IN THIS ISSUE: REGULATORY ROUND UP Special features Protecting Your CompanyCultureDeveloping BiosimilarsNo mother should die....

JOURNAL OF THE BRITISHASSOCIATION OFPHARMACEUTICALPHYSICIANS

PHARMACEUTICAL PHYSICIAN

SEPTEMBER 2016 VOLUME 26 | NO6

Resourcing Solutions for Medical Affairs, Pharmacovigilance and Clinical Development

Providing Pharmaceutical Physicians

www.axess.co.uk

This is just a selection of the current assignments with our pharmaceutical clients. For a confidential discussion please telephone Beth Thomas-Stonier at AXESS Limited on 020 8560 2300. To apply please send your CV to jobs@axess.co.uk quoting the reference number.Visit our website www.axess.co.uk to register for jobs by e-mail – new roles that match your criteria e-mailed to you on the same day that they are posted.

Permanent RolesGlobal Medical Lead COPD Global Pharma – Medical Affairs and Evidence Generation London PP 6700Medical Director UK/Ireland Global Biotech – multiple TAs, significant team W London PP 6677Global Medical Director Global Pharma – support a number of assets in Respiratory W London PP 6701Medical Director UK – Renal International Pharma Surrey PP 6654Associate Director Medical Affairs UK/ Ire – Oncology Global Biotech – team leadership London PP 6664Head of Medical Affairs UK/ Ire – Oncology Global Biotech W London PP 6652Medical Manager UK Oncology International Pharma – colorectal launch and line management Berkshire PP 6364Medical Manager UK Cardiometabolics International Pharma – launch and line management Berkshire PP 6687Senior Global Medical Advisor Specialty Pharma – Oncology launch Middlesex PP 6695Senior Global Medical Advisor Specialty Pharma – GI Middlesex PP 6696Medical Manager UK – Fertility Global Biotech – leading drug / med tech portfolio W London PP 6658Medical Manager UK – Neurology Global Biotech – launch in MS W London PP 6697

Head of Clinical Research Global Pharma – Early Development, team leadership W London PP 6674Discovery Medicine Physician (Medical Director) Immunology Global Pharma – Early Development, FIH, Biomarker London PP 6699Medical Fellow/ Associate Director/ Principal Investigator Early Development, management role, unique model Nottingham PP 6483Director Clinical Development – Oncology Global Pharma W London PP 6634Associate Director Clinical Development – Oncology / Immunology Global Pharma W London PP 6566Clinical Research Physician – Oncology Growing CRO Berkshire PP 6683Senior Study Physician Early Development South Wales PP 6293

Associate Director, Senior PV Physician/Deputy QPPV Specialty Pharma – Global team Middlesex PP 6685Senior Safety Evaluation Physician Global Pharma Full cycle PV, focus on Oncology Hertfordshire PP 6690Global Safety Senior Medical Scientist Global biotech, Strategic EU role Cambridge PP 6641

PHARMACEUTICAL PHYSICIAN

Published 6 times per annum by BrAPPRoyal Station Court, Station RoadTwyford, Reading, Berkshire RG10 9NF. Telephone +44 (0)118 934 1943 Fax +44 (0)118 932 0981 Email info@brapp.org www.brapp.org

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BrAPP grants editorial freedom to the editor of Pharmaceutical Physician.

The views expressed in the journal are those of the authors and may notcomply with the views of BrAPP or the authors' own companies.

© BrAPP ISSN 0960-6548

EDITOR: DR MADHU DAVIES

EDITOR@BRAPP.ORG

EDITORIAL BOARD: DR JANE BARRETT

DR HUGH BOARDMAN

DR DAVID FOWLER

LIZ LANGLEY LIZ@BRAPP.ORG

DESIGN: DANA KIDSON

DANA.KIDSON@GMAIL.COM

EDITORIAL 3

REGULATORY ROUNDUP 4Anne Hetherington

NEWS 6MHRA Update

SPECIAL FEATURE 7Protecting Your CompanyCultureTarquin Bennett-Coles

SPECIAL FEATURE 9Developing BiosimilarsSanjay Jain

MEETING REPORT 142nd Annual REAL WORLDChallenge ConferenceSam Oliver and Amanda Pulfer

SPECIAL FEATURE 20No Mother should die…..

BOOKS 24

TRIBUTES 26Drs John Young, Chris Allenand Gurpal Singh Gosall

Contents

SEPTEMBER 2016 VOLUME 26 | NO6

CARDIFF UNIVERSITY/BRAPP

POSTGRADUATE COURSE IN PHARMACEUTICAL MEDICINEAn interactive, modular course providing broad knowledge-based learning across the specialty ofpharmaceutical medicine; run by BrAPP working closely with Cardiff University.

Modules are mapped to the syllabus for the UK Diploma in Pharmaceutical Medicine exam.

Ten two-day, non-residential modules run in central London from January 2017 to July 2018. (The exception isModule 1 which is held at Cardiff University.)

Expert teaching is provided by a wide spectrum of industry and academic experts and includes an IntegralRevision module and a Critical Appraisal workshop run by Dr Richard Kay..

Places are limited to 25 delegates.

For further information and to register please contact:PGCPM@brapp.org or visit www.brapp.org or call +44 (0) 118 934 1943

SEPTEMBER 2016 volume 26 | No 6PHARMACEUTICAL PHYSICIAN

3

THE METEOROLOGISTS TELL us that1 September is the start of Autumn inthe northern hemisphere. Generallythose of us residing in the UK hope fora so-called “Indian Summer” to make upfor a disappointing July and August –will it come or not – the tension mounts.

No-one, however, could accuse thissummer of being dull. The seismicevents of 23 June have yet to settle andwhichever side of the divide you findyourself, the next months - and perhapsyears - are certainly not going to beboring. It is still hard to predict thefuture implications for our industry inthe UK but it behoves us all to maintainan outward-facing view and keep ourrespective ships on an even keel. AsWinston Churchill, that great Europeanonce said “KBO”.

This issue of PP culminates in the sadloss of three influential physicians who,in their individual ways, have made animpact on pharmaceutical medicine andBrAPP. We pay tribute to Drs JohnYoung, Chris Allen and Gurpal Gosall.At the same time and in lighter vein wesay farewell to Cheryl Merridew,administrator of the Cardiff Course for15 years into the noughties and DrRobert Dewdney, Director of Education,so helpful and committed to the recentchanges in direction and organisation ofthe PGCPM, who are retiring from theCardiff School of Pharmacy. Happydays, we hope, to come.

Our September issue offers its usual mixof interesting articles. Tarquin Bennett-Coles discusses the importance ofcompany culture; a topic oftendiscussed when pharmaceuticalphysicians get together. As one meetsnew entrants to industry it is strikingthat cultural change and theunderstanding of the prevailing cultureof an organisation are sometimes thebiggest hurdles to be surmounted inachieving success. Happy people makesuccessful outcomes!

We are grateful to Anne Hetheringtonfor, once again, a very useful Regulatory

RoundUp and to Sanjay Jain for a timelyreminder of the specifics of biosimilarsdevelopment.

The collection and utilisation of RealWorld Data and Real World Evidenceare topics always sure to elicit debatewhen physicians in clinical researchmeet those directly involved in HTApreparation. A report on the 2nd REALWORLD challenge Conference mayanswer some burning questions or fuelthe debate – don’t miss it.

Hot from a very successful session atthe recent Faculty Education Day, LizClark reviews a handy tome for thosewrestling with the challenge of coachingand leading people – a book foreveryone.

And Paul Robinson returns to PP with afurther insight into how industry mightharness its resources, expertise, moneyand the goodwill of its people toimprove the well-being of patientsaround the world.

It only remains to say that if you arereading this around the time ofpublication that we wish all candidatesfor the forthcoming Diploma inPharmaceutical Medicine examinationsgood luck and success.

Dr Madhu Davies

EDITORIAL

Dr Madhu Davies

REGULATORY ROUND UP

By Anne Hetherington, Senior Regulatory Consultant

HERE IS THE LATEST ROUND UP OF REGULATORY NEWS FROM THE LEADING

AGENCIES, INCLUDING THE EUROPEAN MEDICINES AGENCY (EMA), THE MEDICINES

AND HEALTHCARE PRODUCTS REGULATORY AGENCY (MHRA) AND THE FOOD AND

DRUGS ADMINISTRATION (FDA). EMPHASIS IS PLACED ON THOSE NEW

REGULATIONS WHICH IMPACT ON CLINICAL AREAS.

PLEASE CLICK ON THE LINKS BELOW TO TAKE YOU TO THE RELEVANT ITEM.

WE HOPE THAT YOU WILL FIND THIS DIGEST OF INTEREST. IF YOU HAVE ANY

COMMENTS OR QUERIES PLEASE CONTACT US AT INFO@ENVIGO.CO.UK.30 ST THOMAS PLACE,CAMBRIDGESHIRE BUSINESS PARK, ELY,CAMBRIDGESHIRE CB7 4EX, UK T +44 (0) 1353 645 590

ENVIGO.COM

September 2016 volume 26 | No 6

4PHARMACEUTICAL PHYSICIAN

1. EUROPEAN MEDICINES AGENCY (EMA)News and press releases• Involving general practitioners in

regulatory decisions on medicineshttp://www.ema.europa.eu/ema/index.jsp?curl=pages/news_and_events/news/2016/04/news_detail_002519.jsp&mid=WC0b01ac058004d5c1

• Regulatory information - EUrecommendations for compositionof 2016/2017 seasonal influenzavaccineshttp://www.ema.europa.eu/ema/index.jsp?curl=pages/news_and_events/news/2016/04/news_detail_002505.jsp&mid=WC0b01ac058004d5c

• Antimicrobial resistancehttp://www.ema.europa.eu/ema/index.jsp?curl=pages/special_topics/general/general_content_000439.jsp&mid=WC0b01ac058002d4e9

• Progress in science, medicine andhealthhttp://www.ema.europa.eu/ema/index.jsp?curl=pages/news_and_events/

news/2016/05/news_detail_002531.jsp&mid=WC0b01ac058004d5

• Can regulators influence theaffordability of medicines?http://www.ema.europa.eu/ema/index.jsp?curl=pages/news_and_events/news/2016/05/news_detail_002529.jsp&mid=WC0b01ac058004d5

Updates• Implementation of the

pharmacovigilance legislationhttp://www.ema.europa.eu/ema/index.jsp?curl=pages/regulation/general/general_content_000520.jsp&mid=WC0b01ac05804fa031

• Monitoring of medical literatureand entry of adverse reactionreports into EudraVigilancehttp://www.ema.europa.eu/ema/index.jsp?curl=pages/regulation/general/general_content_000633.jsp&mid=WC0b01ac05808ce84c

• 2015 annual report of theEuropean Medicines Agency

Anne Hetherington

http://www.ema.europa.eu/docs/en_GB/document_library/Annual_report/2016/05/WC500206482.pdf

• Guidance for implementation ofeligibility requirementshttp://www.ema.europa.eu/docs/en_GB/document_library/Regulatory_and_procedural_guideline/2015/05/WC500187018.pdf

• Adaptive pathwayshttp://www.ema.europa.eu/docs/en_GB/document_library/Regulatory_and_procedural_guideline/2015/11/WC500196726.pdf

• Needs for paediatric medicineswww.ema.europa.eu/ema/index.jsp?curl=pages/regulation/document_listing/document_listing_000096.jsp

Scientific guidelines• Reflection paper on extrapolation

of efficacy and safety in paediatricmedicine development (draft)http://www.ema.europa.eu/docs/en_GB/document_library/Regulatory_and_procedural_guideline/2016/04/WC500204187.pdf

• Draft concept paper on anaddendum to the guideline on theevaluation of medicinal productsindicated for treatment of bacterialinfections (CPMP/EWP/558/95 Rev.2) to address paediatric-specificclinical data requirements (draft:consultation open)http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2016/04/WC500205026.pdf

• Draft guideline on clinicalinvestigation of new medicinalproducts for the treatment of acutecoronary syndrome (draft:consultation open)http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2016/04/WC500205365.pdf

• Compilation of individual product-specific guidance on demonstrationof bioequivalence (Revision 3)

(adopted)http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2016/04/WC500204549.pdf

• Appendix 2 to the guideline on theevaluation of anticancer medicinalproducts in manhttp://www.ema.europa.eu/docs/en_GB/document_library/Other/2016/04/WC500205159.pdf

• Concept paper on the revision ofthe 'Guideline on theenvironmental risk assessment ofmedicinal products for human use'(draft: consultation open)http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2016/05/WC500205987.pdf

• Draft guideline on goodpharmacogenomic practice (draft:consultation open)http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2016/05/WC500205758.pdf

2 MEDICINES AND HEALTHCAREPRODUCTS REGULATORY AGENCY(MHRA)

• Devices which incorporate anancillary medicinal substancehttps://www.gov.uk/government/publications/devices-which-incorporate-an-ancillary-medicinal-substance

REGULATORY ROUND UP

September 2016 volume 26 | No 6PHARMACEUTICAL PHYSICIAN 5

NEWS

From: Medicines and Healthcare products Regulatory Agency

September 2016 volume 26 | No 6

6PHARMACEUTICAL PHYSICIAN

MHRA AND MAKING ASUCCESS OF BREXITThe Agency's response to the outcomeof the EU referendum.FOLLOWING THE OUTCOME of the EUreferendum, the Medicines andHealthcare products Regulatory Agency(MHRA) is working closely with theGovernment to analyse the best optionsand opportunities available for the safeand effective regulation of medicinesand medical devices in the UK.

While negotiations continue, the UKremains a full and active member of theEU, with all the rights and obligations ofEU membership firmly in place.Working with our partners, stakeholdersand customers, our focus remains:protecting health and improving lives.

■

Medicines regulationPLAYING A FULL, active role inEuropean regulatory procedures formedicines remains a priority. Wecontribute significantly in both thecentralised and decentralised regulatoryprocedures, including new rapporteurand reference member state (RMS)appointments, and maintain ourprogrammes for implementing EUlegislation as required by ourobligations as a Member State. We arealso fully engaged in European andnational scientific advice services and indelivering our EU inspection-relatedduties.

■

Devices regulationOur role in regulating medical devicesand in vitro diagnostic (IVD) devices

remains integral. We oversee theessential work of the five UK NotifiedBodies; together they are responsiblefor assessing the majority of devicescurrently placed on the EU market. Ourpreparations to implement proposednew Regulations for Medical Devicesand IVDs continue.

■

Vigilance and market surveillanceWE MAINTAIN OUR role in vigilance,market surveillance and taking directaction, where needed, to protectpatients and public health, and wecontinue to co-ordinate with otherCompetent Authorities, across Europeand internationally, in these and otherareas.

MHRA will be engaging widely with ourstakeholders to fully understand andmaximise the opportunities of Brexit.

Statements are also available from theBritish Pharmacopoeia and the NationalInstitute for Biological Standards andControls (NIBSC)

Customers, partners and stakeholdersapproaching MHRA continue to haveaccess to our internationally recognisedexpertise and we maintain the highestquality services. For further information,please get in touch with your usualcontact points in the Agency.

■

September 2016 volume 26 | No 6PHARMACEUTICAL PHYSICIAN

SPECIAL FEATURE:Protecting Your Company Culture

As You Hire and Expand Into New Markets

By Tarquin Bennett-Coles, Carmichael Fisher

7

I JOINED THE life science talent searchsector after a rewarding period as ateacher. It was clear to me in theclassroom that if you created the rightenvironment then the students weremuch more receptive to the curriculumbeing delivered. This was never easy asyou not only had to convince asceptical group that you were acting intheir interests whilst considering thateach child would learn and develop atdifferent speeds throughout the courseof the year. I often reflect on howsimilar this is to creating a newcompany and then forming the rightculture.

New people joining a business can havea big impact on the overall performanceof the group. If the culture is strongthen the existing team will gently re-inforce the expectations, behaviours andkey messages of the business whennew people come on-board. If theculture is weak then what can getpassed on is the individual linemanager’s views, which may not bealigned with the leadership.

Great culture and corporate identity arecrucial parts when it comes to thesuccessful retention of staff.Understanding exactly what you wantyour company culture to represent andstand for is the first step. The rawenergy of a start-up culture is what candrive the team to work beyond anycontractual hours and have them preachpassionately about the company’smission to the taxi driver, friend orrelative. It is also what keeps them loyalin a highly competitive market.

Staff will be looking for a culture wherethey feel they belong. I still recall the

powerful Apple TV campaign from 1997“Think different” and it making me feelcomfortable being part of the “Apple”family. Who doesn’t want to beassociated with Gandhi, Einstein,Picasso or Kermit? Shire pharmaceuticalshave got the right idea with two coremessages for the business – “to be asbrave as the people we help“ and“enabling people with life-alteringconditions to lead better lives.” Theseare noble phrases and make it easy foremployees to feel proud to be part ofthe company and to defend the mission.

The particulars of how team culture isenacted might change and evolve overtime, but as long as staff remainmotivated by the core values then theculture will persist. That said the culturethat has been so instrumental in gettingthe business to where it is today, maybe the very thing that holds it back inthe future. Keep an open mind. Beprepared to accept that there areaspects of your culture that may need tochange. Disruptive market changes maytake the company in a new direction.

One local firm that has successfullytransitioned from just 45 to nearly 1,000staff and from one to 10 offices in adecade is Abcam. How have theymaintained their culture? According toJane Cooke, Director People &Organisational Development, the keyfocus has been; scalability, flexibility,adaptability and making sure they kepttheir entrepreneurial focus by hiringstaff who could continue to driveinnovation and keep them ahead of thegame. They also built a formal cultureassessment into their recruitmentprocess. If you can clearly articulateyour culture then you can begin to

Tarquin Bennett-Coles

SPECIAL FEATURE:Protecting Your Company Culture

As You Hire and Expand Into New Markets

PHARMACEUTICAL PHYSICIAN

piece together interview questions andassessments that will unearth thepresence of these qualities in potentialemployees. This will seriously helpmitigate the risk of hiring the “wrong”person particularly when you may haveto hire people who might be workingremotely for you.

Don’t be afraid to base culture-relateddecisions around behaviours that arealready delivering unique value to yourcompany. If you’re planning a big officemove and the team is spending halftheir time collaborating in the kitchen,this might be the cue to create moreinviting communal areas. If the staff iscomposed mostly of millennials whoalways hit their targets, then institutingearly-morning start times might workagainst productivity instead of for it.

Preserving culture in a company that isseveral times larger than it was a fewyears ago is difficult and it might noteven be a realistic goal. On the positivefront culture is a moveable feast. It isadaptable and renewable. Rather thanmandating company-wide practices,embrace the notion of individual teamculture. Having recently read theexcellent “Small Big” by Steve Martin(ex-life science industry) and RobertCialdini it is clear that small changescan spark big influence and thatdifferent units or country teams mayneed to be allowed to generate theirown distinct personalities, as long asthey’re all moving in a unified directionin tune with the vision.

Look outside your sector as this mayhelp you spot new ways of supportingemployees that will help highlight whattop talent is looking for in terms ofculture, benefits, compensation andlifestyle. It is useful to remember thatculture is made of people – theirattitudes, work ethics, and personalities.It is not made out of processes andchecklists. Hire well and be open totake on new people who will not onlyfit with your culture, but who will alsoadd to it.

When bringing on new people taketime to introduce them to the history ofthe company and get them excitedabout where the business is going.Inductions are an incredibly importantpart of this communication. Ensure thatthe induction takes time to introducethe company and culture to everyemployee. As businesses grow, one ofthe biggest problems experienced is thatthe company starts to develop silos. It ispart of human nature to developconnections with people that we feelwe have most in common with,however, this can cause problems andweaken the culture at work if the“division” makes others feel alone ornot part of the ‘it crowd’.

Think about ways you can still treatpeople differently so they feel likeindividuals as you expand. Flexiblebenefits systems can be very useful inallowing staff to choose benefits thatthey want during a particular stage oftheir working life – swapping pensioncontribution for paid holiday can be apowerful motivational tool. Consideroffering events and activities thatencourage interaction such as sportsclubs, outings or a social committee.These activities can help createfriendships and positive workingrelationships between differentdepartments.

Ultimately culture is a living thing thatwill change over time and will alterwith the number of people andpartnerships the company is involvedwith. Get it right and you can create anenvironment that will help retain yourbest staff, energise your innovators anddrive sales growth in the business. Butbe watchful because it can go the otherway too.

This article has also been posted byTarquin on the onenucleus site.

tbennett-coles@carmichaelfisher.com

September 2016 volume 26 | No 6

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September 2016 volume 26 | No 6PHARMACEUTICAL PHYSICIAN

SPECIAL FEATURE:

Developing Biosimilars

By Sanjay Jain, Principal Consultant, Biologics, Envigo

9

INTRODUCTION[1-4]

A RECENT REVOLUTION inbiotechnology has resulted in a newclass of medicine, the biologic – alarge molecule (200-1000 fold the sizeof a small molecule) typically derivedfrom living cells and used in thetreatment, diagnosis or prevention of disease. These medicines have asuccessful track record in treatinghuman disease as nearly 200 biologicshave transformed the lives of over 800million patients with serious illnessesacross the globe. By understanding themechanisms of diseases, e. g. multiplesclerosis, biologic medicines can bedeveloped to target and modifypotentially altering the course ofdisease rather than simply treatingsymptoms. Currently, over 400 biologicmedicines worldwide are being studiedin serious illnesses, e. g. Alzheimer’sdisease.

The on-going expiry of dataprotection/patents for the original bio-therapeutics has led to the developmentand subsequent authorisation of copyversions, termed 'similar biologicalmedicinal products' (biosimilars) byvarious regulatory authorities across theglobe. Recent years have demonstratedthat biosimilar medicines are a rapidlygrowing field and now emerging as anew segment in the biopharmaceuticalssphere. In general, the principles ofbiosimilar drug development apply toall biological medicinal products.Regulatory agencies have established aportfolio of guidance to support theincreasing number of applications theyare receiving for biosimilar-relatedscientific advice and subsequentlymarketing authorisations of thesemedicines.

BIOLOGICS AND BIOSIMILARSVS. GENERICS DRUGS[1-4]

A ‘biosimilar’ or ‘similar biological’ or‘follow-on’ medicine is similar toanother biological medicine which hasalready been authorised for use. It is amedicine that contains one or moreactive substances made by or derivedfrom a biological source (e. g. cellularor complex organisms; bacterium oryeast) often by genetically modifyingcell constructs or cell lines. Some ofthem may be already present in thehuman body and can be relatively smallmolecules (e. g. human insulin), orcomplex molecules (e. g. monoclonalantibody, mAb).

A biological substance is produced by orextracted from a biological source andneeds a combination of physicochemicaland biological testing together with theproduction process and its control for itscharacterisation and the determination ofits quality, e. g. recombinant proteins,mAbs, medicinal products derived fromhuman blood and human plasma,immunological medicinal products andadvanced therapy medicinal products.The manufacturing process for biologicmedicines requires dozens of stepsinvolving hundreds of variables and isgenerally more complex thanmanufacturing processes for chemicaldrugs.

The active substances of thesemedicines are larger and more complexthan those of non-biological medicines.Only living organisms are able toreproduce such complexity and the waythey are produced may result in adegree of variability in molecules of thesame active substance, particularly indifferent batches of the same medicine.

Sanjay Jain

SPECIAL FEATURE:

Developing Biosimilars

PHARMACEUTICAL PHYSICIAN

These inherent features result in greatercomplexity surrounding the regulationof such products. Therefore, biosimilarscannot be considered generics. The laterhave simpler chemical structures andare considered to be identical to theirreference medicines.

EUROPEAN MEDICINESAGENCY[1]: GENERALCONSIDERATIONS:Under the authority of the EuropeanCommission (EC), the Committee forMedicinal Products for Human Use(CHMP) is responsible for managing theEuropean Medicines Agency’s (EMA)position regarding medicines for humanuse, including biosimilars. In a joint taskforce, the CHMP works in partnershipwith the Biosimilar Medicinal ProductsWorking Party (BMWP), the BiologicalsWorking Party (BWP), the SafetyWorking Party (SWP) and thePharmacovigilance Working Party(PhVWP) to provide Europeanguidelines for biosimilars.

Compared to the Food and DrugAdministration (FDA)’s currentstandpoint on biosimilar legislation, theEMA has provided a more establishedand experienced mechanism forconsultation. A biosimilar application hasto meet the “8+2+1” rule - it cannot befiled until eight years after the referenceproduct approval. Further to this abiosimilar cannot be approved (ormarketed) until ten years after thereference approval. The marketexclusivity may be extended by a furtheryear for the reference product if thesponsor obtains approval for a secondsignificant new indication during theinitial eight year exclusivity period (thisis the “+1” in the rule). Biosimilars canonly be authorised (or marketed) for useonce the period of data exclusivity(normally 10 years in the EuropeanUnion, EU) on the original 'reference'biological medicine has expired.

PRE- AND POST-MARKETINGPROCEDURES:At the time of submission of the similarbiological application, the protection

period of the reference medicinalproduct (RMP) should have expired inorder to allow the applicant to rely onthe dossier of the RMP, identified for thepurpose of calculating expiry of theperiod of data protection, may be for adifferent strength, pharmaceutical form,administration route or presentation thanthe similar biological medicinal productor biosimilar. The details of the RMPused for the comparability exercise mustbe stated. It is a requirement to identifya RMP which is authorised in theEuropean Economic Area (EEA). Withthe aim of facilitating the globaldevelopment of biosimilars and to avoidunnecessary repetition of clinical trials,the EC has confirmed that it intends toaccept batches of RMPs sourced fromoutside the EEA in certain studies for thecomparability exercise. The batchessourced outside the EEA must berepresentative of the RMP authorised inthe EEA, as demonstrated through anextensive analytical comparison and mayrequire comparative pharmacokinetic(PK) and pharmacodynamic (PD) data.A close collaboration with the UnitedStates (US) FDA is foreseen to ensureharmonisation of requirements, withregard to the acceptance of US-sourcedRMP.

When referring to a centrally authorisedRMP, the 10-year or 8-year protectionperiod, as applicable, should haveexpired and the eligibility should havebeen confirmed. The relevant protectionperiod should be counted as startingfrom the date of notification of themarketing authorisation (MA) decisionto the Marketing Authorisation Holder(MAH) and can be found in the OfficialJournal of the EU as well as in theCommunity register of medicinalproducts for human use on the ECwebsite. The calculation of theprotection period should take intoaccount the notion of global MA. Itcontains the initial authorisation and allvariations and extensions granted to theMAH of the initial authorisation.

To verify compliance with EC GoodManufacturing Practice (GMP) Principles

September 2016 volume 26 | No 6

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and Guidelines and/or to verify specificmanufacturing and control activitiesrelated to the assessment of anapplication, pre-authorisation GMPinspections are possible. The GoodClinical Practice (GCP) standards appliedto clinical trials carried out forbiosimilars are the same as thoseapplied to any other medicinal product.

The requirements for submission of asummary of the pharmacovigilancesystem are the same as for any MAapplication.

US FDA[2]: GENERALCONSIDERATIONS:The US has been slower to provide anestablished legal pathway for biosimilarapprovals. In the US, most, but not all,biological products are licensed underthe Public Health Service Act (PHS Act).Small-molecule prescription drugs areapproved under the Food, Drug andCosmetic Act (the FD&C Act). The Actrequires a firm who manufactures abiologic for sale in interstate commerceto hold a license for the product. Abiologics license application (BLA) is asubmission that contains specificinformation on the manufacturingprocesses, chemistry, pharmacology,clinical pharmacology and the medicaleffects of the biologic product. If theinformation provided meets FDArequirements, the application isapproved and a license is issuedallowing the firm to market the product.

The FDA has stated that under certaincircumstances, data from animal/clinicalstudies performed against a referenceproduct that does not hold a US licencemay be used to address biosimilarity.However, data would need to besubmitted to bridge to a US licensedreference product. The agency hasstrongly advised in-depth consultationfor any company wishing to develop abiosimilar so as to best optimise theprocedure.

By and large, the FDA has openlyacknowledged their lack of guidanceand experience in the area of

biosimilars and is happy to consult theEMA for advice. However, there remaincertain and significant differences inlegal frameworks. An “interchangeable”biological product is biosimilar to thereference product, and can be expectedto produce the same clinical result asthe reference product in any givenpatient. If administered more than onceto an individual (as many biologicalproducts are), the risk in terms of safetyor diminished efficacy of alternating orswitching between use of the biologicalproduct and the reference product willnot be greater than the risk of using thereference product without such analternation or switch. Once determined“interchangeable” two biologicalproducts will thus be able to besubstituted for each other (i. e.interchanged) by a pharmacist withoutthe intervention of the health careprovider. Pharmacists will beresponsible for knowing whichbiological products are interchangeableand which will require prescriberprescription before substitution. To date,the FDA has not approved a biologicalproduct as a biosimilar orinterchangeable. However, since thepassage of the Affordable Care Act in2010, the FDA has been establishingstandards for licencing to ensure thesafety and effectiveness of biosimilars.The FDA understands that severalcompanies are developing biosimilarproducts and may submit applicationsfor approval under the new law.Scientists, clinicians, and otherpersonnel at FDA are currently workingout the details of the review andlicencing process.

WHO AND OTHERREGULATORY AGENCIES[3,4]:In 2009, the WHO developed a set ofglobally accepted standards to assurethe safety, efficacy and quality ofbiosimilars. These have been developedin the wake of increased interest inthese medicines by local regulatoryauthorities seeking to develop nationalstandards.

In general, the reference product should

be authorised in the country or regionin question. All aspects of quality andheterogeneity should be assessed,including direct comparisons with thereference product. Non-clinical datashould include pharmacodynamic,pharmacokinetic and comparativerepeat-dose toxicity studies in a relevantspecies, and clinical studies are requiredto demonstrate similar safety andefficacy. Immunogenicity should alwaysbe investigated in humans beforeauthorisation. A pharmacovigilanceplan is required when an application issubmitted and a risk management planmay be necessary in some cases.

PHARMACOVIGILANCE,INTERNATIONAL NON-PROPRIETARY NAME,SUBSTITUTION ANDINTERCHANGEABILITY[4-11]:Extensive pharmacovigilance programsare needed to protect patients andensure any adverse events (AEs,including immunogenicity) are quicklydetected, reported and attributed to thecorrect product and manufacturer.Healthcare systems must ensure that allbiosimilars can be rapidly and accuratelyidentified by national regulators,healthcare providers and patients. In

SPECIAL FEATURE:

Developing Biosimilars

September 2016 volume 26 | No 6PHARMACEUTICAL PHYSICIAN

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SPECIAL FEATURE:

Developing Biosimilars

PHARMACEUTICAL PHYSICIAN

Europe and the US, it is obligatory forthe manufacturers of all biosimilars tosubmit comprehensivepharmacovigilance and riskmanagement plans when applying forapproval. These should include: pre andpost-authorisation comparative testing,regular tests to ensure that themanufacturing processes are the same,and risk management in case of AEs.

WORLDWIDE EXPERIENCE:MARKET POTENTIAL OFBIOSIMILARS[12-17]:Over the coming years, it is anticipatedthat a new generation of simple as wellas complex biosimilars will bedeveloped as leading biologicmedicines. These are worth anestimated US $81 billion in globalannual sales, and likely to lose theirpatents by 2020. The biologics market isexpected to grow significantly in thecoming years, with biosimilars a smallbut growing proportion of it.

Biosimilar manufacturers arerequired/expected to invest in clinicaltrials, manufacturing and post-approvalsafety monitoring programs similar tothat of the original innovator companies.The cost of developing a generic smallmolecule is around US $2-3 million,whereas biosimilars have been estimatedto cost around US $75-250 million toreach approval. This is largely owing tothe clinical and comparability studiesrequired demonstrating biosimilarity.

More than 700 follow-on biologictherapies are currently in developmentand 245 biopharmaceutical companiesand institutes now developing or alreadymarketing biosimilars throughout theworld. Biosimilars promise to producebig savings, typically offering 20-30%discounts on innovator biologics andlikely to deliver savings of as much as US$33 billion by 2020 across the EU alone.The US will permit interchangeability,and this is expected to speed uptake ofbiosimilars there. A WHO proposal for avoluntary global naming scheme couldlevel the playing field for biosimilars andtheir reference biologics.

Germany provides the most favourableenvironment for biosimilar drugs, whileItaly is the least favourable. Differences inreimbursement practices and incentives, aswell as variations in medical and clinicalpractices, have resulted in differentoutcomes across EU member states. TheUK is also viewed as a favourableenvironment for biosimilars, with its longculture of generic utilisation and relativelyhigh launch prices. Italy seems to have theleast favourable environment forbiosimilars, with a strict price regulationsystem. France also has a strict priceregulation system and compulsorydiscounts for biosimilars. Sweden hassome of the highest manufacturer-levelprices in Europe. The US market situationfor biosimilars is of particular interestbecause it is the centre for biotechinnovation; and it spends more onbiologic products than any other nation.

SUMMARY ANDCONCLUSION[18-24]

Biosimilars are not generic medicinalproducts, since it could be expectedthat there may be subtle differencesbetween similar biological medicinalproducts from different manufacturersor compared with reference products.Transforming complex therapeuticproteins from the laboratory into thelarge-scale production of safe andeffective medicines requires highlyspecialised knowledge, processes,scientific standards and on-goinginvestment in quality.

Biosimilar development is a potentiallycompetitive area with high-value follow-on products. EU guidance andexperience in this field is more maturecompared to the US. There is anacceptance that reduced data packagesmay be acceptable, but only ifappropriate justification can be made.The EMA/CHMP guidelines are widelyconsidered the standard, with countriessuch as Australia, Canada, Japan, Koreaand South Africa using them as a basisfor their own regulations.

The harmonisation of the biosimilarsapplication procedure between the FDA

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and EMA seems challenging in the nearfuture. Aside from this, now that a longwait for new US guidelines is over, the

new focus is on the future and industrywidely anticipates their finalisation bythe FDA, post public opinion. Whether

follow-on guidelines are more product-specific is yet to be disclosed.

Biosimilars are a relatively new andemerging market. Although a number ofbiosimilar proteins have been approved,especially in Europe, issues onsubstitutability, extrapolation to otherdisease indications, and selection ofreference standards and comparators,remain to be standardised at a globallevel. Also, in order to supportpharmacovigilance monitoring, thespecific medicinal product given to thepatient should be clearly identified.

In conclusion, based on the rapidexpansion of biosimilars and investmentwithin this area, this field has emergedas a new biotechnology segment andmany more biosimilars are likely to beapproved in the coming years. Seekingscientific advice is highly recommended,and if a putative biosimilar product isnot considered ‘similar’, the developerwill be facing a full developmentprogramme.

SPECIAL FEATURE:

Developing Biosimilars

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| REFERENCES1. EMA's scientific guidelines on biosimilar medicines, http://www.ema.europa.eu/ema.

2. US FDA, Guidance for Industry: quality considerations in demonstration biosimilarity to areference protein product, 2012. http://www.fda.gov/Drugs/DevelopmentApprovalProcess.

3. WHO, Expert Committee on Biological Standardisation. Guidelines on evaluation of similarbiotherapeutic products, 2009.

4. www.amgen.com/pdfs/misc/biologics_and_biosimilar_overview, 2014.

5. EMEA CHMP Guideline on immunogenicity assessment of biotechnology-derivedtherapeutic proteins, EMA, 2007.

6. Schellekens H. Biosimilar therapeutics – what do we need to consider? NDT Plus, 2009, 2(S1):i27-i36.

7. Locatelli F and Roger S. Comparative testing and pharmacovigilance of biosimilars.Nephrology Dialysis Transplantation. 2006: 21 (S5).

8. WHO, Programme for International Drug Monitoring, 2012.

9. Siegel JP. Petition to the U.S. Department of Health and Human Services, FDA, 2014.

10. CDER, US FDA, Proprietary Name Review: BLA 125418 – Zaltrap, 2012.

11. Drug Safety Update, Antiepileptic drugs: new advice on switching between differentmanufacturers’ products for a particular drug. MHRA, 2013, 7(4):A1.

12. Mellstedt H et al. The challenge of biosimilars. Annals of Oncology, 2008, 19:411-419.

13. First Word SM Dossier, Biosimilar drugs in Europe: threat or opportunity to innovation?2011.

14. Biosimilar Development. Sandoz, 2011. http://www.sandoz-biosimilars.com/aboutus/development.shtml.

15. Taylor L. Over_700_biosimilars_now_in_development_worldwide_reporthttp://www.pharmatimes.com, 2014.

16. Taylor L. Germany: "EU's most favourable market for biosimilars",http://www.pharmatimes.com, 2014.

17. Willrich A et al. Tumor necrosis factor inhibitors: clinical utility in autoimmune diseases.Transl Res. 2014:S1931-5244.

18. Bui LA et al. Key considerations in the preclinical development of biosimilars. Drug DiscovToday. 2015, 20 (S)1:3-15.

19. Alten R and Cronstein BN. Clinical trial development for biosimilars. Semin ArthritisRheum. 2015, 44 (6 S):S2-8.

20. Socinski MA et al. Clinical considerations for the development of biosimilars in oncology.MAbs. 2015, 7(2):286-293.

21. Li EC et al. Considerations in the early development of biosimilar products. Drug DiscovToday. 2015, 20 (S)2:1-9. Alliance for Safe Biologic Medicines: Information Center, 2012.

22. Alliance for Safe Biologic Medicines: Information Center, 2012.

23. MHRA, The introduction of similar biological medicinal products (biosimilars), 2012.

24. Jain S. An expert report on ‘VIB’s Biosimilars: Capitalising on the market opportunitiesfrom biosimilars’, Belgium, IDDB Scientific Database, Thomson Reuters, UK, 2008.

MEETING REPORT:The REAL WORLD Challenge: Demanding a More Targeted Approach?

Report by Sam Oliver and Amanda Pulfer (Joint Managing Directors, pH Associates)

Amanda Pulfer

HOSTED BY PH ASSOCIATES IN

COLLABORATION WITH ABPI

26TH APRIL 2016

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INTRODUCTIONTHIS MEETING REPORT summarisesthe presentations and discussions at thesecond annual ‘REAL WORLDChallenge’ conference, hosted by pHAssociates in collaboration with theABPI at the King’s Fund on the 26thApril 2016. The theme of this year’sconference was ‘Demanding a MoreTargeted Approach?’ focusing on thechallenges associated with measuringthe most relevant, robust and persuasiveoutcomes in ever more targeted patientpopulations.

The conference was chaired by SamOliver and Amanda Pulfer (JointManaging Directors, pH Associates) withpanel members Dr Katie Pascoe (ABPIValue and Access Manager) andDr Rebecca Lumsden (ABPI Head ofScience Policy), and presentations fromProfessor Richard Barker OBE (Director,Centre for the Advancement ofSustainable Medical Innovation),Professor Sarah Garner (AssociateDirector Science Policy and Research,National Institute for Health and CareExcellence), Sebastian Stachowiak(General Manager, UK & Ireland, ShirePharmaceuticals), Professor Atul Mehta(Consultant Haematologist, Royal FreeHospital) and Professor Nancy J Devlin(Director of Research, Office of HealthEconomics). The conference wasattended by more than 100 delegateswho participated in lively discussions.

THE WORLD OFPHARMACEUTICALS ISCHANGINGRandomised clinical trials (RCTs) remainthe ‘gold standard’ in terms of the leastbiased way of demonstrating theefficacy of new medicines and

therapies. Ensuring that patients havetimely access to effective and safetreatments remains one of the keychallenges of the global healthcaresystem; therefore, how best to considerdata from clinical trials alongsidecomplementary evidence remains achallenge for decision makers and mayvary depending on the disease, thetreatment and a range of confoundingfactors. Real world data (RWD) isimportant for demonstrating the widerbenefits of treatments used in normalclinical practice, enabling demonstrationof the effectiveness, safety and value(both economic and patient-centric).Furthermore, real world evidence (RWE)is increasingly recognised as animportant component of the clinical andeconomic evidence base supportingpharmaceutical companycommunications with key stakeholders(payers, healthcare professionals andpatients) and health technologyassessment (HTA) submissions toregulatory bodies.

RWE: PUTTING PATIENTS ATTHE HEART OF THEMEDICINE LIFECYCLERWE and Targeted Medicines Professor Barker provided an overviewof the role of RWE in supporting thedevelopment of and access to targetedmedicines.

Innovative targeted medicines are beingdeveloped to treat ever more clearlydefined sub-groups of patients,particularly in the field of oncology butalso in more common diseases such asdiabetes. There has also been a gradualincrease in the number of drugsdeveloped for treating rare diseases.The smaller and often more disparate

nature of the target patient groups fornew treatments can lead to obviouschallenges for efficiently recruitingeligible patients into clinical trials.However, the increasing access to RWDcreates the opportunity to provide muchneeded patient outcomes data, althoughthere remains a need for more targetedpatient-centric outcome measures to sitalongside the traditional clinicaloutcome measures.

Recent UK initiatives such as thePrecision Medicine Catapult[1], aimed atmaking the UK a global leader fortargeted medicines development, andthe opportunities afforded by theavailability of a wide range ofpopulation-based RWD assets, such asthe UK Biobank (a national healthresource with wide therapy area focus)[2],the Systemic Anti-Cancer Therapy(SACT) chemotherapy dataset (includesdata from all cancer chemotherapyproviders)[3] and the 100,000 GenomesProject (focused on patients with rare

diseases and those with cancer)[4], placethe UK in a uniquely strong position inthe precision medicines arena. The UKposition is further strengthened by anumber of new developments, includingthe European Medicines AgencyAdaptive Pathways to Licensingscheme[5], based on staged approval andRWD collection for safety, efficacy andvalue evidence generation; the newCancer Drugs Fund[6]; and the UKGovernment Accelerated Access Review,aimed at speeding up NHS patientaccess to innovative medicines[7].

Obtaining fit for purpose RWD,appropriately presenting and adequatelyjustifying the use of RWE in submissionsto regulatory bodies is essential toensuring decision makers fullyappreciate the sources of bias andconfounders inherent in RWD whenconsidering RWE alongside all otheravailable data including RCTs. Theconference participants acknowledgedthe value of RWE in facilitating the

development of and access to targetedmedicines and identified a variety ofchallenges associated with datacollection and use of RWE, summarisedin Box 1.

Professor Garner provided an overviewof the role of RWE in supporting earlyaccess to medicines.

The current HTA framework requires asequential approach from regulatorsthen HTA assessors with regard to thedecision to fund access to newtreatments. In the event that the HTAdecision is not favourable or wherethere is uncertainty about the decisionthere is no clear way of collaborating toidentify evidence gaps and plans toaddress them. There is a wealth of RWDcaptured by the NHS which provides aunique opportunity to develop novelapproaches for bringing data togetherfor consideration by NHS decisionmakers and HTA bodies. However, theinherent variability and bias associatedwith RWD can lead to uncertainty inhow best to utilise RWE for HTA. Anideal approach would involve anadaptive licensing framework, with earlyengagement of the pharmaceuticalcompany with decision makers to agreeon the best approach and

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| BOX 1: Challenges and value of real world evidence in supportingdevelopment and access to targeted medicines

RWE Value RWE Challenges

• RWE is more representative of the wholepopulation, as opposed to a clinical trialpopulation

• RWE allows the study of populations whowould be excluded from RCTs

• RWE is relatively quick to collect

• RWE can supply different outcomes to a RCT

• RWE gives a better indication of value of amedicine, not just safety and efficacy

• RWE can show the resource implications ofmanaging adverse events

• RWE can reflect the effect of real life, such asa busy schedule, polypharmacy or co-morbidities on compliance and outcomes

• Missing/inconsistently recorded/inaccuratedata recorded in medical records

• Lack of patient reported outcomes in medicalrecords

• Potential for bias impacts conclusions

• Need for adjustment to deal with potentialconfounders

• Capacity/willingness of health careorganisations to work with pharmaceuticalcompanies to collect data

• Fear of contradicting RCT results

• Systems integration to link/extract datasetsis costly and time consuming

• Data linkage between sectors (e.g. primaryand secondary care) remains difficult

• Absence of comparators in the analysis

• RWE often generated in an early use groupnot representative of a typical population

• Uncertainty over acceptance of RWE by policymakers

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PHARMACEUTICAL PHYSICIAN

methodologies to be employed topresent RWE for HTA. Such anapproach would not only work in thebest interests of commercialstakeholders and decision makers butultimately also patients.

One approach to an adaptiveframework would be to conduct aconcurrent regulatory and HTA reviewof the evidence base for newmedicines to allow fundingagreements to be put in place andenable early access to innovativetreatments during Phase III forpatients with no other treatmentchoices. This approach would providedecision makers with access toincreased relevant RWE on which tobase regulatory and funding decisions,whilst ensuring that patient safetyremains the cornerstone of access tonew medicines. Collaboration at thisearly stage would also allow theidentification of evidence gaps withinthe initial submission, allowing thevarious stakeholders to mutually agreesuitable approaches andmethodologies for filling these gapsprior to final regulatory and HTAreview. Professor Garneracknowledged that NICE recognisesassessment of RWD methodologies asa current challenge due to a clinicaltrial heritage; however, she challengedthe industry to use RWD insubmissions emphasizing theimportance of clearly justifying its

inclusion. The conference participantshighlighted the importance ofevidencing the robustness of the data,clearly acknowledging sources of bias,and the wider context (including thelifecycle of the product andconsideration of UK data in the globalcontext), when preparing HTAsubmissions.

RWE and Rare DiseasesMr Stachowiak and Professor Mehtaprovided an overview of the role of RWEin developing therapies for rare diseases.

The number and scale of the hurdlesthe pharmaceutical industry must clearin order to deliver life-saving raredisease medicines to patients areimmense, sometimes insurmountable.These include the small numbers andwide geographic spread of patients,poor disease awareness amongstclinicians due to limited clinicalexposure, and misdiagnosis due to theheterogeneity of rare diseases. Thechallenge of running clinical trials inthe face of these hurdles and thelimited opportunity to recover thecapital investments for productresearch and development has ledregulatory agencies to implementincentives for health and biotechnologyindustries, including the adoption ofthe Orphan Drug Act in the US, Japanand Australia, and a common policy onorphan drugs in European MemberStates.

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Professor Richard Barker OBE

Given the increasing availability andaccess to RWD it represents a vitalresource for evidence generation insupport of the development andevaluation of treatments for rarediseases, by improving diseaseunderstanding and demonstrating longterm safety and effectiveness oftreatments to inform the budgetarydecisions of healthcare providers. RWE,in particular evidence derived fromdisease registries, has already played animportant role in improvingunderstanding of rare diseases suchFabry Disease. The speakers emphasisedthe importance of collaborative workingbetween the pharmaceutical industry,physicians, the NHS and regulatorybodies in order to solve the challenges

posed by orphan drug development andensure timely access to treatment forpatients in need. Conferenceparticipants agreed that RWE is vital inan area where patient groups are toosmall to determine significant differences

in clinical trials. A wealth of RWD areavailable, including from the expertpatients themselves, yet currently thesedata remain vastly under-utilised.

RWE and Patient Preference – beyondthe Quality Adjusted Life Year (QALY)Professor Devlin gave an overview ofthe role of patient reported outcomes asa source of RWE supporting HTAsubmissions, summarising that “Nobodyknows the patient better than thepatient themselves”.

Traditional Patient Reported Outcome(PRO) instruments including assessmentsof quality of life often overlook patientpreferences for particular treatmentattributes, such as mode of

administration of treatment, and widersocietal impacts. With the increasedemphasis on a more patient-centricapproach to medicines development,there is a greater need to understandthe broader impact of treatment,

including: patient preferences fortreatment; the impact of disease andtreatment on patients health andwellbeing; the impact on theircarers/family; and the wider societalimplications of disease and treatment,such as work productivity. Importantly,HTA bodies worldwide are movingtowards more explicit, transparentconsideration of patient-reported databeyond the traditional QALY used incost-utility modelling. This change inemphasis has sparked increasing interestin the development of individualisedPRO instruments, which seek tomeasure the domains of health of

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RWD… REPRESENTS A VITAL RESOURCE FOR EVIDENCE GENERATION IN

SUPPORT OF THE DEVELOPMENT AND EVALUATION OF TREATMENTS FOR RARE

DISEASES…

17

Professor Nancy Devlin The Panel

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importance to each individual, and theweight they place on each domain, inorder to create a more ‘personal’ pictureof the patient’s health and wellbeing.

Professor Devlin highlighted the futurepotential for a greater consideration ofthe patient perspective on health andexperience of treatment and an

increased emphasis on use of RWE inHTA. Conference participants agreedthat the patient voice is not adequatelyconsidered in HTA decisions andexpressed the view that in the currentpatient-centric era consideration ofpatient preference when conductingrisk/benefit analyses during the decisionmaking process is essential.

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| REFERENCES1. Precision Medicine Catapult. Available from: http://pm.catapult.org.uk/. Accessed on

12/05/2016.

2. UK Biobank. Available from: http://www.ukbiobank.ac.uk/. Accessed on 12/05/2016.

3. SACT: Systemic Anti-Cancer Therapy Chemotherapy Dataset. Available from:http://www.chemodataset.nhs.uk/ . Accessed on 12/05/2016.

4. The 100,000 Genomes Project. Available from:https://www.genomicsengland.co.uk/the-100000-genomes-project/. Accessed on12/05/2016.

5. European Medicines Agency Adaptive Pathways. Available from:http://www.ema.europa.eu/ema/index.jsp?curl=pages/regulation/general/general_content_000601.jsp&mid=WC0b01ac05807d58ce. Accessed on 12/05/2016.

6. The Cancer Drugs Fund. Available from:https://www.england.nhs.uk/ourwork/cancer/cdf/. Accessed on 12/05/2016.

7. Accelerated Access Review. Available from:https://www.gov.uk/government/organisations/accelerated-access-review. Accessed on12/05/2016.

Continuing delegates who have just completed YEAR 1 should re-register and taught modules recommence in October 2016.

New registrations for this academic year can be accepted at any time but places are limited to 25 attendees and taught moduleswill commence in January 2017.

The Course is modular and follows the syllabus for the Diploma in Pharmaceutical Medicine. Each module is of two working days’duration.

Module 1 is conducted in Cardiff at the University but the remaining 9, including a tailored Revision session, are delivered inLondon in a modern purpose-designed, well-resourced training venue. The Course is not residential and many attendees living inand around London have found daily attendance easy and better for their own quality of life.

The course has undergone serious remodelling over the past two years to enhance delivery and ensure busy candidates andpharmaceutical physicians in training can learn constructively and proactively.

CARDIFF UNIVERSITY/BRAPP

POSTGRADUATE COURSE IN PHARMACEUTICAL MEDICINEAcademic year 2016/2017BrAPP is pleased to announce that we are now accepting registrations for thePostGraduate Course in Pharmaceutical Medicine (PGCPM).

For further details:please visit the BrAPP website www.brapp.org and use the PGCPM buttonand to register, please call the BrAPP office on +44 (0) 118 934 1943 and

speak to Liz Langley or Karen Young. Email PGCPM@brapp.org

SPECIAL FEATURE:

No mother should die…

By Paul Robinson and Yogeeta Manglani, Merck Sharp & Dohme Ltd

September 2016 volume 26 | No 6

20PHARMACEUTICAL PHYSICIAN

IN 2013, WE described an MSD multi-agency project to eliminate RiverBlindness with the use of our anti-helminth, Mectizan1. But pharmacompanies have more to offer than justmedicines & vaccines – we have ourexpertise, our financial resources and,most importantly, the good will of ouremployees to improve wellbeing aroundthe world. Take a look at ‘MSD-for-Mothers’ (or ‘Merck for Mothers’ as it isknown in the US & Canada).

MSD-for-Mothers has a very simplevision – that no mother should die frompregnancy or childbirth. Thankfully, in

our high tech, well-resourced NHS,these events are extremely rare, butthey do happen. UK maternal mortalityis estimated at 9 per 100,000 live births,equating to about 70 deaths per year2.Morbidity, of course, will be muchhigher. But across Europe, figures(where they are reliably collected) canbe much higher with something close to2000 deaths per annum.

And the sad truth is that most if not allof these can be prevented by access toreproductive education, contraception,early contact with healthcareprofessionals during pregnancy, access

Paul Robinson

| BOX 1: Problem: Post-partum haemorrhage (PPH)

PPH is the leading cause of maternalmortality in low-income countriesand contributes to nearly a quarter ofmaternal deaths globally. Thecommonest intervention for PPH,oxytocin, is limited its need forrefrigeration to maintain potency.The ability to maintain cold-chainacross the drug distribution andstorage network is inconsistent, thusrestricting their use in the verycountries with the highest burden ofmaternal mortality.Ferring Pharmaceuticals hadavailable a room-temperature-stable(RTS) carbetocin, which could be apractical intervention for reducingPPH. Together, FerringPharmaceuticals, MSD and WHOhave initiated a randomized, double-blind, non-inferiority trial to evaluatethe effectiveness of RTS-carbetocincompared to oxytocin in 30,000women delivering vaginally across 10countries. If the results of the studyshow that RTS-carbetocin is a safeand an effective alternative tooxytocin, this could have substantialimpact on the prevention of PPH andmaternal survival worldwide[3].

to good quality healthcare facilities forthe birth itself and escalation of care ifnecessary. This is not just important forthe mother – the prognosis of a child

whose mother does not survive isaffected too, with a doubling ofmortality before the age of 2 years. Thelife of the family is changed forever.

Recognising that this is a multi-factorialproblem, no one company, agency orgovernment can solve it alone. That iswhy 5 years ago, MSD set aside $500mand made a 10 year commitment towork with others to help reach the UNSustainable Development Goal 3.1 ofreducing maternal mortality globally toless than 70 per 100,000 live births.Whilst the money is important, thecommitment of the company to use itsskills and resources are equally so.Where the problem has been a securesupply chain for medicines, our supplychain experts have helped. Where theissue has been one of setting standardsfor birthing facilities and then training tothose standards, our training and qualityexpertise has been invaluable. Andwhere changing behaviour of healthcare workers is needed, who better thanour marketing teams?

We have been joined in this effort by across-functional alliance, who haveestablished “Safe Motherhood Week”,worked closely with governments, otherpharma companies and non-governmental bodies such as “Doctorsof the World”. Our employees areengaged by supporting in a variety ofways, from maternity-related donations

SPECIAL FEATURE:

No mother should die…

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| BOX 2: Problem: Accessing healthcare services

Despite universal health coverage across many European countries, access to healthcare is limitedfor many vulnerable groups, such as migrants and refugees who may not know how to accesscare or lack the necessary documentation. Consider the current refugee crisis in Greece, with inexcess of 300,000 refugees, many of whom are pregnant women or with young childrenLiving in makeshift camps, in disused airports and old Olympic stadiums, these young women relyon mobile health units, walk-in polyclinics and social pharmacies using donated and unwantedpharmaceutical supplies. MSD for Mothers is working with Doctors of the World (Greece) toprovide these services, but also to demonstrate their clinical value to policy makers in the hopethat they become government-funded services in the near term.

| BOX 3: Problem: Supply Chain

Despite universal health coverage across many European countries, access to healthcare is limitedfor many vulnerable groups, such as migrants and refugees who may not know how to accesscare or lack the necessary documentation. Consider the current refugee crisis in Greece, with inexcess of 300,000 refugees, many of whom are pregnant women or with young childrenSenegal has made significant progress in reducing maternal mortality, from 540 deaths per100,000 live births in 1990 to 315 in 2015. One of the factors contributing to maternal mortality isa lack of access to a reliable supply of contraceptives. In 2011, nearly 80 percent of governmenthealth facilities experienced stock-outs of contraceptive supplies and only 30 percent of womenseeking contraceptives were able to obtain them.Together with the Gates Foundation, and working with the Senegalese Ministry of Health andSocial Action, MSD for Mothers has introduced an innovative supply chain model designed to helpimprove the availability of contraceptives at health facilities.The model has three key features:• Private sector logistics specialists are rewarded based on their performance to forecast and

order contraceptives, distribute them and collect data on actual consumption, freeing thehealthcare workers to focus on essential medical tasks.

• Improved contraceptive choice helps ensure that women can choose and continue to use themethod that best meets their needs.

• Improved data on deliveries and payments using a new, electronic information system.Stock-outs have reduced to <2%, and the feasibility of expansion is now being assessed, to otherparts of the region and to other essential medical supplies.

SPECIAL FEATURE:

No mother should die…

PHARMACEUTICAL PHYSICIAN

through to 3 month volunteeringsecondments around the world.

We have a long way to go before ourvision is realised, and like most multi-stakeholder projects, it will not be

possible to tease out our contributionfrom the synergy of the whole.

The important thing is that we strive fora day when no woman dies, givingbirth to life.

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| REFERENCES1. Prevention is better than cure, but eradication isn’t bad either. Robinson PJ,

Pharmaceutical Physician, 2013: 23(5); 6-7

2. Knight M, Tuffnell D, Kenyon S, et al on behalf of MBRRACE-UK. Saving Lives, ImprovingMothers’ Care - Surveillance of maternal deaths in the UK 2011-13 and lessons learned toinform maternity care from the UK and Ireland Confidential Enquiries into MaternalDeaths and Morbidity 2009-13. Oxford: National Perinatal Epidemiology Unit, Universityof Oxford 2015

3. Room temperature stable carbetocin for the prevention of postpartum haemorrhageduring the third stage of labour in women delivering vaginally: study protocol for arandomized controlled trial Widmer M, Piaggio G , Abdel-Aleem H et al Trials (2016) 17:143

PHARMACEUTICAL PHYSICIAN CONTACT: Liz Langley or Karen YoungInfo@brapp.org 0118 934 1943

Reach your target market:Advertise here or on theBrAPP website.

REVIEWS

September 2016 volume 26 | No 6

24PHARMACEUTICAL PHYSICIAN

THE COACHING HABIT: SAYLESS, ASK MORE & CHANGE THEWAY YOU LEAD FOREVERMichael Bungay StanierISBN: 9780978440749THIS SMALL BOOK is aboutempowering others and doing soefficiently through getting them toanswer their own questions throughexquisite focus. Whilst itstitle risks giving theimpression that this is abook for coaches or leaders,its content is actuallybroadly applicable tohelping someone deal withan issue which requiresresolution. As experiencedexperts in a time constrainedworld it is easy to slip intothe habit of giving advicewhen a more empoweringapproach might be appropriate, and yet,as the author remarks, "the seeminglysimple behaviour of giving a little lessadvice and asking a few more questionsis surprisingly difficult". This bookgives you tools to do just that.

The backbone of the book consists ofseven core coaching questions,accompanied by a brief rationale for theapproach described and practicalguidance on implementing behaviourchange. Of the seven questions, mypersonal favourite is "What's the realchallenge here for you?" Those sevenwords invariably refocus the issue athand, cutting through the mists of whatmight be going on, most of which is notactually of use in sorting things out.

Presented alongside the seven corequestions themselves are elements of a"Question Masterclass" which guides the

reader through using the questions in acoaching encounter. Videos illustrateeach point alongside examples of thesort of concise and incisive phraseologythat can be so elusive when involved inreal life exchanges of this nature.Unlike some books, it is notoverburdened with examples – the onesgiven are all “best in class”, obviating

the need for more.

Despite having undertakenextensive coach andmanagement training over theyears, I still got an immenseamount out of this book. Oneof the things I particularlyliked is that it is a truedistillate of wisdom andexperience in this area and itsextensive signposting toreference material including

TED talks, websites and podcasts, whichinvites the reader to explore further,particularly if reading the e-book on anInternet enabled device; functionality Ifind that I am using more and more.

In summary, an immense amount ofdistilled wisdom and material to explorefurther in a nutshell which deserves it’s4.5 Amazon star rating.

Liz ClarkVice President,

Medical Affairs, Norgine

THE PATIENT GROUPHANDBOOKA practical guide for research anddrug development Eds Anthony Hall and Nicolas SireauPublisher Findacure Publications. ISBN978 15233201032THE EDITORS ARE to be congratulatedon bringing together the elements that

make up highly relevant andinteresting guide book.People come to clinicalresearch for all sorts ofreasons. Many of us studyscience and find that clinicaldevelopment is a good wayto utilise our interests andcapabilities. Others come toclinical research through needor desperation. Dr NickSireau has a professionalinterest in rare diseases having served invarious capacities with variousorganisations. His day job is in pharma.And he has sons with alkaptonuria. Thisrare disease is poorly served by pharma.So not only did Dr Sireau set up aconsortium which was then successfulin being funded by the European Union7th Framework programme to repurposea drug for the condition, now in clinicaltrials, but he has also educated,campaigned, set up a ‘fundamentaldiseases partnership’ (Findacure) andfound time to collaborate on books tohelp the rest of us with pharmaceuticalphysician, Dr Tony Hall.

I wasn’t sure what to expect when Ipicked the guide up. Possibly dry,possibly impenetrable? No. The editorshave harnessed the skills of 52 authorscontributing 25 lively chapters to bringanyone working in any aspect ofpharma, pre or post-authorisation, apractical playbook of how to go aboutdeveloping a drug as an ‘outsider’.Whilst ostensibly focussing on thechallenges of rare diseases with theirspecific considerations, the guide spansall types of clinical development and isrelevant to commercialisation as wellsince it considers in detail engagementwith the key stakeholder groupsincluding patients and payers.

I found the perspective refreshing andilluminating. Having had a verytraditional pharma upbringing it wasuseful to be reminded of what it feelslike to be breaking in across establishedpharma and building new bridges andrelationships with a relentless focus onsuccess: getting a useful drug to patients

who need it. – Hence alsohighly relevant to any readerworking for a start- up oryoung company trying tomake its mark amongst thebehemoths. Creativity,communication, collaboration:these are the strands whichlink the chapters for me andwhether you work for acompany employing 105,000or 5 individuals there is much

to reflect upon and consider harnessingfor your own development- be thatpersonal or work-related.

The book is clearly laid out and the fonteasy to read. The chapters flowsmoothly with each author projectingtheir ‘voice’ in their own style. Thebook feels very personal whilst at thesame time factual, practical andaccessible. This is a book for the layreader and professional reader alike andcould lead to interesting and productiveconversations between these groups.

This is a ‘buy’. Madhu Davies

PS: All proceeds from book sales go toFindacure’s charitable projects. You canview the full contents and purchase yourcopy (in both Kindle and paper format)from Amazon.

REVIEWS

September 2016 volume 26 | No 6PHARMACEUTICAL PHYSICIAN 25

TRIBUTES:

DR JOHN YOUNG FRCP FRCPATH

FFPM

DR CHRIS ALLEN – 1963 – 2016

DR GURPAL SINGH GOSALL 1971-2016

September 2016 volume 26 | No 6

26PHARMACEUTICAL PHYSICIAN

DR JOHN YOUNG FRCPFRCPATH FFPMIT IS WITH immense fondness that Iremember Dr John Young, who wasMedical Director at MSD for over 20years, retiring in 2007. During his tenure,MSD contributed to huge progress inmedicine including the launches ofInnovace, Zocor, Cozaar, Singulair,Fosamax and many more. John was anall-rounder, in the days when MedicalDirector was responsible for MedicalAffairs, Clinical Research, RegulatoryAffairs and Drug safety. He had a cannyability to spot trouble and take avoidingaction before it became a crisis, and if itdid become a crisis, his cool logical headnegotiated it with minimal fuss. He had astrong sense of fairness, trusted thosearound him and was always available foradvice but never micro-managed. Manyof the senior pharmaceutical physiciansof today passed through his medicaldepartment during their training andwere the better for it.

John qualified from St Thomas’ Hospitalin 1968, and trained as a clinicalbiochemist in the NHS before joiningthe pharmaceutical industry. He heldsenior positions with the Faculty ofPharmaceutical Physicians and the ABPIduring his career. He was a staunchsupporter of the Diploma inPharmaceutical Medicine and of BrAPP.

In retirement he enjoyed spending timewith his family and his beloved boat.He died soon after the diagnosis ofadvanced pancreatic cancer, highlightingthe ongoing need for better medicinesfor this challenging disease.

Paul Robinson

I WAS GREATLY saddened to hear ofthe sudden death of my friend andcolleague John.

I first encountered him as a newlyappointed associate medical director atE R Squibb and Sons. My portfolio hadthe soon to be approved ACE inhibitorCaptopril and Pravastatin. MSD was atthe same time preparing to launchenalapril and simvastatin.

Both pairs of drugs were new and quitea challenge for clinicians and John and Iwere the “brokers” trying to stop therespective marketing teams fromknocking lumps out of each other intheir efforts to gain a small advantage inpursuit of sales dominance.

John was on the ABPI medicalcommittee at the time and so was verykeen not to have his marketingcolleagues appear before the Code ofPractice committee on a recurring basis.Thus we both needed to find a way tomanage the situation. As a solution, we

Dr John Young

set up informal meetings away fromeither company’s offices to talk overcopy that was already signed off toensure that we did not need to makeABPI complaints on a regular basis. Ourdebates were what is describeddiplomatically as robust as neither of uswanted to give ground that might put usat a disadvantage, but in the end senseprevailed. John could appear quitestern, but our discussions were cordialand very helpful as I do not recall eithercompany needing to make the trip toWhitehall to during the ACEI campaign.Life was a bit more contentious when itcame to the statins but we still avoidedthe ABPI most of the time.

John and the late John Domenet weremy proposer and seconder forfellowship of the Faculty and I felt veryhonoured to be endorsed by twophysicians for whom I had the utmostrespect.

When later I moved to a global job in adifferent company, I had much lesscontact with John; I missed our“sparring” sessions. As we both took onroles within the Faculty our paths beganto cross again very regularly and it wasalways a great pleasure to work withhim. At all times he was professional,diplomatic but there was a dry wit thatmeant that there was often a twinkle inhis eye even when we disagreed.

John’s professionalism, integrity and witwill be greatly missed, I am sure that hewill be ensuring that copy is compliantin a much better place.

David BlowersHon Chairman BrAPP

DR CHRIS ALLEN – 1963 – 2016CHRIS WAS BORN in Bristol, andtrained in medicine and subsequently inanaesthetics at King’s College Hospital,London. There he met a young nurse,Janet, who became his wife. After NHSwork, Chris joined Merck Sharp &Dohme in the UK, as Medical AffairsDirector, working with products that

have become essential medicines ineveryday practice, such as Fosamax(alendronate), Sinemet and Primaxin.Immediately prior to his departure tothe US Chris had played an importantrole in BrAPP serving on the committeeand becoming Honorary Treasurer.These were interesting times for theassociation and Chris was never afraidof tackling issues head-on. The trainingof pharmaceutical physicians wasimportant to him and BrAPP’sdeveloping portfolio of courses whichcomplemented other offerings was animportant source of income for theassociation. He was very much involvedin the decision to relocate fromWimpole Street to Bedford Row.

In 1997 Chris, Janet and their youngson, Jack, relocated to the United Statesand he worked in Medical Affairs at theglobal level until his death.

A man of varied interests and passions,Chris was an avid scuba diver andearned his 3rd degree black belt inKarate. He enjoyed family travel andfinding out of the way and unusualtourist stops. His work presentationswould frequently be interspersed withbeautiful locations he had visited. Withhis wife he shared a love for footballand heavy rock concerts. He was aknowledgeable wine buff andappreciated quality gin.

Professionally, Chris was a pastpresident of the International Federationof Pharmaceutical Physicians and theAmerican Research Physicians Society

and served on the selection committeefor the Pharmaceutical Physician of theYear.

Chris is survived by his wife Jane, hisson Jack and his parents.

Chris Allen was the spice ofpharmaceutical medicine life. Heseemed completely immune to theviscosity of large organizations.Technically, his versatility was well-known. His prior training inanaesthetics and intensive care, awhole-body specialty if ever there wasone, had doubtless been a goodpreparation. Unexpectedly, I met Chrisat a specialist conference one day. Wewere both there to learn. Chris had justtaken up this new field with a new drugdevelopment project: 'Did I tell you thatI am now a chylomicron ?' heannounced brightly. The following yearit was Chris lecturing to the specialists atthe conference, having mastered andadvanced the field in 12 months flat.Beyond his remarkable medical andscientific abilities, Chris had wisdomwell beyond his years. Patient safetyand scientific integrity always came first.Only secondarily would Chris turn to(and inevitably succeed in) finding thediplomatic avenue, through which what

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September 2016 volume 26 | No 6PHARMACEUTICAL PHYSICIAN 27

Dr Chris Allen

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PHARMACEUTICAL PHYSICIAN

was best for patients and what wassound science would be driven; it wasnever the other way round. His electionas President of IFAPP, and the successhe made of that role, also reflectedthese principles of patients first, sciencesecond, politics a distant third.Christopher Allen was the epitome ofpharmaceutical medicine.

Tributes from Dr Paul Robinson andProfessor Tony Fox

DR GURPAL SINGH GOSALL1971-2016THIS IS YET ANOTHER very sad anduntimely death. Gurpal Gosall,previously in 2002 winning acclaim forsubmitting The World’s Funniest Joke ina LaughLab experiment conducted bythe University of Hertfordshire and mostrecently becoming Deputy MedicalDirector and Chief Clinical InformationOfficer for Lancashire Care NHSFoundation Trust, died suddenlyfollowing a myocardical infarction on 14August.

BrAPP members and colleagues willremember that Gurpal has assisted us indelivering a wonderful bespoke two-dayCritical Appraisal Course for the pastfour years. This year he delivered thefirst session to PGCPM delegates on 21July. He was his usual ebullient andvery amusing self. We will miss him

hugely. For your interest we includeGurpal’s own LinkedIn entry:

“I am a Consultant General AdultPsychiatrist at the Royal BlackburnHospital. I am also the Deputy MedicalDirector and Chief Clinical InformationOfficer for Lancashire Care NHSFoundation Trust.

Computing, programming and designhave been interests of mine since thedays of the ZX Spectrum and BBChome computers in the 1980s.Nowadays I'm into web design anddesktop publishing. Combined with myinterest in education, I have developedan international reputation for providinginnovative and top quality trainingmaterials in mental health and evidence-based medicine.

It started in 2000 with Superego Cafe,the website for trainee psychiatrists, anddeveloped into revision courses for theMRCPsych exams, continuingprofessional development and criticalappraisal. In 2013 a new subsidiary, TheCritical Appraisal Company, waslaunched to meet the demand for ourunique training approach in healthcareorganisations and the pharmaceuticalindustry, not just in the UK but alsoacross the rest of Europe, the MiddleEast and Australasia.

I'm always interested in newopportunities so get in touch!”

Gurpal was born in 1971 inHuddersfield, West Yorkshire. Followinghis preliminary education in WestYorkshire, he went on to read Medicineat Girton College, Cambridge. Afterspending his initial clinical years at hisbeloved Guys and St Thomas’ HospitalLondon, Gurpal undertook his specialisttraining in Psychiatry in the North Westof England. For the last eleven years hehas been Consultant General AdultPsychiatrist, and of late he had beenawarded the position of Deputy MedicalDirector and Chief Clinical InformationOfficer at Lancashire Care NHSFoundation Trust.

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Dr Gurpal Singh Gosall

Gurpal and his wife, Narinder, who hemet at school, have gained aninternational reputation as medicaleducators. As a couple they havelectured in Australia, Singapore, India,UAE, USA, Hong Kong, Japan, Thailandand throughout Europe. Together, Drs GS Gosall & N K Gosall have recentlypublished their fourth edition of theirtextbook, A Doctor’s Guide to CriticalAppraisal, and work had alreadycommenced on the fifth edition.

Gurpal’s boundless energy andenthusiasm touched many lives in his 45

years. His colourful personality, wit,charm, intelligence and positivity hasleft a lasting legacy, and he will besorely missed by everyone who knewhim.

This may give you a feel for hiscommitment to the education of fellowdoctors as well as to his patients andmost importantly his family. A visit tovarious training websites forpsychiatrists will reveal that we are notalone in feeling the void created by hisdeath. Our thoughts are with Narinderand their son, Dilip.

TRIBUTES:

September 2016 volume 26 | No 6PHARMACEUTICAL PHYSICIAN 29

CHERYL MERRIDEW AND DR ROBERT DEWDNEYON A MUCH more upbeat note, we say farewell to two stalwarts of the CardiffSchool of Pharmacy team who have featured in a number of people’s lives over theyears – Mrs Cheryl Merridew who you will remember worked for Profs DavidLuscombe and Sam Salek back in the day when the Course was known as theCardiff Course. She has been working for Dr Robert Dewdney, Director ofEducation, who also retired at the end of August and was instrumental in revitalisingthe PostGraduate Course in Pharmaceutical Medicine in Cardiff and has workedtirelessly with BrAPP to produce an improved and more focussed curriculum. Wethank them both for their positive interaction with BrAPP and its members and wishthem a fulfilled and busy retirement from academia.

Cheryl Merridew and Dr Robert Dewdney