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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:

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

For more information about our services visit:

Learn how to implement EU GMP standards in medical cannabis. The EU GMP presents the requirements for facility, equipment, documentation, and process control for the production of herbal products.

For more information about our services visit:

The FDA takes steps to promote faster access to new medical technologies that are safe and effective: Streamlining premarket procedures, modernizing the 510(k) program, expediting programs for devices that enhance safety and/or resolve critical unanswered medical needs. The recently issued guides include new pathways, expansion of existing programs, and supporting tools such as checklists and assessment worksheets.

Topics in this Newsletter

510(k) Programs

1. Special 510(k) (UPDATED)

2. Abbreviated 510(k) (EDITED CONTENT)

3. Safety & Performance Based Pathway (NEW)

Additional Premarket Programs

4. Humanitarian Device Exempt (HDE) Program (UPDATED)

5. Safer Technology Program (STeP) (NEW)

More FDA Actions

6. Electronic submissions;

7. Benefit-risk determinations;

8. Acceptance review policy (RTA);

9. Accreditation of testing labs (ASCA)

Adapting the repeatedly criticized 510(k) program to advances in safety and technology; providing clearer requirements and more timely review & response, and lowering workload for FDA and costs for the industry.

Let’s take a short tour of some of the ideas and changes that these documents bring about.

What’s new with the 510(k) program?

The 510(k) program accounts for the vast majority of devices that enter the market each year. It is based on the concept of “substantial equivalence”. The FDA now issues final guidance documents for the Special 510(k) Program, the Abbreviated 510(k) Program, and the Safety and Performance Based Pathway, as well as a Format for Traditional and Abbreviated 510(k)s.

1. The special 510(k) program

This program is intended specifically for changes of own existing device, and only if the methods to evaluate changes are considered well established. FDA reviews special 510(k) applications within 30 days of submission. This final guidance expands the scope of the program.

The significant changes in the program:

• Now, under certain circumstances, changes to the intended use may be made.

• Now, under certain circumstances, changes that alter the fundamental scientific technology may be made.

• If performance data is necessary, it is required that methods are well established and that all data supporting substantial equivalence can be reviewed in a summary or risk analysis format.

NOTE: This pathway therefore may NOT be appropriate,

for example, when a novel sterilization method is used; or methods rely on animal/clinical data; or the changes are complex – with many scientific disciplines involved, change from single-use to re-usable, etc. – so that determining the substantial equivalence depends on the FDA’s interpretation of the underlying data.

2. The abbreviated 510(k) program

An alternative approach to the traditional 510(k): Instead of performing a “head-to-head” comparison with a predicate device in order to demonstrate the substantial equivalence, you declare conformity to voluntary consensus standards / special controls / FDA guidance.

This program is NOT new, but merely received a guidance document separate from the special 510(k) program. It includes a short outline of the content required.

NOTE: This pathway is not necessarily “abbreviated” or shorter.

Also, the review time is 90 days, as for the traditional 510(k). However, under some circumstances, when it is difficult to collect data regarding a predicate, it might be more efficient to submit summary reports describing how to reference standards were used or how the device complies with the special controls. Addressing the FDA early to find out which pathway is appropriate, would be a good idea.

3. Safety and Performance Based Pathway

An optional submission pathway, an extension of the abbreviated program. It is intended for well-understood devices, listed by device type, for which the manufacturer would have to meet objective criteria set by the FDA: criteria that would be consistent with safety and performance characteristics of modern predicates. Along with the guide describing the general pathway, five additional draft guidance documents were issued, describing the required performance criteria for specific devices:

Foley catheters

Recording cutaneous electrodes 03Ø06

Orthopedic spinal plating systems

Non-spinal screws & washers

Magnetic resonance (MR) coils

The basics you should know about this pathway:

• It’s not actually different from the abbreviated 510(k).

• The requirements may be more specific, thus clearer to the

manufacturer (that’s a bonus).

• May be suitable when attaining information regarding an

the actual predicate is impossible/impractical.

Additional programs and pathways at focus :

4. The Humanitarian Device Exemption (HDE) Program

HDE program receives updated final guidance, accompanied by the newly revised guidance for Humanitarian Use Device (HUD) Designations. Both follow changes resulting from the “Cures Act”.

The purpose of this program is to encourage the development of devices for the diagnosis and treatment of rare medical conditions.

The main updates:

• Expansion of the HUD designation: The designation is given when the relevant population is up to 8000 individuals per year in the USA, instead of the previous threshold of less than 4000.

• A device may still receive HUD designation in the pediatric population even when the total condition population exceeds 8000 patients if the pediatric population affected does not exceed 8000 patients.

• For diagnostic devices, the threshold applies to not more than 8000 who would be subjected to the diagnosis with the device, including positive and negative results.

• As was before, in order to make use of an approved HUD in patients, oversight of an Institutional Review Board (IRB) in the medical facility is required, and review and approval for the specific individual use are also required. This was previously also required to be performed by the IRB. Now more flexibility is introduced, as an appropriate local committee (ALC), that may be a standing committee with the appropriate expertise, is allowed to review and approve the specific HDE use, and not only the IRB, which may be considered less accessible. IRB facility overview is still required.

• A filing checklist, and tools for the probable benefit-risk assessment are included in the appendices.

5. Safer Technology Program for Medical Devices (STeP)

More action in promoting patient safety:

The draft guidance for this new voluntary program is issued

– complementary to the “Breakthrough Device Program” (BDP), for medical devices that are expected to significantly improve the safety of currently available treatments.

Devices and device-led combination products, that are subject to review under 510(k), De Novo, or Premarket Approval (PMA) submissions, and that are not eligible for the BDP, may enjoy the expedited STeP approach:

• First apply through a Q-submission (pre-sub) to be included in the program;

• Once accepted, go through a prioritized and expedited review of regulatory submissions, with senior FDA management engagement, and assistance with the plan of device and data development.

To apply, the sponsor should explain the innovative approach and how the benefit-risk profile would be improved:

• Does the device reduce the occurrence of a known serious adverse event/device failure mode / user-related hazard or error?

• Does the device improve the safety of another device or intervention?

NOTE: The Breakthrough program which is intended for life-threatening

/ irreversibly debilitating conditions, is mandated by law and would still be prioritized over STeP. This is expressed in the draft with the repeating phrase: “as resources permit”.

Thus, only time will tell if STeP achieves its purpose to open an actual additional expedited pathway.

More FDA actions to streamline, simplify, expedite, clarify…

6. The FDA goes paperless – electronic submissions are on the way

Following the requirements of the FD&C Act, draft guidance regarding electronic submissions was issued. But don’t get rid of your printers just yet – it will take a little while.

The guidance tells us that:

• Application types that would be required to be submitted solely in an electronic format, include 510(k), PMA, De

Novo, Investigational Device Exemption (IDE), HDE, and more.

• Individual, per-type guidance documents will be developed, specifying required formats and implementation timetable.

• IDE compassionate use requests and adverse event reports will be exempt from this requirement.

ATTENTION: In contrast to most guidance documents, which contain nonbinding provisions, this guidance and the following

individual ones – once finalized, will contain both nonbinding AND binding provisions under the statutory authorization of Congress: I.e., sponsors will be required by law to comply with the specified formats & schedules.

7. Clarifying benefit-risk considerations for higher-risk submissions

Two final guides were issued (1, 2), both actually discuss the same subject: determining uncertainty and benefit-risk in PMA, HDE, De Novo, and BDP submissions.

Some key concepts:

• Greater uncertainty may be accepted when there’s a true clinical need: serious/unanswered/small patient population / high anticipated benefit for quick patient access.

• Higher uncertainty  greater need for premarket data; Lower uncertainty data shift to post-market may be allowed.

• Post-market data is always required. It is critical to show that it can be collected in a timely manner, especially as risk/ uncertainty increases.

• A new worksheet is provided as an appendix; Recommended as a basis for the benefit-risk assessment process.

• FDA wants patient perspectives – are the patients really willing to accept the risk and the uncertainty?

8. Saving time for FDA reviewers and for sponsors

– acceptance review policy

Final updated “Refuse to Accept” (RTA) guidance was issued for 510(k) and for De Novo submissions. These outline the preliminary procedure the FDA performs to assure administrative completeness of submissions (including timetable), which takes place before the substantive review that assesses the quality of the information.

Some highlights:

• A checklist of required criteria is provided for each submission type (in the appendices).

• FDA will, within 15 days of submission, electronically notify the submitter if: (a) submission was accepted and under substantive review;

(b) the submission was refused PLUS indication of the missing checklist items, or;

(c) FDA did not complete acceptance review on time, thus transferred

submission to substantive review.

• This notification identifies the lead FDA reviewer assigned for the submission.

• The De Novo guidance includes a recommended content checklist as well, relevant also for the substantive review.

• RECOMMENDED: Follow the checklist, complete it, and include it as part of the application. Do NOT leave sections out (if not applicable – a state so & justify). Letters from subject matter experts are helpful.

9. Accelerating review processes by accrediting testing labs to FDA-recognized standards

Draft guidance for The Accreditation Scheme for Conformity Assessment (ASCA) Pilot Program was issued.

OBJECTIVE: Streamline reviews – once a manufacturer presents results from an accredited body, FDA can accept them without a thorough review. The pilot begins with standards for biological evaluation and for electric safety.

Gsap experts will be happy to assist you in choosing the regulatory track!

suits your product and company, and to support you in the submission process.

This Newsletter Prepared by:

Orly Chillag – Talmor, Ph.D.

Quality & Regulatory Project Coordinator

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