Author: Yotam Portnoy

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

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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.

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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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Gsap seeks solutions to the challenges of the medical cannabis industry to place Israeli companies at the forefront of the world. A snapshot of the company’s growth and the great achievements of its customers

The new Medical Device Regulation (MDR) have been approved on May 2017 and the date for its implementation was May 2020, but recently its implementation was postponed due to the Corona pandemic and currently the target date is May 2021.

In this Newsletter, I will briefly highlight the changes in the new regulation related to clinical data collection.Beyond the many changes in aspects such as: new classifications, risk levels, Notified Bodies, certification processes and more, clinical evaluation requirements have been updated as well. The new regulation requires now a constant “live” connection between the risk management and the Clinical Evaluation and requires adjustment of the risk management processes and interphase with the clinical evaluation.                               

The sponsor is essentially required to assess each risk through clinical investigations, clinical evaluations, and of course through post-market clinical follow-up. Overall, referring to risk management, the MDR is in alignment with EN ISO 14971:2019 and EN ISO 13485:2016. While developing or amending the clinical plan, it should be taken into account that any change derived from the new regulation may also have implications on the clinical program. I.e. the question of medical device classification can have such implications and it is therefore advisable to characterize these implications before establishing the clinical program.

The transition from MDD (Medical Device Directive) to MDR has resulted in significant additional information in aspects of clinical data collection which is manifested in 20 new articles (articles 62-82). For Europe these are a fundamental changes and alignment with norms that are accepted worldwide in the medical device arena. The additional articles specify in fact requirements that have been relatively ambiguous so far, among other things, they specify requirements regarding:

●the responsibility of the sponsor;

●ethical considerations;

●subject consent process;

●reference to vulnerable populations;

●safety information reports;

●insurance etc.

In addition to these articles Annex XV, which extend the MDD Annex X, explains what information is required to appear in various core documents such as:

●Clinical investigation report,

●Investigator`s Brochure,

●Clinical Investigation plan and others.

In terms of definitions, the MDR defined “Clinical Evidence”, extend the equivalence requirements to be more stringent and increased oversight of PMS (Post Marketing Surveillance) data. Despite the considerable extensions, more detailed standards and requirements will be found in the ISO 14155 and of course in ICH GCP.

Article 61 provides a concrete requirement for the need to conduct clinical trials with reference to implants or Class III For the other classifications, the requirement for conducting clinical trials is derived from the level of clinical information collected by the sponsor throughout the life cycle of the product. It is the responsibility of the sponsor to characterize the Clinical Evidence required for the product according to its characteristics and intended use. Given that the clinical information is limited, additional data, based on clinical investigation conducted in accordance with the GCP Guidelines, ISO 14155: 2011 and the Declaration of Helsinki would be required to complete gaps.

Article 62 indicates potential purposes for the clinical trial, these operations should be performed under the product design, the “normal” conditions of its intended use, including manufacturing and packaging. The clinical operations may be carried out to characterize the performance, benefits of its use as well as its safety implications. The structure of the trial and its design will be derived from the concrete need. Those operations may be:

relatively small in scope and their purpose will be to continue learning and improving aspects of product performance (Pilot studies) or, alternatively,

more extensive operations designed to present device performance under the conditions and constraints required to its function in the intended environment (Pivotal Study). Pivotal studies will most often be performed when the product is mature and expected to function as required and present its intended performance in accordance with the Claims.

The responsibility for maintaining clinical knowledge about the product on its variety of models and versions is the sole responsibility of the sponsor. When existing clinical knowledge changes or loses its validity as a result of changes in the product, adaptation of the clinical data collection plan should be considered. That process should use existing knowledge to establish updated conclusions and characterize the gap, and clinical investigation may be executed in order to complete the gap. Usually, a solution will be found that combines these two approaches.

In conclusion, for any product intended to be marketed in Europe, a continuous clinical information collection process is required throughout the product life cycle. The aforementioned sources of information include: literature and scientific publications, clinical operations, and information gathering from marketed products. The nature of the information collected and its purpose will be defined and adjusted to the product requirements and to the risk’s assessments. This process importance is further elaborated under the new regulation and plays a critical role in the dynamic assessment of the benefits and risks of using the medical device.

In a nutshell, changes in clinical requirements under the MDR:

This Newsletter Prepared by:

Matti Hoggeg, M.Sc,

Clinical Section Manager

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The International Medical Device Regulators Forum (IMDRF) recognizes that a global approach to auditing and monitoring medical device developers and manufacturers could improve the devices’ safety and the regulators’ oversight on an international scale. Back in 2012, the IMDRF identified a work group to develop specific documents for advancing a Medical Device Single Audit Program (MDSAP).

The MDSAP Program allows an MDSAP recognized Auditing Organization to conduct a single regulatory audit of a medical device manufacturer that satisfies the relevant requirements of the regulatory authorities participating in the program.

Gsap has led MDSAP readiness activities with its Medical Device customers. We have a professional and knowledgeable team to support you in defining and aligning your business regulatory and quality strategy in accordance with the new approach of the MDSAP.

International partners that are participating in the MDSAP:

• Australia’s Therapeutic Goods Administration (TGA)
• Brazil’s Agência Nacional de Vigilância Sanitária (ANVISA)
• Health Canada – Santé Canada – MDSAP is mandatory from January 2019
• Japan’s Ministry of Health, Labour and Welfare (MHLW)
• USA – Food and Drug Administration (FDA)

MDSAP in General

• MDSAP covers regulatory aspects as well as:
o Registration
o Licensing
o Adverse event reporting
• MDSAP participating countries have direct access to the audit reports
• Audit is focused on requirements of ISO 13485:2016 and the regulatory requirements of the applicable jurisdictions (A manufacturer may exclude the requirements of a jurisdiction where the organization does not intend to supply medical devices)
• Audits conducted by approved Auditing Organizations (AO; Updated, official list is available at FDA site)

Preparation for the MDSAP

• Perform gap assessment for all procedures and processes
• Develop and implement risk assessment program
• Reach out to approved Auditing Organizations (AO)
• Fill AO’s questionnaire (to be used for additional assessment)
• Get a quote for services
• List products, registrations and licenses for applicable markets
• List types of products under the scope of the company
• Schedule an audit
• Be prepared for audits – # of days based on # of tasks to be audited

Gsap will be happy to support you in getting ready for the MDSAP requirements!

For more information visit Medical device Industry page

This Newsletter Prepared by:

Marina Lebel, B.Sc, CQE

VP Medical Device

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Who isn’t talking about the EU MDR and the new challenges ahead? At Gsap we want to do as well as talk. Gsap has led MDR readiness activities with its Medical Device customers.  We have a professional and knowledgeable team to support you in defining the business and regulatory strategy in light of the new landscape.

Medical Device Regulation (MDR) requires stringent standards of quality and safety for medical devices which will lead to a higher level of protection for patients and users. It seeks to increase premarket control (especially for high-risk devices), smooth communication between the different EU markets, increase surveillance at the post-market phase, and enhance traceability (UDI) and transparency (EUDAMED).

EU MDR for whom?

For beginners in the Medical Device industry, meeting MDR requirements is mandatory for those wishing to sell their products in Europe. Since one of the main changes is the inclusion of devices without a medical purpose (such as esthetic products), there are new players in the Medical Device Landscape.

EU MDR by when?

By May 26th, 2020. No grandfathering, all existing devices must comply with new requirements by this deadline or when the NB certificate runs out (not later than May 26th, 2024).

EU MDR by whom?

Currently there 2 notified bodies approved for MDR audits TUV SUD and BSI.   BSI’s future is questionable with the Brexit, making TUV SUD the only feasible player on the field. 

How can you get ready now for the EU MDR?

Determine the intended purpose of the device for Declaration of conformity including technical documentation by:

• Medical Device classification (CLASS I \ CLASS IIa \ CLASS IIb \ CLASS III)
• GSPS (General Safety and Performance Requirements replaces ‘essential requirements’).
• Traceability by UDI & EUDAMED registration
• PMS activities
• Biocompatibility changes

Main changes vs MDD

• Wider coverage of devices without a medical purpose
• New obligations for authorised representatives, distributors and importers
• New European database (EUDAMED)
• Unique Device Identification (UDI)
• PRRC – appointment of Person responsible for regulatory compliance
• Stricter requirements on:

1. Risk management as a continuous iterative process throughout entire lifecycle of a device
2. Pre-market controls of high-risk devices
3. Clinical evaluation and investigation
4. Use of hazardous substances

Gsap will be happy to help you get ready for the MDR storm!

This Article was Prepared by:

Marina Lebel, B.Sc, CQE

VP Medical Device

For more information about our services visit:

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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