CRED Practical Document Writing and Management

CRED: Document writing and management 31 July – 1 August, TOPRA Office, London

Preliminary Programme

Day 1: The Theory

Time Presentation

Speaker

09:00 Registration and Coffee 09:20 Welcome from TOPRA 09:25 Welcome from Chairman • Overview of the day 09:30 Introduction and AIM •

TOPRA

Joseph Irwin Lakeside Regulatory Consulting Services Ltd

Importance of good writing – Aim, Structure, Language • Style - Accuracy, Brevity, Clarity (ABC) • AIM: o Purpose of document o Who is my reader? What do they know already? o What are they going to do with the information? • Types of Documents – Internal reports, CTD, CTA, IND, briefing packages, responses to questions, cover letters • Tools such as Mind Mapping to gather all the data and information, and agree a “message” • When structure is already defined – ICH M4, Internal, Regulatory Authority (Eg EMA briefing packages) • When to stick to structural templates, when to deviate How to organise/build a document

10:15 Structure •

Joseph Irwin Lakeside Regulatory Consulting Services Ltd

11:00 Coffee

11:20 Language •

Hilary Gray Indivior UK Ltd

What makes a document hard to read? (long words, sentences, paragraphs) • Clear language important when English not first language of reader and/or document will be translated • Readability tools, e.g. Clarity Index, as objective measures of readability vs style preferences • Active v passive tense • Sentences – avoiding flannel and waffle

Time Presentation

Speaker

• Level of detail to help minimise future changes • Paragraphs & signposting • Smith v Brown example (Turk, C.C.R. (1978) Do You Write Impressively? Bulletin of the British Ecological Society, ix(3) 5–10) • Medical Writing accurate and detailed R&D reports • Summarising published literature

12:20 Lunch 13:05 Presentation of text •

Hilary Gray Indivior UK Ltd

Understanding Regulatory requirements • Importance of an Internal Style Guide and sticking to it (examples of style guides) • Templates • Tabulation vs written text • Requirements for Figures, tables

13:35 Case Study 15:00 Case Study presentations & discussion 16:00 An Agency’s perspective • Agency Expert - Opinion • Examples of good submissions • Must dos / Don’t do

Sue Harris (Formerly MHRA)

16:45 Close of Workshop - Day 1

CRED: Document writing and management 31 July – 1 August, TOPRA Office, London

Day 2: The Practice

Time Presentation

Speaker

09:00 Registration and Coffee 09:20 Welcome from Chairman • Overview of the day 09:30 Project Management •

Patricia Colin MDSSPRO

Getting from data to submission

Process

• •

RACI matrix

• Don’t forget reviewing and QC checking of data

10:00 Working with teams •

Tacye Connolly TOPRA

Defining objectives

Managing the teams and peers Managing disagreement

• •

10:30 Technical reports •

Patricia Colin MDSSPRO

Writing technical reports

Good practice Confidentiality

•

•

11:00 Coffee 11:15 Dossier Management •

Kathryn Brouder BioMarin Europe Ltd.

How it recorded, maintained and archived • a. Paper • b. Electronic - compatibility of the document - the size of the document (MB, KB) - the software required to read the documents (standard or specific) • Hyperlinking • CTD granularity • Change Management • ‘Global’ dossiers • How to deal with old, historical, non-CTD, paper dossiers • Avoiding drift What happens to the documents between leaving our desks and arriving on the reviewer’s desk • Why styles and technical requirements are important • What the Reviewer sees (has everyone seen an eCTD in practice?)

12:15 Regulatory Operations and Publishing •

Kathryn Brouder BioMarin Europe Ltd.

Time Presentation

Speaker

• How to handle images, do we need them and are they readable?

13:00 Lunch 13:45 MS Word - things all authors should know •

Pete Bennett Gilead Sciences International Limited

Use templates and styles and toolbars if given, do not invent your own • Heading • Captions • Tables • Table of Contents • Cross referencing within a document • Hyperlinking Regulatory Communications e.g. letters to agencies – best practice • Making the Agency letter an effective communication tool for assessors Writing Overviews – summarising the detail in a clear way • How to distil complicated details in a clear manner • Must dos / Don’t do

14:15 Regulatory Communications •

Tacye Connolly TOPRA

14:45 Writing Overviews •

Pete Bennett Gilead Sciences International Limited

15:15 Workshop – summarising complicated documents in an Overview Tea and coffee to be served during the workshop

All

16:45 Q&A and Wrap up of the day 17:00 Close of Workshop - Day 2

All

Delegates will be encouraged to ask questions throughout the day so as to ensure the meeting is as interactive as possible.

CRED Practical Document Writing and Management Introduction and AIM

31 July – 1 August 2018

Joseph Irwin FTOPRA, Director, LRCS Ltd

ENABLING AND PROMOTING EXCELLENCE IN THE HEALTHCARE REGULATORY PROFESSION

Learning Outcomes

 Review of communication both inside and outside the company  Review of process of generating concise communications for difficult or complicated topics  Understanding of the communication skills we have and the ones we need to develop

Importance of good writing

We are all writing history ● Everyday many emails and

communications are passing through our computers. ● Some critical ● some bland ● How do we distinguish? ● It is important to remember we are all writing the history of the product we work on.

Importance of good writing

Rapid communications are still permanent ● Sometimes we view modern communication systems as transient. ● Yet these records are more permanent that documents. ● All open for review during audits and inspections.

Importance of good writing

We are all good communicators ● To be here today it is because we are all good communicators ● We work in a highly technical area, working on complicated products ● We need high levels of education and further education ● We had to get through the interviews for our current and past positions ● Many of you managed to convince your line manager this course would help you in further career development

Importance of good writing

Good communications • Over the next two days we want to lift the bonnet and look at the workings of communications • Look at what we are communicating? • What is the purpose? • How we engage? • Who is our audience?

Importance of good writing

What are your expectations from this course?

CRED Practical Document Writing and Management Structure

31 July – 1 August 2018

Joseph Irwin FTOPRA, Director, LRCS Ltd

ENABLING AND PROMOTING EXCELLENCE IN THE HEALTHCARE REGULATORY PROFESSION

Learning Outcomes

 Review of company processes  Review of mind mapping techniques  Review of eCTD file structure  Review of building a submission

Structure

Company Processes ● When starting a document it is import to determine what is the document for? ● Documents maybe generated in line with SOPs ● Documents maybe generated in line with Laboratory Notebooks ● Documents maybe a structured output from laboratory equipment ● Listings maybe in line with a Statistical Analysis Plans (SAP) ● Yet none of these answer the question

Structure

Company Processes ● Documents are more and more tracked in detailed project plans where teams are allocated time to work on Document A, B C ● This is especially important in NDA/MAA submission where multiple documents are moving forwards in parallel ● Then there are overviews, Integrated Summaries and other cross review documents than need to be generated across multiple reports ● This requires the Project Team to be able to work on multiple documents, giving a consistent analysis of the data

Structure

Ad Hoc documents ● The project team will also be handling the questions and answers, request for new information or managing new information that could affect ongoing clinical trials or the overall submission. ● Management of ad hoc documents can be particularly difficult to resource as there are time restraints, resource restraints and often little guidance on the structure of these documents ● The lack of structure can make it difficult to work on but gives a freedom that highly defined structured documents lack. ● Main issue is how to determine how much time and resource level needed compared to other documents which will have internal benchmarking.

Structure

Thinking Process ● To determine what is the document for? ● Documents maybe for internal reporting purposes ● Documents maybe source data/ component for a CTD, CTA, IND, briefing packages, responses to questions, cover letters or other uses. ● Many of these documents have detailed guidance on how to prepare them. Though there will be other with lack of guidance or poor instructions. ● There is also the need to conserve structure of submissions from Agency to Agency as far as possible so a core structure/ content maybe required by the team to ensure the same information has been submitted in each market. ● This maybe the case for clinical trials applications where consistency across the IND, IMPD and other CTA documents is maintained globally.

Structure

Mind Mapping ● Some companies offer a series of mind mapping Tools for help build a image of what you want to submit. These include such packages as: ● Coggle is an online mind map that you can use in Chrome. ● Imindq ● FreeMind ● MindMapple ● Text2mindmap ● Sketchboard ● Really, you could use it anywhere where you want to organize things and make certain you understand all tasks you’ve got ahead of you.

Structure

Sometimes it is best to use simple idea ● Flipchart and Post it notes are a great way of working in a team environment

Structure

Design of a submission

Structure

Structure

Validation

High The error is a serious technical error which prevents the processing of the submission and will require resubmission. The submission is considered not received by FDA. Medium The error may impact the reviewability of the submission but cannot be determined without further inspection by the review staff. The submission might be considered received by FDA. Low The error is a technical error which may or may not impact the reviewability or the integrity of the submission. The submission will likely be considered received by FDA.

Description: More than one version of the us-regional.xml file exists Severity Description: High US DTD Version Problem: More than one us-regional.xml was found in the same sequence; the M1 element contains two leafs for regional files. Corrective Action: Resubmit with only one us-regional.xml and only one reference to a regional file per submission sequence. Guidance Source: General good practice to ensure reviewability.

Description: Unsupported DTD version in index.xml file Severity Description: High Problem: You are using an unsupported DTD version in the index.xml file. Corrective Action: Resubmit your submission using a version of the DTD that is supported. You may resubmit using the original sequence number of the submission. Guidance Source: ICH eCTD Specification V3.2.2; FDA eCTD Website

Structure

Need to meet Technical Conformance Guides eCTD Technical Conformance Guide (Guide) provides specifications, recommendations, and general considerations on how to submit electronic Common Technical Document (eCTD) based electronic submissions to the Center for Drug Evaluation and Research (CDER) or the Center for Biologics Evaluation and Research (CBER) 745A(a) of the Federal Food, Drug, and Cosmetic Act (FD&C Act) with respect to electronic submissions for certain investigational new drug applications (INDs); new drug applications (NDAs); abbreviated new drug applications (ANDAs); certain biologics license applications (BLAs); and master files submitted to CDER or CBER. https://www.fda.gov/downloads/Drugs/DevelopmentApprovalProcess /FormsSubmissionRequirements/ElectronicSubmissions/UCM465411.p df

Structure

Future structure and design • No submission is a solitary submission but a series of submissions over time. Consideration is needed on the building of the submissions e.g. NDA, Variations that fit together on the eCTD backbone.

Structure

Structure

Learning Outcomes: Recap

 Review of company processes  Review of mind mapping techniques  Review of eCTD file structure  Review of building a submission

Thank you

CRED Practical Document Writing and Management Language

31 July – 1 August 2018

Hilary Gray, Senior Manager Regulatory Strategy, Indivior

ENABLING AND PROMOTING EXCELLENCE IN THE HEALTHCARE REGULATORY PROFESSION

Learning Outcomes

 The importance of language in communicating clearly  Avoiding common mistakes  The importance of readability and how to measure it  Reducing wordiness  The importance of sentence construction  Developing your writing style

“ But I know not how it comes to pass, that professors in most arts and sciences are generally the worst qualified to explain their meanings to those who are not of their tribe .”

Jonathan Swift 1676-1745

The importance of language

• You are writing to communicate • Science: • Memos • Reports • CTD modules 3, 4 and 5 • Argument & Rationale: • CTD module 2 - Summaries & Overviews • Response to Questions • Briefing packages for meetings

Do I need good language skills?

Yes, good written English language skills are absolutely necessary ● Clear, unambiguous communication ● Text may be translated to other languages

However…

There comes a point at which clarity is more important than grammar ● Do not stress about minor points, for example: – Oxford comma

– -ise or –ize spelling – Punctuation of lists

Be clear, be consistent

What is your first language?

Do not assume that English is the first language of writer or reader Avoid: ● Slang – “Back in a tick” ● Euphemisms – “Vertically challenged” ● Humour ● Sarcasm Be mindful that words have different meanings in different countries ● “fortnight” ● “lift”

Foreign phrases and abbreviations

Avoid using where possible ● Write “for example” instead of “e.g.” ● Write “twice a day” instead of “b.i.d.” If you do use them, then make sure you use them correctly ● Vs. or v.s.? ● I.e. or e.g.? Custom used to be to italicise foreign words and phrases ● Now seen as old fashioned ● However, you may need to update older documentation ● Be consistent!

Common Latin abbreviations

e.g.

exempli gratia

for example

etc.

et cetera

and so on

i.e.

id est

that is

through the agency of or on behalf of

p.p.

per procurationem, per pro

v. or vs.

versus

against

v.s.

vide supra

see above

et al

et alii, et alia

and others

ca.

circa

about

cf.

confer

compare

N.B.

nota bene

note well

viz.

videlicet (‘it is permitted to see’)

namely, to wit

Common mistakes

There are three little words that sound the same. They’re different words – their meaning varies.

Where were you planning to go? We’re going to the beach.

A shower takes less water than a bath, so take fewer baths and more showers.

Less v fewer

Less means ‘not as much’ and is used with uncountable nouns ● For example “I have less annual leave than you.”

It can also be used to modify adjectives in a comparative sense ● For example “That equipment is less expensive to service than this brand.”

Fewer means ‘not as many’ and is used with countable nouns ● For example “I have fewer vacation days than you.”

Less v. fewer - exceptions

It is always incorrect to refer to less people ● People are individuals and come in numbers, not in amounts. When discussing money and time, and numerical amounts of quantity, it is usual to use “less than” ● For example, “The tablet blend weighed less than 7 kg.” or “I have less than an hour to prepare these samples.” This is because we are referring to the magnitude of the measured quantity (7 kg, an hour) rather than a count of individual units ● So, we say less than 7 kg, not fewer than 7 kg, because we are not referring to seven individual kilograms, but to a single amount of tablet blend that happens to weigh 7 kg.

Plural vs possessive

Tablets – plural, more than one tablet Tablet’s – possessive, belonging to one tablet Tablets’ – possessive, belonging to more than one tablet.

Beware

Its – possessive, belonging to something It’s – contraction of it is or it has

Capital letters

Lower case for all generic drug names; treat as nouns ● albuterol sulphate, sildenafil citrate, ibuprofen

Upper case for all trade and brand names; treat as proper names ● Ventolin, Viagra, Nurofen

Trade marks – registered or not?

What is the difference between TM and ® after a brand name?

TM is an expression of intent for a Trade Mark ● Does not require registration ● May indicate that a registration application has been made ● Does not convey legal rights ® denotes a registered trade mark ● Provides legal protection in each country with a registration ● It can be an offence in some markets to use ® without a registration

Companies may choose to use TM when they are entitled to use ® ● For example, packaging for multiple countries where not all are registered

The importance of readability

Measuring readability

• Subjective feedback not very useful • “I don’t like your style” • “It’s too wordy”

• Objective feedback is useful • Several measuring tools available • Scientific mindset understands and values measurements • Helps identify potential fixes • Reduce wordiness • Reduce sentence length

Readability tools

• Built into Microsoft Word ® • General guide • Based on US education system • Does not help review of clarity

Clarity Index

A measure of readability based on ● Number of long words – Defined as 3 syllables or more ● Average number of words in a sentence

Base on a sample of about 200 - 300 words ● General text, not tables ● Word will give you word count ● Roughly 2 – 3 paragraphs if working from a paper version

Clarity Index

Calculate number of words per sentence ● Count the number of major punctuation marks . : ; ! ? – (ignore commas) ● Calculate X = Calculate percentage of long words ● Identify & count long words in your sample ● Calculate Y = × The clarity index is X + Y

Clarity Index

< 20 childish 20

notices and signs

25 30

emails, letters and memos

general reports 35 - 40 technical/scientific reports >40 too complex and difficult to read

In conversation, most people subconsciously use an index of 25-30

For regulatory documentation, aim for an index of 30 - 40

EMEA guidance

Total number of words: Number of sentences: Average sentence length:

279

12 23

= X

77 ( 28 %) = Y

Words of more than two syllables:

CLARITY INDEX

51

You can now objectively describe why it is difficult to read!

Documents become difficult to read if they contain too many:

● Long words

● Long sentences

● Long paragraphs

Long words – why do we use them?

Unavoidable due to subject matter ● Drug names ● Standard terminology ● Acronyms – Each letter is a syllable

Avoidable long words/wordiness ● Excessive use of passive tense

● Euphemisms ● Neologisms – “the data has been graphed”

Wordiness

• Novice writers often feel that they have to pad out their writing with important sounding phrases and long words to give the content credibility. • We are taught passive academic style at University, which is wordy. • We think we need to write passive, wordy style • We like to read concise, active style • Turk, C.C.R. (1978) Do You Write Impressively? Bulletin of the British Ecological Society, ix(3) 5–10 • “ On average, Smith’s style was preferred, not only because it was more readable, but because it inspired greater confidence in his quality as a scientist .”

• Utilised • Discontinue • Occurrence • Demonstrate • It is apparent that… • In view of the fact that… Reducing wordiness - alternatives

• Dispatched • Proceeded • Your co-operation will be greatly appreciated.

Reducing wordiness - alternatives • Utilised…………………………… • Discontinue……………………. • Occurrence…………………….. • Demonstrate………………….. • It is apparent that…………. • In view of the fact that….. • Dispatched…………………….. • Proceeded …………………….. • Your co-operation will be greatly appreciated.

• Used • Stop • Event • Show • Apparently • Since • Sent • Went • Thank you

Wordiness - verbs

Three types of verb:

Active verb

● Bob hit James

Passive verb ● James was hit by Bob Verbal noun ● The hitting of James was carried out by Bob.

A regulatory nursery rhyme

The ascent of the hill was carried out by Jack and Jill, in order for a pail of water to be fetched by them. A downward fall was undergone by Jack and a breakage of his crown took place. An additional fall or tumbling was subsequently experienced by Jill .

Documents become difficult to read if they contain:

● Long words

● Long sentences

● Long paragraphs

Sentences

A sentence is a unit of thought. ● Should stand on it’s own ● Ended by . ? ! : ; -

Minor punctuation marks can help break up the sentence, ie , ( ) “ ‘

When describing a difficult idea or concept then keep the structure of the sentence simple.

The core message should be early in the sentence, as the reader notices and retains this better.

Length of sentences

On average 20 words, but best to vary the length and structure for interest ● Avoid too many long sentences, as the idea gets lost. ● Too many short sentences reduce the flow of the text. ● The writing can become dull and tiring if all the sentences are the same structure and length. ● Variety is the spice! Keep sentences short by: ● Keeping to one thought or idea per sentence. ● Using active verbs where possible. ● Avoiding unnecessary words or phrases. If you have a difficult concept – say it out loud

Developing your personal writing style

Style is the way something is written; it does not describe the content or science ● Word choice ● Use of adjectives ● Balance of active/passive ● Clarity index ● Sentence construction

● Lists, paragraphs, tables, figures You will have your own style

● It is rarely a question of right or wrong, but what is best for the reader ● Skilled writers can adapt their style for the needs of each document

Working with different styles

• Summarising from different sources • Literature references • CSRs • Technical reports • Other internal documents/documentation • Harmonise language to the document you are writing

wherever possible • Naming convention • Technical terminology

Learning Outcomes: Recap

 The importance of language in communicating clearly  Avoiding common mistakes  The importance of readability and how to measure it  Reducing wordiness  The importance of sentence construction  Developing your writing style

Reference

Effective Writing – Improving scientific, technical and business communication. Christopher Turk and John Kirkman. ISBN 0-203-78134-1 (Adobe eReader Format) ISBN 0-419-14660-1 (Print Edition)

CRED Practical Document Writing and Management Presentation of text

31 July – 1 August 2018

Hilary Gray, Senior Manager Regulatory Strategy, Indivior

ENABLING AND PROMOTING EXCELLENCE IN THE HEALTHCARE REGULATORY PROFESSION

Learning Outcomes

 Importance of presentation  Understanding what authors can and can’t control  Balance of text vs tables and figures  Use of templates  Importance of style guides

Importance of presentation

Think of your reader…

A well presented and ordered document gives a positive message about the author: ● Organised ● Rational ● Attention to detail ● Considerate of the reader

Do not discourage your regulatory reviewer with bad presentation before they have even read a word! ● For “fine detail” readers, this is a distraction to the content

Presentation of text

Not controlled by Author ● Organisation/Headings ● Format ● Font ● Page size ● Line spacing ● References

Controlled by Author ● Subheadings ● Paragraph length ● Tabulation of data vs prose ● Use of tables and figures ● Lists

● Format of Tables ● Signature pages ● Appendices ● …

Not controlled by the author…

Regulatory requirements - examples

ICH: ● E3: Clinical Study Reports ● M4: Common Technical Documents

FDA: ● Guidance for Industry: Formal Meetings Between the FDA and Sponsors or Applicants of PDUFA Products

EMA: ● CHMP protocol assistance/scientific advice briefing document template

Templates - why

Meet regulatory guidelines and expectations Consistent, professional presentation ● Important for multi-document dossiers such as CTD Allow authors to focus on the content and message ● Take away decisions on formatting ● Aids multi-author documents ● Do not have to be experts on Microsoft Word ® functionality

Templates

Most organisations have a “house style” for internally generated documents

● Memos ● Letters ● Reports Defines the presentation and format, such as: ● Font ● Page size ● Line spacing ● Logos ● References ● Format of Tables

Templates

Commercially available templates for regulatory documentation ● CTD Dossier sections ● Briefing packages ● Responses to questions

All define layout & styles

Some also contain guidance text

Some require installation of macros, ribbons, widgets

Example - CHMP briefing document template

Style guides

Public ● WHO (World Health Organisation) ● AMA (American Medical Association) ● ACS (American Chemical Society) ● …and many others

Company based ● Branding, presentation, technical specifications – FDA Visual Identity Guidelines – TOPRA slides ● Content style

Content style guides: Examples

● British or American English spelling? ● Date and Time format – 31 Jul 2018, 24 hour clock ● Number usage ● Symbols and Equations – No spaces between numbers and symbols ● Units – SI, use ml not mL ● Presentation of tables & footnotes ● Reference/citation conventions – Harvard (Smith 2010) or Vancouver (1)?

Controlled by the Author…

Documents become difficult to read if they contain too many:

● Long words

● Long sentences

● Long paragraphs

Paragraphs

A paragraph is a theme Good paragraphing makes for easier reading Short paragraphs make reports look easier to read ● Rule of thumb of about 6 sentences per paragraph ● Sometimes a one sentence paragraph is a very effective way to grab the reader’s attention and to make a key point Bulleted lists are a good way of summarising key information and breaking up paragraphs ● Useful in introductions and summaries Consider using subheadings

Signposting

Signpost the paragraph ● The first sentences of the paragraph are “topic sentences”. ● They briefly introduce the theme of the paragraph to the reader, and should be short sentences of no more than 14 or 15 words. ● Speed readers use the signposts when they skim a document to decide how closely they need to read it. ● See most broadsheet newspapers for examples.

Tables & figures

Humans receive information visually

Well presented tables & figures make the document appear more interesting

Break the “wall of text” with ● Graphs ● Diagrams ● Flow charts ● Pictures

Tables

● Numerical data much easier to review if tabulated ● Shows organisation of data ● Do not duplicate information in text – Do pick out and discuss any data of interest in the text, for example unusual or out of trend figures ● Avoid tables with one line of data unless part of a series of tables ● Pay attention to formatting

Narrative listing of data

During the clinical studies, adverse events with an incidence greater than 1.0 % were headache (7.3 %), fatigue (4.5 %), nausea (2.9 %), abdominal pain (1.6 %), somnolence (1.4 %) for the active (n=1730), and for the placebo (n=1250) they were headache (7.8 %), fatigue (2.8 %), nausea (1.9 %), abdominal pain (0.3 %), somnolence (0.6 %)

Tabular summary of data

Table 1 Adverse events with an incidence > 1.0 % in placebo- controlled studies

Active (%) (n=1730)

Placebo (%)

(n=1250)

Headache

7.3 4.5 2.9 1.6 1.4

7.8 2.8 1.9 0.3 0.6

Fatigue Nausea

Abdominal Pain

Somnolence

Figures (graphs, diagrams & pictures)

Use whenever they add to the understanding of the text ● Plots of PK data ● Patient flow charts for screening and assignment in studies ● Manufacturing process flow charts ● Non-standard equipment ● Tissue changes in non-clinical studies If your figures take up more space than the text, then review carefully ● They are an aid - do not use instead of explanations ● Be careful with formats

Learning Outcomes: Recap

 Importance of presentation  Understanding what authors can and can’t control  Balance of text vs tables and figures  Use of templates  Importance of style guides

References

CHMP briefing document template http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2 010/06/WC500093259.doc WHO (World Health Organisation) style guide http://www.ianphi.org/_includes/documents/sections/toolkit/who_style- guide.pdf AMA (American Medical Association) style guide http://www.amamanualofstyle.com/ ACS (American Chemical Society) style guide Effective Communication of Scientific Information Editor(s): Anne M. Coghill, Lorrin R. Garson ISBN13: 9780841239999

CRED Practical Document Writing and Management

The Regulator’s Perspective

31 July 2018

Sue Harris Unit Manager MHRA (Retired)

ENABLING AND PROMOTING EXCELLENCE IN THE HEALTHCARE REGULATORY PROFESSION

Learning Outcomes

 Principals of assessment  The dossier from the regulator’s viewpoint  Examples of submissions – good and bad  Hints and Tips – the Do’s and Don’ts

What is Assessment???

What is Assessment???

Assessment is a balancing act……………….

What is Assessment???

On the one hand…………………. Regulators have a key responsibility to protect public health .

On the other hand…………………… Regulators have a responsibility not to impose unnecessary burdens on the pharmaceutical industry, as this may delay the introduction of new medicines and treatment regimens.

We are looking for a positive benefit to risk ratio.

Working with the Regulators

Understand our remit…………………….

X We are NOT there to TELL you what to do!  We ARE there to ADVISE and HELP you

The Dossier

Thought for today ………………

The quality of the dossier is key to the success of a regulatory submission.

It is the data in your dossier that enable us to make an informed decision on the benefit / risk ratio.

If you’re not sure………

Just ask…………….

Regulators are happy to provide:

 Scientific advice  Regulatory advice

To help you prepare the best dossier possible

What Do We Find During Dossier Review?

 Acceptable data and supporting statements  Mistakes, transcription errors, grammatical / spelling errors, inconsistency between sections  Gaps/omissions - Not in line with legislation / mandatory requirements - Not in line with guidance - Aspects not discussed / sections of CTD not completed - Out of date information e.g. CEPs / ASMFs  Inappropriate strategy/approach  Compliance issues

Module 2 - What Makes a Good Quality Overall Summary (this is NOT a question!)  Follows scope/outline of body of data in Module 3

 Short, concise

 No new data/information

 Aim to provide Quality Assessor with a critique of M3:  Rather than a ‘cut and paste version of M3  Emphasize critical key parameters of drug substance/product  Provide justification where guidelines not followed  Discuss key issues which integrate information from Quality module and supporting information from other Modules e.g. qualification of impurities via toxicological studies included in Module 4, Non-Clinical.

 Make it worth reading!

Example of a GOOD dossier

Nonapeptide Implant

 Drug substance a synthetic nonapeptide analogue of naturally occurring gonadotrophin releasing hormone.  Complex product

 Sterile non-biodegradable miniaturised implant  Osmotically driven drug delivery technology

Nonapeptide Implant

A B C

D

E

A Membrane (polyurethane) B Osmotic Engine (NaCl + excipients) C Piston (Elastomer) D Drug formulation (Nonapeptide + DMSO) E Diffusion moderator

Nonapeptide Implant

Development Pharmaceutics COMPONENTS  - Nonapeptide Formulation  -Reservoir  -Diffusion Moderator  -Membrane  -Piston  -Osmotic Engine  -Subassembly  - Implant Primary Packaging LEACHATES IN-VITRO PERFORMANCE

Nonapeptide Implant

METHOD OF MANUFACTURE

 -Preparation of Components

 -Assembly and sterilisation of Sub-assemblies

 -Final Product Manufacture i.e. Sub-assembly, drug formulation and diffusion moderator are combined with the protective cap and packaging materials to produce the final packaged product.

Nonapeptide Implant

Why was this application so good????  Well presented, comprehensive, logical dossier  Complied with the guidelines  All aspects of the product fully addressed  Quality DESIGNED into the product

Example of a BAD dossier

Example of a bad dossier!!!!

 A New Chemical Entity submitted under Article 8(3), via the Decentralised procedure.  NL were reference member state  UK one of four concerned member states.  Applicant sought scientific advice from both the RMS and the UK before preparing the dossier.

RMS Day 70 Preliminary Assessment report

RECOMMENDATION

Based on the review of the data on quality, safety and efficacy, the RMS considers that the application for xxxxx in the treatment of yyy, is not approvable since "major objections" have been identified, which preclude a recommendation for marketing authorisation at the present time. The details of these major objections are provided in the preliminary list of questions (Section V).

RMS Day 70 Preliminary Assessment report

12 Major objections on quality 123 points for clarification on quality

2 major objections on the pre-clinical 7 points for clarification on the pre-clinical

5 major objections on the clinical (including the indication) 26 points for clarification on the clinical (including he risk management plan)

1 major objection on Module 1 3 points for clarification on Module 1

RMS Day 70 Preliminary Assessment report

20 Major objections

159 points for clarification

From the RMS!!!!!!!!

The indication – major objection

RMS comment: The proposed indication xxx is not in line with the proposal the applicant pointed out during the meeting with RMS, where it was emphasized that the indication sought for was planned to be second-line (see further below). The applicant is requested to elaborate on this change in strategy.

Module 3 – Major Objection

General The quality of all Module 3 sections is very poor, as reflected by the large number of major objections and other concerns, and should be significantly improved. The applicant should demonstrate that it is aware of current European quality guidelines, understands and is able to control the manufacturing processes of the proposed drug substance and drug product in order to ensure an adequate quality.

Outcome

The application was withdrawn.

Pharmaceutical assessor’s comment:

…………………this is probably the worst application that I have seen in 30 years!!!!

More bad examples…….

Single-dose injection – containing a preservative!

Various formulations containing different preservatives were evaluated. The product was not sterile without a preservative, benzyl alcohol is toxic and methylhydroxybenzoate has too wide a pH range. Chlorobutanol was selected on the basis that it maintained sterility and is stable at room temperature in acidic solutions.

Think about the consequences of your actions!

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Antibiotic Lyophilised powder for solution for Injection - GMP Issue ??

 Manufacturing site in China

 Assessor requested further information on the lyophilisation process

 Applicant responded with a lot more data

AND

 A video ……………………. (which we DIDN’T ask for!!!!)

Hints and Tips………. or, How to make your Assessor a happy bunny………..

Tips for a happy assessor

 Proof read your submission  Consider what it will be like to assess your dossier  If it doesn’t make sense to you then we don’t stand a chance…  Quality, not quantity  Summarise where appropriate

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Hints and Tips

 Follow the guidelines – or justify fully if you don’t  Presentation: - First impressions count! - GOOD ENGLISH (don’t rely on spellchecker) - minimise errors - legible graphs etc.  Consistency

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Hints and Tips

Do:  Know your member states  Choose your RMS carefully  Ask for advice if unsure  Follow advice received from competent authorities or justify otherwise  Tell the full story  Be concise and avoid repetition Don’t:  Ignore advice received from competent authorities  Throw everything you have into the dossier and hope for the best  Tell a partial story…then fill in blanks later

Hints and tips

Do:

 Be honest - explain inconsistencies or issues in the data  Provide good quality tables and figures with labelling

 Give comparisons on the same page  Read and consider relevant guidance

Don’t:

 Ignore inconsistent or troublesome data  Provide unclear figures or data not in English language  Assume that data support your theory without further discussion 123

Learning Outcomes: Recap

 Principals of assessment  The dossier from the regulator’s viewpoint  Examples of submissions – good and bad  Hints and Tips – the Do’s and Don’ts

“ Quality is never an accident. It is always the result of intelligent effort. There must be the will to produce a superior thing .”

John Ruskin (1819 – 1900)

Acknowledgement:

Dr. Linda Anderson Expert Pharmaceutical Assessor MHRA

CRED Practical Document Writing and Management Project management

31 July – 1 August 2018

Patricia Vest, Director, MDSSPRO

ENABLING AND PROMOTING EXCELLENCE IN THE HEALTHCARE REGULATORY PROFESSION

Learning Outcomes

 To learn the principles of project management  To learn how to apply it to your own projects  To be more efficient in managing projects

Why to use the project management concept?

To deliver the project on time To deliver the project within the expected costs To deliver the project according to the client expectations ● Who is your client? − A competent authority

− The stakeholders − The notified body

What do we need ?

To have clear objectives To know what the requirements are To know what the process is To have a budget To have a team

Principles of project management

A project is usually managed in 5 phases

Conception Initiation

Definition and planning

Launch and execution

Performance and control

Project close

Conception/Initiation

This is a feasability analysis to decide if the project is taking place ● Business needs

● Costs ● Price ● Timeline ● SWOT

Project planning

This is defining a roadmap with SMART objectives (specific, measurable, attainable, realistic and timely) This involves: ● Cost, quality, available resources, and a realistic timetable ● Use of RACI matrix

Project planning

What is a RACI matrix? ● Responsible ● Accountable

● Consulted ● Informed

Project planning

How to do a RACI matrix? ● Identify all the tasks involved in delivering the project and list them on the left-hand side of the chart in completion order. ● Identify all the project roles and list them along the top of the chart. ● Complete the cells of the chart identifying who has the responsibility, the accountability and who will be consulted and informed for each task. ● Ensure every task has a role responsible and a role accountable for it. ● No tasks should have more than one role accountable. Resolve any conflicts where there is more than one for a particular task. ● Share, discuss and agree on the RACI Matrix with your stakeholders before your project starts.

Project planning

Example of RACI matrix

Project planning

What the deliverables are: ● Scope Statement ● Work Breakdown Schedule (WBS)

● Milestones ● Gantt chart

● Communication Plan ● Risk Management Plan

Project planning

Example of Gantt chart

Project planning

Project Execution

This involves the following activities: ● Develop team ● Assign resources ● Execute project management plans ● PM directs and manages project execution ● Task assignments are executed ● Status meetings ● Update project schedule ● Checking the quality of the deliverables

Project performance and monitoring

to check the project is on track using KPIs ● Measuring if a project is on schedule and budget ● Specific task deliverables are being met ● Effort and Cost Tracking ● Project Performance

Project closure

Project completed. Contractors hired are terminated at this time. Valuable team members are recognized. Small work events for people who participated in the project to thank them for their efforts. Meeting to evaluate what went well in a project and identify project failures.

Learning Outcomes: Recap

 Principles of the project management  How to use it  A better understanding of the project management

CRED Practical Document Writing and Management Working with teams

31 July – 1 August 2018

Tacye Connolly Director of Policy, TOPRA

ENABLING AND PROMOTING EXCELLENCE IN THE HEALTHCARE REGULATORY PROFESSION

Learning Outcomes

 Role of working in teams  Defining team objectives  Tips for managing the teams and peers  Managing disagreement

In the context of preparing regulatory documents

What makes a successful team?

Shared understanding of mission Commitment to teams goals Clearly defined roles and responsibilities Agreed ground rules Established decision making model Good communication

Role of Regulatory Affairs (1)

Corporate/Central

Local/Regional

• Central involvement in development process • Core dossier • Global regulatory strategy • Core labelling profile • IND, CTA, NDA, MAA • Scientific advice • Due-diligence/Reg Intel. • Global SOPs • Pharmacovigilance • Medical • ePublishing • Global business development

• Country/Region specific data • Product information • Local developments and specific variations • Local/regional RA strategy • Technical support, CTAs • Pharmacovigilance • Due-diligence/ Local Reg. Intel. • Local SOPs • Medico-Marketing • ePublishing • Local business development

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Role of Regulatory Affairs (2)

• Technician • Technical writer • Document manager • Data manager • Manufacturer • Scientist • Editor • Proof reader • Information specialist • Expert • Philosopher

• Manager • Team leader • Team player • Project manager • Politician/Diplomat

• Negotiator • Organiser • Strategist

• Seller • Buyer

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Regulatory Input into Product Development

Gene - Function - Target Association

Life- cycle manage- ment

Disease selection Target family selection

Candidate selection to FTIH

PoC to commit to Phase III

Phase III

Target to Lead

FTIH to PoC

File & Launch

Lead to Candidate

During Development Can we get Orphan Designation? Eligible for Accelerated Designation Do we need a Paediatric Investigational Plan

How do we maximise life cycle management?

Following Initial Opportunity Assessment What lessons can we learn from previous development projects?

Prior to Submission Does the data support the proposed labelling? What can we learn from competitor’s experiences?

Initial Product Profile What studies will be needed? What are the issues we need to discuss with reg authorities?

Prior to Large Scale Clinical Trials Have we agreed our development plan with Regulators? Does the trial design meet regulatory/clinical end points?

Prior to First Time in Human What do the animal data tell us? Do we need to amend our target group on the basis of tox findings?

Interactions During Development

Formulation

Clinical Research

Sales and Marketing

RA

Preclinical Research

Manufacturing

Quality

Defining Team objectives

• What is the objective? • Gain approval for MAA

• Minimise lifecycle management • Maximum sales? Who are your stakeholders and customers?

Think of your Stakeholder Relationships as one of Internal and External customers and/or suppliers

External Customers Internal Customers

YOU

Internal Suppliers

External Suppliers

Defining objectives

• What is the objective? • Gain approval for MAA

• Minimise lifecycle management • Maximum sales? Who are your stakeholders and customers? Ensure you’re objectives are feasible And that they are shared!

Strategic planning process

Managing teams and peers

Regulatory has a lot of interactions with different disciplines and levels of seniority • Clear understanding of your role • Confident in your knowledge and input • Listen • Understand other positions and concerns • Maintain good communication • Project management

Managing disagreements

Understand peoples starting positions Understand your team

Managing disagreements

Understand peoples starting positions Understand your team Stay focused on your objectives Try to reach a compromise if you can Celebrate your successes!

Reminder

• Technical and regulatory competences are essential to be a successful RA professional

BUT TO MAKE THE DIFFERENCE • Good communication skills • Good management skills

• Good planning skills • Good leadership skills

plus the ability to sell yourself, your ideas, your product and your profession are all important for your personal success and the added value of Regulatory Affairs.

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Learning Outcomes

 Role of working in teams  Defining team objectives  Tips for managing the teams and peers  Managing disagreement

CRED Practical Document Writing and Management Technical reports

31 July – 1 August 2018

Patricia Vest, Director, MDSSPRO

ENABLING AND PROMOTING EXCELLENCE IN THE HEALTHCARE REGULATORY PROFESSION

Learning Outcomes

 To identify the structure of a technical report  To be more efficient at doing it  To be clearer  To adapt the content to the type of report

Structure of a technical report

Introduction

● To set the scene

Description of the objective Material and methods Results and analysis Conclusion

Examples of technical reports

Biocompatibility report Clinical evaluation report Validation of sterilization Toxicology report Technical file

What is the Objective?

Describe clearly the objective of the report ● Demonstrate the safety of the device? ● Demonstrate compliance with requirements? – Which ones? ● Demonstrate compatibility between medicine and device? ● Demonstrate performance of the device not affected by sterilization?

How to put it in the global picture?

Identify other documents linked to the assessment ● Internal Procedure ● Regulation ● Applicable standard ● MEDDEV

● GLP ● GMP

Describe material and method?

Why? ● T o give confidence to the reader the conditions used are correct ● To demonstrate compliance with the regulatory/ISO requirements How? ● Describe the material used (equipment, raw material, type of animal, type of cells, media…) ● Describe the methodology used