Month: June 2021

Rare Disease Clinical Trials: Clinical Zoom In

Posted on by Anna Barad

Over 300 million people are living with at least one of identified rare diseases around the world. Rare diseases currently affect 3.5% – 5.9% of the worldwide population. 72% of rare diseases are genetic, 70% of those genetic rare diseases start in childhood.

The fact that there are often no existing effective cures offers development products regulatory priority, this benefit together with appropriate investigational planning can lead to fast drug approval.

This newsletter covers:

What is a Rare Disease?

●A disease that affects a small percentage of the population. About half of the people affected by rare diseases are children. Most rare diseases are serious or life-threatening. Patients with rare diseases may have no available therapies for the disease.

●An Orphan Drug is a drug for rare diseases. Orphan drugs follow the same regulatory development path as other pharmaceutical drugs. However, the drug can be tested on fewer patients to get approval.

The drugs for rare serious or life-threatening disorders with unmet medical needs may qualify for expedited approvals.

Regulatory priority addressed to unmet medical need

The regulations are intended to speed the availability of new therapies to patients with serious conditions, especially when there are no satisfactory alternative therapies while preserving appropriate standards for safety and effectiveness. The regulatory agency such as FDA recognizes that certain aspects of drug development that are feasible for common diseases may not be feasible for rare diseases and that development challenges are often greater with the increasing rarity of the disease.

●The agencies call for earlier attention to drugs that have promise in treating serious or life-threatening conditions.

●Encourages early consultation for sponsors to plan efficient trial design.

●Applies flexibility in situations to address particular challenges posed by each disease

How to Define the rare disease trial population

●Broad inclusion criteria can allow identification and better characterization of disease phenotypes for which therapy development may be more needed.

●The use of enrichment strategies such as demographic, pathophysiologic, historical, genetic or proteomic, clinical, and psychological characteristics can help to demonstrate treatment effectiveness.

●Choosing patients with a greater likelihood of having a disease-related endpoint event or a substantial worsening in condition.

●Choosing patients more likely to respond to the drug due to their physiology or disease characteristics and /or disease subtypes.

●Include pediatric patients with rare diseases in the study to develop data on the full range of people with the disease.

Challenges in Clinical Considerations

Sponsors developing drugs for rare diseases face many challenges. These may include the small number of disease-affected individuals, lack of understanding of the natural history of the disorder, lack of precedent for drug development (e.g., established clinical endpoints, validated biomarkers), phenotypic heterogeneity, and the need to conduct trials in pediatric populations.

●Consider the benefits and risks of the drug.

●Consider the seriousness of the disease and if there is an unmet medical need.

●Anticipated safety issues and trial stopping rules, halting rules, and patient early termination.

●Plans for an independent data monitoring committee (DMC).

●Inclusion of patient perspectives in the drug development plan.

●Plans to conduct extension studies to evaluate longer-term safety and durability of effect.

●Considerations related to novel endpoints including the development of clinical outcomes assessments e.g., patient-reported, observer reported, clinician-reported, performance outcome measures.

●Plans for pediatric studies must comply with appropriate regulatory and ethical requirements, including the additional safeguards for children.

Use of biomarkers

●Predictive biomarkers may be used for proof-of-concept.

●Drugs that are intended to be used in a biomarker-defined subtype of patients may require a companion diagnostic that shall co-development with the drug. Companion diagnostics are tests that provide information essential for the safe and effective use of a corresponding drug,

●Pharmacodynamic/response biomarkers allow guide dose-response for more precise dose-finding for therapeutic modalities. Biomarkers can be used to monitor specific parameters and adjust doses so that the biomarkers are kept within specific ranges. 

●A response biomarker can be used to show that a biological response has occurred in an individual who has been exposed to a medical product, therefore, provide supportive evidence of efficacy.

Natural history-controlled studies

A natural history study is a pre-planned observational retrospective or prospective study that follows a group of people over time who have or are at risk of developing, a specific medical condition or disease. A natural history study collects health information in order to understand how the medical condition or disease develops and how to treat it. A natural history study can be submitted as a baseline, in absence of a concurrent comparator, demonstrating the disease course for untreated patients along with data that charts the disease course of patients given the proposed therapy to show how the natural progression is changed or perhaps halted by the therapy.

Retrospective natural history studies most commonly use information in existing medical records can provide quick data.

Prospective natural history studies collect and analyze new data generated from identified patients at specified time points after the natural history study has been initiated provide systematically and comprehensively captured data.

Choose sufficient study duration to capture clinically meaningful outcomes in course of the disease.

Be specific when formulating your research objectives, select potential prognostic characteristics, and disease features that may help formulate a sensitive clinical endpoint

Collect data from clinical examination findings, laboratory measurements, imaging, reports of patient functioning and feeling include the standards of care and concomitant therapies.

Include patients across a wide spectrum of disease severity and phenotypes.

Use standardized collection methods and medical terminology to enhance the value and usefulness of natural history study data.

Efficacy Endpoints

●For many rare diseases, well-characterized efficacy endpoints appropriate for the disease are not available.

●Endpoints should be selected base on the range and course of clinical manifestations associated with the disease, the clinical characteristics of the specific target population and the aspects of the disease that are meaningful to the patient and that could be assessed to evaluate the drug’s effectiveness.

●Biomarkers can be used as a surrogate endpoint that is considered reasonably likely to predict clinical benefit when analytical and clinical validation of the biomarker test is confirmed by the regulatory agency before starting the clinical trial. Endpoints that are considered reasonably likely to predict clinical benefit, even if not well-established may be used as a basis for accelerated approval for treatment of serious or life-threatening diseases.

●Exploratory evidence from phase I and II trials helps to choose the dose and timing of endpoints evaluation in the advanced stages of the clinical development program.

●When the primary endpoint is clinically meaningful but susceptible to individual interpretation, the trial may benefit from having additional supportive secondary endpoints (e.g., laboratory measurements).

●The validity, sensitivity, reliability, or interpretability of an endpoint may be different for patients with mild or severe forms of the same disease.

Efficacy vs Effectiveness

The term efficacy refers to the findings in an adequate and well-controlled clinical trial or the intent of conducting such a trial and the term effectiveness refers to the regulatory determination that is made on the basis of clinical efficacy and other data.

Studies in healthy subjects may determine which factors influence a drug’s disposition or pharmacodynamic effects, dedicated clinical trials that inform dosing and usage instructions in the target population with a rare disease may be limited. The information from such studies and analyses can inform trial design and serve as supportive evidence of effectiveness. Data generated from such studies and analyses can efficiently optimize conditions for drug use e.g., dose, schedule, patient selection, etc.

In rare disease drug development, given the limited number of available patients, it is crucial to standardize the collection and handling of data to ensure quality and interpretability.

Increased measurement variability reduces statistical power.

Safety

A smaller number of patients may be acceptable when the intended treatment population is small.

Many rare diseases are genetic in origin and characterized by more than one phenotypic subtype. Prevalence estimates should include all phenotypic subtypes of a disorder anticipated to respond to the investigational drug.

Natural history studies can help distinguish drug-related adverse effects from underlying disease manifestations.

Many rare diseases severely affect children, and for diseases that affect both children and adults, sponsors should explore the early inclusion of pediatric patients in clinical studies.

Whenever ethically and practicably feasible, to facilitate interpretation of adverse event causality, especially with respect to the incidence and severity of adverse events that could be a manifestation of the disease under study.

A trial protocol with a safety cohort running parallel to the efficacy trial would include patients with the disease who investigators think might benefit from the investigational drug but who do not meet all the registration trial eligibility criteria. Such patients can be enrolled in the trial, avoiding the need for a separate trial and protocol. However, these patients are not randomized and are excluded from the efficacy analysis.

References

●Rare Diseases: Common Issues in Drug Development Guidance for Industry, January 2019

●Rare Diseases: Early Drug Development and the Role of Pre-IND Meetings Guidance for Industry, October 2018

●Enrichment Strategies to Improve Efficiency of Drug Development, May 2018

●Guidance for Industry Expedited Programs for Serious Conditions – Drugs and Biologics, May 2014

●Patient-Focused Drug Development: Collecting Comprehensive and Representative Input, June 2020

●Patient-Reported Outcome Measures: Use in Medical Product Development to Support Labeling Claims, December 2009

●Providing Clinical Evidence of Effectiveness for Human Drug and Biological Products, May 1998

●Patient-Reported Outcome Measures: Use in Medical Product Development to Support Labeling Claims, December 2019

I●n Vitro Companion Diagnostic Devices Guidance for Industry and Food and Drug Administration Staff, August 2011

●BEST (Biomarkers, Endpoints, and other Tools) Resource, FDA-NIH Biomarker Working Group, December 2016

This Newsletter Prepared by:

Inna Grau, M.Sc. Clinical Trial Manager

For more information about our CRO services visit:
CRO services

Novel Food Regulation in Israel – From Directive to Regulation

Posted on by Anna Barad

The food industry is constantly evolving and we are exposed to the need for new ingredients and products for food and drink. In order to sell food or food products containing components that are not approved for use according to the regulations in Israel, a “Novel Food” approval must be obtained from the National Food Service at the Ministry of Health.

This newsletter will cover the following topics:

What is Novel Food in Israel?

Novel Food is defined as food that had not been consumed to a significant degree by humans in Israel before 19 Feb 2006, when the first Regulation on novel food in Israel came into force. ‘Novel Food’ can be newly developed, innovative food, food produced using new technologies and production processes, as well as food which is or has been traditionally eaten outside of Israel. 

In order to be categorized as “Novel Food”, the food should belong to one of the following groups:

  • Has a new primary structure at the molecular level (e.g. new sugar), which has undergone a deliberate change in the primary structure at the molecular level (e.g. genetically modified food) or originates from a genetically modified organism (GMO).
  • Contains or is isolated from plants, animals, microorganisms, fungi or algae (except for enzymes that have a long history of safe consumption in Israel) and does not appear in the lists of edible plants, fungi and algae.
  • Has a new production process that results in a change in its nutritional value, metabolism or the level of unwanted substances in food (excluding cleaning and disinfection processes).

Examples of Novel Food that was approved to use in Israel include Docosahexaenoic acid (DHA) and Eicosapentaenoic acid (EPA)- rich oil extracted from Schizochytrium sp. microalga, agricultural products from third countries (chia seeds), food derived from new production processes (UV-treated milk) and 2′-O-Fucosyllactose produced by genetically engineered Escherichia coli bacteria.

Cultured meat is an in-vitro culture of animal cells through tissue engineering. These cultured animal cells are grown in a controlled laboratory environment to mimic specific cuts or parts of meat that would be traditionally sold in the market. In the EU, cultured meat would be regulated by the Novel Food Regulation (EU Regulation No 2015/2283) because “food consisting of, isolated from, or produced from a cell culture or tissue culture from animals, plants, micro-organisms, fungi or algae is considered one of the novel food categories listed in the regulation.” Due to growing trade with the European Union (EU), the Israeli food legislation and standardization system are increasingly harmonized to European standards. Similar to Europe, in Israel, cultured meat will fall under the Novel Food category and will be evaluated under the Novel Food premarket authorization process. To date, the application for cultured meat approval by the National Food Service has not been submitted yet in Israel.

Novel Food Regulation

  • Relevant Agency:

The National Food Service at the Ministry of Health is responsible for assuring the safety, quality, and authenticity of food for consumers. This is the regulatory agency responsible for the development of food standards and regulations dealing with foods sold in Israel. The agency is also in charge of imported food licensing.

  • Regulations
  • Novel Food Directive 2006 (004-08)

As detailed in the 004-08 directive for Novel Food implemented since the beginning of 2006 and published on the National Food Service website, any food that can be categorized as Novel (including genetically modified food)  undergoes a thorough evaluation process by the National Food Service prior to its market authorization including aspects related to its safety, nutrition, and consumption of the food in Israel. The underlying principles underpinning Novel Food in Israel are that Novel Foods must be:

  • Safe for consumers
  • Properly labeled, so as not to mislead consumers
  • If novel food is intended to replace another food, it must not differ in a way that the consumption of the Novel Food would be nutritionally disadvantageous for the consumer.

Food that was authorized as Novel food will be listed in the Novel food/food components approved list published on the National Food Service website.

Safety Evaluation of Novel Food

Novel food or components of Novel food (including genetically modified microorganisms) must undergo rigorous safety assessments by a team of experts. It must meet all requirements and tests and be safe to use and consume (case-by-case) prior to its marketing.
Safety evaluation of genetically engineered food is related mainly to possible risk factors affecting human health consuming the food such as:

  1. An increase in the level of the food’s natural toxins. There are foods that naturally contain a certain amount of toxic substances whose amount naturally does not cause a risk from consuming them. For example, vegetables from the Solanaceae family, such as tomatoes, eggplant, potatoes, etc. In this kind of foods, an evaluation is performed assessing whether following the genetic change, there is an increase in the level of natural toxins.
  2. The presence of new proteins in foods that may be allergens (substances that cause an allergic reaction in people who are sensitive to these substances). In food that has undergone genetic modification, an evaluation is performed assessing whether the modification changed the existing natural proteins to become allergens or whether new proteins that were added cause allergies in humans.
  3. The presence of substances in genetically modified food that were not present in previous foods and may affect metabolic processes in the body. In performing a genetically modified food safety assessment, an evaluation is performed assessing whether new substances have been added to the food that were not there before, such as hormones and histamines, which may affect physiological processes in the human body.

An engineered food whose genetic alteration causes an unwanted effect, such as increased toxicity or allergens, is not approved.

To date, the engineered food products that have been independently tested and approved by various food authorities around the world have not been found to have health concerns.

Novel Food Pre-Marketing  Authorization Process:

The Public Health (Food) Protection Law – 2015 which came into force in 2016, enshrines the authority of the Ministry of Health to establish safety provisions and regulations regarding the import, sale, and production of Genetically Modified Food (GMO). The main innovation is that the law not only anchors the regulatory authority of novel food safety but also gives the Minister of Health the authority to prescribe provisions regarding its labeling.

In addition to the Public Health Protection Law, there are a number of specific food regulations such as Public Health Regulations (Food) (Gluten Marking), Public Health Regulations (Food) (Marking a Breast Milk Substitute), Public Health Regulations (Food) (Food Additives), Public Health Regulations (Food) (Pesticide Residues), and the Public Health Regulations (Food) (Nutritional Labeling).

  • The protection of public health (food) (nutritional labeling) regulations, 5778 – 2017

On December 25, 2017, the Israeli parliament’s Labor, Welfare and Health Committee approved new regulations for the Protection of Public Health (Food- Nutritional Labeling) which entered into force on January 1, 2020. Currently, Israel has no governmental policy on the labeling of Genetically engineered food products (see below).

Genetic Engineered Food

Marketing and labeling of genetically modified food products have caused public turmoil around the world.

The legislative situation in the world and in Israel:

  • United States:
    There are regulations of various regulatory bodies that deal with food control, such as regulations of the Food and Drug Administration (FDA). At the US there is a requirement to perform a safety assessment for genetically modified food, but there is no special labeling requirement for these products.
  • Europe:
    In April 2004, Europe entered into force a Regulation (EC 1829/2003) regulating the EU (European Union) guidelines on the safety and labeling of genetically modified food as well as guidelines for approving the release to the environment of genetically modified organisms (GMOs). As part of the installation, there is an obligation to label genetically modified food components or that originate from a genetically modified organism.  
  • Israel:
    In Israel Genetically engineered food is addressed by two committees: The Ministry of Health’s New Food Committee, which discusses food safety, and the Ministry of Agriculture’s Main Committee which discusses Transgenic Plants. Israel is a world leader in agricultural technologies with advanced research on the subject of genetic engineering in plants. Today there is no cultivation of genetically engineered plants for commercial purposes in Israel and therefore there is no local agricultural product that has been genetically engineered. The food industry in Israel does use genetically modified raw materials imported from the USA and other countries, mainly corn, soybeans, and canola oil.

A regulation that legally sets the guidelines regarding Novel Food including genetically modified food and its labeling is in the final stages of legislation. Each novel food before its approval undergoes a risk assessment that includes aspects related to the safety, nutrition, and consumption of the food according to a new food registration procedure that has been implemented since the beginning of 2006 and published on the Food Service website. With the entry into force of new food regulations, the obligation to label genetically modified food components will apply, in addition to a safety examination as has been done to date.

Labeling of Engineered Food

The topic of labeling has become an important topic in discussions about engineered foods all over the world. Government ministries, consumer organizations, and food marketing entities in Israel and around the world believe in the consumer’s right to know whether they have used genetic engineering technology in food production or components from it and therefore require the labeling of these products. In Europe, there is extensive activity on the subject and there are clear requirements for labeling genetically modified food, which are regulated by relevant regulations. In contrast, currently in the U.S. and Canada, it is believed that labeling is not necessary because these foods undergo safety assessment prior to marketing, by a team of experts advising government officials responsible for food control, and only products that are safe to use are authorized for marketing. 

In Israel, the Food Service adopts the approach that believes the public has “a right to know” and works to regulate the issue of food labeling that has been legally genetically modified. Once installations will pass, it would create a mandatory labeling requirement for food items that contain genetically engineered ingredients.

Health Vs. functional claims labeling on Novel Food products

In the USA a health claim (i.e a statement about a relationship between food and health) labeled on food products (including Novel Food) is not allowed unless it was approved by the FDA. The functional claim of the food is allowed to be added to the label. The functional claim must be correct but is not approved by the FDA (a disclaimer stating that the claim was not reviewed and approved by the FDA must be shown on the label).

In Europe, there is no differentiation between functional and health claims. Each claim labeled on the food must be correct, established with scientific proof demonstrating the direct relationship between the claim and the food function, and approved by EFSA (European Food Safety Authority).

In Israel, no claim for food is currently allowed (except for phytosterols). Once the Novel Food installations will pass, functional claim labeling for food will be allowed- for Novel Food only.

This Newsletter Prepared by:

Tsufit Gross, Ph.D.

Pharma and Biotechnology Regulation Project Manager

For more information about our Novel Food services visit:
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