Article 15, of Council Directive 93/42/EEC, a.k.a., the Medical Device Directive (MDD) delineates the requirements for “Clinical investigation.” Basically, Article 15 provides the guidelines for device manufacturers that have product or are planning to introduce product, into a European Union (EU) Member State, for the purpose of conducting a clinical investigation.

Long gone are the days when device manufacturers had a simple clinical protocol in their hands and a box full of devices to verify product safety and efficacy. In days of old, device manufactures typically pursued a terpsichorean (look-it-up) approach to clinical trials effectively dancing around regulations that were often vague. Revisions to the MDD now clarify and solidify regulatory requirements for device manufacturers wishing to pursue clinical investigations within the EU. Failure to comply with Article 15 of the Directive will result in device manufacturers failing to obtain approval to pursue clinical investigations within the EU.

In today’s increasingly complex medical device market, not performing a clinical investigation will result in device manufacturers being shut out of the European market. In fact, without data collected as a result of a well-run clinical investigation, Dr. D can safely hypothesize: “Device manufacturers will be shut out of most markets without supporting clinical data.”

The MDD – 93/42/EEC
Article 15 – Clinical Investigation

1. In the case of devices intended for clinical investigations, the manufacturer or the authorized representative, established in the Community, shall follow the procedure referred to in Annex VIII and notify the competent authorities of the Member States in which the investigations are to be conducted by means of the statement mentioned in Section 2.2 of Annex VIII.

2. In the case of devices falling within Class III and implantable and long-term invasive devices falling within Class IIa or IIb, the manufacturer may commence the relevant clinical investigation at the end of a period of 60 days after notification, unless the competent authorities have notified him within that period of a decision to the contrary based on considerations of public health or public policy. Member States may however authorize manufacturers to commence the relevant clinical investigations before the expiry of the period of 60 days, insofar as the relevant ethics committee has issued a favorable opinion on the program of investigation in question, including its review of the
   clinical investigation plan.

3. In the case of devices other than those referred to in paragraph 2, Member States may authorize manufacturers to commence clinical investigations immediately after the date of notification, provided that the ethics committee concerned has issued a favorable opinion on the program of investigation in question including its review of the clinical investigation plan.

4. The authorization referred to in paragraph 2 second subparagraph and paragraph 3, maybe made subject to authorization from the competent authority.

5. The clinical investigations must be conducted in accordance with the provisions of Annex X. The measures designed to amend nonessential elements of this Directive, inter alia by supplementing it, relating to the provisions on clinical investigation in Annex X shall be adopted in accordance with the regulatory procedure with scrutiny referred to in Article 7(3).

6. The Member States shall, if necessary, take the appropriate steps to ensure public health and public policy. Where a clinical investigation is refused or halted by a Member State, that Member State shall communicate its decision and the grounds therefor to all Member States and the Commission. Where a Member State has called for a significant modification or temporary interruption of a clinical investigation, that Member State shall inform the Member States concerned about its actions and the grounds for the actions taken.

7. The manufacturer or his authorized representative shall notify the competent authorities of the Member States concerned of the end of the clinical investigation, with a justification in case of early termination. In the case of early termination of the clinical investigation on safety grounds this notification shall be communicated to all Member States and the Commission. The manufacturer or his authorized representative shall keep the report referred to in Section 2.3.7 of Annex X at the disposal of the competent authorities.

8. The provisions of paragraphs 1 and 2 do not apply where the clinical investigations are conducted using devices which are authorized in accordance with Article 11 to bear the CE marking unless the aim of these investigations is to use the devices for a purpose other than that referred to in the relevant conformity assessment procedure. The relevant provisions of Annex X remain applicable.

What you need to know
The first responsibility for device manufacturers, associated with introducing devices for clinical evaluation into a Member State, is the notification made to the Competent Authority responsible for the Member State, where the clinical investigation will be performed. If multiple Member States are to be included in the clinical investigation, then multiple Competent Authorities will need to be notified. Simply stated, “That is the law.” Notification can also be made through the device manufacturer’s European Authorized Representative, for device manufacturers not having a manufacturing presence within the EU.

Dr. D knows that device manufacturers love to play the waiting game in regards to regulatory requirements. That being said, there is a 60-day notification period associated with performing clinical investigations. This 60-day period applies to Class III devices, implantable devices, Class IIb devices that can be categorizes as long-term invasive, and Class IIa devices that can be categorized as long-term invasive. The doctor is not always the purveyor of bad news, contrary to popular belief, so Dr. D will commence with the good news first. If a review by the applicable ethics committee, within a Member State(s), views the proposed clinical investigation and the protocol favorably, they can approve the investigation to commence in under 60-days. Do you remember the old saying, “no news is good news?” If at the end of 60-days, if Competent Authorities have not provided a negative opinion, the clinical investigation can commence at the end of the 60-day notification period.

Now for the bad news. The Competent Authorities are charged with protecting the public health of the constituents of their Member States; and they have the right to say NO, if they have concerns over the proposed clinical investigation and the written protocol.

Additionally, for lower-risk devices, not mentioned in the doctor’s previous paragraph, manufacturers can commence with their investigations immediately after notification is made, providing the appropriate ethics committee has ruled favorably in regards to the proposed clinical investigation and the protocol. Once approval is received, the device manufacturer can commence with executing the clinical investigation. A salient point that device manufacturers should never overlook is the requirement to ensure the clinical investigation is conducted in accordance with Annex X of the Directive. Annex X of the MDD delineates the requirements for performing “Clinical Evaluations.”

One point the doctor feels compelled to make and will continue to do so over and over again is that the Competent Authorities are charged with protecting public health for their Member State. That being said, if a Member State refuses a clinical investigation or makes a decision to halt a clinical investigation (they have the legal right); the Member State making the decision must share the decision with all Member States and the Commission. Additionally, if a Member State believes the clinical investigation requires modification, this too must be shared with other Member States participating in the clinical investigation. The notification must include the grounds the decision for modification was premised on, and the recommended modifications to the clinical investigation.

Conversely, the device manufacturer or the manufacturer’s Authorized Rep, is tasked with notifying the Competent Authorities for each Member State participating in the clinical investigation, upon conclusion of the investigation. If the clinical investigation is ended earlier than the planned schedule, a written rationale is required delineating the reason(s) behind the early termination. If the clinical investigation is terminated for safety reasons, the reasons must be communicated to all Member States and the Commission.

One watch out for device manufacturers is to ensure data management associated with the clinical investigation and the subsequent reports should be managed in accordance with Annex X of the Directive. Why? Because the Competent Authorities may ask for this information, so it needs to be, “at their disposal.”

One final point, when devices are CE Marked and are authorized for entry and use within the EU, in accordance with Article 11 of the Directive, paragraph 1 and 2 of Article 15 do not apply, unless the proposed clinical investigation is for a new intended use, for which the CE Marked device is not currently approved. Regardless, Annex X of the Directive will still remain as a relevant compliance requirement.

What you need to do
Device manufacturers need to ensure approval is received from the Competent Authority for each Member State for which a clinical investigation will be performed. If the device manufacturer is located outside of the European Economic Community (EEC), the correct conduit for this notification will be their Authorized Rep. Your notified body can guide you through the process. It is extremely important that device manufacturers understand that there is a 60-day review period during which the Competent Authorities and ethics committees, for each Member State, will review the proposed clinical investigation and protocol. Approval can occur in less than the mandated 60-day period; however, Dr. D’s experience is that this early approval is a rare event.

Once the clinical investigation commences, Member States have the right to suspend or order modifications to clinical investigations if a potential risk to public health is discovered. Conversely, device manufactures have the right to suspend an investigation for this very same reason. What device manufacturers need to do is to ensure all of the appropriate notifications are made when: (a) a decision is made to end a clinical investigation early; (b) suspend or end a clinical investigation due to a concern over the potential risk to public health; or (c) when the clinical investigation reaches conclusion, as documented within the approved protocol.

It is extremely important, in fact, it should be considered mission critical, that clinical investigations be executed in accordance with Annex X of the Directive. Remember, the Competent Authorities have the legal right to access the data collected during the clinical investigation. Their expectation is that device manufacturers will comply with all of the provisions delineated within Annex X. Failure to comply and the Competent Authorities can unleash an onslaught of regulatory pain for device manufacturers. This is especially true for clinical investigations that harm participants. 

Takeaways
Clinical investigations are a mandated requirement for device manufacturer’s intent on entering new devices into the EU. Gone are the days when loosely-run clinical investigations/trials, a competitor’s trial, or limited-use data was accepted as part of the application process. Device manufacturers are required to comply with Article 15 for new clinical investigations. That being said, the takeaways for this edition of DG are:

1. Approval is required from each Member State participating in the proposed clinical investigation;
2. There is a mandatory 60-day review period;
3. Member States can say no to a proposed clinical investigation;
4. Member States can suspend or request modifications to a clinical investigation;
5. Device manufacturers can suspend or end a clinical investigation early;
6. Device manufacturers need to ensure the appropriate notifications are made when they decide to suspend or end a clinical investigation early;
7. Once the clinical investigation protocol has been executed and the investigation comes to its planned ending, device manufacturers must notify Member States; and
8. All clinical investigations must be executing in accordance with the provisions delineated with Annex X of the Directive. 

Until the next installment of DG, when Dr. D will provide guidance for complying with Article 16 (Notified Bodies) of Council Directive 93/42/EEC, the MDD – cheers from Dr. D and best wishes for continued professional success.

References:

1. Council Directive 93/42/EEC. (1993, June). Council Directive 93/42/EEC concerning medical devices. Retrieved December 21, 2010, from http://eur-lex.europa.eu
2. Devine, C. (2009, July). Exploring the effectiveness of defensive-receiving inspection for medical device manufacturers: a mixed method study. Published doctoral dissertation. Northcentral University. Prescott Valley, AZ.