Author: Anna Barad

The Covid-19 Pandemic is one of the greatest challenges modern medicine has ever faced. Hospitals and research labs all over the world are testing many different therapies on coronavirus-positive patients in an effort to find a potential COVID-19 treatment. There are thousands of clinical trials investigating treatments and preventative measures for COVID-19.

This newsletter will review the prominent drugs, the Israeli achievements, and where Gsap helps promote the fight against Coronavirus.

Topics in this newsletter:

• Treatment of COVID-19
• Promising Israeli drugs to treat Corona virus
• Effects of Pfizer (Tozinameran/Comirnaty) in the Israeli population

Current approaches to COVID-19 therapies generally fall into two categories: antivirals which prevent the virus from multiplying and immune modulators which help the immune system to fight the virus or stop it from overreacting dangerously.

During a public health emergency, such as COVID-19, the FDA can issue an emergency use authorization (EUA) to help make new medications and medical products more available to patients. Having a EUA does not mean that the FDA has approved the medication or product. Rather, the intent of a EUA is to make it easier for patients to receive a new potential treatment when no other options are available.

Treatment of COVID-19

Remdesivir – First drug to gain approval from the

Remdesivir is the first drug to gain approval from the FDA for the treatment of Covid-19 made by Gilead Sciences under the brand Veklury, it works by interfering with the creation of new viruses, inserting itself into new viral genes. Remdesivir was originally tested as an antiviral against Ebola and Hepatitis C, only to deliver lackluster results. But once the Covid-19 pandemic emerged, researchers found that it could stop the coronavirus from multiplying in cells. A large clinical trial was then launched, which found that the drug reduced the recovery time of people hospitalized with Covid-19 from 15 to 11 days. The FDA responded to this data last May by issuing an emergency authorization for Remdesivir’s use in critically ill patients who need supplemental oxygen. In August, they expanded that approval after another study found that patients with less severe forms of Covid-19 seemed to benefit modestly from a five-day treatment course of Remdesivir. The revised approval allows the use of the drug on all patients hospitalized with Covid-19, regardless of how severe their disease is.

Yet many experts remained skeptical of remdesivir’s benefits. They pointed out, for example, that there’s no statistically significant evidence that remdesivir actually prevents deaths from Covid-19. In Nov 2020, the World Health Organization recommended against using remdesivir. Based on a review of all the published trials so far, they concluded that evidence of its benefits is lacking.

FDA Authorizes Monoclonal Antibodies for Treatment of COVID-19

Monoclonal antibodies are laboratory-made proteins that mimic the immune system’s ability to fight off harmful pathogens such as viruses. Casirivimab and imdevimab are monoclonal antibodies that are specifically directed against the spike protein of SARS-CoV-2, designed to block the virus’ attachment and entry into human cells.

In November 2020, the U.S. Food and Drug Administration issued an emergency use authorization (EUA) for basiliximab and imdevimab to be administered together for the treatment of mild to moderate COVID-19 in adults and pediatric patients (12 years of age or older weighing at least 40 kilograms) with positive results of direct SARS-CoV-2 viral testing and who are at high risk for progressing to severe COVID-19. This includes those who are 65 years of age or older or who have certain chronic medical conditions.

In a clinical trial of patients with COVID-19, casirivimab and imdevimab administered together were shown to reduce COVID-19-related hospitalization or emergency room visits in patients at high risk for disease progression within 28 days after treatment when compared to placebo. The safety and effectiveness of this investigational therapy for use in the treatment of COVID-19 continue to be evaluated.

A Randomized Trial of Convalescent Plasma in Covid-19 Severe Pneumonia demonstrate no significant difference between the convalescent plasma group and the placebo group

Convalescent plasma is frequently administered to patients with Covid-19 and has been reported, largely on the basis of observational data, to improve clinical outcomes. Minimal data are available from adequately powered randomized, controlled trials.

The New England journal of medicine published in February 2021 a Randomized Trial of Convalescent Plasma in Covid-19 Severe Pneumonia. Adult patients with severe Covid-19 pneumonia in a 2:1 ratio receive convalescent plasma or placebo (A total of 228 patients were assigned to receive convalescent plasma and 105 to receive placebo). The primary outcome was the patient’s clinical status 30 days after the intervention, as measured on a six-point ordinal scale ranging from total recovery to death. On day 30 day, no significant difference was noted between the convalescent plasma group and the placebo group in the distribution of clinical outcomes according to the ordinal scale.

Corticosteroid use in COVID-19 patients

Corticosteroids (often called steroids) are used to tamp down inflammation and for conditions such as allergies and asthma. The Covid-19 pandemic brought a new interest in these drugs, and a raft of new clinical trials was launched. In June 2020, the steroid dexamethasone was the first shown to reduce Covid-19 deaths. A study of more than 6,000 people found that dexamethasone reduced deaths by one-third in patients on ventilators, and by one-fifth in patients on oxygen. It may be less likely to help and may even harm patients who are at an earlier stage of Covid-19 infections, however. In its Covid-19 treatment guidelines, the National Institutes of Health recommends only using dexamethasone in patients with Covid-19 who are on a ventilator or are receiving supplemental oxygen.

In September 2020, researchers reviewed the results of trials on dexamethasone, along with two other steroids, hydrocortisone, and methylprednisolone. Overall, they concluded, steroids were linked with a one-third reduction in deaths among Covid-19 patients.

Promising Israeli drugs to treat Coronavirus 🇮🇱

EXO-CD24

The EXO-CD24 substance, developed at the Ichilov Medical Centre in Tel Aviv, successfully completed its first phase of clinical trials.

CD24 is a small heavily glycosylated GPI-anchored protein. CD24 is a key player in the vast majority of human cancers and also plays an important role in controlling the homeostatic proliferation of T cells. Hence, CD24 can negatively regulate inflammation.

The treatment is a biologic therapeutic agent based on exosomes carrying CD24. The rationale for this treatment is that exosomes overexpressing CD24, isolated and purified from T-REx™-293 cells engineered to express CD24 at high levels, can suppress the cytokine storm and are delivered directly to the target organ (the lungs) using exosomes as a highly body-compatible delivery vehicle. This enables a strong reduction of the required dose and reduces the risk for adverse events.

The treatment was administered to 30 patients with moderate-to-severe symptoms of Covid-19. Twenty-nine of them recovered in up to five days. No placebo was used in the first stage of the trial, and the next phase of the clinical trials will continue to examine the effects and efficacy of the treatment.

 During a recent visit to Israel, Greek Prime Minister Kyriakos Mitsotakis offered to have a hospital in Greece take part in clinical trials.

Allocetra

Israeli immunotherapy company Enlivex Therapeutics reported positive interim results of Phase II clinical trial of its Allocetra product in severe and critical Covid-19 patients. The interim clinical results relate to eight Covid-19 patients who were treated with Allocetra, six of whom were in severe condition and two of whom were in critical condition. Seven completely recovered and were discharged from the hospital, after an average of 4.7 days following Allocetra administration. The eighth treated patient in the Phase II study has experienced a clinical improvement following treatment with Allocetra and is currently classified as a moderate/severe condition. The company says that the Allocetra treatment has been well tolerated with no treatment-related serious adverse events. On December 3, 2020, the Company reported positive interim results of Phase II investigator-initiated clinical trial of Allocetra in COVID-19 patients in severe/critical condition.

The interim clinical results relate to eight COVID-19 patients who were treated with AllocetraTM in Phase II clinical trial, six of whom were in severe condition and two of whom were in critical condition. Key results and conclusions from both the ongoing Phase II clinical trial, as well as a previously-reported investigator-initiated Phase Ib study include:

• Seven out of seven (100%) patients treated through November 26, 2020 had complete recovery from their respective severe/critical condition and were discharged from the hospital, after an average of 4.7 days following AllocetraTM administration.
• Taken together with previously-treated patients in the concluded Phase Ib study, twelve out of twelve patients (100%) through November 26, 2020 had complete recovery from their respective severe/critical condition and were discharged from the hospital, after an average of 5.5 days following AllocetraTM administration.
• The eighth treated patient in the Phase II study (and 13th treated patient overall), who enrolled in the Phase II study in critical condition on November 27, 2020, has experienced a clinical improvement following treatment with AllocetraTM and was classified as moderate/severe condition on December 3, 2020. Clinical outcome will be included in the next interim results update.
• AllocetraTM treatment has been well tolerated with no treatment-related serious adverse events.

Corona virus vaccines news

Vaccines typically require years of research and testing before reaching the clinic, but in 2020, scientists embarked on a race to produce safe and effective coronavirus vaccines in record time. Researchers are currently testing 71 vaccines in clinical trials on humans, and 20 have reached the final stages of testing. At least 78 preclinical vaccines are under active investigation in animals.

Effects of Pfizer (Tozinameran/Comirnaty) in the Israeli population

In November 2020 Pfizer and the German company, BioNTech made history by announcing that their coronavirus vaccine had an efficacy rate of over 90 percent, far surpassing expectations. It was the first time anyone had found such evidence. Just over a month later, in December 2020, the Food and Drug Administration granted it the first emergency use authorization ever given by the United States to a coronavirus vaccine.

In January 2020, BioNTech researchers started molding a genetic molecule called messenger RNA (mRNA) which create the genetic instructions for building a coronavirus protein, known as a spike. When injected into cells, the vaccine causes them to make spike proteins, which then get released into the body and provoke a response from the immune system. In May a clinical trial was started.  

In Phase 1 trials, the researchers found that Comirnaty caused volunteers to produce antibodies against SARS-CoV-2, as well as immune cells called T cells that respond to the virus. In July 2020, the companies announced the launch of a Phase 2/3 trial with 30,000 volunteers. In September, Pfizer and BioNTech announced that they would seek to expand the trial to 44,000 participants, and in November 2020, Pfizer and BioNTech released a preliminary analysis of the first 94 cases. Comirnaty has an efficacy rate of 95 percent. While Comirnaty caused no serious side effects, it frequently caused short-lived fatigue, fever, and muscle aches. These impressive results led rapidly to authorizations across the world.

Israel is currently leading the world in vaccination. Israel vaccinated 53.7% of its 9 million inhabitants, with at least the first dose of the vaccine (Until the first of March(. Pfizer and Israeli health officials released new data that shows that the Comirnaty vaccine is greatly reducing transmission, which is one of the most asked questions in the world right now. The Israeli Health Ministry found that the full two doses of Pfizer reduce infection by 89.4% in asymptomatic cases, where there are no visible or tangible symptoms. In cases that bring symptoms, Pfizer seems to work to provide a startling 93.7% level of protection. The vaccine was also 92% effective at protecting people from severe illness after two shots, with a strong 62% protection level after a single dose. Three weeks after the first dose, people reported a 72% level of protection. Scientists expect this percentage to increase over time, as immunity builds in the body.

F.D.A. Panel Gives Green Light to Johnson & Johnson’s Vaccine

Johnson & Johnson’s Covid-19 vaccine was endorsed at the end of February 2021 by a panel of experts advising the Food and Drug Administration, clearing the last hurdle before a formal authorization.

Johnson & Johnson’s formulation worked well in clinical trials, particularly against severe disease and hospitalizations, even though it did not match the sky-high efficacy rates of the first two vaccines made by Pfizer-BioNTech and Moderna.

Johnson & Johnson launched a Phase 3 trial in September, which they paused on Oct. 12 to investigate an adverse reaction in a volunteer. The trial resumed eleven days later. Although Johnson & Johnson initially set out to recruit 60,000 volunteers, it capped the trial at 45,000 in December as cases rose.

Institute for Biological Research start second trial phase for COVID-19 vaccine

The Israel Institute for Biological Research announced the start of phase two with a vaccine for the COVID-19 virus (IIBR-100/ BriLife). The study was started with a dose-escalation phase (phase I) during which subjects (18-55 years old) were randomly allocated to receive a single administration of BriLife at low, mid, or high dose or saline or two administrations of IIBR-100 at a low dose, or saline, 28 days apart.

Based on results obtained during phase I, and cumulative phase I data review, the expansion phase (phase II) was started, during which larger cohorts, as well as elderly age subjects, were randomly allocated to receive prime-boost administration of BriLife 28 days apart. The subjects will be followed for a period of up to 12 months post-last vaccine administration to assess the safety and efficacy of the vaccine.

Gsap has the honor to accompany the Israel Institute for Biological Research through the various stages of development and clinical trials.

This Newsletter Prepared by:

Sara Blumenstein Pharma & Biotechnology Regulatory Section Manager

For more information about our Pharmaceuticals services visit:

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:

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

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

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All companies aim to have high-quality products and services, it is the rare few that actually achieve this desirable goal. The way to achieve this goal is by asking and answering 3 questions: 

• Do we have a culture for quality and how is that we know this?  
• Do we have a quality product and how is that we know this?
• How can we develop and maintain an efficient and effective QMS?

 This article gives you practical tools for answering these 3 questions and demonstrates how Gsap can help you to establish a culture for quality, manufacture quality products, and have a sustainable, efficient, and effective quality system. 

Do we have a culture for quality and how is that we know this? 

 A major survey, conducted by CEB (Corporate Executive Board Company) in 2013 under the topic “Culture of Quality Benchmarking survey”, used the following tool to estimate the culture for quality in In hundreds of organizations.

  Gsap can help you implement this simple tool in your organization:

  Step 1 – Data collection:

Ask employees in the organization to specify for each of the following 4 statements, whether they agree or disagree with the following statements.

● “I hear quality in the organization”

● ”I see quality in the organization”

●”I feel quality in the organization”

● ”I transfer quality in the organization”

Present the data in the following table and calculate the scores:

Step 2 – Benchmark and Criteria: 

Compare your scores with the score received in the CEB survey for companies with high quality/culture for quality. 
In those companies the following results were received: 

                               Table #3 – “Culture for quality” survey benchmark per quality index   

 Step 3 – Data analysis and actions to be taken:

If you find that your company is in the 3^rd quintile or lower, it is time to define some steps to improve the situation. We, at Gsap, can help you do that by identifying the root causes and building together with you a strategy for change. Some of the root causes for low culture for quality may be:

 ■ Failure to implement company values from top management to each and every employee  

■ Failure to maintain consistent leadership emphasis and help leaders recognize where their actions contradict stated quality policies and objectives.

■ Failure to ensure that quality messages are credible and relevant. For diverse organizations that operate in multiple geographies, this means finding a way to tailor messages without ceding control and being globally consistent yet locally relevant.

■ Failure to demonstrate peer prioritization of quality by generating a social climate that encourages employees to support each other in generating quality ideas, without this effort appearing to be pushed from the top down.

■ Failure to build employee ownership through targeted guidance, setting forth enough guidance to give employees the confidence to act, yet not so much that independent decision making is stifled.

Do we have a quality product and how do we know that?

In 2011 the FDA published their initiative for “Case for Quality”, saying that “Compliance to regulations is not enough…

The goal for the case of quality is to afford patient access to high-quality medical devices”

The aim of this initiative was to arm the industry with practical metrics to implement that meet both the business needs and the product needs so that the Right-First-Time mentality from the initial day of development will return as much as possible.

The FDA defined matrixes in 3 major areas.

Our quality experts in Gsap can help you establish these matrixes, properly collect the data, analyze the results, and set actions for improvement.

Following are some effective Implementation principles

● Manage the Metrics –
Define & control: Collection of raw data, Calculations, Harmonization of definitions, Analysis method, Root cause investigation, etc. to avoid erroneous results that drive wrong decisions.

● Interpret in context –
to understand causes, cross analyze with other metrics and identify how to improve control. Use risk-based approach. 

● Apply internally –

Apply within the organization – not compare scores with other organizations out of context.  

Pre-Production Metric:

        Total # of changes (product & process across projects) 

________________________________________________________

                                Total # of projects

Goal:
To drive the Right-First-Time (RFT) mindset in the R&D phase such that post-design transfer changes (after design freeze) due to inadequate product /process development are not needed.

Calculation: 
►Only include changes required due to the inadequate product or process development

► Harmonize the definition of “changes” across organizations and classify the significance of varying levels of changes based on risk.

► Determine what constitutes a project (“project” encompasses all aspects of the product being transferred to production).

► Ideal to measure the changes required during (1) Design transfer (after design freeze), (2) Production, (3) On-market

Production Metric

        Total # of units manufactured right first time (within or across lots)

              __________________________________________________________

                                      Total # of units started

Goal: 

To gather nonconformance information during production operations related to inadequate product/process development.

Analysis of this information will enable us to assess the effectiveness of the development process and improve it. 

Calculation:

►Include all non-conformances initially (to get a first past yield) & Scrapes

►Triage the root causes

►Track and trend on a rolling basis

►Ensure terms are defined consistently across products and sites

►Raw materials/component failures are not to be included.

Post-Production Metric

Here we have several matrices:  

(3) Unplanned Service Records (% out of total units in service)  

(4) Installation failures (% out of total installations)

(5) Complaints (% out of total units sold, including non-safety complaints)

(6) MDRs (% of units with “Medical device reporting”, out of total units sold)

(7) Recalls (% of products that had to be recalled, out of total units sold)

 Calculation & Analysis

►Step 1: Calculate and track

each of the post-production metrics.  Identify trends, and have predetermined action limits.
►Step 2: Use advanced calculations to incorporate product risk profile information into the calculation of each indicator (see table below).
►Step 3: Use comparative analyses to conduct through mechanisms such as dashboard.

Finally:

You can incorporate pre-production & production metrics with post-production.
This can give you an enterprise-wide view of the risk to product quality

How can we develop and maintain an efficient and effective QMS?

An effective QMS is a QMS that achieves its goals and objectives. But, in order to have a sustainable quality culture, being effective is not enough – we also need to be efficient. 
Having an efficient QMS means a system that meets the company’s needs. A smart and “thin” and agile system where you have zero unnecessary bureaucracy.

Gsap quality experts can help you to build the QMS that is right for you!

 Our quality services include the following:

Gsap experts are here for you, to help you establish a culture for quality, build quality products, and have a sustainable, efficient, and effective quality system!

This Article Prepared by:

Marina Lebel, B.Sc, CQE

VP Medical Device

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