ISO 14155 (2011) Good Clinical Practices for Medical Devices Is Here

It's time to update your procedures!
Coming into force very, very soon.

The International Standards Organization (ISO) has finally done it. Earlier this week they published the good clinical practices for medical device clinical investigations: ISO 14155 "Clinical investigations of medical devices in human subjects—good clinical practices" (2011). You can buy your very own copy at www.iso.org for 158 Swiss francs, search for 14155.

 

Once the standard is harmonized via publication in the Official Journal of the European Union it comes into force immediately; it will be tough, so you should start updating your procedures for European studies now. What's the "proof" that enforcement is immediate? And what will it mean for your study? Read on.

No phase-in period—the tedious proof
You can take my word for it, or you can follow the tedious proof presented in the next paragraphs to convince yourself about the enforcement date. We will look only at the Medical Device Directive (MDD); you can follow the same logic for the Active Implantable Medical Device (AIMD) directive on your own.

Annex ZA of the standard
Annes ZA of the standard states: "Once this standard is cited in the Official Journal of the European Communities under that Directive and has been implemented as a national standard in at least one Member State, compliance with the normative clauses of this standard confers, within the limits of the scope of this standard, a presumption of conformity with the relevant Essential Requirements 6a of that Directive and associated EFTA regulations."

Which means—in American English—once the standard is cited in the Official Journal, you will meet the Essential Requirements of the MDD for clinical investigations if you conform to the standard.

Essential Requirements of the MDD
Turning our attention to the MDD, in Article 3 we read:

"Article 3
Essential requirements
The devices must meet the essential requirements set out in Annex I which apply to them, taking account of the intended purpose of the devices concerned.”

And in Article 4 of the MDD paragraph 2, we read:

“Article 4
2. Member States shall not create any obstacle to:
— devices intended for clinical investigation being made available to medical practitioners or authorized persons for that purpose if they meet the conditions laid down in Article 15 and in Annex VIII,”

And in Article 5 of the MDD, paragraph 1, we read:

“Article 5
Reference to standards
1. Member States shall presume compliance with the essential requirements referred to in Article 3 in respect of devices which are in conformity with the relevant national standards adopted pursuant to the harmonized standards the references of which have been publishes [sic, published] in the Official Journal of the European Communities; Member States shall publish the references of such national standards.”

Harmonized standards
You can check the MDD at ec.Europa.eu to see if the standard has been harmonized to the directive. Scroll down on the page to see the long list of harmonized standards. As of today, the 2003 versions of the clinical investigation standards are still in force. I'm told it takes 5-6 months before the a new ISO standard is cited in the Official Journal and harmonized to the directive.

 
 

Frequently asked questions—my guess at the answers
Your Notified Body is your final arbiter for enforcement of the new ISO standard for ongoing studies. A good rule of thumb is that the standard applies to your investigation from the time it is harmonized and going forward, but does not apply retrospectively to activities that are already completed.

[1] When the standard comes into force, what happens to clinical investigations that are currently enrolling?

The new rules will apply to the remainder of the investigation. This means investigators and study staff must to be trained to the new standard and their heavier responsibilities, new data forms for collecting device deficiencies should be created, and the like. It may be useful to develop an educational pack for the Ethics Committees.

[2] When the standard comes into force, what happens to clinical investigations that are completed (last subject is out) and I am analyzing the data?

The final report, i.e. clinical investigation report, should follow the format and content of the standard.

[3] When the standard comes into force, what happens to clinical investigations I am setting up? Let's say I have investigators and sites, and I have EC approval, but I have not yet enrolled the first subject?

Your clinical investigation procedures and quality management system should be updated now to meet the intense requirements of the new standard. Because you haven't enrolled subjects yet, you can expect to redo most of your administrative set-up if it wasn't done in conformance to the new standard.

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CDG Can Update Your Procedures

CDG was actively involved in writing ISO 14155 (2011). We understand the intention behind the words and can help explain standards-speak in a way you can understand. We can review your procedures, provide recommendations to bring them into conformance, or write additional procedures if needed.

Our style is to work collaboratively with a point-person on your side so that you are involved in the process every step of the way. Phone or email us at 773-489-5721 or [email protected].

 

Best Regards,
Nancy J Stark, PhD
President, Clinical Device Group Inc

Comments

[Ron Jeffrey]

Hello - My question. If all clinical work is done in the USA and my class 2 device is CE marked and sold in the EU, must I have meet 14155 (current) to claim compliance to 6a?
Thank you

[Nancy J Stark]

Hi Ron,
Clinical trials are only subject to the rules of the country in which they are done. A completed clinical trial won't have to be "improved".

But a trial that is in progress in Europe will need to be brought into compliance with ISO 14155 as soon as it is cited in the Official Journal.

[Frank Schmidt]

Dear Nancy and team, we heard recently that under the new 14155, the point of enrollment will be the patient's signature of the informed consent form. Is this correct? Do you know if this was one of the key-conditions for the FDA delegates to accept the standard?
Thank you very much

[Nancy J Stark]

Hi Frank,
Yes, it is true, the point of enrollment occurs at the same time as the patient signs the informed consent. And yes, it was a requirement of FDA in spite of many persuasive arguments to the contrary.

My take on it is that FDA is concerned that subjects will sign a consent form, be found ineligible for the study, and this in-eligibility won't be reported. FDA kept saying things like "we don't want them to be lost" or "we want to know what happens to everyone."

I really think it was more of a semantic issue than a real one. Just keep a log of everyone who sign the consent form and is thereby enrolled, then keep another log of subjects who are exited from the study because they aren't eligible, and think of a new word for "enrolled", such as subjects who "joined" the study.

[Patrick Bohan]

Dear Nancy,
Thanks for the opportunity to direct questions to you. Any guidance on what note 3 (3.2, AE definition, page 2) means? "For users or other persons, this definition [of AE] is restricted to events related to investigational medical devices."

[Nancy Stark]

Hi Patrick,
The idea was that if an investigational device injured a caregiver it should be reported. But we didn't want this requirement to carry over outside of the scope of investigational devices, lest we step on TC 210 post market surveillance toes.

Nancy

[Patrick Bohan]

Thanks Nancy. Understood. Along the same lines: in pharma trials, it is typical to collect only SAEs (i.e. no more AEs) 30 days after the last dose of the investigational drug. In the case of an implantable device, however, when is it reasonable to stop collecting AE data and only collect ADEs, SAEs, incidents and deficiencies? 6.4.1 of ISO 14155:2011 seems to suggest that we must always collect them (that means collecting, say, colds and flu data even 12 months after an implant) whereas A.14.d appears to suggest that it is up to the sponsor in the CIP to define such timelines. If the CIP defined all AEs until 30 days after implant and then only SAEs, ADEs and incidents/deficiencies for the rest of the study, would that work?

[Nancy J Stark]

Hi Patrick,
You raise an interesting question about how much is enough. We left the standard a little vague on this because we felt the CIP (with approval) should rule the study to provide flexibility.

I think your plan sounds like a good one.

Nancy

[hana gadassi]

we are engaged in developing combinatin product-Drug delivery system.The first step is creating micro channels in the skin using a elctro programable device.After this initial step we apply drug patch on the skin.All clinical studies are condcted under ICH 6. What we are missing if we do not follow 14155? Do we need to follow /do some thing differently?We collect sae only about 1-2 weeks folllowing stop of the study unless their is an event that needs follow up.

[Michael Yessik]

Hello:

The description is of 14155:2011, but the snapshot from the Europa site shows 14155-1:2009 and 14255-2:2009. Are these identical?

[mary spadola]

Where can one get access to a printable version of the updated ISO 14155-2011

[Nancy Stark]

Good question Mary. You can buy it online from either www.iso.org or www.aami.org or from the standards body of any other country. You will have to pay about $80.

Nancy

[Henry Chung]

Dear Nancy:

Does ISO 14155 applies to countries like Singapore, China or only to EU?

[Nancy]

Hello Henry,

It is my understanding that With the exception of India, most of the member states of AHWP have stated they will implement ISO 14155:2011 for the conduct of medical device clinical investigations in their country. This includes countries such as China, Singapore, Indonesia and many more. It does not include Japan.

[Lisa]

Does anyone know when the standard might be listed in the Official Journal?

[Nancy]

Hi Lisa,
My European friends say "any day now", but it has not been adopted as of 30March2012.
You can check at this website: http://ec.europa.eu/enterprise/policies/european-standards/harmonised-standards/medical-devices/index_en.htm Search for "14155" and see if the 2011 version is listed. Nancy

[Louise]

Dear Nancy,
I was wondering if the ISO guidelines require ALL adverse events and device deficiencies to be reported to the sponsor regardless of the type of study. The guidelines are little vague on this aspect.
For example, if the study is a post-marketing observational study, can the AE/DD reporting be limited to serious and unexpected only?

[Nancy]

Hello Louise,
Good question. We have to look to who has the power. The standard, all by itself, has no power or authority whatsoever. When the EU harmonized the standard they did so with regard to getting Notified Body approval for commercialization--that would mean post-market studies are outside the scope of the standard.
The committee who wrote the standard wanted to encourage everyone to use the standard in all human research situations. Hence the vagueness. But look to the law, only human investigations prior to commercialization are covered.
Nancy