. May Ng (may.ng@arq-on.

com) is the founder of Asian regulatory and quality consultancy AR-

Qon and Alexandra Baer is senior regulatory affairs at Croma-Pharma

(alexandra.baer@croma.at). Comments made during the forum are

the participants’ personal views and do not represent company or

official comment.

Kisan/shutterstock.com

Medtech Intelligence@ClinicaMedTechClinica Medtech Intelligence