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The United States Food and Drug Administration (FDA), the European Commission, and other regulators have made patient safety a strategic priority, by developing UDI regulations for Medical Devices and In Vitro Diagnostic (IVD) Devices, and are aiming for a globally harmonized and consistent approach, aligned with the IMDRF (International Medical Device Regulator Forum) Guidelines.

Topics in this article:

• What is the UDI?
• What is the purpose of UDI?
• UDI in the US
• FDA UDI Compliance Dates
• EU MDR UDI
• Implementation of the UDI system

What is the UDI?

The UDI (Unique Device Identification) is a series of numeric or alphanumeric characters that is created through a globally accepted device identification and coding standard. It allows the unambiguous identification of a specific medical device on the market.

The UDI may consist of plain text (human-readable) and AIDC (machine-readable) and is composed of two parts:

• Device Identifier (DI) – A unique numeric or alphanumeric code specific to a device version or model. The Device Identifier (DI) is the first part of a UDI.
• Production Identifier(s) (PI) – Numeric or alphanumeric codes that identify production information for a device and can include the following:
  • Lot or batch number;
  • Serial number;
  • Expiration date;
  • Manufacturing date;
  • Distinct identification code (for Human Cell and Tissue).

• Reprinted from https://www.reedtech.com/

What is the purpose of UDI?

The UDI system facilitates easier traceability of medical devices, significantly enhances the effectiveness of the post-market safety-related activities for devices and allows for better monitoring by competent authorities. It also helps to reduce medical errors and to fight against falsified devices. The use of the UDI system finally should also improve purchasing and waste disposal policies and stock management by health institutions and other economic operators.

Which products are subject to the UDI system?                                                                                                        

The UDI system should apply to all medical devices, except custom-made and performance study/investigational devices.

UDI in the US

The US Food and Drug Administration (FDA) released in September 2013 a UDI rule which establishes a UDI system applying to all medical devices placed on the US market.

The Unique Device Identification System final rule (UDI Rule) requires device labelers (typically, the manufacturer) to:

US UDI requirements 

1. Include a unique device identifier (UDI) on device labels and packages, except where the rule provides for an exception or alternative (a UDI is not required to be placed on any shipping container (logistics unit)).
   • If a device is intended for more than one use and intended to be reprocessed before each use, the device labeler must also mark the UDI directly on the device.
2. Submit device information to the Global Unique Device Identification Database (GUDID), i.e. the US FDA UDI regulatory database.After receiving a DI and a PI nomenclature from an agency, companies must register the DI in GUDID. The database does not store PI information, as this generally changes from batch to batch.

How to obtain a US UDI?

There are currently three agencies approved by FDA to issue UDIs: GS1, HIBCC, and ICCBBA. Each agency has its own labeling system. All three agencies issue Device Identifiers and nomenclatures for creating Production Identifiers, the main components of a UDI.

While the UDI is created through the guidelines of an approved issuing agency, the medical device manufacturer is responsible for performing a submission of the identifier along with several product data attributes.

FDA UDI Compliance Dates

FDA established a staggered series of compliance dates based on the medical device risk classification system.

• Reprinted from https://medicaldeviceacademy.com/

* Final guidance from the US Food and Drug Administration pushes back enforcement deadlines for certain Unique Device Identification (UDI) requirements for Class I and unclassified medical devices due partially to the agency’s coronavirus pandemic-related priorities.

According to the final guidance, FDA will delay enforcement of UDI labeling, date formatting as well as Global Unique Device Identification Database (GUDID) submission requirements for Class I and unclassified devices until September 24, 2022. Enforcement of compliance deadlines for these requirements had previously been set for September 24, 2020.

EU MDR UDI

The European Commission has also developed UDI requirements that are part of the EU Medical Devices Regulation (MDR) and the In-Vitro Diagnostics Regulation (IVDR). The European Union Medical Device Regulation (EU MDR) Articles 27, 28, and 29 and Annex VI of the regulation cover UDI.

EU MDR UDI requirements 

• Full UDI on Device Label and packaging, presented in human-readable plain text and Automatic ID and Data Capture (AIDC) technology, e.g. 1D/2D barcode, RFID (shipping containers shall be exempted from the UDI requirement)
• Permanent UDI marking on reusable devices  
• Submit device ID and attributes to the EUDAMED database, i.e. the EU regulatory database for regulated medical devices. 
• Reporting requirements: include UDI in annual reports, post-marketing surveillance and the Patient Implant Card   

The EU MDR uses the concept of “Basic UDI-DI.” This is general code for a product line or set of related models that have the same intended use. The Basic UDI-DI is separate from the UDI-DI, which is a unique DI that is specific to a particular model.

The Basic UDI-DI is not required on labeling or the device itself but is used in Certificates of Conformity, Summaries of Safety and Clinical Performance, Eudamed submissions, and other documentation.

 EU MDR UDI database

The Eudamed database will store EU UDI information. Manufacturers/Authorized Representatives/Importers will be required to keep records of all UDIs assigned for their devices. Companies are strongly encouraged to store their UDI information electronically and back it up in multiple locations because the EU UDI requirements go into effect before the Eudamed database comes online in 2022. Parts B and C of Annex VI of the regulation cover the information required.

How to obtain an EU UDI?

There are currently four agencies approved by the EU to issue UDIs: GS1, IFA GmbH, HIBCC, and ICCBBA.

Deadline for a medical device to comply with the EU UDI requirements

• Reprinted from https://www.europe-it-consulting.ch/?lang=en

Implementation of the UDI system

The general steps for establishing the required UDIs are outlined below:

1. Determine which products/configurations/accessories/kits require UDI
2. Select and register with the accrediting agency of your choice
3. Obtain the necessary DIs from the accrediting agency
4. For each DI, determine what PI information will be included based upon the product labeling
5. Select your barcode format and modify labeling as required to accommodate
6. Prepare the necessary infrastructure to support the UDI process, including:

− Updates to quality system processes to ensure DIs are created and maintained properly

− Updates to label creation, printing, and inspection processes

− Installation and validation of label printing equipment as needed

In parallel, you must register with the relevant UDI databases. 

Gsap experts have the expertise and resources to help you establish compliance processes to meet UDI requirements, and will be happy to assist you to create the right UDI label solution for your medical device.

Liat Aharon Pollak,

RA & QA Project Manager

For more information about our services visit:

How did Gsap experts accelerate Healthcare companies during the COVID-19 pandemic?

Interview with Our CEO Dr. Sigalit Ariely-Portnoy

Read more at: https://www.haaretz.co.il/st/inter/Global/magazine/Haaretz/2020/12%20Dec/hitech/index.html#p=50

We are pleased to share with you that on October 22, 2020, The US Food and Drug Administration (FDA) approved the first drug to treat COVID-19: Veklury (remdesivir), an antiviral medicine manufactured by Gilead Sciences Inc. to be administered  IV to patients needing hospitalization. Veklury-Remdesivir was originally developed to treat the Ebola virus, however, did not meet the efficacy endpoint in the Ebola clinical trial. In a large study led by the US National Institutes of Health (NIH), it was shown that the drug shortened the course of illness from an average of 15 days to about 10 days in hospitalized patients.

Veklury was submitted under the New Drug Application (NDA) track and granted a Fast Track designation by the FDA, which among other things, maximized the opportunities for Gilead to engage with the agency in its development of Veklury, for the treatment of COVID-19. Based on this designation, on April 6th, 2020, FDA granted Gilead’s request and accepted its proposal to allow for a rolling review of its development program for Veklury. Under this process, Gilead could submit the NDA sections for FDA review as they appear. Under traditional processes, the FDA’s review of an NDA does not begin until the sponsor has submitted the entire application to the Agency.

Notably, on the basis of the Department of Health and Human Services (HHS) determination that there is a public health emergency that involves the virus that causes COVID-19, and while Veklury was an investigational drug and not approved for any indication, the FDA issued (on February 2020) an Emergency Use Authorization (EUA) for emergency use of Veklury for the treatment of suspected or laboratory-confirmed COVID-19 patients. Emergency use authorization is NOT the same as FDA approval or licensure. EUAs do not remain in effect indefinitely and FDA is continuously evaluating the continued appropriateness of the EUA.

In summary, from the approval process of Veklury, we can learn that nowadays the FDA is committed to expediting the development and availability of COVID-19 treatments. As part of the FDA’s Coronavirus Treatment Acceleration Program, the agency is focusing on moving new medical products to patients as soon as possible, while at the same time determining whether they are effective and if their benefits outweigh their risks.

This Newsletter Prepared by:

Tsufit Gross, Ph.D

Pharma and Biotechnology project manager

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The Nobel Prize for Chemistry was awarded this year for the invention of Genetic Scissors: a tool for rewriting the code of life.

Emmanuelle Charpentier and Jennifer A. Doudna have discovered one of gene technology’s sharpest tools: the CRISPR/Cas9 genetic scissors. Using these, the DNA of animals, plants and microorganisms can be changed/edited with extremely high precision.

This technology has had a revolutionary impact on the life sciences, is contributing to new cancer therapies and may make the dream of curing inherited diseases come true.

Since the discovery of CRISPR/Cas9, the research of this tool has led to a blooming landscape of pre-clinical and clinical studies in humans.
FDA considers any use of CRISPR/Cas9 gene editing in humans to be gene therapy, thus requiring extensive regulatory efforts in order to bring such products from early concept to clinical application. 

Gene therapy products are regulated by the FDA’s Center for Biologics Evaluation and Research (CBER). Clinical studies of gene therapy in humans require the submission of an investigational new drug application (IND) prior to their initiation in the United States, and marketing of a gene therapy product requires submission and approval of a biologics license application (BLA). 

At Gsap, our team of Advanced Therapies experts is excited to be at the frontier of this field, with a unique portfolio of process development, preclinical, clinical and regulatory services, assisting our clients to bring gene-therapy products from early POC to realization into clinical use.

If you develop a gene-editing product, do not hesitate to contact us!

This Newsletter Prepared by:

Diana Gershtein, M.Sc., M.B.A.

Cell Therapy Section Manager

For more information about our services visit:

Topics in this Newsletter:

• FDA COVID-19 EUA – in Vitro diagnostics (IVDs) 
• Europe – emergency market access for IVD manufacturers 
• Israel – AMAR accelerated review and approval
• Gsap involvement in promoting novel COVID-19 IVD

Emergency efforts are being taken to find optimum medical products to prevent infection, diagnose and treat patients during the COVID-19 pandemic. Multiple diagnostic, therapeutic, and preventive interventions for COVID-19 are being trialed. Robust evaluation of diagnostics tests (premarket and postmarket) to ensure accuracy will be vital; inaccurate tests will be worse than no tests. If products prove to be efficacious against COVID-19, achieving global benefit will require prompt access for all people in need. All our fates are bound together, and any helpful products must be recognized as global assets.

Nonetheless, effective regulatory supervision, emergency prequalification, robust authentication measures, and procurement policies that support quality, with abjuring of national export restriction policies, the informal market, and illegal online websites, combined with trusted public engagement campaigns, will be needed to reduce substandard and falsified medical products.

The dedicated Commission working group of the Member States competent authorities for In-Vitro Diagnostics (IVDs) serves as a forum for continuous exchange of technical and regulatory information on IVDs including COVID-19 rapid tests has indicated that the majority of CE-marked rapid tests are compliant with EU law. However, they identified several devices with fraudulent documentation, incomplete technical files, or unsubstantiated claims. Some of those were sold as alleged self-tests. The several Member States have warned against the use of rapid self-tests or even prohibited them.

WHO referral laboratories for COVID-19 are currently performing validation studies of commercial assays. European Commission and the Member States are funding fast-track clinical validation studies of rapid diagnostic tests for COVID-19 by hospital laboratories in several EU Member States.

ECDC is working in close cooperation with the European Commission, Member State authorities, FIND (https://www.finddx.org/), and WHO on ongoing validation of these rapid tests and will inform the EU/EEA countries on results as soon as those are available.

FIND is a global non-profit organization driving innovation in the development and delivery of diagnostics to combat major diseases affecting the world’s poorest populations. It is a WHO Collaborating Centre for Laboratory Strengthening and Diagnostic Technology Evaluation.

Governments all over the globe encourage the development of novel COVID-19 diagnostic products by providing grants to support these initiatives.

In parallel FDA and other regulatory agencies establish policies and guidelines for emergency use authorizations during the COVID 19 crisis:

1. FDA taking overdue steps to accelerate COVID-19 diagnostic testing

As US healthcare providers face shortages of medical devices and equipment during the COVID-19 pandemic,the Food and Drug Administration has moved to expedite market authorizations for certain products needed to address the public health emergency.

Key criteria for obtaining a EUA designation from the FDA include:

•  Presence of a chemical, biological, radiological or nuclear agent (in this case, the coronavirus) that poses a serious disease or condition;
• Qualifying device must meet a “may be effective” standard for treating the targeted disease or condition (in this case, COVID-19), which entails a lower threshold of required evidence compared to FDA’s standard “effectiveness” criterion applied in normal premarket reviews;
•  Ability on FDA’s part to determine via risk-benefit analysis the device’s known and potential benefits regarding treating, diagnosing or preventing COVID-19;
•  Lack of adequate, FDA-approved/cleared or available alternative treatments.

On February 29, 2020, FDA issued a Policy for Diagnostics Testing in Laboratories Certified to Perform High Complexity Testing under CLIA prior to Emergency Use Authorization for Coronavirus Disease-2019 during the Public Health Emergency: Immediately in Effect Guidance for Clinical Laboratories and Food and Drug Administration Staff. This policy was further updated on March 16, 2020, to include serological tests.

Under this guidance, labs that are certified under the Clinical Laboratory Improvement Amendments of 1988 (CLIA) to perform high-complexity testing may offer in vitro diagnostic tests for the detection or diagnosis of COVID-19 while pursuing an Emergency Use Authorization (EUA).

Recommended performance information 

The newly released guidance provides minimum validation testing requirements for these diagnostic tests, including specific guidance for the limit of detection, cross-reactivity, inclusivity, and clinical evaluation.

If clinical data are not available, FDA may consider accepting data solely from bench testing. 

For more information: https://www.fda.gov/regulatory-information/searchfda-guidance-documents/policy-diagnostic-testscoronavirus-disease-2019-during-public-healthemergency

FDA requests that developers notify the agency once their tests are validated and submit a completed EUA request within 15 business days of validation. While a lab awaits EUA for its test, FDA recommends that the lab send the first five negative and the first five positive specimens for testing using another EUA authorized assay as an independent check on its validity. 

Categorization of laboratory tests under and EUA

The FDA indicates when issuing a EUA for a diagnostic device whether the test can be performed at a point-of-care setting or only in a laboratory able to handle more complex tests.

FDA may also establish appropriate conditions on the performance of the test. The complexity categorization is effective for the same period as the EUA and is independent of that made under Clinical Laboratory Improvement Amendments (CLIA) regulations.

Requesting a EUA designation

1. Initiate “pre-EUA” activities and engagement with FDA to discuss potential designations (via email): COVID19DX@FDA.HHS.GOV

This step is particularly recommended for companies whose devices are in advanced stages of development since rapid access to healthcare providers is crucial.

2. Submit a formal EUA designation request to FDA. The submission should include as much safety, effectiveness, and risk-related data as is available pertaining to the device in question. The depth and extent of such information will depend largely upon whether a device submitted for EUA consideration has already been cleared or approved for use by the FDA, or if a EUA designation would involve using a previously cleared or approved device in a manner for which it was not intended.

3. If acceptable, FDA issues approval letter Timelines for EUA submission reviews and determinations are made on a case-by-case basis. The FDA usually issues these designations “within hours or days” provided that manufacturers have met necessary criteria and engaged inadequate pre-EUA activities. For EUA devices, Quality System requirements and device listing are waived. Certain conditions of approval must be followed, such as having processes in place for reporting adverse events, recording keeping, etc. 

NOTE

The FDA determines effective dates of EUAs, and at the end of a EUA declaration period, these individual authorizations are terminated. Manufacturers of EUA-designated devices that have not previously obtained FDA market authorization must then dispose of such devices still on the US market Pursuant to section 564(b)(2)(B) and (b)(3). Any study or future use of a EUA product beyond the term of a declaration is subject to investigational product regulations. For devices cleared or approved for other intended uses outside the scope of their EUAs, manufacturers must ensure that such devices return to “normal use.”

To date, the FDA has issued EUAs in the areas of in-vitro diagnostics, personal protective equipment, “other medical devices,” and therapeutics. A full, current listing of all EUAs is available online at the FDA’s website.

2. Europe – emergency market access for IVD manufacturers

European Union member states face similar crises as the US and other countries regarding shortages of medical devices and equipment needed to treat COVID-19 patients, driving the need for emergency access to European healthcare markets for these products at a faster rate than for the standard conformity assessment routes to obtain a CE Marking certification. 

Expedited EU Conformity Assessment procedures

Under normal circumstances, obtaining a CE Marking certificate in Europe for a medical device, IVD, or Personal Protective Equipment (PPE) involves a conformity assessment either from a Notified Body or a self-declaration for low-risk products and low categorized products. Notified Body conformity assessments of these devices and PPE products can range from several months for some PPEs to roughly a year or longer for high-risk medical devices and IVDs.

In an emergency, public health situations both the European Commission, as well as EU member states individually, have the ability to temporarily permit access to EU markets for devices and PPE products that have not gone through or have not yet completed the required conformity assessment.

NOTE

Specific requirements for marketing eligible medical devices, IVDs, and PPE products via emergency pathways are imposed singly by European member states. Individual Competent Authorities thus grant permissions for emergency market access in their respective countries. The national competent authorities are listed here Manufacturers should take into account variance in terms of processes and requirements from one EU member state to another if pursuing emergency access.

Emergency EU market access specific to COVID-19: medical devices and IVDs 

Devices without CE Marking will only be allowed temporary European market access in cases where no alternative products or treatments are available pertaining to the COVID-19 pandemic, and a request has been made to the EU member state where the devices are placed on the market. Member states will assess requests on a case-by-case basis. Requests can be made by all Economic Operators.

The European Commission has issued a guidance document on medical devices, active implantable medical devices, and in vitro diagnostic medical devices in the COVID-19 context which is a compilation of relevant questions and answers concerning the conformity assessment process for medical devices including IVDs aiming for diagnosing and treating COVID-19. https://ec.europa.eu/docsroom/documents/40607

3. Israel – AMAR emergency use temporary approval

AMAR, the medical devices division of the Israeli Ministry of Health (MOH) is responsible for the approval and registration of medical devices and IVDs in Israel. During the COVID-19 global crisis, AMAR has taken a similar emergency use approach as the FDA, allowing accelerated approval for emergency purposes by providing temporary approval. Regarding test validation, the recommendations are for minimal testing which includes: limit of detection (LoD), clinical evaluation, inclusivity, and cross-reactivity.

Same as FDA EUA, Quality System requirements for AMAR emergency use approval are waived. Certain conditions of approval must be followed, such as having processes in place for reporting adverse events, Post Marketing Surveillance(PMS), record keeping, etc.

Permanent registration approval is pending PMS data gathered during the emergency use period and continued product performance as per initial data submitted.

Companies pursuing the emergency use approval for medical devices and IVDs intended for the treatment and identification of COVID-19 receive a temporary approval letter based on demonstrated performance data to support the intended use: analytical sensitivity and analytical specificity and if available, data from testing fresh, contrived, banked or archived specimens.

4. Gsap involvement in promoting novel COVID-19 IVD technologies under EUA

Gsap group of experts have been supporting companies in developing novel diagnostic solutions for identifying COVID-19 patients. 

This experience includes regulatory, quality, and clinical services and leading conference call meetings with the Israeli MOH AMAR division:

1. An Israeli company developing a rapid, point of care, screening test for identifying COVID-19 patients:

• Issuance of a preliminary regulatory strategy based on the FDA policy for Diagnostics Testing, EmergencyUse Authorization for Coronavirus Disease-2019 during the Public Health Emergency.

• Leading pre-EUA discussions with AMAR

• Development of clinical performance protocol

• Regulatory submissions for receipt of Ethics Committees approval for a multi-center trial

2. An Israeli company developing a Decision Support Tool (software) for prediction of COVID 19 infection:

• Develop a clinical performance plan

• Leading pre-EUA discussions with AMAR

• CRO, Regulatory, and quality support

This Newsletter Prepared by:

Einat Dekel, D.V.M

Quality & Regulatory Project Manager

For more information about our services visit:

Dr. Sigalit Arieli Portnoy, CEO and Founder of Gsap, talks in an exclusive interview about accelerating the development and approval processes of drugs and medical equipment for COVID, including from foreign companies, and reports On the enormous scope of action that accompanies a sense of mission.

For more information about our services visit:

What needs to be reviewed?

1. Technical Documentation which must include:
   ●Device description and specification
   ●Information to be supplied by the manufacturer
   ●Design and manufacturing information
   ●General Safety and Performance Requirements (GSPR)
   ●Benefit-Risk Analysis and Risk Management
   ●Product Verification and Validation
2. Classification
3. Clinical Data
4. Biocompatibility – the updated ISO 10993-1 is applicable now both as per the MDD and the MDR.

 Where to Start?

1. Classification – classify your device as per the rules laid out in Annex VIII of the regulation.
2. General Safety and Performance Requirements (GSPR) replaces the Essential Requirements. Fill one out for each device.
3. Post Marketing Surveillance (PMS) – look at the clinical PMS data you have and make sure you have a plan and a report.
4. Make sure your PMS is linked to your Risk Management. Clinical data for your own device will be critical for the Clinical Evaluation Report (CER) to establish equivalence and minimize any further Clinical Study requirements.
5. Risk Management – No longer one document. This should be a group of documents that address all the requirements of both ISO 14761 and the MDR.
6. Biocompatibility – you must have a plan (Biological Evaluation Plan) and a report (Biological Evaluation Report) that complies with all the updated and latest Biocompatibility ISO standards. (The 10993 series.)

What to do?

1. Classification – This will lead to updating the Declaration of Conformity.

2. GSPR – any gaps identified (validations or issues that have not been reviewed in the past) must be closed. *** See table below for an example of the GSPR vs. the Essential requirements

3. PMS (Post Marketing Surveillance), PMCF (Post Marketing Clinical Follow Up) – start the implementation of the plan as soon as possible and write a summary report of all data collected to date.

4. Risk Management – verify that hazards have been identified and that the clinical risks have been mitigated.

5. Any Biocompatibility testing that has not been done and cannot be rationalized should be performed.

6.  Make sure your QMS adheres to the requirements of the MDR – the following requirements are unique to the MDR: 

• A documented strategy for regulatory compliance
•   Manufacturers need to verify UDI (Unique device identifier) assignments for their device both before they hit the market and periodically after they are released
•  A designated person or group of people responsible for regulatory compliance (PRRC)
•  Documented procedures for clinical investigation and evaluation
•   Specific PMS documents – PMS plan and a Periodic Safety Update Report (PSUR), including incidents      and field safety corrective actions (FSCA)
•  Management of the supply chain and economic operators
•   Implantable devices
•   European data base on medical devices (EUDAMED)
•   Common specifications
•   Vigilance

 Example of the GSPR vs. the Essential requirements

Gsap will be happy to support you in getting ready for the MDR storm!

This Newsletter Prepared by:

Ossie Milanov, BA

Quality & Regulatory Project Manager

For more information about our services visit: