Month: April 2020

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): [email protected]

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.

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As time passes, keeping track of all the changes in the Global Medical Cannabis market is becoming more and more challenging.
The current newsletter will provide clarity where possible, regarding the design and implementation of Clinical Trials.
Valid Clinical Trials are necessary for the expansion of labeling in the US.
In Europe in general, and in Germany in particular, labeling requirements are less precise and the authorities allow for physicians’ discretion in prescribing Cannabis.

Currently, Israel is known worldwide as a pioneer in Medical Cannabis research and Clinical trials. More than 50 Israeli startups are developing Medical Cannabis products. Most Israeli start-ups are gradually maturing and progressing to clinical trials, mainly for PK, Phase 1, and Phase 2. Since 2011, over 45 clinical trials have been conducted in the field of Cannabis worldwide, with most of these studies being preliminary studies, about 5 phase 3 studies (including GW Pharmaceuticals and Takeda studies), and about 10 phases 2 studies.

The main research question investigated usually is the efficacy of the research product, but most studies also explore safety aspects where the most popular indications are central nervous system disease, Inflammation, and cancer. The quality of the results and the scientific value of these studies are “varied”; therefore, practitioners should develop the ability to monitor the quality of execution and planning of clinical trials. As a result of what we have learned and observed, we believe that proper planning and execution of a Clinical Trial is critical to achieving regulatory approval in a timely manner.
We wish everyone a fruitful and prosperous year, and of course, may it be the year of Cannabis.

Designing medical Cannabis clinical trials

Clinical studies are a significant and necessary portion of the process of developing and approving medical products. Cannabis-based medical products also require clinical trials and the submission of detailed clinical study reports of the clinical trials in order to be included in the Registration file that will be submitted to the authorities. This review will address two key aspects:
• Basic principles in clinical trials design
• Guiding considerations in the design of medical Cannabis clinical trials

Clinical trials should be designed and conducted according to three general principles:

1. Protection of Clinical Study Subject
This principle provides guidance for planning and execution in a way that ensures the patient’s well-being and rights while emphasizing special populations in a way that requires compliance with the ICH E6 Good Clinical Practice requirements and ISO 14155 when the clinical investigation involves medical devices.

2. Scientific Approach in Clinical Study Design Conduct and Analysis
This principle requires a scientific approach in designing the research objectives, executing, collecting the results, and analyzing them, to ensure obtaining reliable data and the required answers for the intended questions.

3. Patient Input into Study Design
Aimed at integrating, receiving feedback, and involvement of patients and patient organizations in the design and implementation of the study. This is done in order to plan and conduct a feasibility study that addresses the real needs of patients.
The characteristics of clinical research in Cannabis, as well as preclinical steps in product development, are derived from the regulatory submission path and therefore great importance should be given to determining the correct regulatory strategy for each product and at the
earliest stage. Although clinical trials are sometimes not mandatory, clinical trials are almost always performed.
These clinical trials will be performed for the purpose of accumulating safety and efficacy information, for marketing needs, financial needs, and or needs to confirm assumptions about the efficacy of the product under different indications, different administration routes, combined with other treatments, etc. This review focuses on the design and conduct of the clinical trials in accordance with the regulatory requirements of a nonherbal pharmaceutical product, these requirements are the most rigorous and demanding and ensure as much as possible the reliability of the scientific insights that can be derived from the research.

Cannabis research requires special attention to these requirements because prior information on cannabinoids / Cannabis use in medical products is limited. This is due to, among other things, a lack of reliable scientific and clinical information in the field of Cannabis research and is the result of conducting studies that are lacking in their design and without the use of common methods to reduce BIAS.
Once the indication has been thoroughly studied and the relevant literature reviewed, the research rationale and assumptions sought by the research can be formulated. In each case, the research and its objectives will be planned with reference to, and in connection with, the broader clinical program and the stages of the project or product.

The research design should focus on the guidelines outlined below at both the planning and execution levels:

1. Study Population
The characteristics of the study target population are derived first from the target product population, the study as a whole will characterize the effect of the investigated product on a particular population and the conclusions, in principle, will be relevant to that population. Later on, the criteria for inclusion and exclusion will also include considerations related to safety, ethics, DDI (Drug-Drug Interaction), background and medical history, etc.

Cannabis studies should also take into account, the extent to which patients have been exposed to Cannabis use in the past, the psychoactive consequences of THC, and the patients’ ability to consume the product as required. In general, the characteristic of the study population can be said to be a delicate balance between reducing the variability between patients in order to increase the chances of demonstrating the therapeutic effect on the one hand, and the implications of these decisions on the ability to recruit patients for research and approve treatment based on research in a population characterized by limited variability on the other hand.

2. Intervention
The dosage, treatment duration, route of administration, and a number of treatments have a major impact on “Product Success / Research”.
Dosage, treatment regimen, and administration have a direct effect on product usability, the absorption of active ingredients, their effectiveness, as well on their safety, and economics. Cannabis studies show a wide variety of forms of administration, ranging from topical ointment form through to nasal and oral vaporizers, sub-lingual, and even rectal administration. Each of the forms of administration has pros and cons. For example, using a vaporizer significantly reduces smoking damage and allows for an “ Entourage Effect” and has close proximity to the traditional Cannabis consumption, but requires patients to be supplied with a vaporizer which significantly increases the operative and regulatory requirements both during and after the study. Oral administration is relatively simple to use and operate but is characterized by a slower and less effective absorption of the active ingredients. Apart from these, the “intervention” consideration also corresponds to the indication itself and the target patient population, which dictates restrictions on how the patient consumes the product being tested.

3. Control Group
The requirement for controlled research is a “gold standard” in clinical studies design and usually, research cannot be carried out with good reliability without a control arm. The need for a control arm/ group results from a phenomenon that has been documented since the 1930s and is called the “Hawthorne effect.” In general, this effect shows that solely just the participation of the subject in the clinical trial results in a change not related to the medication. The purpose of the control group and its value derived from the fact that it allows us to analyze the effects of the treatment only regardless of the effect of other external factors not related to the medication/treatment.
There are different types of controls, for example; a Comparison of the research drug or treatment with another drug or other conventional treatment as well as a placebo. This aspect is particularly challenging in Cannabis trials as it is difficult to create a “placebo” in Cannabis products especially when the tested product is consumed via inhalation and/or contains a THC component that gives a unique feeling and allows for easy differentiation of treatment arms by the patient. Due to this reason, cross-over and double-dummy studies for example are more relevant in the cannabis territory.

4. Response Variables
Endpoints are derived directly from the study objectives and are used to assess and characterize the treatment effects. The endpoints selection has a critical impact on the success of the study and is the result of a complex set of considerations. The endpoints are first and foremost intersected with the indication, regulatory requirements, and statistical considerations, but also take into account broader elements of the clinical development program such as follow-up and future planned studies, patient needs and limitations, competitors and competition, etc. Early studies will usually use measures related to safety and tolerability as a Primary endpoint, while efficacy questions can be also expressed in Secondary endpoints. In the more advanced stages of product development, the priority is changed and the main objective will focus on the question of effectiveness while safety information collection continues throughout the life cycle of the product in order to produce safety knowledge at different levels of product exposure.

5. Reduce or Assess Bias
Bias is an accumulation of factors that can compromise the reliability of clinical trial results.
The bias is derived from the unique research structure and needs to be addressed to reduce it as much as possible. The two most powerful tools for reducing bias are “RANDOMIZATION” and “BLIND”.

Randomization means randomly assigning patients to the treatment arms. This randomization is expressed as an equal probability for each patient to be included in each arm, thus avoiding the conscious and unconscious bias of patient allocation and balancing the baseline characteristics of the treatment groups (The larger the group in the trial, the value of the randomness set increases).

BLIND or MASKING, however, requires that the patient or the research team (SINGLE BLIND \ DOUBLE) do not know to which treatment arm the patient is assigned. Creating a proper blind study creates operative challenges that need to be addressed in order to avoid psychosomatic effects and biases.

Apart from this, every procedure in the study that can influence the results of the study should be considered to ensure that its application is not affected by bias.

6. Statistical Analysis
When the structure of the trial and the selected endpoints are determined, a suitable statistical model should be formulated to analyze the results of the study and a preliminary plan for the analysis of the results should be formulated. It is difficult to overstate the importance of bio-statistician involvement in model selection, sample size, decision making during the study, and of course in analyzing the results and presenting them. As mentioned before, these aspects have great importance in the planning phase and any changes may affect other aspects. Apart from this, during the Study Execution, the Sponsor is expected to ensure that the study conduct is done according to the approved plan and in compliance with the study protocol. In Cannabis trials this challenge is particularly tangible as these are studies with relatively high operative and regulatory complexity. In cases where the design and conduct are properly performed, authentic results are guaranteed which reflect product performance
appropriately.

This Newsletter Prepared by:

Sigalit Ariely-Portnoy, Ph.D

CEO

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