Readability Testing of Package Information Leaflets and Bridging for the Generic Industry

1
Readability Testing of Package Information
Leaflets and Bridging for the Generic Industry

• By Kurt Kinsey
• Pharma-EU s.r.o.
• Malostranske Namesti 23
• Prague 1
• 118 00
• Czech Republic
• Telephone [phone]
• kurt_at_pharma-eu.com

2
Overview

• Introduction to readability testing
• What is readability testing?
• Readability Testing and Timing for MRP, DCP, CP
  and National Procedures
• MRPs
• DCPs
• Central Procedures
• National Procedures
• Renewals and variations
• Experience and Feedback with Readability Testing
  in the Generic Industry
• Ensuring success with Bridging

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Introduction to Readability Testing

• All Health Agencies across Europe required User
  Testing since October, 2005 for, CP, MRP and DCP.
• Implementation was staggered across Europe, but
  all 27 members now require it for MRP and DCP
  applications.
• Completion of the testing has not been required
  for most national procedures to date (UK is the
  exception).
• The UK required all PILs for nationally approved
  products to be tested or bridged by July 2008.
• A few member states are now requiring all PILs to
  be tested as well for their existing nationally
  authorised products. FR and DE in particular.
• In summary, readability testing has not been
  required for most national procedures and
  variations (exceptions being the UK).

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Why User Test ?

• The leaflet must reflect the product licence (the
  Summary of Product Characteristics (SPC) of the
  product to which it refers. Differences between
  the SPCs for the same medicine available from
  different MA holders led to inconsistent
  information in the PIL, resulting in frequent
  complaints from patients.
• Many leaflets were lengthy due to the complexity
  of the SPC, and were poorly laid out. Patients
  quickly lost interest in the document, failing to
  read or understand information crucial to the
  safe use of the medicine.

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Why User Test ?

• Readability testing qualifies that the medical
  information contained in the leaflet is usable
  i.e. understood by potential users of the
  medication.

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Why Bridge?

• To show these requirements are met while not
  being forced to perform repeated readability
  testing of PILs with similar text and key safety
  messages, for closely similar or related products
  with standardized styles and formats.

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What is User Testing ?

• How many people here have experience with user
  testing? Do I need to refer to the methodology?

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Readability Testing Methodology

• Diagnostic user testing was pioneered in
  Australia in the early 1990s and was recommended
  in guidelines on Readability in Europe by the
  European Commission in 1999. It is a performance
  based, flexible development tool which identifies
  barriers to peoples ability to understand and
  use the information presented, and indicates
  problem areas which should be rectified
•  
• It is particularly useful as part of a leaflet
  development process
• Medicinal products have benefited by user testing
  in the result of high quality, user friendly and
  uniformly formatted PILs.

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Before Testing

• Before Testing
• PILs should first be ordered and prepared in the
  QRD format.
• PILs should be written and reviewed to ensure
  they are prepared for readability testing.
• Using nationally mandated texts can be
  problematic.
• Mock Ups should be created to EMEA readability
  guidelines.

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Questionnaire Development

• Key issues for safe use of the medication should
  be identified.
• A systematic approach and development process
  should be used and reported to explain how key
  issues for safe use were addressed and how the
  questions are proportionate to the PIL in
  question.

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Questionnaire

• A questionnaire is developed that contains 12-20
  questions specific to safety issues of the
  medicine in question.
• EMEA guidance on assessing readability testing
  states that 12-15 questions should be used. This
  is not always practical, as more complex
  medicines may require further testing to
  adequately test the key issues for safe use.
• i.e. linezolid, nevirapine

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How will the testing be performed?

• The individual tests are conducted with one to
  one, face to face structured interviews.
• The interviewer should be experienced and have a
  medical or pharmaceutical background.
• This is important to satisfy any enquiries or
  questioning of how correct answers are assessed.
• PIL writers should be involved in the User
  Testing as they will gain valuable experience.

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How many participants need to be tested?

• Minimal of 3 rounds of testing on 23-25
  participants
• Preliminary Testing
• Minimally 3-5 participants are tested to
  determine if there are any major revisions needed
  to the PIL.
• 1st Round of Testing
• Minimally 10 participants are tested to achieve a
  passing result
• Minor revisions may be performed after this as
  needed.
• 2nd Round of Testing
• Minimally an additional 10 participants are
  tested.
• Additional rounds of testing may be required if
• A passing result is not achieved
• The PIL is revised during the registration
  procedure.
• The Health Authorities will advise as how to
  proceed.
• A bridging report may suffice and save time and
  .

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What Aspects Need to be Assessed?

• The 3 main criteria that should be assessed
• Traceability of the information.
• Comprehensibility of the information.
• Applicability of the information.

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Who should participate?

• Care should be used to when recruiting
  participants to ensure
• inclusion and exclusion criteria are met.
• Certain member states have differing
  requirements.
• We have had success recruiting participants who
  represent the most likely demographic samples to
  experience difficulty with PILs.

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Reporting the Testing

• Detailed reports are needed for compliance.
• Different competent authorities require certain
  specific information.
• Ensure your reporting contains information as
  needed conforming to the most rigorous assessing
  authorities (it may be useful for future
  bridging)
• Qualitative data should be reported

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Readability Testing and Timing

• MRP
• DCP
• Centralised Procedures
• National Procedures
• Variations and Renewals

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Timings for the PIL readability testing

• Testing takes at least 3 weeks for 2 rounds to be
  performed in an ideal environment.
• We have performed complete tests in 1 week for
  urgent situations.
• Most testing houses require at least 6 weeks.
• More time may be needed if the reference PIL is
  problematic to user test. Leave time for text and
  art work revisions.
• A very detailed report should be submitted to
  adequately address revisions made to the PIL if
  necessary.

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MRP

• Require a readability test or bridging study for
  validation.
• Early Preparative Work for MRP PIL Readability
  Testing
• The PIL should be reformatted to QRD and reviewed
  to ensure positive readability testing results.
• For Generics, comprehensive SmPC comparisons
  should be complete at least 3-6 months prior to
  dossier completion and the core SmPC PIL
  compiled.
• Copying the originators or nationally approved
  text can lead to problems during readability
  testing
• Discussions with the Competent Authority
  regarding the PIL should be addressed for the
  sake of readability
• Preliminary testing is usually required to
  support revisions if needed.
• User testing should begin at least 3 months
  before the completion of the dossier to allow
  time for preparation of the submission and PIL
  revisions if needed.

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DCP

• Require a readability test, but it can be
  performed during the clock stop.
• Hungary has been the only noted exception to this
  rule.

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DCP

• The PIL should be reviewed by an experienced
  person with readability testing prior to
  beginning the procedure.
• Copying the originators text can lead to problems
  during readability testing
• Testing should not be required for validation of
  the dossier (Hungary is a noted exception)
• The Preliminary Assessment Report issued at Day
  70 (including comments on SPC, PIL and labelling)
  . will include a comment on whether user
  consultation of the PIL has been performed or is
  foreseen, or the justification for its absence is
  acceptable.
• The RMS will have the main responsibility for the
  assessment of the PIL.
• Proposed core SmPC and PIL discussed with RMS and
  tentative timings.
• Readability testing may be performed during the
  clock stop once the the SmPC and PIL are agreed.
• In situations where readability testing is
  performed prior to the procedure, the MA Holder
  should be prepared to perform additional testing
  after Day 70 assessments as the PIL and SmPC may
  have extensive revisions.

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Centralised Procedure

• Centralised procedures have not consistently
  required readability
• testing when the reference product has been
  tested and approved
• by the innovator. Centrally approved products
  should have a
• readability tested reference PIL available.

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EMEA Guidance for the CP

• Articles 59(3) and 61(1) of Directive 2001/83/EC,
  as amended, require
• that the package leaflet reflects the results of
  consultations with target
• patient groups (user consultation) to ensure
  that it is legible, clear
• and easy to use and that the results of
  assessments carried out in
• cooperation with target patient groups are
  provided to the competent
• authority.
• A user consultation is always required in the
  following situations
• First authorization of a medicinal product with a
  new active substance,
• Medicinal products which have undergone a change
  in legal status,
• Medicinal products with a new presentation,
• Medicinal products with particular critical
  safety issues.

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EMEA Guidance for the CP

• However, reference to already approved package
  leaflets may be acceptable where appropriate,
  based on a sound justification by the applicant.
  Examples of when this may be considered
  acceptable as well as the considerations to be
  taken into account when choosing the types of
  reference package leaflets are detailed in
  theGuidance concerning consultations with target
  patient groups for the package leaflet.
• This topic should be discussed during the pre
  submission scientific advice.

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EMEA Guidance for the CP

• Originators have not been required to perform
  testing prior to the procedure.
• Testing has been performed post approval.
• In the case of generics it is not 100 clear if
  you can use the reference products PIL.
• The key safety messages in the PILs for generic
  applications
• should be identical to the CP reference products.
  However,
• the generic applicant does not have rights of
  access to the
• innovators PIL readability test data so will
  generally have to
• test their PIL to prove compliance style and
  formats will
• differ and can contribute significantly to test
  outcome.
• However, bridging is in theory possible.

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National Procedures

• Required by the UK consistently.
• Performed before procedure. (Germany will allow
  it to be performed during a clock stop)
• Other member states have staggered
  implementation.
• Compliance looming in France and Germany.

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Variations and Renewals

• Reformating existing PILs to QRD
• New PIL readability tests where approvals
  pre-dated mandatory PIL testing
• Bridging reports may be possible in other cases
• Readability testing implementation across EU has
  been staggered.
• Wait for health agencies to require.
• Variation Renewal Applications 
• Testing has not been required to date across the
  EU on a consistent basis

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Experience and Feedback with Readability Testing
in the Generic Industry

• Feedback from the competent authorities for UK
  National requirements, CP, DCP and MRP
  readability testing has been minimal for testing
  performed by us and submitted by partner
  companies.
• The MHRA has required all PILs for UK PILs to be
  tested
• Generics required to test or bridge all PILs
• Work sharing initiatives marginally successful
• Bridging results not capitalised on 100
• Countless PILs tested by originators and generics
  for the same APIs
• MHRA sometimes now require a separate PIL other
  than a MRP or DCP approved PIL for products in
  their nation.
• Acceptance has been 100 for Pharma-EU

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Experience

• The PILs themselves have been assessed and there
  is generally always some revision required during
  the procedures.
• When the PIL (previously readability tested by
  the MA holder) has been assessed and revisions
  have been required, additional rounds of
  readability testing are rarely ordered. Bridging
  suffices or in most instances, the revised PIL is
  approved. (DCP can be an exception to this rule
  as it is common to have major revisions needed
  to the PIL that are considered to compromise the
  readability)
• For generic MRP and DCP procedures, the reference
  PIL has now commonly already been readability
  tested by the innovator. Generics commonly copy
  this PIL, so additional testing has become more
  of a compliance issue, rather than an exercise in
  PIL development.

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Copying the Originators PIL

• Certain originator companies are performing poor
  quality PIL development and testing, so the
  reference PIL can have difficulty passing
  readability tests. This occurs commonly in our
  experience.
• The competent authorities are reluctant to
  approve revisions when a PIL has previously been
  tested and approved.
• The testing becomes simply an issue of
  compliance. We have tested numerous PILs for the
  same APIs over the past few years.
• From a testing house for generics our position
  is
• Achieve a passing result to support the
  originators findings.
• Use qualitative data to provide constructive
  feedback for revising the PIL and leave the
  decisions to the competent authority.

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Work Sharing and Bridging Experience to Date

• Work sharing initiatives amongst smaller
  companies such as the BGMA scheme for the UK have
  saved our partner companies hundreds of thousands
  of Pounds/Euros in unnecessary testing.
• Bridging has been accepted as a common means for
  complying.
• Bridging has literally saved our partner
  companies over a million Euro in unnecessary
  testing.
• Cooperate with testing houses that have work
  sharing initiatives. Dont let your company be
  cornered into performing millions of Euros of
  unnecessary readability testing, when we already
  know the results!

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Ensuring success with Bridging

• Bridging is defined as using the readability
  testing results of the PIL for one medication to
  support the readability of the PIL for a similar
  or the same medication.
• Bridging is commonly used for generics.
• There is no known way of gaining access to
  originators readability testing results for use
  in bridging to date without their direct consent.

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Bridging

• An approved quality PIL and Readability Test are
  needed to reference for bridging.
• It is a cost effective and pragmatic way to
  comply with the burden of readability testing.
• Weve achieved success with bridging for the UK
  Patient Information Quality initiative and saved
  budgets over 1 million Euro on unnecessary
  readability testing.
• Bridging is also used for MRPs and DCPs when
  applicable.
• It is more useful and direct for developing
  uniform, patient friendly PILs at this stage.
• It is our clients 1st choice before complete
  readability testing now.

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Bridging Guidance

• EMEA Guidance concerning consultations with
  target patient groups for the package leaflet
• The evidence from tests on similar package
  leaflets may be use
• where appropriate. Examples of when this may be
  considered
• acceptable based on a sound justification by the
• applicant/marketing authorisation holder are
• extensions for the same route of
  administration e.g. intravenous/intramuscular or
  oropharyngeal/laryngopharyngea,
• same safety issues identified,
• same class of medicinal product. 

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Bridging CMD Guidance

• The CMD further defines 5 criteria which should
  be met to justify a bridging report
• Same drug class, Line extensions for the same
  route of administration
• Complexity of the message and language used
• Same safety issues identified
• Same patient population
• Same format of the PIL

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What to expect with Bridging

• The worst result you can achieve with a properly
  prepared and presented bridging study
• A focus test (takes about one week to perform and
  costs 2,000 euro normally) followed by approval
• The best result you can achieve with a bridging
  study
• Approval

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Bridging Strategy

• Bridging can be most effectively performed when
  there is a strategy in place
• Bridging on an Ad Hoc basis can be problematic if
  the PILs do not conform to a House style
  format.
• Additional focus testing can be required
• When performing readability testing, care should
  be used to ensure the most complex PIL of a line
  extension, or therapeutic group is tested first
  and consideration should be used for which one
  will be used by the most broad patient base.
• It is ideal and most effective to test the PIL
  considered most complex in its class
• This helps support the readability of similar
  PILs with less or slightly differing information.

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Bridging Strategy Example

• If you have a group of PILs for Product X with
  differing
• pharmaceutical forms, but the same API, which
  would be the
• most complex? (Generally Speaking)
• Infusion for Injection
• Tablets
• Capsules
• Prolonged release tablets
• Powder For Oral Suspension

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Preparing PILs for Bridging

• PIL writing should be taught within the company
  to the responsible people to ensure uniformity
• There are different styles which are acceptable,
  but one school of thought should be subscribed to
  within a company.
• In originator companies, RD writes PILs. In the
  generics, it is usually a RO.
• Glossaries and templates should be used for PIL
  writing
• When preparing Module 1 for MRP or DCP, the PIL
  should be presented in the company house style,
  not an exact copy of the reference PIL.
• It is difficult and sometimes impossible to
  bridge different writing styles to a certain
  company house styles.
• When you copy an originators PIL, chances are we
  will not be allowed access to Readability Testing
  Reports performed on PILs in their house style.

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Effective Bridging

• Bridging is most effective when the daughter
• PIL is written and prepared for Bridging to the
• Parent PIL or PILs!
• This shows assessors care was used not to
  compromise readability
• It definitely shows the pragmatic approach of
  bridging and leads to success

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Successful Bridging

• In order for bridging to be successful both the
  parent PIL or PILs and daughter PIL should
  meet most of the criteria
• Indication (identical or similar).
• Pharmaceutical form (it is most common to bridge
  different forms and strengths).
• Headings and Subheadings (should be identical).
• Placement of information (ensure messages are in
  same location on the PIL).
• Key messages for safe use (similar).
• Writing style should be similar.
• Same wording should be used wherever possible.
• Layouts, headings and descriptions should follow
  the same format.

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Successful Bridging

• Formatting of sections should be identical or
  closely similar.
• Complexity of the message should be similar.
• Meaning a PIL with 2 listed contraindications
  should not be used to try and support a PIL with
  10 contraindications.
• The artwork should be similar .
• Same dimensions of template.
• Same use of graphics, fonts and print size.
• It has become common to bridge PILs to 2
  previously tested PILs to ensure all criteria is
  met. Multiple Parent PILs can be used.

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Number 1 Point for Bridging

• The number 1 point for ensuring a successful
  bridge is well
• prepared PILs and readability tests! The
  reference PIL should be
• written to the highest quality and supported with
  a Readability
• Test. The PIL being bridged should also be
  written to the highest
• quality incorporating the text of the Parent PIL
  or PILs where
• ever possible.

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Bridging Reports for Different Nations

• Yes, it is possible.
• MEB has previously allowed for UK (MHRA) approved
  tests to be submitted with bridging studies for
  assessment.
• Success depends upon assessors in AFSSAPS and
  BfArM appraisal of the situation.
• National licenses have quite a few differences
  when compared, so additional testing may be
  required.
• Major originator companies are trying to use the
  UK testing results for the French market.

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Budgeting for Readability Testing

• For nations other than the UK, where readability
• testing will become a major burden, work
• sharing initiatives and well thought out bridging
• strategies will save the Generics Industry
• Millions!

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Thank you for your attention!

• If there are any other questions, please do not
  hesitate to contact me 
• Kurt Kinsey
• Pharma-EU s.r.o.
• Malostranske Namesti 23
• Prague 1
• 118 00
• Czech Republic
• Telephone [phone]
• kurt_at_pharma-eu.com

47
References

• European Commission's Draft Guidance Revised
  September 2006 Guideline on the Readability of
  the Label and Package Information Leaflet of
  Medicinal Products for Human Use
• European Commission's Guidance May 2006
  Guidance concerning consultation with target
  patient groups for the package leaflet
• EFPIA Document March 2002 General
  Recommendations for Readability User Testing of
  Package Leaflets for Medicinal Products of Human
  Use Submitted and Approved under the European
  Centralized Procedure
• CMD(H) October 2007 Consultation with Target
  Patient Groups - meeting the requirements of
  article 59(3) without the need for a full test -
  recommendations for bridging