Software

European Union: 

Software is defined as a set of instructions that processes input data and creates output data.

Software definitions per MDCG 2019-11 given,

 How to qualify the software as a medical device/in vitro diagnostic medical device software

Shall meet the definition of software according to the MDCG 2019-11 and the definition of a MD/IVD  according to Article 2(1) of MDR/IVDR

 MDR classification rules: Rules 9, 10, 11, 12, 13, 15 and 22 Annex VIII

IVDR Classification rules:To classify in vitro diagnostic medical device software all rules shall be considered.

EU Regulations References:

Is your software a Medical Device? Info graphic

MDCG 2019-11 Qualification and classification of software - Regulation (EU) 2017/745 and Regulation (EU) 2017/746

US FDA Software as Medical Device (SaMD)

“software intended to be used for more than one or more medical purposes that perform these purposes without being part of a hardware medical device.”

 How to qualify the software as a medical device/in vitro diagnostic medical device software

Meet the definition of software according Federal Food Drug & Cosmetic (FD&C) Act section 201(h) device definition.Some of the software functions are excluded from device definition.

 IMDRF Guidance documents.

Softwareas a Medical Device (SaMD): Key Definitions (IMDRF/SaMD WG/N10FINAL:2013)

Softwareas a Medical Device (SaMD): Possible Framework for Risk Categorization andCorresponding Considerations (IMDRF/SaMD WG/N12FINAL:2014)

Softwareas a Medical Device (SaMD): Application of Quality Management System (IMDRF/SaMD WG/N23 FINAL:2015)

Software as a Medical Device (SaMD): Clinical Evaluation(IMDRF/SaMD WG/N41FINAL:2017)

 

US FDA Export Certificates

  

When should an Export certificates are requested: To export a medical device to foreign government

 Prerequisites of export certificates,

Export Certificates type	Legally marketed devices in the United States	Establishment Registration	Device Listing	Labelling	QSR	Comply with laws of exporting country
Certificate to Foreign Government (CFG)	Yes	Yes	Yes	Yes. applicable labeling requirements	Yes	Yes
Certificate of Exportability: Section 801(e)(1)	No	Yes	May be	Device labeled as “intended for export” or “for export only	No	Yes
Certificate of Exportability: Section 802	No. Devices meet performance standards per Section 514 of the FD&C Act –for Class II and III devices not legally marketed	Yes	May be	Establishments substantially conform to CGMPs   Device is not adulterated Devices are in accordance with specifications of foreign purchaser	No	Yes. Devices are marketed in the countries listed in Section 802 (b)(1)(A)(i) and (ii) of the FD&C Act

  Other export certificates are,

• Non-Clinical Research Use Only Certificate
• Export Permit Letters (EPL) per Section 801(e)(2) for Class III, investigational
•  Simple Notifications per Section 802(g)

 From whom CFG is obtained: CDRH

The Center for Devices and Radiological Health (CDRH) is responsible for issuing export certificates for medical devices. To obtain an export certificate, a request must be submitted and CDRH will provide approval or denial of the request.

 How to obtain a CFG: CDRH Export Certification and Tracking System (CECATS)

FDA Unified Registration and Listings System (FURLS) have  CDRH Export Certification and Tracking System (CECATS) System. CECATS allows manufacturers to request export documents, including Certificates to Foreign Governments.

The following information are required for CFG,

• Section 1 - Requestor Information
• Section 2 - Manufacturer Information
• Section 3 - Distributor Information
• Section 4 – Product Information
• Section 5A – Was the product ever recalled?
• Section 5B – INJUNCTION
• Section 5C – SEIZUR
• Section 6 – List Country(ies) for which the Certificates are requested
• Section 7 – Indicate what product information should appear on the certificate.
• Section 8 – Should the country destination be listed on the certificate?
• Section 9 – Exporter's Certification Statement (ECS)
•  

All establishment should register with FDA via FDA Online Account(FDAOAA) 

FDA OAA account ID and password may be used to access or create subaccounts for CDRH Export Certification and Tracking System (CECATS)

CECATS may be accessed after logging into the FDA Unified Registration and Listing Systems (FURLS)

Timelines:

Certificates issued within 20 business days if applicable requirements are met

References

Types of Export Certificates: https://www.fda.gov/medical-devices/exporting-medical-devices/types-export-certificates

 

US FDA Q Submissions

 Manufacturers shall interact with FDA using Q-Submissions program. They can request clarification regarding medical device submissions.

The following feedback mechanism are described in guidance

• Pre-Submissions
• Informational Meetings
• Study Risk Determinations
• Formal Early Collaboration Meetings
•  Submission Issue Meetings
•  Day 100 Meetings for PMA Applicants

Q-Submission requests must be submitted through the Document Control Center (DCC). Two copies are required (One copy must be an electronic copy or eCopy).

FDA shall share the acknowledgement letter containing Q number to the applicant.

Q-Sub Type: Pre-Submissions

• This type of submission used during product development and/or application preparation
• Voluntary program and no user fees required
• Feedbacks are received mainly through in-person meeting, teleconference or email
• Timeframe is 75 to 90 days and FDA will respond with in 21 days for urgent public health issues

Recommended information

• Cover Letter
•  CDRH Premarket Review Submission Cover Sheet (Form FDA 3514)
• Table of Contents
• Detailed Device Description
•  Proposed Intended Use/Indications for Use
• Summary of Previous Discussions or Submissions Regarding the Same Device
•  Overview of Product Development
• Specific Questions for FDA Feedback
• Preferred method to receive FDA Feedback
• Meeting Format, Preferred Dates and Times, Planned Attendees, and Audiovisual Equipment Needs, if meeting or teleconference is requested

Q-Sub Type: Informational Meetings

• Manufacturer will share the information to FDA without expecting any feedback.FDA is in listening mode.
• Timeframe: 90 days

Recommandated information:

• Cover Letter
• CDRH Premarket Review Submission Cover Sheet  
• Brief  Statement
•  Proposed Agenda
• Preferred Meeting Format
• Dates and Times (minimum of three)
•  Planned Attendees
• Audiovisual Equipment Needs, if any

Q-Sub Type: Study Risk Determinations

• Used to determine a study risk determination for not exempt studies.
• FDA will provide a study determination letter and FDA’s determination is final

Recommended information:

• Cover Letter
•  CDRH Premarket Review Submission Cover Sheet
•  Detailed Device Description
•  Study Protocol
•  Description of how the device will be used
•  Description of the population
• Sponsor’s name and contact person(s), including titles, address, phone number, fax number and email address

Q Sub Type-Formal Early Collaboration Meetings

There are two types.

1.Determination Meeting: Applicable for PMA or PDP applicant.

FDA shall determine the type of valid scientific evidence that will be necessary to demonstrate that the device is effective for its intended use.FDA shall assess whether clinical studies are needed to establish effectiveness

2. Agreement Meeting: Applicable for class III product or any implant.

This meeting is conducted to reach agreement on the key parameters of the investigational plan, including the clinical protocol

 Click here to know more about Early Collaboration Meetings Under the FDA Modernization Act (FDAMA); Final Guidance for Industry and for CDRH Staff

Q Sub Type- Submission Issue Meetings

• This meeting is used to discuss the deficiencies identified during premarket applications
• Time frame:21 days

Recommended information:

• Cover Letter
• CDRH Premarket Review Submission Cover Sheet
• Reference to Premarket Submission Number
•  Brief Statement (including purpose, scope, or objectives of meeting)
• Proposed Agenda Including Deficiencies for Discussion
• Focused Questions
• Preferred Meeting Format
• Preferred Dates and Times (minimum of three)
•  Planned Attendees
•  Audiovisual Equipment Needs, if any

Q Sub Type- Day 100 Meetings for PMA Applications

This meeting is to review the status of PMA .

Click here to know more about Guidance on PMA Interactive Procedures for Day-100 Meetings and Subsequent Deficiencies – for Use by CDRH and Industry

References :

Requests for Feedback on Medical Device Submissions: The PreSubmission Program and Meetings with Food and Drug Administration Staff: http://www.fda.gov/downloads/MedicalDevices/DeviceRegulationandGu idance/GuidanceDocuments/UCM311176.pdf

 

 

Standards for Medical Devices

 Standards is a document, that is prepared by subject matter experts and approved by a recognized body.

This provides guidance on the design, use or performance of materials, products, processes, services, systems or persons.

International Standardisation Bodies 

• ISO: International Standardization Organisation (www.iso.org )
• IEC: International Electrotechnical Commission (www.iec.ch )
• ITU: International Telecommunication Union (www.itu.int )

European Standardisation Bodies

• CEN: European Committee for Standardisation (www.cen.eu)
• CENELEC: European Committee for Electrotechnical Standardisation (www.cenelec.eu)
• ETSI: European Telecommunications Standards Institute (www.etsi.org)

International standards are developed by International Standardisation Bodies.

ISO 14971:2019 Medicaldevices — Application of risk management to medical devices. 

European standards are developed by European Standardisation Bodies.

EN 60601-1-6:2010/A2:2021 Medical electrical equipment - Part 1-6: General requirements for basic safety and essential performance - Collateral standard: Usability

European Harmonised standards

European standard adopted on the basis of a request made by the Commission for the application of Union harmonisation legislation.

Harmonised standards are published in Official Journal of the European Union.

Devices that are in compliance with harmonized standards shall be presumed to be in conformity with the requirements of European Regulation. (Article 8)

US FDA Recognized Consensus Standards

FDA identify or recognize a standard established by a national or international standard developing bodies.Manufacturers of medical devices may submit a declaration of conformity to demonstrate they have met relevant requirements in the Federal Food, Drug, and Cosmetic Act (FD&C Act).

Guidance on Appropriate Use of Voluntary Consensus Standards in Premarket Submissions for Medical Devices: https://www.fda.gov/regulatory-information/search-fda-guidance-documents/appropriate-use-voluntary-consensus-standards-premarket-submissions-medical-devices

US FDA Recognized Consensus Standards Database:

https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfstandards/search.cfm

 

References

REGULATION (EU) No 1025/2012

REGULATION (EU) 2017/745

REGULATION (EU) 2017/746

Standards and Conformity Assessment Program: https://www.fda.gov/regulatory-information/search-fda-guidance-documents/appropriate-use-voluntary-consensus-standards-premarket-submissions-medical-devices

US FDA Breakthrough Devices Program

Expedited Access Pathway and Priority Review for medical devices are replaced by Breakthrough Devices Program. (Section 515B(b) of the Federal Food, Drug & Cosmetic Act)

This program speedup the breakthrough technologies development, assessment, and review, while preserving the statutory standards for premarket approval, 510(k) clearance, and De Novo marketing authorization.

This program allows the manufacturer to interact with the FDA's experts to efficiently address topics/issues/concerns as they arise during the premarket review phase.

Devices subject to PMAs, 510(k) or requests for De Novo designation are eligible for breakthrough device designation if both of the following criteria are met: statutory criteria

1. The device provides for more effective treatment or diagnosis of life-threatening or irreversibly debilitating human disease or conditions

2. 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

Breakthrough Technology: Consider technological advances or new use of an existing technology. Consider potential to lead to clinical improvement.

Manufacturer can submit breakthrough designation at any time prior to sending your marketing submission  by submitting a "Designation Request for Breakthrough Device" Q-Submission.

Content of Application:

• Device description
• Proposed indication for use
• Regulatory history
• How your device meets the statutory criteria for a Breakthrough Device
• What type of marketing submission you plan to submit to the FDA for your device

Timelines:

Deficiency letter- within 30 days of receiving your request

FDA's decision to grant or deny- within 60 days of receiving your request

References:

Guidance Breakthrough Devices Program:https://www.fda.gov/regulatory-information/search-fda-guidance-documents/breakthrough-devices-program

Device advice Breakthrough Devices Program: https://www.fda.gov/medical-devices/how-study-and-market-your-device/breakthrough-devices-program#s3

 

 

US FDA Emergency Use Authorization (EUA)

 An Emergency Use Authorization (EUA) is a mechanism allows the use of medical countermeasures during public health emergencies.

FDA may allow the use of unapproved medical products, or unapproved uses of approved medical products in an emergency.

Medical countermeasures examples, FDA-regulated products (biologics, drugs, devices).

Public health emergencies examples: Covid 19, Anthrax, Ebola Virus, H7N9 Influenza, Zika Virus.

 When EUA is used:

Domestic emergency/ Military emergency/ Public health emergency involving heightened risk of attack with a chemical, biological,radiological, or nuclear (CBRN) agent and Material threat affecting national security or the health and security of United States citizens living abroad.

 Process of EUA.

 EUA Declaration:Health and Human Services (HHS) Secretary issues an EUA declaration.

The below figure shows the EUA sumission process.

EUA submission contents,

Based on below criteria,FDA may issues EUA,

• Serious or Life-Threatening Disease or Condition
• Evidence of Effectiveness :"may be effective" standard for EUAs provides for a lower level of evidence than the "effectiveness" standard that FDA uses for product approvals
• Risk-benefit analysis the device’s known and potential benefits regarding treating, diagnosing or preventing disease
• Lack of adequate, FDA-approved/cleared or available alternative treatment

The FDA commissioner issues a letter that authorizes the EUA. The letter must state:

• the diseases or conditions the product may be used to diagnose, prevent, or treat within the scope of the EUA
• the known and potential benefits of the product
• conclusions concerning the safety and potential effectiveness of the product
• an assessment of the available scientific evidence; and
• required and additional conditions of authorization

Usually EUA last for 1 year after approval,but EUA shall be renewed until public health emergency lasts.

References:

Federal Food, Drug, and Cosmetics Act, as amended. Codified at 21 U.S.C. 301 et seq.

https://www.fda.gov/regulatory-information/search-fda-guidance-documents/emergency-use-authorization-medical-products-and-related-authorities

 

US FDA Humanitarian Use Device(HUD)/Humanitarian Device Exemption(HDE)

 To market a medical device in US, manufacturer shall provide a reasonable assurance that the device is safe and effective.

Under HUD/HDE allow the manufacturer to show their device is safe and provides a probable benefit

HUD: 21 CFR 814.3(n)

A Humanitarian Use Device (HUD) is a medical device intended to benefit patients in treatment or diagnosis of a disease or condition that affects or is manifested in not more than 8,000 individuals per year in the United States.

 Manufacturer shall get a HUD designation request and receive approval from the FDA’s Office of Orphan Products Development.

After HUD designation is granted, submit an HDE application to the Center for Devices and Radiological Health (CDRH) or Center for Biologics Evaluation and Research (CBER).

 HUD Designation:

Sponsor submits a HUD Designation Request to FDA’s Office of Orphan Products Development (OOPD). FDA will send an acknowledgement letter with an assigned HUD number for each application.

FDA will provide decision within 45 days to the applicant

• Approval
• Disapproval
• Request Additional Information

Content of HUD Request

• Cover Letter
• Description of the Disease or Condition
• Population Estimate
• Description of the Device and Scientific Rationale for its Proposed Use
• Supporting Documentation with Appended References

Content of HDE Request

• Copy of/reference to HUD designation letter
• Explanation of why device not otherwise available
• Statement that no comparable device is legally marketed (approved or cleared)
• Device description
• Indications for Use
• Valid Scientific Evidence
• Explanation of why probable benefit outweighs risk
• Manufacturing Information
• Amount being charged
• Request for Profit(if requesting exception to profit prohibition)
• Labeling

Documents issued by FDA for Product HDE Approval

Once FDA approve the HDE, Manufacturer will receive the following documents,

The following are posted on the FDA’s public PMA database:

• Approval Order
• Summary of Safety and Probable Benefit (SSPB)
• Labeling
• Consumer Information (short summary of the device and its intended use)

·     FDA Review –

1. Sponor shall get the HUD designation first.Sponsor submits the ecopy to FDA CDRH's or CBER’s Document Control Center (DCC). FDA will send the acknowledgement letter.

2.FDA Filing Review: administrative and limited scientific review (21 CFR 814.112)

Within30 calendar days FDA will notify below to manufacturer: Decision: Filled or Not Filled

3. Substantive Review 21 CFR 814.116:Lead reviewer will assess the application( In-depth scientific, regulatory, and quality systems review) and share the below information to manufacturer.

• Interactive review
• Issue Major Deficiency Letter.HDE request will be placed on hold.
• Advisory Panel Meeting. Public meeting to review the HDE 

Decision:

Approval Order: Device may be marketed. Identifies conditions of approval. FDA provides the Annual Distribution Number (ADN), if the FDA determines that the HDE holder is eligible to sell the device for profit.

Approvable Letter: Minor deficiencies that must be resolved in order for the application to be approved.

Major Deficiency Letter: Major deficiencies that must be resolved in order for the application to be approved. It doesn’t require new clinical and/or substantive nonclinical evidence.

Not Approvable Letter: Significant deficiencies that must be resolved in order for the application to be approved. It requires new clinical and/or substantive nonclinical evidence.

 References:

HDE : https://www.fda.gov/medical-devices/humanitarian-device-exemption/getting-humanitarian-use-device-market#review

HDE database: www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfHDE/hde.cfm

 HDE Guidance: www.fda.gov/downloads/RegulatoryInformation/Guidances/UCM336515.pdf