This lecture is regarding compliance for post-marketing activities for updating the product label(U.S.) or the Summary of ...
   A new FDA final rule, "Requirements on Content and    Format of Labelling for Human Prescription Drug and    Biologica...
   A label is now divided into highlights of    prescribing information, contents of the full    prescribing information ...
   FDA has instituted a flexible implementation    schedule that phases in the new labelling    requirements; more time t...
   A prescription drug product label (also known as a    professional label, package insert, direction circular, and    p...
   Confusing medical information maybe    contributing to the approximately 300,000    preventable adverse events occurri...
   The new labelling reorders and reorganizes    sections found in the previous labelling    format (next slide).   Unde...
Comparison of previous labelling format with revised format. (Subheadings may vary for
   A label begins with highlights, a succinct, half-page summary of    the information that health care practitioners mos...
Example of highlights section (for a fictitious drug).
   Highlights does not include all the    information necessary to use a drug safely    and effectively. For this reason,...
   Product Names and Date of Initial FDA Approval. The listing of other names for the    product can be important to avoi...
   Dosage and administration. The recommended dosage regimen for the    given indications is provided, along with the sta...
   Adverse Reactions. Listed are the most common ADRs, their    frequencies, and how they should be reported to the    ma...
   Changes in Content. The clinical pharmacology section describes    drug-drug interaction study results and alerts prac...
   ADRs observed in post marketing clinical trials are included with the    clinical trial experience.   Post marketing ...
   A separate section on patient-counseling    information has been added in response to    the requirement that all FDA-...
   Patient information (including patient package    inserts and medication guides) is designed to    communicate to pati...
   The information practitioners refer to most    frequently and consider most important (e.g.,    boxed warning, indicat...
   FDA has instituted a flexible implementation    schedule that phases in the new labelling    requirements ( Table 1 )....
Applications Required To Conform to New          Time by Which Conforming Labelling Must Be  Requirements*                ...
   The labelling of a drug product submitted for approval    under an ANDA will have to have the same format as the    la...
   Brand name drug labelling must accompany    drug product samples.   The new requirements do not apply to non    presc...
   Submitting labelling in electronic and structured    product labelling (SPL) format will support    initiatives to imp...
   The new electronic labelling will be a key element    of and primary source of medication information    for Daily Med...
   Update of the revised European Labelling    Guideline – the European Summary of Product    Characteristics (SEP 2009)
• Overview of the new recommendations• Data based on requested clinical studies inpaediatric population• How to calculate ...
. Explain the importance of the European SmPC Guideline• Discuss the changes due to the revision of the SmPC  Guideline• O...
   Guidelines on Product Characteristics   http://www.ema.europa.eu/htms/human/raguidelines/productinformation.h    tm
   Directive 2001/83/EG as amended serves as legal base    changed 2004 with effect on product information   Guideline o...
Implementation of new requirements for information onpaediatric use  Art. 11 Dir. 2001/83/EC  Paediatric Regulation 1901/2...
   The summary of product characteristics contains a description of a    certain medicinal product’s properties and the c...
   Definitive statement between the competent    authority and the marketing authorisation holder   Basis of information...
   The SmPC Guideline…    Gives advice on the principles of presenting    Requires to maintain the integrity of each se...
   Each section of the SmPC should first deal    with those issues that apply to the core    population followed by speci...
   Data of relevance for administration in    paediatric population must be addressed    under a dedicated sub-heading in...
   The wording should be clearly and concisely   Indicate: treatment, primary or secondary    prevention or diagnostic i...
   Product indicated for use in children     specific age groups as appropriate   Product not indicated for use in child...
New: Subsection “paediatric patients”: always to be includedPaediatric indication not yet authorised   “The <safety> <and>...
New subsection: “Paediatric population” Warnings specific to the paediatric population  or any subset of the paediatric p...
   Sections 5.1 – 5.3 should normally mention    information relevant to the prescriber and to other    health-care profe...
 Pharmacotherapeutic group (ATC Code) Mechanism of action (if known) Pharmacodynamic effects   Clinical efficacy and s...
New Section : “Paediatric population”  Results of all clinically relevant data (pharmacodynamic and   efficacy) according...
   Any findings of non-clinical testing    of relevance for the prescribers    recognising the safety profile in the au...
4.8 Undesirable effects → Completely rewrittenNEW: Summary of safety profile as an introduction  • “Most serious or most f...
   The content of this section should be justified in    the Clinical overview of the marketing    authorisation applicat...
a. Summary of the safety profileb. Tabulated summary of adverse reactionsc. Description of selected adverse reactionsd. <P...
1.   • Information about the most serious and/or most frequently occurring     adverse reactions2.   • Non-serious adverse...
   Single table or structured listing of adverse reactions    (from clinical studies and post marketing)   State the sou...
Principles:  a. Highest frequency should be chosen  b. Different terms representing the same phenomenon     should ordinar...
Number of patients studied in controlled trials: 21000 • If an adverse reaction has a risk to occur in ≤ 1 in 7000   patie...
• Information characterising  ◦ specific adverse reaction which may be useful to prevent, assess or manage the    occurren...
A paediatric sub-section should always be included (unless  irrelevant) Any clinically relevant differences (i.e., in nat...
   A man, 54 years of age, swallowed two tablets    Lapidar 100 mg with a glas of juice   1 hour later he experienced ex...
   Dose was twice as high as recommended.   Grapefruit juice instead of water   The man had worked at night and was the...
Assessment must also consider: • Existence of similar cases (post marketing, from clinical studies) • Pharmacologic plausi...
…all adverse reactions from:1. clinical trials2. post-authorisation safety studies3. spontaneous reporting for which a cau...
Fda guidance for food and drug labelling   professor pirouzi
Fda guidance for food and drug labelling   professor pirouzi
Fda guidance for food and drug labelling   professor pirouzi
Fda guidance for food and drug labelling   professor pirouzi
Fda guidance for food and drug labelling   professor pirouzi
Fda guidance for food and drug labelling   professor pirouzi
Fda guidance for food and drug labelling   professor pirouzi
Fda guidance for food and drug labelling   professor pirouzi
Fda guidance for food and drug labelling   professor pirouzi
Fda guidance for food and drug labelling   professor pirouzi
Fda guidance for food and drug labelling   professor pirouzi
Fda guidance for food and drug labelling   professor pirouzi
Fda guidance for food and drug labelling   professor pirouzi
Fda guidance for food and drug labelling   professor pirouzi
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Fda guidance for food and drug labelling professor pirouzi

  1. 1. This lecture is regarding compliance for post-marketing activities for updating the product label(U.S.) or the Summary of Product Characteristics (SmPC - EMEA) based on product related post-market updates on new indications, target populations, post marketing Safety data, productEfficacy and pharmacology data.
  2. 2.  A new FDA final rule, "Requirements on Content and Format of Labelling for Human Prescription Drug and Biological Products," became effective in June 2006. The rule is part of FDAs initiative to manage the risks of medical product use and minimize adverse events. The new labelling reorders and reorganizes sections found in the previous labelling format. FDA has designed new labelling to help health care practitioners easily find, read, and convey information important for the safe and effective use of prescription drugs.
  3. 3.  A label is now divided into highlights of prescribing information, contents of the full prescribing information (FPI), and the FPI. The highlights section is a half-page summary of the information that health care practitioners most commonly refer to and view as most important.
  4. 4.  FDA has instituted a flexible implementation schedule that phases in the new labelling requirements; more time to achieve compliance is provided for older products. The revision of labelling for products approved or submitted for approval under an abbreviated new drug application (ANDA) depends on the labelling of the listed drug referenced in the ANDA. The new requirements do not apply to nonprescription drug products.
  5. 5.  A prescription drug product label (also known as a professional label, package insert, direction circular, and package circular) is a compilation of information about a product written by the manufacturer and approved by FDA. Labelling is based on the agencys thorough analysis of the new drug application (NDA) or biological license application. The labelling, or prescribing information, is thus subject to FDA regulations and is a requirement for all approved drug and biological drug products. A label contains information necessary for safe and effective use and is written primarily for the health care practitioner.
  6. 6.  Confusing medical information maybe contributing to the approximately 300,000 preventable adverse events occurring each year in U. S. Hospitals. Research has shown that these adverse events may be reduced by prioritizing the warning information on the label. Based on multiple public meetings and surveys, FDA identified the most common ways practitioners use prescription drug labelling and the prescribing information they consider most important and applied its findings to the revisions.
  7. 7.  The new labelling reorders and reorganizes sections found in the previous labelling format (next slide). Under the new system, a label is divided into highlights of prescribing information, contents of the full prescribing information (FPI), and the FPI.
  8. 8. Comparison of previous labelling format with revised format. (Subheadings may vary for
  9. 9.  A label begins with highlights, a succinct, half-page summary of the information that health care practitioners most commonly refer to and view as most important (next slide). This section provides immediate access to the information most crucial for a drugs safe and effective use and contains numerical cross-references to more details in the FPI. In designing the highlights section, FDA used established techniques to enhance the communication of large amounts of complex information. Highlights summarizes the information from the FPI that is most important for prescribing a drug safely and effectively and logically organizes it to enhance accessibility and retention. The design combines multiple textual and graphic elements (e.g., tables, bulleted lists, boldface, italics).
  10. 10. Example of highlights section (for a fictitious drug).
  11. 11.  Highlights does not include all the information necessary to use a drug safely and effectively. For this reason, it is prefaced with a limitations statement that reads, "These highlights do not include all the information needed to use drug X safely and effectively. See full prescribing information for drug X. "
  12. 12.  Product Names and Date of Initial FDA Approval. The listing of other names for the product can be important to avoid confusion. The date of approval provides context on the relative newness of a product, since there may be limited clinical information about a new product compared with one that has been on the market for some time. Boxed Warning. Many drug product labels contain a boxed warning, often referred to by health care practitioners as a black-box warning, to emphasize certain risks. The boxed warning that appears in the highlights section may be a condensed version of the complete boxed warning in the FPI and is limited to 20 lines.[1] Cross-references maybe made to additional safety information in the FPI. Recent Major Changes. Changes that have been made to certain sections of the FPI are listed. Marginal notations appear in the corresponding sections of the FPI to indicate where the changes occurred. Indications and Usage. Listed are the indications for use of a drug, the major limitations to use, the pharmacologic class, and the mechanism of action.
  13. 13.  Dosage and administration. The recommended dosage regimen for the given indications is provided, along with the starting dosage, dosage range, whether the drug should be taken with or without food, critical differences among population subsets, monitoring recommendations, and significant clinical pharmacologic information. Dosage Forms and Strengths. The available dosage forms and strengths are detailed. Contraindications. No relative contraindications are listed, only circumstances when the drug should absolutely not be used. The contraindications statement must be included even if there are no contraindications. Warnings and Precautions. An abbreviated summary of the most clinically significant adverse drug reactions (ADRs), how to monitor them, and how to treat them is provided.
  14. 14.  Adverse Reactions. Listed are the most common ADRs, their frequencies, and how they should be reported to the manufacturer and to FDA. Drug Interactions. The drug interactions are briefly described. Use in Specific Populations. This section, which was previously integrated into the precautions section, summarizes important information about use in specific populations. Patient Counseling Information. The practitioner is reminded of information important to convey to the patient. Contents. The contents section serves as a navigational tool that references all the sections and subsections in the FPI, some of which may not be referenced in highlights (Figure 3). The contents sectional so allows for hyperlinks in electronic formats.
  15. 15.  Changes in Content. The clinical pharmacology section describes drug-drug interaction study results and alerts practitioners to the extent of particular interactions. The contraindications section now describes only known hazards and no longer includes the statement "allergic to any component of the drug." A contraindication exists only when the risk from use clearly outweighs any possible therapeutic benefit. “None” is stated when no contraindications are known, and no relative or hypothetical contraindications are listed. The order in which contraindications are listed is based on their likelihood and the size of the population affected. The warnings and precautions sections are consolidated into one section containing the most critical safety information. This new section also includes clinically significant ADRs that require discontinuation of the drug, dosage adjustment, or addition of another drug; that could be prevented or managed with appropriate patient selection or avoidance of concomitant therapy; and that significantly affect patient compliance.
  16. 16.  ADRs observed in post marketing clinical trials are included with the clinical trial experience. Post marketing spontaneous-ADR reports are listed separately. This section no longer contains a "laundry list" of ADRs. It provides additional detail on the nature, severity, and frequency of ADRs and their relationship to dosage and patient demographics. Contact information for reporting ADRs is provided. Some product identification information (color, scoring) is located in both the how-supplied section and the dosage forms and strengths section to preserve the integrity and enhance the understanding of both sections. The clinical and nonclinical toxicology sections, which were previously optional, are now required.
  17. 17.  A separate section on patient-counseling information has been added in response to the requirement that all FDA-approved patient information be reprinted in or accompany drug product labelling. The requirement regarding the inclusion of all FDA-approved patient information also applies to older products not otherwise subject to the new content and format requirements.
  18. 18.  Patient information (including patient package inserts and medication guides) is designed to communicate to patients in understandable language the most important information they need to use a product appropriately. Patient counseling information is specifically written for health care practitioners to inform them about what information is important to convey to the patient at the time of prescribing for the drug to be used safely and effectively.
  19. 19.  The information practitioners refer to most frequently and consider most important (e.g., boxed warning, indications and usage, dosage and administration, dosage forms and strengths, and storage and handling) is located at the front of the prescribing information. As a result of feedback from two national physician surveys,[1,2] the indications and usage section and the dosage and administration section are now at the beginning of the FPI.
  20. 20.  FDA has instituted a flexible implementation schedule that phases in the new labelling requirements ( Table 1 ). The schedule bases compliance on the date the application was submitted to the agency. More time to achieve compliance is provided for older products; labelling for newer products (typically those with more complex labelling and those with labelling that practitioners refer to more often) must be updated first.
  21. 21. Applications Required To Conform to New Time by Which Conforming Labelling Must Be Requirements* Submitted to FDA for Approval Applications submitted on or after June 30, 2006 Time of submission Applications pending on June 30, 2006, and June 30, 2009 applications approved 0-1 yr before June 30, 2006 Applications approved 1-2 yr before June 30, June 30, 2010 2006 Applications approved 2-3 yr before June 30, June 30, 2011 2006 Applications approved 3-4 yr before June 30, June 30, 2012 2006 Applications approved 4-5 yr before June 30, June 30, 2013 2006 Applications approved more than 5 yr before Voluntarily at any time June 30, 2006* Includes new drug applications, biological license applications, and efficacy supplements.
  22. 22.  The labelling of a drug product submitted for approval under an ANDA will have to have the same format as the labelling of the listed drug referenced in the NDA Except for changes required because of differences approved or because the drug product and the referenced listed drug are produced/distributed by different manufacturers. Such differences in labelling may include differences in expiration date, formulation, bio availability, or pharmacokinetics; labelling revisions done to comply with current FDA labelling guidelines or other guidance; or omission of an indication or other aspect of labelling protected by patent or accorded exclusivity.
  23. 23.  Brand name drug labelling must accompany drug product samples. The new requirements do not apply to non prescription drug products (including those approved under an NDA).
  24. 24.  Submitting labelling in electronic and structured product labelling (SPL) format will support initiatives to improve patient care through electronic prescribing and improve the drug labelling review process so that FDA can provide immediate access to the most recent drug information. SPL-formatted labelling will be available on the Facts@fda website (www.fda.gov/cder/news/FactsatFDA.htm), a comprehensive resource designed to give one- stop access to information about all FDA- regulated products
  25. 25.  The new electronic labelling will be a key element of and primary source of medication information for Daily Med, a new interagency online health information clearinghouse created cooperatively by FDA and the National Library of Medicine. Daily Med will make current information about FDA-regulated products available free of charge to health care professionals and patients. This is an important step toward providing practitioners with electronic access to up-to-date information on drug safety and effectiveness at the point of care. http://dailymed.nlm.nih.gov
  26. 26.  Update of the revised European Labelling Guideline – the European Summary of Product Characteristics (SEP 2009)
  27. 27. • Overview of the new recommendations• Data based on requested clinical studies inpaediatric population• How to calculate frequencies of unwanteddrug reactions based on clinical studies, postauthorisation safety studies and spontaneousreports• Similarities and differences betweenEuropean Guideline and FDA labellingpractice
  28. 28. . Explain the importance of the European SmPC Guideline• Discuss the changes due to the revision of the SmPC Guideline• Outline the use of the medicinal product in the paediatric population• Explain the similarities and differences in comparison to FDA labelling practice from the perspective of global labelling and company core safety data documentation
  29. 29.  Guidelines on Product Characteristics http://www.ema.europa.eu/htms/human/raguidelines/productinformation.h tm
  30. 30.  Directive 2001/83/EG as amended serves as legal base changed 2004 with effect on product information Guideline on the Summary of Product Characteristics Most relevant documents revised in September 2009 due to above changes Template on SmPC (as by revised QRD template) as a consequence of both revisions MedDRA-SOCs for grouping adverse drug reactions Excipients-Guideline Standard Terms of EDQM Guideline on risk Assessment on Human Reproduction and Lactation: From Data to Labelling revised guideline and new recommendations for labelling
  31. 31. Implementation of new requirements for information onpaediatric use Art. 11 Dir. 2001/83/EC Paediatric Regulation 1901/2006, especially. Art. 2 (3), Art. 28Extensive revision of Undesirable Effects section after extensive discussions improved description of the safety profileAdditional information on pharmacogenomic aspectsAdditional changes due to current guidance documents Declaration of active substance of biotech products Considering advanced therapies Composition Storage conditions
  32. 32.  The summary of product characteristics contains a description of a certain medicinal product’s properties and the conditions attached to its use. Example: ◦ Name ◦ Composition (declaration) ◦ Pharmaceutical form and strength ◦ Authorised applications (indications) ◦ Adverse reactions ◦ Cautions and safety regulations ◦ Shelf-life ◦ Storage conditions ◦ Holder of marketing authorisation (firm) The summary of product characteristics is prepared for the use of "professional people" and contains a certain amount of professional language. Patients are therefore advised to seek information either in the package leaflets, from general practitioner or at the pharmacy.
  33. 33.  Definitive statement between the competent authority and the marketing authorisation holder Basis of information for health professionals It is not the remit of the SmPC to give general advice of the treatment of a particular disease
  34. 34.  The SmPC Guideline… Gives advice on the principles of presenting Requires to maintain the integrity of each section Allows cross-references to other sections when these contain relevant additional information. A SmPC is to be presented for each pharmaceutical form and strength.
  35. 35.  Each section of the SmPC should first deal with those issues that apply to the core population followed by specific information for any relevant special population (e.g. children or elderly). Consistent medical terminology should be used throughout the SmPC. Public Assessment Reports provide detailed information.
  36. 36.  Data of relevance for administration in paediatric population must be addressed under a dedicated sub-heading in all sections except contra-indications Knowledge should be presented as precisely as possible Decision of the Paediatric Committee (PDCO) must be included
  37. 37.  The wording should be clearly and concisely Indicate: treatment, primary or secondary prevention or diagnostic indication When appropriate, define the target population especially when restrictions to the patient populations apply Age group should be stated Study endpoints are normally not included
  38. 38.  Product indicated for use in children specific age groups as appropriate Product not indicated for use in children New: Indication should state, that the product is for use in adults only Product currently not indicated for use in children New: “Lack of information” does not mean contraindication, but information may be provided in section 4.2 or 5.1 according to assessment and decision taken by PDCO
  39. 39. New: Subsection “paediatric patients”: always to be includedPaediatric indication not yet authorised “The <safety> <and> <efficacy> of X in children from the age of x to y <has><have> not <yet> been established; <no data are available><currently available data are described in section <4.8><5.1><5.2>>.“no longer: “The experience in children is limited.” or “There is no experience in children.”Contraindicated for children in general or in specific age groups Refer to 4.3 ContraindicationsNot recommended for children in general or in specific age groups Indication not relevant – dedicating the product to e.g. adults “safety or efficacy concerns to be explained” – Refer to 4.8 Undesirable effects or 5.1 Pharmcodynamic properties as appropriateNew: Recommendations as specific as possible Description of application specifics Adjustment to daily life: school, out-school activities etc..
  40. 40. New subsection: “Paediatric population” Warnings specific to the paediatric population or any subset of the paediatric population Any necessary warning or precaution in relation to long-term safety (consideration of development phase in childhood, gender, daytime activity, sleeping behaviour and rhythms)
  41. 41.  Sections 5.1 – 5.3 should normally mention information relevant to the prescriber and to other health-care professionals taking into account the approved therapeutic indication(s) and the potential ADRs  Statements should be brief and precise  Sections should be updated regularly
  42. 42.  Pharmacotherapeutic group (ATC Code) Mechanism of action (if known) Pharmacodynamic effects Clinical efficacy and safety (statistically compelling and clinically relevant, using absolute figures, pharmacogenetic data) Paediatric population Additional information on “conditional approval” and under “exceptional circumstances“
  43. 43. New Section : “Paediatric population”  Results of all clinically relevant data (pharmacodynamic and efficacy) according to age groups 1. Exploratory studies: results according to the main criteria within the population studied 2. Confirmatory studies: precise and comprehensive summary of study results. 3. Additional clinical data as appropriate  Reasons for deferring a paediatric investigation plan – <it is considered appropriate to conduct studies in adults prior to initiating studies in the paediatric population> – <studies in the paediatric population will take longer to conduct than studies in adults> <additional non-clinical data are considered necessary> – <major quality problems prevent development of the relevant formulation(s)>.  Reasons to notify a waiver for paediatric development
  44. 44.  Any findings of non-clinical testing of relevance for the prescribers recognising the safety profile in the authorised indication(s) not already mentioned in in other SmPC sections described in brief with qualitative statements Regarding use in the paediatric population (subheading): Results of all relevant non-clinical data in juvenile animals Discussion of clinical relevance Environmental risk assessment as appropriate
  45. 45. 4.8 Undesirable effects → Completely rewrittenNEW: Summary of safety profile as an introduction • “Most serious or most frequently occurring adverse reactions, together with common risk factors” factors • “Consistent with the important identified risks mentioned in the Safety Specification of the Risk Management Plan“ • Refer to 4.4 Special warnings and precautions as appropriateNew: Information on source data behind table of adverse reactions • Clinical studies, PASS and/or post marketing reports etc.New: A paediatric sub-section should always be included (unless irrelevant)New: Guidance on estimation of frequency of adverse reactions, but nochange of definition of frequency definitionsNew: Combination products: attribution of adverse reactions to components
  46. 46.  The content of this section should be justified in the Clinical overview of the marketing authorisation application based upon a best- evidence assessment of all observed adverse events and all facts relevant to the assessment of causality, severity and frequency.
  47. 47. a. Summary of the safety profileb. Tabulated summary of adverse reactionsc. Description of selected adverse reactionsd. <Paediatric population>e. <Other special population(s)>
  48. 48. 1. • Information about the most serious and/or most frequently occurring adverse reactions2. • Non-serious adverse reactions that are frequent in the beginning of the treatment but may disappear with its continuation3. • Adverse reaction associated with long-term use4. • Consistent with the important identified risks mentioned in the Safety Specification of the Risk Management Plan5. • Consistent with the table of adverse reactions Example: ‘At the beginning of the treatment, nausea, diarrhoea, headache or vertigo may occur; these reactions usually disappear within a few days even if treatment is continued. The most commonly reported adverse reactions during treatment are dizziness and headache, both occurring in approximately 6% of patients. Serious acute liver injury and agranulocytosis may occur rarely (less than 1 case per 1,000 patients)’
  49. 49.  Single table or structured listing of adverse reactions (from clinical studies and post marketing) State the source of data Structured presentation according to MedDRA SOCs (system organ class) Frequency groupings should follow standard terms established in each official language using the following convention: • very common (≥ 1/10) • common (≥1/100, <1/10) • uncommon (≥ 1/1,000, <1/100) • rare (≥ 1/10,000, <1/1,000) • very rare (<1/10,000) • not known (cannot be estimated from the available data)
  50. 50. Principles: a. Highest frequency should be chosen b. Different terms representing the same phenomenon should ordinarily be grouped together as a single adverse reactionAdverse reactions from clinical trialsFrequency category based on pooled data and crude incidence ratesAdverse reactions from safety studiesFrequency category based on the point estimate of the crude incidence rate
  51. 51. Number of patients studied in controlled trials: 21000 • If an adverse reaction has a risk to occur in ≤ 1 in 7000 patients, the frequency category class should be “rare”.Number of patients studied in controlled trials: 33000 • If an adverse reaction has a risk to occur in ≤ 1 in 11000 patients, the frequency category class should be “very rare”. • Only, if more than 30000 patients are included in the clinical development program it will be allowed to assign frequency class “very rare” to a so far not reported adverse reaction.
  52. 52. • Information characterising ◦ specific adverse reaction which may be useful to prevent, assess or manage the occurrence of an adverse reaction in clinical practice ◦ individual serious and/or frequently occurring adverse reactionsfor particular severe cases ◦ may describe for example reversibility, time of onset, severity, duration, mechanism of the reaction (if of clinical relevance), dose relationship, relationship with duration of exposure or risk factors• Measures to be taken to avoid specific adverse reactions should bementioned under 4.4 and cross-referenced here.• Any adverse reactions resulting directly from an interaction should bementioned here and cross-referenced to section 4.5.• In the case of combination products, information should be included inthis sub-section pointing out particular adverse reactions
  53. 53. A paediatric sub-section should always be included (unless irrelevant) Any clinically relevant differences (i.e., in nature, frequency, seriousness or reversibility of adverse reactions) between the safety profiles in adult and paediatric populations, or in any relevant age groups, should be described and stratified by age group.Other special populations: Information on any clinically relevant differences (i.e., in nature, frequency, seriousness or reversibility of adverse reactions, or need for monitoring specifically observed in other special populations such as elderly, patients with renal impairment, patients with hepatic impairment, patients with other diseases or a specific genotype
  54. 54.  A man, 54 years of age, swallowed two tablets Lapidar 100 mg with a glas of juice 1 hour later he experienced extreme tiredness and fall in sleep for 2 hours Circumstances of use: Correct indication, dose, administration etc.? Causal relationship: Alternative explanations for sleepiness? Severity: Life threatening? Expectedness: What does the SmPC say?
  55. 55.  Dose was twice as high as recommended. Grapefruit juice instead of water The man had worked at night and was therefore extremely tired Circumstances of use: Not the right dose, grapefruit may enhance the plasma concentration etc. Causal relationship: At least a reasonable possibility Exists Severity: Not life threatening Expectedness: Tiredness is labelled, sleepiness isn`t
  56. 56. Assessment must also consider: • Existence of similar cases (post marketing, from clinical studies) • Pharmacologic plausibility • Pharmacokinetic aspects • Bibliographical data, epidemiological studiesThe ultimate questions: • Is it necessary to include this phenomenon (sleepiness) in product information? • If so, where to include it and how to “frame’’ it (as a “stand alone” adverse reaction and/or result of an interaction and/or result of overdose)?
  57. 57. …all adverse reactions from:1. clinical trials2. post-authorisation safety studies3. spontaneous reporting for which a causal relationship between the medicinal product and the adverse event is at least a reasonable possibility, based for example: a. • on their comparative incidence in clinical trials b. • on findings from epidemiological studies c. • on an evaluation of causality from individual case reports.Adverse events, without at least a suspected causalrelationship, should not be listed in the SmPC.

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