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The Investigational Device Exemption (IDE)

Definition

An Investigational Device Exemption (IDE) is a regulatory submission allowing, if approved, the use of a device (called in this context a investigational device) to be used in clinical investigation (clinical study/clinical trial) in order to collect safety and effectiveness data.

As per 21 CFR 812.1, ” an approved investigational device exemption (IDE) permits a device that otherwise would be required to comply with a performance standard or to have premarket approval to be shipped lawfully for the purpose of conducting investigations of that device”. 

In essence, you ask the FDA to allow your device to be used in clinical investigation as you want to collect substantial clinical evidences to support a future FDA submission for in fine placing the device in the U.S. market.

Introduction

An investigational device exemption (IDE) allows the investigational device to be used in a clinical study in order to collect safety and effectiveness data. Clinical studies are most often conducted to support a PMA. Only a small percentage of 510(k)s require clinical data to support the application. Investigational use also includes clinical evaluation of certain modifications or new intended uses of legally marketed devices. All clinical evaluations of investigational devices, unless exempt, must have an approved IDE before the study is initiated. – The U.S. Food & Drug Administration (FDA).

The Code of Federal Regulations Title 21 Part 812 (21 CFR 812) contains the procedures and requirements governing the IDE and the conduct of clinical research of devices. 

A Pre-Sub meeting may be held prior to the submission of an IDE in order to seek FDA input on the IDE components. As a reminder, a Pre-Sub meeting provides the opportunity for a submitter to obtain FDA feedback prior to an intended premarket submission (i.e., IDE, PMA, HDE, De Novo request, 510(k), Dual, BLA, IND). The Pre-Sub is a type of Q-Submission. If a manufacturer has had a Pre-Sub meeting, the advantage is that it can now tailor the information to what FDA has indicated it expects for the particular device. 

IDE Application

A sponsor of a significant risk device study must submit a complete IDE application to FDA. There are no preprinted forms for an IDE application; however, an IDE application must include certain required information. The sponsor must demonstrate in the application that there is reason to believe that the risks to human subjects from the proposed investigation are outweighed by the anticipated benefits to subjects and the importance of the knowledge to be gained, that the investigation is scientifically sound, and that there is reason to believe that the device as proposed for use will be effective – The U.S. Food & Drug Administration (FDA).

Several required elements must be included in an IDE application such as:

  • A report of prior investigations – containing at least a bibliography of all publication, copies of all published and unpublished adverse information, copies of other significant publications if requested by an Institutional Review Board (IRB) or FDA, a summary of all other unpublished information, if nonclinical laboratory data are provided, a statement that such studies have been conducted in compliance with the Good Laboratory Practice (GLP) regulations or a rational if not.
  • An investigational plan (21 CFR 812.25) – including at least the purpose of the investigation, a protocol, a risk analysis, a justification for the investigation; a description of the patient population, a description of the device, the monitoring procedures and additional records and reports. The investigational plan must be approved by each participating study site’s IRB.
  • A description of the methods, facilities, and controls used for the manufacture, processing, packing, storage, and installation of the device.
  • An example of the agreement to be signed by the investigators and a list of the names and addresses of all investigator.
  • Certification that all investigators have signed the agreement, that the list of investigators includes all investigators participating in the study, and that new investigators will sign the agreement before being added to the study.
  • A list of the names, addresses, and chairpersons of all IRBs that have or will be asked to review the investigation and a certification of IRB action concerning the investigation.
  • The name and address of any institution (other than those above) where a part of the investigation may be conducted
  • The amount, if any, charged for the device and an explanation of why sale does not constitute commercialization
  • Copies of all labeling for the device.
  • Copies of all informed consent forms and all related information materials to be provided to subjects.
  • Any other relevant information that FDA requests for review of the IDE application.

The required content of an IDE is provided in 21 CFR 812.20, including the specific order in which the information should be presented. FDA is, however, somewhat liberal on sequence, as long as all the information is included and presented in a logical fashion. 

As a reminder, a clinical study performed in the U.S. must have a U.S. sponsor (A clinical study sponsor is a person, company, institution, group, or organization that oversees or pays for a clinical investigation and collects and analyzes the data). Therefore, a foreign manufacturer must have a U.S. entity submit the IDE.

Format

The signed IDE application is submitted to FDA in triplicate, either with three paper copies, or with two electronic copies (using the eCopy Program) and one paper copy. The submission must be signed by the sponsor’s authorized representattive and delivered via courier to the document mail center of the Center for Devices and Radiological Health (CDRH).

The paper copy volumes must be paginated and bound in volumes must no more than two inches (about 5 cm) thick. FDA requires standard U.S. letter size paper (8.5 x 11 inches) white paper for all submissions. Specific FDA guidance on the Pre-Sub program can be found in the FDA guidance document Requests for Feedback and Meetings for Medical Device Submissions:The Q-Submission Program.

The electronic copy must conform to the requirements in FDA guidance document eCopy Program for Medical Device Submissions, including requirements for cover letter, file type (.pdf), bookmarks, file naming, file size limitations, etc.

Cover Letter

The FDA specifies that a cover letter describing the submission and/or a Form 3514 (Voluntary form used to help provide basic administrative info for all types of premarket notification submissions) is required to be included in the IDE. The cover letter should include:

  • A statement that the information provided is an original IDE submission.
  • The device information (Device name, intended use)
  • The sponsor contact information
  • The manufacturer information
  • If the organization submitting the application is not the sponsor, such as a consultant or a lawyer, include contact information for the correspondent organization or individual.
  • If applicable, a description of Q-Submission/Pre-Submission meetings, any discussion with the FDA reviewing division, the Q-Sub number and a copy of the written feedback, the name of the FDA contact person and the minutes of the meetings.
  • The identification of any waiver requests and the justification
  • Referenced Files: Identify any files that are referenced in the IDE application, such as Premarket Approval, Premarket Notification 510(k), IDE, or device master files. If files were not submitted by the sponsor, include a letter from the owner of the files that grants FDA permission to reference the files in its review of the current application.

Devices Studies Types and IDE Study Types

Device studies are categorized into three types according to the regulations of 21 CFR 812:

  • Exempt studies: These studies are exempt from the requirements of 21 CFR 812. Examples of exempt studies include diagnostic device studies (e.g., in vitro diagnostic studies), consumer preference testing, testing of a device modification, veterinary devices, animal studies, custom devices, etc. (see 21 CFR 812.2 (c).
  • Significant risk (SR) device studies: These studies require an approved IDE from the FDA and must comply with the complete regulations at 21 CFR 812.
  • Nonsignificant risk (NSR) device studies: These studies must meet the abbreviated IDE requirements at 21 CFR 812.2(b). 

For SR and NSR device studies, the following IDE Study Types are available:

  • Early Feasibility Study (EFS) – To provide proof of principle and initial clinical safety data with a limited clinical investigation (<15). Study performed usually early in development, typically before the device design has been finalized, for a specific indication (e.g., innovative device for a new or established intended use, marketed device for a novel clinical application).
  • First in Human (FIH) Study – When a specific indication is evaluated for the first time in human subjects. Note that a FIH can be a EFS, but not all FIH studies would be considered EFSs.
  • Traditional Feasibility Study – To capture preliminary safety and effectiveness information on a near-final or final device design. To adequately plan an appropriate pivotal study. Does not necessarily need to be preceded by an EFS.
  • Pivotal Study – To collect definitive evidence of the safety and effectiveness of a device for a specified intended use, typically in a statistically justified number of subjects. May or may not be preceded by an early and/or a traditional feasibility study.
Recommended Reading
References
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Conformity Assessment Options for Products Failing under the MDR

The conformity assessment route for CE marking varies according to the assigned class of device as describes in MDR Article 52 and in the MDR Annex IX, Annex X and Annex XI depending on the device class, manufacturers have some choice regarding the conformity assessment route.

Table - Conformity Assessment Options

Device Class
Conformity Assessment Procedure

 Class I

Annex II and Annex III

 Class I (special)Devices with measuring function, sterile, or reusable

Annex II, Annex III and Annex IX

or

Annex XI Part A

  Class IIa

Annex II, Annex III and Annex IX of each category of devices

or 

Annex X coupled with Annex XI Part A or Annex XI Part B

 Class IIb

Annex II, Annex III and Annex IX, of each generic category of devices

or 

Annex X coupled with Annex XI Part A or Annex XI Part B

 Class IIb (special): Implantable devices

Annex II, Annex III and Annex IX 

or

Annex X coupled with Annex XI Part A or Annex XI Part B

 Class III

Annex II, Annex III and Annex IX

or

Annex X coupled with Annex XI Part A or Annex XI Part B

 Custom-made Devices

(a) Not implantable: Annex XIII

(b) Implantable Class III: Additionally Annex IX or Annex XI Part A

Mentionned Annexes

Annex II – Technical documentation

Annex III – Technical documentation on post-market surveillance

Annex IX – Conformity assessment based on a quality management system and assessment of the technical documentation

Annex X – Conformity assessment based on type examination

Annex XI – Conformity assessment based on product conformity verification – Part A: Production Quality Assurance 

Annex XI – Conformity assessment based on product conformity verification – Part B: Product Verification

Annex XIII – Procedure for Custom-Made Devices

Reference

Regulation (EU) 2017/745 MDR: 02017R0745 — EN — 24.04.2020 — 001.001 (consolidated version)

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Beyond the MDR and the IVDR: The WEEE Directive, the RoHS2 Directive, the REACH Regulation and other requirements

Table of Contents

Beyond the MDR and the IVDR

In addition to the requirements of the MDR (Regulation (EU) 2017/745) and the IVDR (Regulation (EU) 2017/746), medical device companies that want to place their products in the European Union (EU) market may be subject to other EU directives, EU regulations or other national requirements addressing the control and recycling of the electrical and electronic waste and chemical substances. These include:

These directives and regulations are discussed here. 

The European WEEE Directive

Any company (including in the medical device field) placing electrical devices on the European Union (EU) market must comply with the Directive 2012/19/EU on Waste Electrical and Electronic Equipment (WEEE).

In substance, the goal of the WEEE Directive is to minimize the impact of electrical and electronic goods on the environment by increasing the reuse and the recycling and reducing the amount of waste of electrical and electrical equipment going to the landfill.

The specific symbol below (Fig 1.) indicates that the product should not be discarded as unsorted waste but must be sent to separate collection facilities for recovery and recycling. The WEEE marking must appear on any electrical and electronic equipment placed on the EU market. 

Fig 1. The WEEE marking (crossed-out wheeled bin)

The European RoSH2 Directive

The Directive 2011/65/EU on Restriction of the Use of Certain Hazardous Substances in Electrical and Electronic Equipment (RoHS2) aims to reduce the levels of lead, cadmium, mercury, hexavalant chromium, polybrominated biphenyl (pbb) and polybrominated diphenyl ether (PBDE) flame retardants in products.

In 2017, RoHS2 was amended (introduction of modification) by the Directive (EU) 2017/2102. By consequence, both RoHS2 and Directive (EU) 2017/2102 must be followed.

RoHS2 is a CE Mark directive. This means that a medical device company needs to place a CE Mark on each of its products to confirm that it has taken the appropriate measures to meet RoHS2 requirements, restrictions and provisions.

Medical device companies are responsible for providing conformity assessments, a Declaration of Conformity (DoC) and the Technical Documentation. A reference to the RoHS2 Directive could be added to a current DoC referring to the MDR or to the IVDR, where applicable.

The European Batteries Directive

The Directive 2006/66/EC on Batteries and Accumulators and Waste Batteries and Accumulators (known as the Batteries Directive) regulating the manufacturing and disposal of batteries and accumulators in the EU to protect human health and the environment from hazardous substances such as mercury and cadmium. 

As described by the European Commission, the Batteries Directive prohibits the marketing of batteries containing some hazardous substances, defines measures to establish schemes aiming at high level of collection and recycling, and fixes targets for collection and recycling activities. The Directive also sets out provisions on labelling of batteries and their removability from equipment.

It also aims to improve the environmental performance of all operators involved in the life cycle of batteries and accumulators, e.g. producers, distributors and end-users and, in particular, those operators directly involved in the treatment and recycling of waste batteries and accumulators. Producers of batteries and accumulators and producers of other products incorporating a battery or accumulator are given responsibility for the waste management of batteries and accumulators that they place on the market.

The EU Commission proposed a new Batteries Regulation on 10 December 2020. This Regulation aims to ensure that batteries placed in the EU market are sustainable and safe throughout their entire life cycle.

The European Packaging and Packaging Waste Directive

The Directive 94/62/EC on Packaging and Packaging Waste requires manufacturers to prevent the formation of packaging waste, to ensure that the eight and volume of packaging placed on the market is limited to the minimum and to develop packaging reuse systems to reduce their impact on the environment (restriction of the presence of certain heavy metals in packaging).

In 2018, this directive was amended (introduction of modification) by the Directive (EU) 2018/852. By consequence, both Directive 94/62/EC and Directive (EU) 2018/852 must be followed.

The European REACH Regulation

The Regulation (EC) No 1907/2006 concerning the Registration, Evaluation, Authorisation and Restriction of Chemicals (REACH) regulates the registration, evaluation, authorisation and restriction of chemical substances in the EU market.

REACH aims to improve the protection of human health and the environment through the better and earlier identification of the intrinsic properties of chemical substances.

REACH is a global directive. In contrast, RoHS2 is a specific directive focused on the restriction of certain hazardous substances in waste electrical and electronic equipment.

RoHS2 doesn’t not affect the application of REACH and REACH doesn’t not affect the application of RoHS2.

When overlaps occur, the strongest restriction should be applied. Moreover, exemptions from the substance restrictions in RoHS2 may not be granted if they result in a lowering of the environmental and human health protection afforded by REACH.

Recommended Reading

Sources & References

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Trend Reporting under the MDR and IVDR (Art. 88/83)

Trend Reporting: Definition & Purpose

A trend can be defined as a graphical representation of a variable’s tendency, over time, to increase, decrease or remain unchanged. Usually a trend is represented in a trend control chart, who represents the deviation from an expected trend and it is used to evaluate the stability of a process (American Society for Quality, ASQ)

In the MDR and IVDR context, the purpose is to monitor the number of incidents not classified as serious incidents, over time, via EUDAMED, in order to determine if the benefit-risk analysis of the device has changed.

MDR/IVDR Requirements about Trend Reporting

Article 88 MDR and article 83 IVDR mention the requirements for the trend reporting. Both articles have different requirements for medical devices and IVDs. (See Comparison Table below).

About devices falling under the MDR

Manufacturers shall report any statistically significant increase in the frequency or severity of incidents that are:

  • not serious incidents, or
  • incident that are expected undesirable side-effects that could have a significant impact on the benefit-risk analysis, and which have led or may led to risks to the health or safety of patients, users or other persons that are unacceptable when weighed against the intended benefits.

The significant increase shall be established in comparison to the foreseeable frequency or severity of such incidents in respect of the device, or category or group of devices, in question during a specific period as specified in the technical documentation and product information. 

The manufacturer shall also specify how to manage these incidents and provide the methodology used for determining any statistically significant increase in the frequency or severity of such incidents, as well as the observation period, in the post-market surveillance (PMS) plan.

About devices falling under the IVDR

Manufacturers shall report any statistically significant increase in the frequency or severity of incidents that are:

  • not serious incidents, or
  • incidents which have led or may led to risks to the health or safety of patients, users or other person or of any significant increase in expected erroneous results established in comparison to the stated performance of the device.

The significant increase in expected erroneous results shall be established in comparison to the stated performance of the device as specified in the technical documentation and product information.

The manufacturer shall also specify how to manage these events and provide the methodology used for determining any statistically significant increase in the frequency or severity of such events or change in performance, as well as the observation period, in the post-market surveillance (PMS) plan.

About Competent Authortites

Competent authorities may assess these data and require the manufacturer to take action. In that case, the competent authority shall inform the Europeaan Commisison, the other competenet authortires and the notified body that issuedcthe certificate of the results of such assessment and of the adoption of such measures.

Comparison Table

Differences are in orange.

EU MDR – Regulation (EU) 2017/745
EU IVDR – Regulation (EU) 2017/746

Article 88

Trend reporting

Article 83

Trend reporting

1. Manufacturers shall report, by means of the electronic system referred to in Article 92, any statistically significant increase in the frequency or severity of incidents that are not serious incidents or that are expected undesirable side-effects that could have a significant impact on the benefit-risk analysis referred to in Sections 1 and 8 of Annex I and which have led or may lead to risks to the health or safety of patients, users or other persons that are unacceptable when weighed against the intended benefits. The significant increase shall be established in comparison to the foreseeable frequency or severity of such incidents in respect of the device, or category or group of devices, in question during a specific period as specified in the technical documentation and product information.

1. Manufacturers shall report by means of the electronic system referred to in Article 87 any statistically significant increase in the frequency or severity of incidents that are not serious incidents that could have a significant impact on the benefit-risk analysis referred to in Sections 1 and 8 of Annex I and which have led or may lead to unacceptable risks to the health or safety of patients, users or other persons or of any significant increase in expected erroneous results established in comparison to the stated performance of the device as referred to in points (a) and (b) of Section 9.1 of Annex I and specified in the technical documentation and product information.

 

The manufacturer shall specify how to manage the incidents referred to in the first subparagraph and the methodology used for determining any statistically significant increase in the frequency or severity of such incidents, as well as the observation period, in the post-market surveillance plan referred to in Article 84.

The manufacturer shall specify how to manage the incidents referred to in the first subparagraph and the methodology used for determining any statistically significant increase in the frequency or severity of such events or change in performance, as well as the observation period, in the post-market surveillance plan referred to in Article 79.

2. The competent authorities may conduct their own assessments on the trend reports referred to in paragraph 1 and require the manufacturer to adopt appropriate measures in accordance with this Regulation in order to ensure the protection of public health and patient safety. Each competent authority shall inform the Commission, the other competent authorities and the notified body that issued the certificate, of the results of such assessment and of the adoption of such measures.

2. The competent authorities may conduct their own assessments on the trend reports referred to in paragraph 1 and require the manufacturer to adopt appropriate measures in accordance with this Regulation in order to ensure the protection of public health and patient safety. Each competent authority shall inform the Commission, the other competent authorities and the notified body that issued the certificate, of the results of such assessment and of the adoption of such measures.

Recommended Reading
References

Regulation (EU) 2017/745 MDR: 02017R0745 — EN — 24.04.2020 — 001.001 (consolidated version)

Regulation (EU) 2017/746 IVDR: 02017R0746 — EN — 05.05.2017 — 000.003 (consolidated version)

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