[TECH LETTER] Claims and their substantiation

This Downloadable Techletter discusses Article 7 of the MDR & IVDR and its implications in terms of the safety and performance data required to substantiate a given claim.

The claims made by a manufacturer regarding the intended use, safety, and performance of their medical device or IVD medical device, both in their form and content, indubitably play an important role toward the commercial success of their product.

It is therefore in the manufacturer’s interest to formulate the most appealing claims possible on the device. This can in certain cases lead to the communication of exaggerated or ambiguous claims on the device, particularly in, but not limited to, promotional material.

It is however imperative for manufacturers to have a clear understanding of what they are allowed or have the obligation to communicate to the user or patient regarding the intended purpose, safety, and performance of their medical devices.

MDR/IVDR Article 7 states in essence that device manufacturers may not communicate any claim on the device which is not adequately supported by objective data. In this context, manufacturers should early in their device development stages define plans and methods in order to capture the safety and performance data necessary to substantiate any claim they intend to make on their devices.

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by Léa Jamelot

[WHITE PAPER] MDR Compliant Technical Documentation

by Léa Jamelot

[ARTICLE] FDA Breakthrough Devices Program (BDP) and Safer Technologies Program (STeP) for Medical Devices

Launched in 2016, the FDA Breakthrough Devices program (BDP) is intended to provide patients with more rapid access to medical devices that are foreseen to enable a more effective treatment or diagnosis of life-threatening or irreversibly debilitating diseases or conditions.
 
The new FDA Safer Technology Program (STeP) which is operational since March 2021, aims to accelerate patient access to medical devices that are expected to improve the safety of treatments targeting diseases that are less serious than those qualifying for the existing BDP.
 
A BDP or STeP designation for a device notably allows companies to benefit from additional FDA input, flexibility with regards to clinical study design and quality system and manufacturing information requirements, and prioritized review during the premarket phase; and can therefore considerably diminish the time necessary for US market approval.
 
This article will review the principles, features, requirements, application processes, and benefits, of both programs.
 
 

The Breakthrough Devices Program (BDP)

The FDA Breakthrough Devices Program (BDP) is a voluntary program intended to ensure patients with timely access to certain medical devices and device-led combination products that provide for more effective treatment or diagnosis of life-threatening or irreversibly debilitating diseases or conditions. It is available for devices and device-led combination products subject to review under a premarket approval notification (PMA), premarket notification (510(k)), or De Novo classification request (“De Novo Request”).
 
Companies designated for the BDP benefit from additional feedbacks from the FDA during the premarket phase, although the designation does not change the statutory standards for PMA, 510(k) clearance, or De Novo marketing authorization. The Breakthrough Devices Program replaced the previous Expedited Access Pathway (EAP) and Priority Review for medical devices.
 
The FDA has issued a guidance document on the Breakthrough Devices Program that provides detailed information on the program principle, on the procedure for designation request, and on the program features.
 
Devices are eligible for breakthrough device designation if both of the following criteria are met:

• The first criterion is that the device provides for more effective treatment or diagnosis of life-threatening or irreversibly debilitating human disease or conditions.
•  The second criterion is that the device also meets at least one of the following:

 
a) Represents breakthrough technology
 
b) No approved or cleared alternatives exist
 
c) Offers significant advantages over existing approved or cleared alternatives
 
d) Device availability is in the best interest of patients
 
When a device is granted the Breakthrough Device Designation, the manufacturer is ensured direct interactive communication with a sufficient number of well-trained FDA staff, including senior management, with expertise in the application of the BDP.
 
Interaction with the FDA to obtain feedback on the device development is managed through a variety of options, including “sprint” discussions (i.e. discussions with the goal of reaching mutual agreement on a specific topic within a set time frame (e.g. 45 days)), request for discussion on a Data Development Plan, and request for discussion to reach clinical protocol agreement.
 
With regards to the last aforementioned point, the FDA will take steps to ensure that the design of clinical trials is as efficient and flexible as practicable. It will, for instance, allow the study design to be adapted during the clinical study and/or approval process.
 
Moreover, the FDA may allow for part of non-clinical and clinical data to be collected in the post-market phase, provided there are no major safety concerns. In addition, with the BDP designation there is also a prioritized review of regulatory submissions, including Q-Submissions, Investigational Device Exemption (IDE) applications, and marketing submissions.
 
Finally, for PMA submissions that typically require a preapproval inspection, the FDA intends to expedite the review of manufacturing and quality system compliance for BDP-designated devices.
 
If the manufacturer can show compliance with the statutory and regulatory requirements by other means than submitting the all the items listed in the FDA guidance “Quality System Information for Certain Premarket Application reviews”, the FDA may accept less quality and manufacturing information. This may occur for instance when the manufacturer has a good track record for quality system compliance and that no new manufacturing issues that could negatively affect product quality or performance are identified. In appropriate cases, the FDA may decide it is acceptable to conduct the inspection of the manufacturing sites after the device has been approved through the BDP.

How to apply for the Breakthrough Devices Program?

To apply for the BDP program, manufacturers shall submit a special Q submission named “Designation Request for Breakthrough Device”. The submission should provide information to describe the device, the indications for use, regulatory history, and it should explain in details the rationale why the device meets the requirements to be eligible for the program. If other requests for FDA feedback are concomitantly pending, manufacturers should consider submitting them after the FDA renders the BDP designation decision as a BDP designation may affect the feedback that FDA provides on the other requests.
 
The FDA will issue a decision on the BDP designation within a maximum of 60 calendar days, and request any additional information it may require within 30 days. The BDP designation request typically takes the form of an approximately 30 page submission file and usually requires a few weeks for preparation, if necessary with the support of a consulting firm.
 
Despite a report that the FDA may be open to making public devices having received BDP designations in the future, the decision to do so remains for the moment at the discretion of the manufacturers participating in the program.
 
It is therefore difficult to obtain reliable data on how frequently BDP designations are solicited and granted. Nonetheless, according to an article published in May 2020 by MedTech Dive who was able to obtain data relating BDP designations from the FDA, there were 11 devices awarded with a BDP designation in 2016, 19 in 2017, and 55 in 2018, 136 in 2019 and 50 and in 2020 as of May.
 
Thus, the BDP program is increasingly gaining popularity, showing roughly a two-fold increase in BDP designations per year since the launch of the program in 2016. Of these, five BDP-designated devices received full marketing authorization in 2019 (three PMAs, one 510(k), and one De Novo).
 
No information regarding the number of devices that won final marketing authorizations under the program in 2020 could be retrieved. Nonetheless, this number is expected to increase proportionally to the number of granted designations.
 
 

The Safer Technology Program (STeP)

The new Safer Technology Program (STeP) for Medical Devices was designed as a complement to the BDP. The STeP is highly similar to the latter, but tailored for medical devices and device-led combination products that are reasonably expected to significantly improve the safety of treatments targeting an underlying disease or condition less serious than those qualifying for the BDP.
 
These may include for example devices intended to treat or diagnose non-life-threatening or reversible conditions. As for the BDP, STeP is also available for devices and device-led combination products subject to review under a premarket approval notification (PMA), premarket notification (510(k)), or De Novo classification request (“De Novo Request”). The FDA issued the final guidance on the Safer Technologies Program on January 6th 2021, and anticipated accepting program entrance requests as of March 8th, 2021.
 
For a device to be eligible for STeP designation, it should meet the following criteria:

• The first criterion is that the device should not be eligible for the Breakthrough Devices Program (BDP) in reason of the less serious nature of the disease or condition treated, diagnosed, or prevented by the device; and
• The second criterion is that the device should be reasonably expected to significantly improve the benefit-risk profile of a treatment of diagnostic by means of substantial safety innovations that provide for at least one of the following:

 
a) A reduction in the occurrence of a known serious adverse event,
 
b) A reduction in the occurrence of a known device failure mode,
 
c) A reduction in the occurrence of a known use-related hazard or use error, or
 
d) An improvement in the safety of another device or intervention
 
Similarly to a BDP designation request, manufacturers should apply for a STeP designation by submitting a Q-Submission requesting inclusion in the STeP program. This request should be highlighted in the accompanying cover letter. The request should provide information to describe the device, the expected safety improvement, the indications for use, regulatory history, and justification as to why the device meets the specific STeP eligibility factors.
 
More information on the contents of a Q-Submission Request for inclusion in STeP may be found in appendix I of the STeP final guidance. Once the program will be operational, the FDA intends to request any additional information it may require on the request for inclusion in STeP within 30 calendar days, and to issue its final decision within 60 days.
 
Once a device is designated for the Safer Technology Program, the manufacturer can choose to interact with the FDA through the same options as for the BDP, including interactive and timely discussions with FDA staff, senior management engagement, early engagement on Data Development Plans, and sprint discussions. Similarly as within the BDP program, the FDA will also allow for a certain degree of flexibility on clinical trial design and for the collection of non-clinical and clinical data.
 
In appropriate cases, the FDA also intends to expedite the review of manufacturing and quality system compliance for STeP designated devices by demanding less quality system and manufacturing information, or waiving the requirement for a preapproval inspection of the manufacturing sites.
 
As the STeP program is not yet operational at the time of writing this article, no data is currently available regarding the number of STeP designations and approvals.
 
In summary, the FDA Breakthrough Devices and Safety Technology Programs provide considerable advantages that can significantly reduce the time for US market access for devices fulfilling either set of specific inclusion criteria described above. It shall be emphasized that the BDP and STeP programs are complementary and will run in parallel. The BDP addresses devices that provide for more effective treatment or diagnosis of life-threatening or irreversibly debilitating diseases or conditions, whereas the STeP is intended for devices expected to increase the safety of treatments or diagnosis of less serious diseases. Once designated for either of the programs, the manufacturer can expect interactive and timely interaction with the FDA, senior FDA management engagement, priority review, and flexibility with regards to the pre/postmarket balance of data collection, clinical study design, and quality and manufacturing information requirements.
 
 

How Medidee can help

Does your medical device potentially meet the criteria for inclusion in the BDP or STeP programs? Our dedicated US market specialists at Medidee are well-experienced with the Breakthrough Devices Program, and may assist you determining whether your product qualifies for inclusion in the BDP or STeP programs, in preparing and submitting your BDP or STeP designation request, and in subsequent interactions with the FDA once the designation is granted. Contact us now!

This article was written by Dr Jérôme Randall.

by Marieke Moliner

[ARTICLE] ISO 14155:2020 changes to be aware of when planning, designing or conducting a clinical investigation

The new ISO 14155:2020 - Clinical investigation of medical devices for human subjects – Good Clinical Practice was released in July 2020. This third edition supersedes the 2011 version, which was updated as to conform with the upcoming MDR.
 
ISO 14155:2020 is expected to be harmonized rapidly without content deviations as it is the European Commission’s priority to provide a reference standard to support the provisions of the MDR pertaining to clinical investigations.
 
Therefore, the Annex Z showing the correlation between the requirements of the standard and those of the relevant Directives and Regulation should soon be released by the CEN (European Committee for Standardization) for harmonization under the European Directives 90/385/EEC for active implantable medical devices (AIMDD) and 93/42/EEC for medical devices (MDD), and under the European Regulation 2017/745 for medical devices (MDR). No official transitional period has been communicated for this updated standard, and thus it is considered applicable as of its date of publication.
 
 

Changes induced by the new ISO 14155:2020

 
Aside from the main documentary changes listed in the foreword of the standard, the major changes to be aware of when planning, designing or conducting a clinical investigation are:
 

• • Clinical investigation is now 2.0: ISO 14155:2020 discusses the opportunity for remote monitoring, the acceptability of digital signature for informed consent forms and the validation process for eCRFs systems.

• • • Clinical investigations must be registered in a publicly accessible database, such as clinicaltrials.gov. The registration must be updated and results must be published after the completion of the investigation. Previously, certain countries required registration, whereas others did not.

• • It is now an obligation to publish the investigation’s results, whether positive, inconclusive or negative. Previously, the standard only encouraged sponsors to do so.

• • New concept of Serious health threat as a signal that indicates an imminent risk of death and requires immediate actions to be taken by the sponsor and/or the investigator.

• • Clinical investigations, like all other medical devices related processes, should be planned, designed and conducted following a risk-based approach. Whether it is related to monitoring or adverse events reporting, risk management activities should be performed throughout the process of a clinical investigation. The newly added Annex H specifies the ties with ISO 14971.

• • Description of the feedback loop with clinical evaluation and risk management activities, such as the use of the clinical evaluation to justify the clinical development stage, and the clinical investigation design and the update of the benefit-risk analysis.

• • Clinical quality management is reinforced, including CAPA process.

• • The selection of the investigation site should be performed carefully, as it is now specified that facilities should be representative of the intended use environment.

• • In case of device deficiencies, the sponsor is now prompted to recover and analyse the faulty device.

• • Contract Research Organizations (CROs) should be qualified suppliers of the sponsor, according to the sponsor’s QMS.

• • The newly added Annex I brings welcome clarifications on the applicability of the requirements of this standard to the different clinical development stages and includes a useful table for the planning and design of clinical investigation in all phases of the medical device lifecycle.

• • The sponsor must select a local representative if the sponsor is not located in the country of the study. Previously, this was requested by certain local regulations, but not in all countries.

As a medical device manufacturer, we recommend you start your transition today:

1. Plan and document your transition activities;
2. Implement ISO 14155:2020 in your QMS and perform a gap analysis to identify any shortcomings with the requirements of the new standard;
3. Provide internal training on the new standard and affected SOPs (related processes such as risk management, clinical evaluation, CAPA, etc. are particularly relevant to consider);
4. Review / Update templates for future clinical investigations (Clinical Investigation Plan, Investigator’s Brochure, etc.);
5. Validate your eCRF system if not already done;
6. Update contracts with your CRO and make sure they are formally qualified as a supplier.

 
This article was written by DR Jérôme Randall.
 
If you are eager to learn more about the changes incurred and gain knowledgeable insights on the application of this standard for clinical investigation planning, design, and conduct, make sure to join our ISO 14155:2020 online training, recognized by Swissethics for Investigator & Sponsor-Investigator Levels. 
 
Furthermore, as a Contract Research Organization (CRO), Medidee will assist you with all aspects of your clinical investigation activities, from creating and submitting Clinical Trial Applications to Ethics Committees and Competent Authorities, through to initiating, monitoring and writing Clinical Investigation Reports. Contact us now!

by Léa Jamelot