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Questions and Answers
What is the meaning of FPPs?
What is the meaning of FPPs?
The essential feature of a batch is its homogeneity.
The essential feature of a batch is its homogeneity.
True
What is the term used for a medicinal product intended for research and development purposes?
What is the term used for a medicinal product intended for research and development purposes?
Magistral Preparations
How are veterinary drugs regulated?
How are veterinary drugs regulated?
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Preclinical studies can provide a clear indication of how a drug will behave in humans.
Preclinical studies can provide a clear indication of how a drug will behave in humans.
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What is the primary reason for the marketing authorization process?
What is the primary reason for the marketing authorization process?
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The Summary of Product Characteristics (SmPC) is a document included in the marketing authorization dossier.
The Summary of Product Characteristics (SmPC) is a document included in the marketing authorization dossier.
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Which types of medicines are typically subjected to a centralized procedure for marketing authorization?
Which types of medicines are typically subjected to a centralized procedure for marketing authorization?
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The requirements for approval of a generic medicine are the same as those for an originator medicine.
The requirements for approval of a generic medicine are the same as those for an originator medicine.
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What is the purpose of a biosimilar medicine?
What is the purpose of a biosimilar medicine?
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The marketing authorization of biosimilar medicines typically takes place at a national level.
The marketing authorization of biosimilar medicines typically takes place at a national level.
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What is the main body responsible for evaluating herbal medicines in the European Union?
What is the main body responsible for evaluating herbal medicines in the European Union?
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What are the two main categories of EU monographs for herbal medicines?
What are the two main categories of EU monographs for herbal medicines?
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Homeopathic medicines are typically regarded as equivalent to other medicines for treating conditions.
Homeopathic medicines are typically regarded as equivalent to other medicines for treating conditions.
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What type of evidence is usually required for the simplified registration of homeopathic medicines?
What type of evidence is usually required for the simplified registration of homeopathic medicines?
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What is the main factor that determines the duration of the registration application process?
What is the main factor that determines the duration of the registration application process?
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Once a marketing authorization is granted, it is valid indefinitely.
Once a marketing authorization is granted, it is valid indefinitely.
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What is a sunset clause in the context of marketing authorization?
What is a sunset clause in the context of marketing authorization?
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What does 'off-label use' of a registered medicine signify?
What does 'off-label use' of a registered medicine signify?
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Off-label use is a common practice, particularly in pediatrics.
Off-label use is a common practice, particularly in pediatrics.
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What is the main responsibility of a doctor using a registered medicine off-label?
What is the main responsibility of a doctor using a registered medicine off-label?
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What is the purpose of the 'named-patient basis' program?
What is the purpose of the 'named-patient basis' program?
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Compassionate use programs are governed solely by the European Medicines Agency (EMA).
Compassionate use programs are governed solely by the European Medicines Agency (EMA).
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What is the main criterion for allowing the use of a medicine in a compassionate use program?
What is the main criterion for allowing the use of a medicine in a compassionate use program?
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Clinical trials in humans typically involve smaller groups of patients compared to commercial trials.
Clinical trials in humans typically involve smaller groups of patients compared to commercial trials.
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Which of the following best describes the role of pharmacovigilance after a medicine is marketed?
Which of the following best describes the role of pharmacovigilance after a medicine is marketed?
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The marketing authorization process for a medicine is typically completed when the medicine is approved for sale in the market.
The marketing authorization process for a medicine is typically completed when the medicine is approved for sale in the market.
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What are some reasons why a manufacturer might decide to stop supplying a medicine to a particular country?
What are some reasons why a manufacturer might decide to stop supplying a medicine to a particular country?
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The marketing authorization of a medicinal product is governed by a single uniform set of rules across all EU countries.
The marketing authorization of a medicinal product is governed by a single uniform set of rules across all EU countries.
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Study Notes
Marketing Authorization of Medicines, Unregistered Drugs
- Marketing authorization is a process for placing medicines on the market.
- The process aims to minimize foreseeable risks associated with placing medicines on the market.
- Finished Pharmaceutical Products (FPPs) are produced in batches, and have the essential quality of homogeneity.
- FPPs can be over-the-counter (OTC) or prescription only.
- Magistral (Magistral Compounding/ Magistral Preparations) are customized medications for individual patients.
- Medicinal products (MPs) are classified by use (human or veterinary) and manufacturing process (FPP, Magistral Preparation/Compounding).
- Human drugs undergo clinical trials and regulatory approval by agencies like the EMA or FDA.
- Veterinary drugs are similarly regulated, but with separate pathways.
- Products not classified as MPs are often considered food supplements, cosmetics, or health products.
- The development of a new drug typically involves stages: chemistry, preclinical studies, industrial process, phase I, II, III and IV, NDA, registration, market introduction.
- Drug approval is a complex, multi-year process requiring thorough testing and regulatory review.
- Preclinical trials have limited value when transferred to humans.
- Clinical trials involve a relatively small number of volunteers and specific conditions
- Drug safety is evaluated during and after marketing authorisation. This involves ongoing review/updates to the benefit-risk ratio. This includes factors like pharmacoepidemiological research and pharmacovigilance.
- The State Institute for Drug Control (SUKL) of the Czech Republic and the EMA (European Medicines Agency) are responsible regulatory bodies for medicine marketing authorisation.
- The FDA (Food and Drug Administration) in the United States also plays a role in regulating the use of medicines.
Outline of the Lecture
- Topics included medicinal products, new drug development, legislation/registration, European legislation, and non-standard regimens for using medicines.
Aims of the Lecture
- To identify the classification of medicinal products and which ones are subject to marketing authorisation
- Understand different marketing authorization processes.
- Describe the process of registering medicines.
- Define differences in registering medicinal products, generics, biosimilars, homeopathics and herbal products,
- To explain what the SmPC is.
- Identify non-standard drug regimens for use.
Medicinal Product (MP)
- A substance or combination of substances with therapeutic or preventive properties.
- Used to restore, modify, or influence physiological functions.
- Used for establishing a medical diagnosis.
- Can be divided by intended use and manufacturing method.
MP - Distribution by Production/Preparation
- FPPs (Finished Pharmaceutical Products) are manufactured by the pharmaceutical industry.
- A batch is a quantity of medicinal products produced in one cycle.
- Batch must have homogeneity, and can be OTC or prescription-only.
- Magistral preparations/compounding are individualized medications prepared for specific needs.
MP - Distribution by Users
- Human drugs undergo rigorous clinical trials and regulatory approval.
- Veterinary drug regulation is handled by agencies like CVM (Center for Veterinary Medicine) or EMA, but with separate pathways.
- Products not deemed to be medicinal products might fall under food supplements, cosmetics, or health products.
Development of a new drug over time
- Details of the steps for evaluating a new drug are clearly outlined. This illustrates the stages in the preclinical and clinical testing of a medication. It is critical to understand the various stages/steps required for developing a new medicine.
Drug Safety Evaluation
- Evaluating the benefit vs. risk ratio of new pharmacotherapy.
- Continues to refine the therapeutic and benefit-risk ratio after marketing.
Introduction to Marketing Authorization of Medicines
- Medicines undergo approval before being placed on the market.
- The main aim of the approval process is risk minimization.
- The regulatory body (SÚKL/EMA) ensures the efficacy, safety, and high-quality of supplied medicines.
Introduction to Marketing Authorization of Medicines
- The full registration dossier includes the necessary data to demonstrate the safety, efficacy and quality of the medicinal product.
- A summary of product characteristics (SmPC) is a critical source of information.
What is and is not subject to Marketing Authorization?
- Manufactured medicines are subject
- Magistral preparations, research/development MPs, blood products, and dietary supplements are not subject.
Regulatory Authority of Marketing Authorization
- The Czech Republic has its own regulatory bodies.
- The EU and US have their respective bodies (EMA, FDA).
Marketing Authorization (MA) Procedures
- Different types of MP authorization procedures are possible.
- These include national, mutual recognition (MRP), centralized, and decentralized.
National Procedure
- Valid only within one country, for products already authorized or awaiting approval in the EU.
Mutual Recognition Procedure (MRP)
- A medicinal product authorized in one EU member state will also be recognized in other states.
Decentralized Procedure (DCP)
- Authorization for multiple EU countries at once on a specific medicinal product.
Rules for the Approval/Marketing Authorization of MP
- Uniform rules in Europe for quality, safety, and efficiency evaluations.
- Requirements and scopes for submitting approval data are detailed in each nation's regulations.
- Necessary documentation from manufacturing to chemical analysis must be comprehensive.
Who Grants EU-Wide Marketing Authorization?
- The EMA gives recommendations to the European Commission which in turn decides on official authorization for an EU-wide release.
- While the EMA/European Commission authorizes many new and innovative medicines, numerous generic or "off-the-shelf" medications are approved at a national level.
Common Technical Document (CTD)
- A common format for technical documentation.
- The result of an agreement between EU, US, and Japan.
- The goal is reducing resources for multiple-territory dossiers.
- Electronic submission is mandatory since 2015.
Structure of CTD
- The CTD has five modules covering administrative, regional/national information, and expert opinions.
- Modules 3, 4, and 5 elaborate on the quality, safety, and efficacy of products, respectively.
Registration Documentation Requirements in the Czech Republic
- Applicants need to be EU/EEA-based to obtain marketing authorization.
- Dossier requirements vary based on the type of application.
- Document language must adhere to the local regulations. Fees are dependent on the type of registration.
Particulars of an Application for Marketing Authorization for a Medicinal Product
- Requires data encompassing all medicinal components; storage and storage conditions; descriptions of control methods, along with related preclinical and clinical trials.
- Details of dosage form (indications, side effects, administration etc).
- Complies with all mandatory packaging regulations.
- Information needed on quality/safety measures should be presented.
The requirements for marketing authorization vary according to the type of medicine
- Registration of originator medications differs from registrations of generic medications, biosimilars, herbal, and homeopathic drugs.
Marketing Authorization for Originator Medicines
- The required tests/trials lasting up to several years demonstrate the safety and efficacy (risk-benefit ratio) of the medication
- Data on all requirements specified are needed for official authorization.
Marketing Authorization of Generic and Hybrid Medicines
- Pharmacological and toxicological tests are not required; demonstrating bioequivalence is instead required.
- Authorization is granted if the medication meets the criteria of being a generic of a medication that has been authorized for at least eight years.
- The INN (International Nonproprietary name) for the medicine is used in the new generic application.
Biosimilars and Their Marketing Authorization
- These are similar biomedicines that are released to the market after the patent for the original medicine expires.
- Require comprehensive testing for parameters like quality, safety, and efficacy.
Comparison of Data Requirements for Approval of a Biosimilar Versus the Reference Medicine
- A detailed comparison of clinical and preclinical study requirements is illustrated. This comparative analysis is useful in understanding the standards required for the biosimilar and the reference medicine.
Criteria for Marketing Authorization for Biosimilars in the EU
- Biosimilars require high similarity in physical, chemical, and biological properties to already existing approved medications.
- Clinical effect must not vary significantly, with manufacturing variation strictly regulated.
Marketing Authorization for Biosimilars
- The authorization is granted at a pan-European level by EMA after comprehensive review.
- This authorization may also be granted at a national level in exceptional circumstances.
Marketing Authorization for Herbal Medicinal Products
- The Committee on Herbal Medicinal Products (HMPC) issues scientific opinions that can be used for preparation, or assessment of an application for marketing or registration of herbal medicinal products within the EU.
Traditional Herbal Medicines
- Traditional herbal medicinal products must meet specific parameters/criterion for usage and conditions (oral, in specific strength and dosage, etc.). Must contain scientific reasoning for use over a considerable time period (at least 30 years).
Herbal Medicines: Regulatory and Scientific Support
- Utilizing the EMA and HMPC is a helpful procedure for gaining access to the European market for new herbal medicines
- National procedures can be used in conjunction with supporting scientific data from the HMPC and the EMA.
Herbal medicines – European Union monographs and list entries
- Helps harmonize regulations among member States.
- Provides a unique reference point when considering a new herbal medicinal product (well-established vs. traditional use).
Well-established use
- This pertains to herbal medicines that have been in use for over 10 years with demonstrable safety and efficacy.
Using EU Herbal Monographs for Applications
- Final EU monographs can be used in applications for both standard and traditional use registrations
- Comprehensive information (with all relevant opinions and clarifications) is available about the application process
Herbal Medicines – European Union List Entries
- List entries are important components for evaluating new applications when applying EU rules for herbal medicines.
- These are used to support safety and efficacy for the medicine and the traditional use by national authorities within the EU.
Marketing Authorization for Homeopathic Medicines
- Homeopathic medicines are viewed differently than other medicines.
- No specific regulatory framework exists in all countries relating to homeopathic medicine.
- Registration procedures differ from traditional medicines.
Homeopathic Medicine – Definition
- Homeopathic medicines are prepared from specific substances and must follow guidelines for manufacturing, such as those included in the European Pharmacopoeia.
Marketing Authorization for Homeopathic Medicines
- Two distinct registration procedures for homeopathic products: simplified or a specific product registration process
- The required quality standards are the same in both processes.
Simplified Registration Procedure for Homeopathic Medicines
- There is an absence of stated therapeutic indication on the packaging
- Dosage and administration methods must be outlined and the product dilution must meet safety standards
Registration by the so-called Procedure for Specific Homeopathic Medicines
- Requires more extensive documentation from the applicant, including evidence from homeopathy literature that verifies the product’s safety and appropriateness for use for a specified therapeutic objective.
- Suitable for minor conditions or ailments that don't necessitate continuous medical attention.
When Will the Registration Application Be Approved?
- A complex evaluation by the regulatory authority determines approval.
- Numerous factors including preparation/quality, product type, regulatory workload/prior experience can influence the approval timing.
- Geographic region could also possibly provide a framework for how a registration will be processed.
When Will the Registration Application Be Approved? (Type of Regulatory Procedure)
- Depending on which authorization procedure is used there are various time frames for approval and completion
- Timeframes vary depending on the individual steps in the procedure, and any potential delays
Decision on Marketing Authorization
- A comprehensive annex is required containing the approved SmPC, package leaflet, and package
- The decision includes classifications (prescription-only, with or without restrictions).
Marketing Authorization Number
- A registration number is provided to uniquely identify each medicine after approval.
- The assignment and generation of the number depends on the type of authorization (e.g. for non-EU countries versus centralized, EU-wide authorization).
Marketing Authorization Number
- The format of marketing authorization numbers may vary between EU countries
- The number may or may not reflect all possible strengths or pharmaceutical forms of a medication
- Some regions may also have a "global" number, whereas other number systems can be more complex.
Marketing Authorization Numbers Assigned by the Institute (SÚKL)
- Details on the structure and components of marketing authorization numbers used by SÚKL (Czech Republic).
- This section provides a key understanding of the unique systems/structures used for each country within the EU relating to medicinal product authorization numbers.
Marketing Authorization Numbers of Centrally Authorised Medicinal Products (EMA)
- Structure of marketing authorization codes used across all the member states of the EU. This provides specific details about the coding system within the European system
- An explanation of each component/segment of the code format used for authorized/centrally authorized medicinal products.
Marketing Authorization Numbers of Centrally Authorised Medicinal Products – Parallel Distribution
- How parallel distribution is reflected in the overall/centralized authorization numbers
Parallel Distribution
- This is used for the distribution of certain medicinal products from one member state to another.
Parallel Import
- This is the process of legally importing medicinal products that have already been authorized but are not being marketed in the particular country
- Medicinal products imported via the parallel import procedure must be identical.
Parallel Import - Labeling
- Essential instructions and information for correctly labeling medicinal products
- The process of labeling for parallel products has detailed requirements that need to be followed.
Summary of Product Characteristics (SmPC)
- The core of information used for healthcare professionals on dosage, use, benefits, and possible risks of a medicinal product.
- The SmPC details the product and its associated aspects and information for physicians and pharmacists concerning the product.
- Each form/strength of a medicine has its own unique SmPC.
Summary of Product Characteristics (SmPC)
- Legally binding document for off-label use also.
- Information is structured and includes medicinal substance, excipients, form, dosage, use, interactions, and adverse reactions.
- Established framework to follow.
Summary of Product Characteristics (SmPC)
- Specific details/components of the SmPC document are illustrated/explained.
- Information regarding the requirements/format for the summary for each component including dosage form, usage information, pharmacological data etc, needs to be carefully followed.
What the SmPC Does Not Include
- Information about off-label uses, restrictions regarding indication(s) based on referrals, or data on specific groups (e.g., pediatric, pregnant, breastfeeding).
- It also doesn't normally include general recommendations for how a disease state could be treated, which may be given in guidelines rather than the SmPC.
Patient Information Leaflet (PIL)
- Information for general users/patients.
- Readability and clarity are tested to ensure good understanding.
Conditional Registration of a Medicinal Product
- A conditional authorization is possible during urgent situations concerning public health, where the benefit has to outweigh immediate patient needs.
Referral Procedure
- A review of specific marketing authorizations, frequently due to identified safety and/or efficacy issues
- Initiated for harmonization or clarification
- A referral can be initiated by EMA, member states, or the company, with notification to all affected nations.
Articles 30, 31, and 107i of Directive 2001/83/EC
- Detailed regulations pertaining to the different types of referrals and the potential outcomes
- Procedures for variations, suspensions, or cancellations of the authorization are found within these articles.
Extension of Marketing Authorization
- The possibility of re-evaluating a medicine for an extension after 5 years
Change/Suspension/Cancellation of Marketing Authorization
- A medicinal product's approval may be subject to change or cancellation if certain conditions are deemed to be present.
Sunset Clause
- A regulation where a marketing authorization ceases if a product is not placed on the market within 3 years, or removed for 3 years consecutively.
- Does not apply to centrally authorized medicinals for instance.
After Marketing Authorization
- Post-marketing processes/steps such as pharmacovigilance, adverse event reporting, periodic updates, risk minimization, and others.
Changes in Legislation since 2024
- Recent updates and improvements for regulations on medicines
- Simplified procedures and combating antimicrobial resistance (AMR) are key elements of the more recent changes.
Non-standard drug regimens
- Non-standard ways to use medicines (unregistered or registered but outside the usual context in the SmPC).
Use of unregistered medicines
- Reasons/justifications for using unregistered medications
- Various specific circumstances may justify the use of unregistered medicines
Named-patient program
- Access to drugs not yet authorized, for conditions with no readily available treatment alternatives in a given country.
Compassionate use
- Use of unregistered medications for individuals with serious and/or life-threatening illnesses and for whom standard treatments are not appropriate or will not provide appropriate relief.
- EMA recommendations and regulations on compassionate use programs.
Compassionate use - Article 83 of Regulation (EC) No 726/2004
- Important aspects of the regulation for compassionate use.
Comparison to Individual Basis Treatment
- Differentiating compassionate use versus "Named-patient" treatment, specifically who is responsible for the product.
Compassionate use recommendations
- EMA recommendations on how unregistered medicines can be used for compassionate use programs, details on what will/will not be considered as a criteria, and also associated requirements/protocols.
- EU's recommendations for compassionate use programs.
Compassionate use - Which medicines can be made available in this way?
- The criteria for a program/procedure for compassionate use are included in this section.
How do compassionate use programmes work?
- How a compassionate use program operates, including the responsibility of the physicians (who need to notify authorities) and how the national authorities ensure that the side effects can be carefully tracked.
Clinical evaluation of medicines
- How patients may be enrolled in clinical trials using unregistered medications.
- Procedures for patients and healthy volunteers to take part in clinical trials.
Use of registered MPs outside the SmCP
- Off-label use, which means authorized products can be used in unconventional ways, outside standard usage as described in the SmPC
Off label use
- Circumstances under which authorization may be granted for using a medicine in a manner/dose/combination not detailed in the official SmPC
- A physician's role and responsibilities when prescribing an off-label treatment
Off label use - Duties of the doctor
- A list of duties a doctor bears when using a product in an off-label manner
- Necessary actions to ensure patient well-being
Off label use
- Responsibilities of the health care facilities/providers
- Requirements relating to off-label procedures
Conclusion
- A summary of the key aspects of marketing authorization, including importance, process, and significance.
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