IN THIS ISSUE: REGULATORY ROUND UP

Special features The French Drug TrialDisaster

Personal Profile Analysis

Retro Feature: From thearchive

JOURNAL OF THE BRITISHASSOCIATION OFPHARMACEUTICALPHYSICIANS

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Providing Pharmaceutical Physicians

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Permanent RolesMedical Director UK/Ireland Global Biotech – multiple TAs, significant team W London PP 6677

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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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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 ROUND UP 4Anne Hetherington

SPECIAL FEATURE 7The French Drug Trial

Disaster

What can we learn?

Dr Daryl Bendel

SPECIAL FEATURE 14Personal Profile Analysis

Recruiting for the future

of Medical Affairs

Matt Edwards and NicolaHarding

SPECIAL FEATURE 19“Who Gets the Cat?”

An amicable divorce model

of a company demerger

Dr Michael Atkins

RETRO FEATURE 22What is R & D?

Drug Discovery January 2010

Dr Matthew Hickling

PERSONAL VIEW 28Tackling the Diabetes

Epidemic

With Digital Therapeutics

Dr Matthew Goodman

NEWS 30MHRA

PEOPLE PAGE 32

Contents

JANUARY 2017 VOLUME 27 | NO

1

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

JANUARY 2017

volume 27 | No 1PHARMACEUTICAL PHYSICIAN

3

AS WE PUT this issue to bed, it isincredible to reflect that BrAPP will be60 years old in 2017. It seems onlyyesterday that we celebrated our goldenanniversary. And then one thinks of allthat has happened in the interveningdecade; not to mention a very turbulentimmediate past year! Whatever one’spolitical leaning, 2016 cannot be said tobe anything short of a sea change. Andonly the coming months and years willshow whether it is merely a blip alongthe way or indeed a shift in worldorder.

To celebrate our Diamond Jubilee wewill be running articles from theinception of the journal (in 1989) and ifanyone has other items to contribute wewill be pleased to receive and publishthem. To start the ball rolling we havechosen a piece written by Dr MatthewHickling, then a Medical Advisor atUCB, and published in January 2010focussing on Drug Discovery. It isinteresting to reflect what has and whathas not changed over the period.

As ever, we are delighted to have theinvaluable Regulatory RoundUp contentfrom Anne Hetherington and whenreading the article from Matt Edwardsand Nicola Harding, you will note thatMedical Affairs physicians are perceivedto need a breadth of knowledge of allthings regulatory to contributesignificantly in today’s industry.Regulatory Affairs andPharmacovigilance disciplines andknowledge maybe under-valued byphysicians working closer to theimmediate market interface but anunderstanding and awareness of thecurrent guidelines and modules (ICHand EMA et al) along with rest of thediverse aspects of our specialty willseparate the successful from the “steadyeddies” as Matt and Nicola call them.

2016 began with the pharma industry inthe headlines and Dr Daryl Bendeloffers a timely review of what happened– as far as we know- in the Rennes trialthat cost the life of one volunteer inJanuary. He asks “what can we learn”

and in essence it seems we can onlylearn that caution is a valuablecharacteristic and that first-in-manstudies remain a small step into theunknown.

Reflecting on the changing times in theindustry, Dr Michael Atkins, provides aview of a “good” way to demerge. Thekey to this seems to be, remember thereare people involved and people havefeelings. Finally, Dr Matt Goodman co-founder of MapMyHealth gives us athought-piece ahead of a two articleseries to follow in 2017 about theharnessing of digital therapeutics to helpturn the tide of the diabetes epidemic.

I personally look forward to 2017 andhope for a peaceful and happy year. Iwish all our readership the same.

PS Please let us have your contributionsto what is YOUR journal. Emailinfo@brapp.org

Dr Madhu Davies

EDITORIAL

Dr Madhu Davies

REGULATORY ROUND UP

By Anne Hetherington, Senior Regulatory Consultant, Envigo Ltd.

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.

January 2017

volume 27 | No 1

4PHARMACEUTICAL PHYSICIAN

1. EUROPEAN MEDICINES AGENCY (EMA)

News and press releases• First statistics on PRIME are

released http://www.ema.europa.eu/ema/index.jsp?curl=pages/news_and_events/news/2016/06/news_detail_002541.jsp&mid=WC0b01ac058004d5c1

• Regulation of advanced therapymedicineshttp://www.ema.europa.eu/ema/index.jsp?curl=pages/news_and_events/news/2016/06/news_detail_002543.jsp&mid=WC0b01ac058004d5c1

• Proposals to revise guidance onfirst-in-human clinical trialshttp://www.ema.europa.eu/ema/index.jsp?curl=pages/news_and_events/news/2016/07/news_detail_002572.jsp&mid=WC0b01ac058004d5c1

• Annual activity report 2015http://www.ema.europa.eu/docs/en_GB/document_library/Report/2016/07/WC500210118.pdf

• Statement on the outcome of theUK referendumhttp://www.ema.europa.eu/ema/index.jsp?curl=pages/news_and_events/news/2016/07/news_detail_002566.jsp&mid=WC0b01ac058004d5c1

Updates• Periodic safety update reports

http://www.ema.europa.eu/ema/index.jsp?curl=pages/regulation/document_listing/document_listing_000361.jsp&mid=WC0b01ac058066f910

• Post-orphan medicinal productdesignation procedures: guidancefor sponsorshttp://www.ema.europa.eu/docs/en_GB/document_library/Regulatory_and_procedural_guideline/2015/11/WC500196994.pdf

• Clinical Trial Regulationhttp://www.ema.europa.eu/ema/index.jsp?curl=pages/regulation/general/general_content_000629.jsp&mid=WC0b01ac05808768df

Anne Hetherington

ENVIGO.COM

• Q & As on how to express thefrequency of adverse reactionswithin the product informationhttp://www.ema.europa.eu/docs/en_GB/document_library/Other/2016/07/WC500210919.pdf

• Guideline on the clinicaldevelopment of medicinal productsfor the treatment of HIV infection,adoptedhttp://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2016/07/WC500209918.pdf

• Guideline on clinical evaluation ofmedicinal products used in weightmanagement, adoptedhttp://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2016/07/WC500209942.pdf

• Clinical investigation on medicinalproducts in the treatment ofhypertension (updated)http://www.ema.europa.eu/ema/index.jsp?curl=pages/regulation/general/general_content_001069.jsp&mid=WC0b01ac0580034cef

• Clinical investigation of medicinalproducts in the treatment of lipiddisorders (updated)http://www.ema.europa.eu/ema/index.jsp?curl=pages/regulation/general/general_content_001073.jsp&mid=WC0b01ac0580034cef

• Guideline on clinical investigationof medicinal products in thetreatment of lipid disorders,adoptedhttp://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2016/07/WC500209944.pdf

• Guideline on clinical investigationof medicinal products in thetreatment of hypertension, adoptedhttp://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2016/07/WC500209943.pdf

• Draft guideline on the clinicalevaluation of direct acting antivirals

for the treatment of chronichepatitishttp://www.ema.europa.eu/ema/doc_index.jsp?curl=pages/includes/document/document_detail.jsp?webContentId=WC500209917&murl=menus/document_library/document_library.jsp&mid=0b01ac058009a3dc

2. EUROPEAN COMMISSION

• Four public consultations onrecommendations related to clinicaltrials are open from 1 June 2016 to31 August 2016http://ec.europa.eu/health/human-use/clinical-trials/developments_en

3. MEDICINES AND HEALTHCARE

PRODUCTS REGULATORY AGENCY

(MHRA)

• Statement on the outcome of theEU referendumhttps://www.gov.uk/government/news/medicines-and-healthcare-products-regulatory-agency-statement-on-the-outcome-of-the-eu-referendum

• Human Factors and UsabilityEngineering – Guidance forMedical Devices Including Drug-device Combination Productshttps://www.gov.uk/government/news/human-factors-and-usability-engineering-guidance-for-medical-devices-including-drug-device-combination-products

• Pharmacy dispensing models anddisplaying prices on medicineshttps://www.gov.uk/government/consultations/pharmacy-dispensing-models-and-displaying-prices-on-medicines

• MHRA GxP Data IntegrityDefinitions and Guidance forIndustryhttps://www.gov.uk/government/news/mhra-gxp-data-integrity-definitions-and-guidance-for-industry

4. FOOD AND DRUGS ADMINISTRATION

(FDA)

Guidance for Industry• Expanded Access to Investigational

Drugs for Treatment Use —Questions and Answershttp://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM351261.pdf

• Charging for Investigational DrugsUnder an IND — Questions andAnswershttp://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM351264.pdf

• Implementation of Acceptable Full-Length and Abbreviated DonorHistory Questionnaires andAccompanying Materials for Use inScreening Donors of Source Plasma http://www.fda.gov/downloads/BiologicsBloodVaccines/BloodBloodProducts/ApprovedProducts/LicensedProductsBLAs/BloodDonorScreening/UCM341088.pdf

REGULATORY ROUND UP

January 2017

volume 27 | No 1PHARMACEUTICAL PHYSICIAN 5

PHARMACEUTICAL PHYSICIAN CONTACT: Liz Langley

Info@brapp.org 0118 934 1943

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

January 2017

volume 27 | No 1PHARMACEUTICAL PHYSICIAN

SPECIAL FEATURE:The French Drug Trial Disaster

What can we learn?

By Dr Daryl Bendel

7

SUMMARYEARLY PHASE DRUG trials have a verygood safety record. In January 2016, ahealthy participant died and a numberof other participants were hospitalisedwith drug-related CNS effects whileparticipating in an early phase study ofthe drug BIA 10-2474 being conductedin France. This article discusses someof the key features of ourunderstanding as to what might havegone wrong, the outcome of the maininvestigations and some of theproposals to further improve the safetyrecord of early phase drugdevelopment.

INTRODUCTIONSerious incidents in healthy participantsin Phase 1 studies are thankfullyextremely uncommon, with studyrelated deaths in healthy participantsbeing exceptionally rare.

In a systematic review of 475 trialsenrolling 27,185 participants, there wasa median [interquartile range IQR] ofzero serious adverse events [0–0] and amedian of zero severe adverse events[0–0] per 1000 treatment groupparticipants/day of monitoring. The rateof mild and moderate adverse eventswas 1147.19 [651.52–1730.9] and 46.07[17.80–77.19] per 1000participants/adverse event monitoringday respectively [17].

Following the TGN1412 trial, Sibille etal[18] noted that 15 deaths in healthyparticipants have been published duringthe last 30 years in Western countries,although probably 100,000 healthyparticipants are dosed every year.Furthermore, only three of the deathswere unavoidable.

The risk of a life-threatening adverseevent in trials with monoclonalantibodies is more difficult to accuratelyestablish. Tranter et al [19] reported anincidence of between 1:425 and 1:1700life-threatening events, but all suchevents occurred in a single trial(TGN1412). Furthermore, it was difficultto establish the number of healthyparticipants exposed.

The death of a healthy participant andserious adverse reactions in four otherparticipants in study BIA-102474-101(BIA) of study drug BIA 10-2474 was anunprecedented event. Although parallelswill be sought between the BIA trialand the TGN1412 trial 10 years earlier,they couldn't in fact be more different.

TGN1412 supports the old maxim, alldrugs are poisons, it’s just a matter ofdose. Starting at a dose of 1/1000th ofthat used in the TGN trial and escalatingto 1/14th of the dose, Tyrsin et al [20]

demonstrated the absence ofproinflammatory cytokine release andtransient IL-10 release at the highestdose indicative of desired selectiveactivation of regulatory T-cells inhealthy participants. The drug,rebranded as TAB08 is now in a Phase1b trial in patients with rheumatoidarthritis. Following TGN1412, the EMAintroduced EMEA/CHMP/SWP/ 28367/07Guideline on strategies to identify andmitigate risks for first-in-human clinicaltrials with investigational medicinalproducts [21], which was predominantlyapplied in the BIA trial.

BIA-102474-101 Unfortunately minimal source dataregarding BIA 10-2474 is available in thepublic domain. L’Agence nationale de

Daryl Bendel

SPECIAL FEATURE:The French Drug Trial Disaster

What can we learn?

PHARMACEUTICAL PHYSICIAN

sécurité du médicament et des produitsde santé (ANSM) released the studyprotocol (BIA-102474-101) [22] whichprovides detailed information regardingthe study design but only basicinformation of the study drugpharmacology and toxicology.Unfortunately the involved parties havechosen to withhold the investigatorbrochure (IB) and clinical trial data,citing commercial confidentiality [31]. Adetailed chronology of events has beenprovided by the ANSM [23]. Much of ourunderstanding of the events is obtainedfrom the Scientific Committee SpecializedTemporary (CSST) [24] and GeneralInspectorate of Social Affairs (IGAS) [25]

reports, bodies that were established toinvestigate scientific (CSST) andcompliance (IGAS) aspects of the trial.

BIA 10-2474 is a long acting reversibleinhibitor of the serine hydrolase fattyacid amide hydrolase (FAAH) thatincreases the level of theendocannabinoid anandamide in thecentral and peripheral nervous systems.This class of drugs were beingdeveloped for a range of conditionssuch as pain, vomiting, anxiety, mooddisorders, Parkinson's disease,Huntington's disease and variouscardiovascular conditions. A number ofdrugs from this class had been safelythrough phase 1 trials and into earlyclinical development; although they hadbeen largely discontinued due to lack ofefficacy [22, 24].

Although BIA10-2474 was stated asbeing reversible, in humans there isalmost complete enzyme inhibition after24 hours, even with plasmaconcentrations below the limit ofquantification. It was reported that thereis a steep dose response curve betweenzero and maximal enzyme inhibition.Potency was reported as being at least100 fold less than for other FAAHinhibitors. On the available data thespecificity of BIA 10-2474 is unclear asit is not specified which targets wereevaluated – there are about 300 targetsin the serine hydrolase family. Ninehuman metabolites had been identified,

with three of them having similarpotency to the parent. Metabolicpathways or potential for polymorphismwas not reported [24].

The toxicology programme that wasundertaken was interesting in that 13week studies were conducted in mice,dogs and monkeys and 26 week studieswere conducted in rats. Additionally,reproductive and developmental toxicitystudies were done in rats and rabbits.No justification has been provided forsuch extensive use of animals, and inparticular, non-human primates prior togoing into Phase 1 human studies. Thislevel of toxicological investigation priorto going into man for a non-novelcompound is highly unusual. The CSSTreport noted the IB had translationimperfections and transcription errors,particularly in the tables and figures thatgenerated ambiguities and difficulties inunderstanding [24].

No end-organ toxicity was reported andcalculations of the starting and maximaldose from 0.25mg to 100mg in humanswere appropriately justified. Whilst easyto find minor comments on the protocolin hindsight, on balance this was anappropriately designed and commonlyused first-in-man programme thatincluded the single (SAD) and multiple(MAD) ascending dose elements, a foodeffect and a proposedpharmacodynamic group. One point inthe protocol that stands out states that ifthe maximum tolerated dose (MTD) isnot reached after completing theplanned sequential groups, additionalgroups can be included to a maximumof 8 groups. Planned dose levels wereup to the NOAEL which is acceptable.Under certain circumstances goingbeyond NOAEL could also be justified.However the proposed rate ofescalation and basis for decision wasnot described in the protocol.

CHRONOLOGY OF EVENTSThe study schedule described in Table 1has been adapted from the ANSMpublication of the chronology ofevents[23].

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It has been reported that the studyprogressed without significant event,through the all the SAD cohorts (0.25mgto 100mg, n = 48 on active treatment),food-effect cohort (40mg, n = 12) andMAD cohorts M1 to M4 (2.5mg daily to20mg daily, cumulative dose of 200mg,n = 24 on active treatment). For MADcohorts M1 to M4 dose escalationdoubled. For MAD cohort M5participants were dosed at 50mg, whichwas a 2.5 fold increment over theprevious level. Usually the rate of doseescalation reduces as exposure levelsreach toxicological limits.

Cohort M5 (50mg per day) starteddosing on 6th January 2016 and on theevening of the fifth day of dosing (10thJanuary 2016), the first participant washospitalised (cumulative dose 250mg).Reports vary as to the nature of hiscondition at this time, and indeed bythe time the remainder of the cohortwas dosed the following morning (day

6), following which the trial was haltedand the remaining 5 participants whoreceived active treatment werehospitalised (cumulative dose 300mg).Symptoms included headache in 5participants including very severe‘thunderclap’ in one, cerebellar signs in3 participants, reduced consciousnessincluding coma in the deceasedparticipant and memory disorders in twoparticipants. The CNS was the onlysystem affected. One participant hadnon-specific changes to thecerebrospinal fluid. MRI findingsincluded bilateral and symmetricaloedema, haemorrhage and gliosis in thehippocampus, thalamus and cortex,suggestive of a metabolic/toxicprocess [24].

Pharmacokinetic data in animals wasunremarkable whereas in humans, therewas a dose-related increase inelimination half-life and consequentlyexposure, possibly due to saturation of

elimination mechanisms. Interindividualvariability of pharmacokinetic

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Continues on page 10 ��

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| TABLE 1: Study Schedule BIA-102474-101Cohort Dose Increment Participants

Active/Placebo

Days since prior dose level

Part 1 SAD

09 July 2015 S1 0.25mg N/A 1/1 Sentinel Group

10 July 2015 S1 0.25mg N/A 5/1 24 hours after first 2 subjects

11 August 2015 S2 1.25mg 5 6/2 31 days after S1

19 August 2015 S3 2.5mg 2 6/2 8 days after S2

26 August 2015 S4 5 mg 2 6/2 7 days after S3

3 September 2015 S5 10mg 2 6/2 8 days after S4

16 September 2015 S6 20mg 2 6/2 13 days after S5

30 September 2015 S7 40mg 2 6/2 14 days after S6

9 October 2015 S8 100mg 2.5 6/2 9 days after S7

21 October 2015 F1 TP1 40mg fasted N/A 12/0 N/A

10 November 2015 F1 TP2 40 mg fed N/A 12/0 N/A

06 October to 15 October 2015 M1 2.5 mg daily * 10 N/A 6/2 In parallel with SAD, 20 fold safety margin

28 October to 06 November 2015 M2 5 mg daily * 10 2 6/2 13 days after last dose M1

17 November to 26 November 2015 M3 10mg daily * 10 2 6/2 11 days after last dose M2

9 December to 18 December 2015 M4 20 mg daily * 10 2 6/2 13 days after last dose M3

6 January 2016 to 11 January 2016 M5 50mg daily * 10 2.5 6/2 19 days after last dose M4

SPECIAL FEATURE:The French Drug Trial Disaster

What can we learn?

PHARMACEUTICAL PHYSICIAN

parameters increased with dose, and atdose level M5, trough levels continuedto rise through dose 5 and dose 6.Variability in some of the humanmetabolites differed to that expectedfrom animal studies. It was reported thatthe onset of FAAH inhibition starts atabout 1.25mg and is almost complete at5mg [24].

PROPOSED MECHANISMS OFTOXICITY The CSST, in their report evaluated thecausality of these adverse events andconcluded that with almost certainty,this was related to the administration ofBIA-10-2474 [24].

Although no comparative enzyme andreceptor binding assays were reportedin the protocol, an in silico studyperformed by Ekins [27] predicted thatBIA 10-2474 would bind to other targetsas well as FAAH. It is possible that thetoxicity seen was due to off-targeteffects seen suddenly at high cumulativedose [24, 26].

Other groups have shown using anautomated computer-based proteome-docking approach that BIA 10-2474interacts with some proteins that havebeen implicated in causingbrain/intracerebral hemorrhages [28].

CONCLUSIONS OF CSST AND IGAS ANDRECOMMENDATIONSOverall the CSST reported that thatstudy was conducted and approved inaccordance with the Regulations ineffect at the time. Recommendationsmade included [24];

i. there should be sufficient preclinicaldata predictive of clinical utility tojustify the investigation of the drug inman;

ii. comprehensive neuropsychiatricscreening should be included inPhase 1 studies for CNS drugs;

iii. for first in human studies, protocolsshould allow doses to be adjusted

based on emerging data, and inparticular, extrapolation should bemade from data from the mostsensitive participant and not merelythe cohort average.Pharmacodynamic data should beused and consideration given as tothe justification for significantlyexceeding the maximalpharmacological effect.

iv. that further staggering of dosing isproposed for the MAD part of thestudy;

v. that dose escalation strategies shouldinvolve common sense in addition tothe usual pharmacological andregulatory considerations;

vi. that there is greater transparency anddata sharing between Agencies forPhase 1 data.

The main findings and conclusions ofthe IGAS report cited three majorfinding in relation to Biotrial, the Phase1 unit who conducted the study,namely; that [25];

- The study should have been stoppedafter the first participant had beenhospitalised and the remainingparticipants should not have beendosed on day 6;

- All other participants should havebeen notified and asked to reconsentbefore continuing participation in thestudy; and

- The incident should have beenreported immediately to ANSM andnot four days later.

Biotrial has rejected these findings on anumber of grounds, the details of whichare provided on its website [29].

Furthermore, it was noted that anumber of the protocol provisions weretoo vague, that the eligibility criteriashould have been more explicitregarding substance use habits of thevolunteers and that there was no legal

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requirement for the sponsor to discloseall pre-clinical data to the ANSM [25].

The EMA has recently issued a conceptpaper for the revision of the existingGuideline on strategies to identify andmitigate risks for first-in-human clinicaltrials with investigational medicinalproducts’(EMEA/CHMP/SWP/28367/07) [21, 30],which recognises that many first inhuman studies are integrated protocolsinvolving a number of parts.

DISCUSSION ANDCONCLUSIONSDespite two high profile tragedies inearly drug development in the lastdecade, the safety record of Phase 1trials is overall very good with theoverall risks approaching those ofnormal daily life. There will always bean element of risk associated with drugdevelopment and in particular earlyphase drug development. Most Phase 1trials are conducted in healthyparticipants who have no opportunity

for clinical benefit; the risks must bemitigated and balanced accordingly.

Our ability to learn and develop suitablerisk mitigation strategies from BIA-10-2474 is significantly undermined by thechoice of those involved to hide behindcommercial confidentiality in notreleasing the IB and clinical trial data [31].Of the three main parties involved inthis tragedy, BIAL, ANSM and Biotrial,only Biotrial as the economically andpolitically weakest party has a legitimateclaim to non disclosure. Both ANSM andBIAL, parties potentially subject to

criticism, could have chosen fulldisclosure and transparency.

The standout feature of the IGAS reportis the fact that this tragedy happened,despite the Regulations being followed.It is notable that there was no legalrequirement for the sponsor to discloseall pre-clinical data to the ANSM [25]

which must once again raise the issue oftransparency. Will we ever know whatwas not disclosed and what therelevance of that non disclosure was?Without the benefit of hindsight, theIGAS criticisms of Biotrial don't amountto much and had no role in the cause ofthis tragedy. Reconsenting participantsfor example needs ethical approval ofthe revised consent form, something thatcannot be achieved overnight.

The CSST report provides evidence thatthis tragedy was almost certainly relatedto BIA-10-2474 [24], and likely due tooff-target effects. Various hypotheseshave been proposed as to how this mayhave happened and how the dose

response curve could have been sosteep. At this stage there are nodefinitive answers.

With the benefit of hindsight, there areclues indicating that BIA-10-2474 maybe a problematic compound. In general,factors such as low potency, poorspecificity, limited or incompletereceptor binding assays, numerousmetabolites, and somewhat counter-intuitively, the absence of anytoxicological findings are signals forpotential problems. In this case, theunusual and extensive toxicology

programme must have raised somequestions. Once human data becameavailable, the suggestion of non-linearityin exposure would suggest a morecautious approach to dose escalation isrequired.

The absence of reported toxicologicalfindings provides a good justification toproceed cautiously, particularly asevidence emerges that humanpharmacokinetics are non-linear andapproaching the NOAEL. It is difficult tounderstand the rationale for the 2.5–foldfinal dose increment and it is difficult tounderstand why ANSM approved this.To illustrate this point, when the firstparticipant was hospitalised, theinvestigator quite understandablyconsidered this to be an unexpected,unrelated event in a participant basedon the absence of toxicology findingsand absence of significant adverseevents in the preceding human data.Furthermore, some minor events thatwere reported in lower dose levels(blurred vision, diplopia of shortduration less than 30 minutes) would,in the absence of toxicology findings,likely be considered unrelated. Had thetoxicology studies for example pointedto the pathology that materialised in

SPECIAL FEATURE:The French Drug Trial Disaster

What can we learn?

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Continues on page 12 ��

THE STANDOUT FEATURE OF THE IGAS REPORT IS THE FACT

THAT THIS TRAGEDY HAPPENED, DESPITE THE REGULATIONS

BEING FOLLOWED.

11

SPECIAL FEATURE:The French Drug Trial Disaster

What can we learn?

PHARMACEUTICAL PHYSICIAN

humans, these minor events wouldhave been viewed differently, doseescalation would likely have precededmore cautiously and different actionwould likely have been takenfollowing the presentation of the firstparticipant.

The study protocol as approved byANSM and the Ethics Committeeallowed for dose escalation up to themaximum tolerated dose (MTD). TheMTD is the dose below that whichprovides intolerable effects. Clearly,and as is evidenced in this case, notknowing the nature of the intolerableeffects, how to identify them early,their treatment or reversibility, doselevel of onset or dose response, meansthat such a study cannot be safelyconducted. MTD studies as commonlydone in Phase 1 cancer trials shouldnot be done in healthy participantsunless there is a good scientificrationale and almost certainknowledge that the intendedintolerable effects can be easilymanaged and will not lead toirreversible harm.

From the data provided, it appears thatthe likely clinically effective dose wouldbe around 1.25mg to 5mg. This couldhave been established in vitro prior tostudy start and confirmed during thestudy by activity of FAAH.

Clause 16 of the current version of theDeclarations of Helsinki states thatmedical research involving humansubjects may only be conducted if theimportance of the objective outweighsthe risks and burdens to the researchsubjects.

It is difficult to see any importance indefining MTD and minimal importancein exceeding the maximal clinical doseby at least 10-fold; in the absence ofany toxicology signal it is not possibleto properly evaluate the risks.

The CSST make the recommendation (v)that for dose escalation strategies in firstin human and Phase 1 studies, thatcommon sense should also be applied.Perhaps we have become too engrossedin following the rules that we lose sightof why we are doing it.

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| REFERENCES1. Johnson JA, Rid A, Emanuel E, Wendler D. Risks of phase I research with healthy

participants: A systematic review. Clinical Trials. 2016, Vol. 13(2); 149–160.

2. Sibille M, Donazzolo Y, Lecoz F. After the London tragedy, is it still possible to considerPhase I is safe? Br J Clin Pharmacol. 2006: 62:4; 502–503.

3. Tranter E, Peters G, Boyce M, Warrington S. Giving monoclonal antibodies to healthyvolunteers in phase 1 trials: is it safe? Br J Clin Pharmacol. 2013, 76:2; 164–172.

4. Tyrsin D, Chuvpilo S, Matskevich A, Nemenov D, Römer PS, Tabares P, Hünig T. FromTGN1412 to TAB08: the return of CD28 superagonist therapy to clinical development forthe treatment of rheumatoid arthritis. Clin Exp Rheumatol. 2016 Jul-Aug;34(4 Suppl98):45-8. Epub 2016 Jul 20.

5. Committee for Medical Products for Human Use (CHMP). Guideline on strategies toidentify and mitigate risks for first-in-human clinical trials with investigational medicinalproducts. EMEA/CHMP/SWP/ 28367/07, 2007 [online]. Available athttp://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2009/09/WC500002988.pdf (last accessed 03 October 2016).

6. Clinical Study Protocol N° BIA-102474-101.http://ansm.sante.fr/var/ansm_site/storage/original/application/6dd89e628484c6c05091b6ebc98947ee.pdf (last accessed 03 October 2016)

7. Chronology of the evaluation and performance of the clinical trial sponsored by BIALlaboratories and conducted by BIOTRIAL in Rennes.

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What can we learn?

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http://ansm.sante.fr/var/ansm_site/storage/original/application/2e76c2230971bbdeea94725c605468e4.pdf (last accessed 03 October 2016)

8. Report by the Temporary Specialist Scientific Committee (TSSC), "FAAH (Fatty Acid AmideHydrolase)", on the causes of the accident during a Phase 1 clinical trial in Rennes inJanuary 2016.http://ansm.sante.fr/var/ansm_site/storage/original/application/744c7c6daf96b141bc9509e2f85c227e.pdf (last accessed 03 October 2016)

9. Enquete sur des incidents graves survenus dans le cadre de la realisation d’un essaiclinique http://www.igas.gouv.fr/IMG/pdf/2016-012R_TOME_2_RAPPORT_DEFINITIF_ENQUETE_INCIDENT_GRAVE_ESSAI_CLINIQUE_PHASE_I.pdf (last accessed 03 October 2016) [French]

10. Eddleston M, Cohen AF, Webb DJ. Implications of the BIA-102474-101 study for review offirst-into-human clinical trials. Br J Clin Pharmacol (2016) 81 582–586.

11. Ekins S. Differences between similar FAAH inhibitors and their in silico target predictions,2016. 21/01/2016 [online]. Available athttp://www.collabchem.com/2016/01/21/differences-between- similar-faah-inhibitors-and-their-in-silico-target-predictions/ (last accessed: 03 October 2016).

12. Cyclica Predicts Mechanism of Neurotoxicity for BIA 10-2474, an Experimental DrugCausing Death in Clinical Trials. http://www.cyclicarx.com/bia-10-2474/ (last accessed 03October 2016)

13. Biotrial Press Release 22nd May 2016. Investigation into the accident during the clinicaltrial in Rennes: The three major shortcomings of the IGAS.http://www.biotrial.com/news/PR-May-22-2016.html (accessed 03 October 2016)

14. Concept paper on the revision of the ‘Guideline on 5 strategies to identify and mitigaterisks for first-in-human 6 clinical trials with investigational medicinal products’ 7(EMEA/CHMP/SWP/28367/07).http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2016/07/WC500210825.pdf (last accessed 04 October 2016).

15. BIAL Laboratory Clinical Trial BIA-102474-101: Publication of the Clinical Protocol.http://ansm.sante.fr/var/ansm_site/storage/original/application/6dd89e628484c6c05091b6ebc98947ee.pdf (last accessed 04 October 2016).

16. WMA Declaration of Helsinki - Ethical Principles for Medical Research Involving HumanSubjects. http://www.wma.net/en/30publications/10policies/b3/(last accessed 04October 2016).

| REFERENCES CONT.

SPECIAL FEATURE:Personal Profile Analysis.Recruiting for the future of medical affairs

By Matt Edwards (Consultant) and Nicola Harding (Partner), the RSA Group

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14PHARMACEUTICAL PHYSICIAN

1. INTRODUCTIONTHE ROLE OF medical affairs in thepharmaceutical industry is changing. In2014, a report by McKinsey & Companyon this key profession predicted that, “anew set of competencies [would be]required [by staff] to navigate the futurehealthcare landscape across the globe”[1].

New technology, such as social media,has placed more clinical decision-making in the hands of patients whilerising R&D and medical costs have ledto demands for greater transparencyand more evidence of costeffectiveness. To navigate this newlandscape, medical affairs professionalsneed the customer skills of asalesperson, the strategic thinking of amarketeer, and a high-levelunderstanding of the clinical, legal andregulatory environments.

Yet recruiting people with such a widerange of talents is a tough challenge.Part of the solution for hiring managerscould be personal profiling, such as thatcarried out by RSA Consulting on itsshortlisted candidates. A recent study bythe company suggests pharmacompanies may benefit from the use ofbehavioural profiling - which hasbecome part of the executive searchprocess – as the next generation ofmedical affairs professionals may sharemany of the key behavioural traits.

2. THE MEDICAL AFFAIRSCHALLENGEMedical affairs plays a key role inpharmaceutical companies. The functionoriginally emerged in response toregulators wanting to separate themedical and commercial arms oforganisations. Today it acts as a bridge

between these functions, and as aconduit of information to and from themarket.

Medical affairs professionalstraditionally used data analysis andeducation to support late-stagedevelopment of pharmaceuticals andmarketed products. These weretechnical roles that relied on strongunderstanding of the cinical data. Anew hire, for example, might only beexpected to provide healthcareproviders with off-label data aboutsafety and efficacy of a product.

Today, the role of medical affairs haschanged and will continue to do so.There are three main trends:

I. Pharmaceutical R&D costs have risenover last five years while productivityhas fallen. According to a report byDeloitte, returns on investment havemore than halved since 2010, with thecost to develop a drug rising by abouta third[2,3]. Companies increasinglyneed detailed analysis and input frommedical affairs throughout the drugdevelopment process on productcharacteristics, market risks andunmet medical needs.

II. Medical affairs professionals need towork with a wider range of data andinfluence a larger variety ofaudiences than ever before. Risinghealthcare costs in the US andEurope have led to widespreadreforms in the provision of services:

a. Some pharmaceutical decision-making is shifting from physiciansto a wide range of otherstakeholders;

Matt Edwards Nicola Harding

b. Healthcare reforms have led togreater demands for transparencyin the relationships betweenpharmaceutical companies anddecision-makers;

c. New types of medical data arerequired to provide evidencebefore new treatments are adoptedby healthcare organisations.

III. Patients have more desire for controlover their own treatment, aided bythe reach and influence of socialmedia and a shifting focus topatient-centred care. Medical affairsprofessionals need to provide

scientific data in an easy-to-understand form, and may need towork closely with patient advocacygroups. The latter requires stringentcodes of conduct and transparentpractices.

3. PROFILE OF APROFESSIONAL

The changing role of medical affairsmeans that professionals need to offer awider range of skills than in the past.They must be:

I. Flexible and adaptable to deal with abroad-ranging role, and able to thriveon uncertainty.

II. Creative thinkers with excellentcommunication skills;

III. Persuasive - to demonstrate tointernal stakeholders how they addvalue, and to be advocators,educating healthcare providers andother external stakeholders;

IV. Technically skilled - to understandthe medical and regulatoryframework of pharmaceuticalproducts. They require a differentskill set from clinical development,as medical affairs has less focus onprocesses and mechanisms.

For pharmaceutical companies tosucceed, they must build new skills andtalent in their medical affairs function.

This involves training existingemployees and helping them adapt theirwork styles but – more importantly –making hiring decisions with the futureof medical affairs in mind.

3.1 ANALYSING BEHAVIOURALTRAITS

Behavioural profiling is a key tool inexecutive search. It’s used to identifycandidate strengths and areas to probeduring interview. Sometimes profiling iscombined with other tools, such asroleplay or aptitude tests. In medicalaffairs, such tools can be critical. Notonly to avoid expensive hiring mistakesin the short term, but to helpcompanies adapt their hiring practicesto deal with long-term changes inhealthcare.

We use in-depth behavioural profiling toidentify the most suitable candidates fora given role – in an impartial,constructive way. This evidence-basedapproach helps the consultancy learnand adapt to the changing needs of thepharmaceutical industry.

Among the profiling techniques used isPersonal Profile Analysis (PPA), apsychological tool registered with theBritish Psychological Society (BPS)[4].PPA is based on DISC theory, a widely-used method for understanding work-based behavioural preferences.

DISC is based on a theory of humanconsciousness published by W.M.Marston in a book called Emotions ofNormal People in 1928. Acontemporary of Carl Jung, hedeveloped his ideas after studying thebehaviours of thousands of people.Marston’s insight was that behaviour isaffected by how people perceivethemselves, other people, and theirsurroundings.

The PPA measures four behaviouraltraits: Dominance (D), Influence (I),Steadiness (S) and Compliance (C).These give an insight into how

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THE CHANGING ROLE OF MEDICAL AFFAIRS MEANS THAT

PROFESSIONALS NEED TO OFFER A WIDER RANGE OF SKILLS THAN IN

THE PAST.

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individuals see themselves in theworkplace. For example, Dominantbehaviours are direct, assertive andambitious because they perceivethemselves to have the power to shapeevents.

3.2 THE PPA IN PRACTICEFor executive search, we use the PPAdeveloped by Thomas International.This tool is a ‘forced choice’ (ipsative)inferencing method. Candidates areexpected to select desirable adjectivesthat they believe describe them, ratherthan ranking (e.g. ‘strongly agree’) theextent to which they agree with astatement.

To complete the PPA, candidateschoose two traits from a block of four –one ‘most like’ and one ‘least like’them. This process is repeated 24 times,giving 48 choices from a total of 96words. The forced choice methodremoves the option of giving neutralresponses, such as ‘neither agree nordisagree’.

Assessment results are compared to thecandidate’s other responses and notscores from a comparison group.Behavioural traits selected as ‘most like’the candidate are combined together tomeasure their ‘work mask’ – how theyperceive themselves at work. Traits they‘least like’ are used to assess theirbehaviour under pressure. Self-imagecombines work mask and behaviourunder pressure.

Candidates’ behavioural profiles arescored both against the brief for the roleand against every other candidate onthe short list using data drivencomparative analysis. However, resultsfrom PPA are a guide only. They are notthe only, or even the main, determinantof hiring decisions. Rather we combinethem with other executive search tools,including further psychometric tests thatlook at an individual’s potential tosucceed, along with deep experience ofthe needs of the pharmaceuticalindustry and individual companycultures.

4. RECRUITING THE NEXTGENERATION

We wanted to understand typical PPAprofiles for today’s medical affairsprofessionals. These reveal behavioursthat staff may adopt in the workplace,which will change dependent on thecompany culture and over time. Atheoretical PPA profile for medicalaffairs, given recent changes in the role,will have:

I. High Influence (I) to influenceexternal stakeholders and endorsetheir value to internal ones;

II. Not too much Compliance (C) as thiscan stifle creativity, although theyneed enough to ensure that whilsthaving the ability to push boundariesthey remain “within the rules”;

III. Relatively low Steadiness (S) asmedical affairs involves a lot ofvariety;

IV. Enough Dominance (D) to driveevents and to make things happen.

We tested how closely this profilemapped the behavioural traits ofmedical affairs professionals usingresults from 105 candidates shortlistedby the consultancy. They all hadsignificant careers in medical affairs, andcompleted their PPA between 2014 and2016. The data were collated byThomas International.

4.1 READING A BEHAVIOURALPROFILE

There are no ‘right’ or ‘wrong’ resultsfrom a PPA. Each letter (e.g. I, D) issimply a different way of approachingchallenges in the workplace. Leaders,for example, are typically perceived ashaving dominant behaviours, but someof the greatest leaders in history havebeen also high on compliance. Anexample is Air Chief Marshall HughDowding, nicknamed ‘stuffy’ by hismen, whose meticulous planning iscredited with defeating Hitler’s plan toinvade Britain during the Second WorldWar.

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Figure 1 shows an example PPA profile.The graph is read from top to bottom,with results above the shaded areabeing ‘working strengths’ and thosebelow it being ‘support factors’. Thiscandidate has ‘I’ as their leading factor,and ‘D’ then ‘C’ as working strengths. ‘S’is a supporting factor. Typically, an

individual has up to three workingstrengths, but never four, as the factorsconflict with each other.

Behaviourally, if they were a leader, thegraph indicates that they would be a‘people person’. They woulddemonstrate behavioural traits high on

assertiveness and persuasion due totheir high ‘D’ and ‘I’ scores, using factsto get their messages across. Theywould also demonstrate good levels ofcompliance.

4.2 BEHAVIOURAL TRAITS FORMEDICAL AFFAIRS

The main behavioural traits displayed bythe candidates is shown in Figure 2. Aspredicted by theory, more than half had‘Influencing’ in their personal profile.These professionals were keen to investin new relationships, explore fresh ideasand begin new projects – key traitswhen liaising with stakeholders and forbuilding trust.

Candidates for medical affairs roles wereunlikely to have ‘Steadiness’ as aworking strength. Reserved and cautiouspersonalities are less suitable for abroad-ranging job that requires medicalcommunication and education skills.

Figure 3 shows the working strengths ofthe candidates. Nearly a quarter hadhigh ‘ID’ showing they were persuasive,dynamic and able to thrive in a variedand fast-changing workplace. None ofthe candidates were pure ‘S’ and fewwere pure ‘C’ – medical affairs is no

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| FIGURE 1: Example PPA Profile

SELF IMAGE - GRAPH III

D I S C

| FIGURE 2: Leading factors in the behaviour of medical affairs candidates

MEDICAL LEADING FACTOR FREQUENCIES

I

S C

D

58%

22%

15%

5%

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longer a ‘steady eddie’ role for technicalspecialists.

Many of the candidates had Complianceas a working strength. This isunsurprising as medical affairsprofessionals need to adhere tostringent codes of conduct, especiallywhen dealing with patient groups orhealthcare regulators. One of the factorsleft unexplored in this data is whetherPPA profiles vary with the age of thecandidates. Medical affairs professionalstend to move away from compliance-based towards strategic roles as theyprogress in their career, and their ‘C’would be expected to fall as a result.

5. CONCLUSIONMedical affairs is changing andcompanies need to respond byrecruiting the best candidates. PPA is auseful evidence-based tool to supportthe recruitment of talent able to respondto the new challenges that will have tobe faced up to and beyond 2020. Aswith every psychometric assessment,these statistics aren’t sufficient to baserecruitment decisions on, but need tobe combined with deep knowledge ofthe industry and personnel as found atspecialist talent consultancies.

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| REFERENCES1. M.Evers, E. Fleming, A. Ghatak, and others, Pharma Medical Affairs 2020 and beyond,

McKinsey & Company, 2014

2. A. Ward, Returns on pharma R&D sink to lowest in five years, Financial Times, 2015(https://www.ft.com/content/2217a2c8-a01f-11e5-8613-08e211ea5317)

3. Deloitte Centre for Health Solutions, Measuring the return from pharmaceuticalinnovation 2015 Transforming R&D returns

in uncertain times, Deloitte, 2015

4. S. Robertson and G. Hodgkinson (reviewers), British Psychological Society PsychologicalTesting Centre Test Reviews: Personal Profile Analysis, British Psychological Society, 2007(https://global.thomasinternational.net/Portals/34/BPS%202007.pdf)

18

| FIGURE 2: Leading factors in the behaviour of medical affairs candidates

MEDICAL LEADING FACTOR FREQUENCIES

C CD CDI CI CIS CS CSD DC DCI DI DIC I IC ICD ID IDC IDS IS ISC SC SCI SI0%

5%

10%

15%

20%

25%

January 2017

volume 27 | No 1PHARMACEUTICAL PHYSICIAN

SPECIAL FEATURE:“Who gets the cat?”

…an amicable divorce model of a company demerger

By Dr Michael Atkins

THIS ARTICLE EXPLORES AN "IDEAL"SCENARIO FOR AN EFFECTIVE

DEMERGER, BASED ON A DIVORCE

MODEL.

19

A DEMERGER (LIKE a divorce) is nevereasy. A successful outcome is aseparation of both parties with minimalexpense, disruption, and drain onresources, whilst dividing up andmaintaining appropriate staff,equipment, motivation, customerallegiances, and moving on to successfulfuture business outcomes (win: win).

“WHY ARE WE SPLITTING UP?” Grounds for a company demerger mustbe clear and may be for one or more ofthe following reasons:

• The business has successfully evolvedin different directions, such thatstaying as one company no longermakes good business sense.

• The business has formed formalalliances with external partners suchthat it makes more business sensethan staying as a single company.

• The company has just got too big tologistically stay as one. This may beespecially true where a companywants to get back to “its roots”.

• “Hostile” reasons*:

o Personality clashes at the mostsenior level (especially family-owned companies).

o One part of the company is failingwhilst another part is successful.

o Actions taken by appointedcompany liquidators.

*This article does not address hostiledemergers or those forced bybankruptcy/insolvency.

“OH MY GOODNESS - THESHOCK!”Once the decision is made at a seniorlevel, a communication (“comms”)strategy must be the first priority. Thatdoes not mean the announcement of ademerger is first item to be actioned.Indeed, months of confidential planningare often required before theannouncement is made as thisinformation will have a significantimpact on people. The challenge lies inengaging staff in the pre-announcementplanning phase and containingconfidentiality. Expect leaks and beprepared to announce early if needs be.Rumours breed demotivation and stressand will reduce productivity. Internalpolitics may escalate.

When sent out, typical “comms” rulesshould apply to include the why, when,how, what and who. Avoid jargon andkeep it simple. Anticipate questions,like:-

• Why is it happening?

• When will it all happen?

• What happens with future jobs?

• What about redundancy (andoutplacement support) and then myholidays still due and my pension?

• What is the location of the newbusinesses?

“I CAN'T THINK STRAIGHT”Not only are there the issues of staffstress and demotivation, a demergermay engender moods of “I don't careanymore” in some and “I can't thinkstraight” in others – either way, ongoing

Michael Atkins

SPECIAL FEATURE:“Who gets the cat?”

…an amicable divorce model of acompany demerger

PHARMACEUTICAL PHYSICIAN

work may lose momentum, compliancewith key processes may slip, and moremistakes made than usual. This is a keytime for senior management to predictthese and plan. Staff should be given abit more time and space. This isprobably a bad time to start majorprojects. Current work to be handedover to new company entities should beprofessionally sorted out. Set deadlinesnot to begin any new activities.Recognise people's motivation whenworking on a task that will be irrelevantto the demerged company entity theyare going to. Are there jobs that staffare doing now that represent a conflictof interests when they move on to anew demerger company entity oroutplacement to another company? Isthere a role for contract staff to helpout?

“LISTEN TO ME !” It is common in mainland Europe is tohave “work council” – staffrepresentatives from all levels andfunctions. This council may alreadyexist – if not, form one to ask adviceand give information, some of whichmay be for the council's ears only atthat time. Workers should use theircouncil representative to voice generalissues and concerns back to seniormanagement and get answers. HumanResources must take a lead incounselling individuals– people'semotions are going to be exposed.Probably the biggest fear is “ I will bewithout a job with no money comingin !”

“WHERE WILL I LIVE? “ New jobs will be created and old onesdisappear. Staff may want to go withone new demerger company and notthe other. Some may be maderedundant. Some positions may be leftunfilled. Will voluntary redundancy bedesirable/available? Watch out that allelements of employment law arefollowed. Be prepared for individualsmounting legal challenges to decisionsmade about their future. Provide adviceon job applications, CVs, andoutplacement. Organise staff interviews

for jobs with the new company entitieswith care.

“WHO GETS THE CAT?”There are many, many legal andfinancial implications of a demerger.Internal experts should form a taskforce to plan. Dividing companyresources must be rational and fair.Disputes must be avoided but that doesnot mean arguments will not ensuewith internal stakeholders. Externaladvice will almost certainly be required.A demerger is not inexpensive.

From information on servers/emails topaper records – who will takeownership of what post demerger? Howcan you access old data? Will anindependent body be needed tomanage data confidentiality postdemerger? Can a less legalistic, amicableapproach be taken (at least in the shortterm) post-demerger to iron out teethingproblems?

“SHOULD I THROW OUT THEWEDDING DRESS ?” A demerger is an ideal time to discardunwanted stuff. However, great careneeds to be taken as some items mayneed to be retained. Think twice beforethrowing documents away. Seek legaladvice - this relates not only to papercopies but to emails. Consider:

• Who needs access to what? Pre-demerger, partition the documentsinto each companies' responsibility.

• What needs to be kept at hand orwhat should be archived?

• Are archived materials properlylabelled/catalogued for easy retrieval?

• How will documents needed by bothcompanies post demerger be handled(especially those which are currentlyconfidential)?

• Are there items of historicalinterest/value that should be put intoa “museum”? Who should hold thatonce demerged?

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• Can you shred unwanted items?

“I FEEL REALLY HURT” In any separation, there will be“winners and losers”. The “winners” areseen to get the new top jobs or theredundancy packages they wanted; the“losers” are either offered jobs theydon’t want or unwanted redundancy.So, expect some unhappy people.How the company deals with the latteris a true mark of a caring employer.Make sure selection processes are seento be and are fair. Offer goodredundancy packages and support infinding new jobs for those who will notbe staying.

There may be transition roles for thosewho have no new job to go to but canprovide invaluable knowledge post-demerger whilst things settle in. Suchjobs must be well remunerated to be

attractive and must not compromise anyredundancy packages.

Expect all the phases of bereavement(especially anger). It's OK to showsympathy and concern. Always respectemotions. Know your employment lawand work to avoid industrial tribunalswith disgruntled staff by doing the rightthings right first time. Retaining a senseof humour (even in the darkest times)can help.

One size never fits all, and be preparedto take exceptions where there aregenuine hardships.

AND FINALLY…For a company that has been close andtogether a long time, staff may want acheerio “wake”?

SPECIAL FEATURE:“Who gets the cat?”

…an amicable divorce model of acompany demerger

January 2017

volume 27 | No 1PHARMACEUTICAL PHYSICIAN 21

PHARMACEUTICAL PHYSICIAN CONTACT: Liz Langley

Info@brapp.org 0118 934 1943

Advertise here or onthe BrAPP website

RETRO FEATURE: What is Research and Development: What is drug discovery?

By Dr Matthew Hickling, Medical Advisor UCB (now Medical Director at IPSEN UK)

Matthew Hickling

AS PART OF BRAPP'S 60TH

ANNIVERSARY CELEBRATION WE WILL

BE PUBLISHING A SELECTION OF

ARTICLES FROM THE EXTENSIVE

ARCHIVE OF PHARMACEUTICAL

PHYSICIAN. WE START THE BALL

ROLLING WITH A PIECE FROM JANUARY

2010.

THIS ARTICLE WILL OUTLINE SOME OF

THE PRINCIPLES, STRATEGIES AND

ACTIVITIES REQUIRED TO PROGRESS

EARLY DRUG DISCOVERY PROJECTS.

January 2017

volume 27 | No 1

22PHARMACEUTICAL PHYSICIAN

INTRODUCTIONTHE ‘ART’ AND ‘SCIENCE’ surroundingdrug discovery and development can beunfamiliar to many physicians workingin the clinic or in commercial functionsof pharmaceutical companies. Yet evena basic understanding of this technicallychallenging and often complex processwill ensure the right questions are askedat the right time when new projects arebeing adopted. The subsequentinvolvement of expert scientists and keyopinion leaders (KOLs) in clinicaldevelopment and product launchactivities can also prove critical in thesuccessful commercialisation of newtherapeutics.

The role of physicians in research maybe informal at the early stage and willvary depending upon the project.However their interaction with scientistsfrom the onset of considering a newtherapeutic project may help in advisingon unmet clinical need, explainingclinical aspects of target diseases as wellas helping identify KOLs who may thensupport projects as they progress.

More formal project interaction andinvolvement starts just before clinicaldevelopment but having a thoroughunderstanding of the key processesprior to this ensures critical issues canbe addressed without delay. With thecost of developing new therapeuticsexceeding 500 million pounds[1] and thetime to market often spanning a decade,more needs to be done to shorten thelearning curve. One solution is toensure the cross fertilisation of ideasand expertise across the industry silos.

NEW TARGET IDENTIFICATIONAn important role for the physician in

research could be supporting scientificcolleagues in the exploration andrationalisation of new ideas on targetsand indications. We easily forget that ourbreadth and depth of clinical experienceis a valuable commodity to the researchcommunity who have never faced'medicine in action'. The ability totranslate clinical observations to alteredpathological pathways or cellular activityto ultimately identify discrete targetsrequires cross discipline expertise at theresearch/early development interface.When proposing new targets fortherapeutic intervention, a number ofcrucial factors need to be considered,these include:

Relevance to human diseaseTargets are often identified byproducing mice lacking the target geneof interest and demonstrating a diseaseresistant phenotype. However closelythe animal model resembles humandisease there is a chance that theprecise role of a given target may bedifferent in mice and humans. Thereforeclinical trials with a suitable therapeuticare often the only way to confirm therole of the target in human diseases.The presence of a target in humandisease tissue can be confirmed usingstaining methods. However thefunctional effects of blocking oractivating a given target may vary withinterspecies differences in downstreamsignalling and function.

Corporate strategyMany good ideas fail at this hurdle;there may not be the capability or desireto venture into new therapeutic areas.Clear communication from the seniorresearch management team is requiredto ensure that the efforts and enthusiasm

to drive research is not dissipated ontargets not aligned with the corporatestrategy.

Commercial viability Involving commercial colleagues at theonset of a research proposal shouldprevent nasty surprises when the likelycost of development dwarfs anypossible return. This will often dependupon the indication, the cost andefficacy of current treatments as well asthe likely therapeutic format. Orphandiseases may be attractive in terms ofthe likely accelerated development plansand favourable pricing strategies eventhough the patient group size may limitthe overall return for a successfulproduct. A successful launch in theorphan disease may however provide aroute to accelerated development inmore common diseases sharing commonsignalling pathways.

Alternatively, new formats for thetreatment of common diseases likerheumatoid arthritis will require frankdiscussions on the competitor landscapeas well as likely differentiating factors.The '10th in class' therapeutic will never

pass the Technology Appraisal hurdle ofthe National Institute for Health andClinical Excellence unless there are clearbenefits in either safety, efficacy or cost.The predictions on cost balanced againstthe clinical benefit and commercialreturn are often hurdles new ideas failto overcome.

However drug discovery is based uponinnovation, searching for new modes ofaction and the modulation of alternativesignalling pathways; therefore there willalways be an element of uncertainty andrisk with innovative targets. As anexample, the success of the anti-TNFscame about from research into septicshock; it would have been unfortunateif this indication had not beeninvestigated.

Scientific validity The problem (or benefit) of new targetsis the degree of uncertainty on thevalue/rationale of the target. To clarifythe main hurdles for new targetprogression, a Target Candidate Profilewill be compiled that outlines inadvance the critical decisions onprogression, key experimental findings

that will be required to gauge successas well as ideas on target diseases andpatient populations. It is much better tokill a project early on, freeing upvaluable time and resource for the nextgreat idea, rather than see it progressinto clinical development wheremillions of pounds are at stake. Eventhen, some element of project validationthrough preliminary research will berequired to test the hypothesis.

THE KEY ISSUES IN NEW TARGETIDENTIFICATIONInvestment in clinical research requirespatience, excellent project managementand a bit of luck. Portfolio planningensures that the company's therapeuticpipeline remains balanced, identifyingdeficits and bottlenecks where BusinessDevelopment colleagues can scopepossible licensing or collaboratingopportunities. Although the journey ofdiscovery may span several years, regularscience meetings enable the discussion ofproject data as well as the consideration ofthe changing competitor landscape. Thisjourney through research will often bemapped out with key decision points,indicating the level of resource andplanning for each particular stage as well

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| FIGURE 1: Interaction between medicine, science and commerce

CorporateStrategy

Commercial Viability

Medical/ScientificValidity

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PHARMACEUTICAL PHYSICIAN

as those critical pieces of data that will'kill' a project should they not beachieved.

THE KEY STAGES IN DRUGDISCOVERYFollowing Target identification, a hit isidentified when a compounddemonstrates favourable propertieswithin a primary screening or bindingassay. The hit will then be confirmedonce the compound is shown todemonstrate a dose-responserelationship in a secondary screening orcell based assay. Lead identificationincludes compounds or series that obeya number of criteria or standards for

structure, pharmacology,pharmacokinetic / pharmacodynamicproperties (PK/PD), toxicity and patents.Following further Lead optimisation,Candidate selection for preclinicaldevelopment and clinical developmentwill follow should the furtherassessment of PK/PD and safetypharmacology/toxicology be favourable.

TO NBE OR NCE? A typical new therapeutic, whetherbiological (NBE: New Biological Entity)or small molecule (NCE: New ChemicalEntity), follows a similar path fromTarget identification to Candidateselection. NCEs however require anumber of screening cascades to filterout molecules with unfavourableproperties at different stages; NBEs such

as monoclonal antibodies (mAb) havelimited constructs which will requireless manipulation. Once a new target isadopted, the choice/class of therapeuticwill be considered; a decision againbased upon corporate strategy, scientificrationale and in-house expertise. Forexample, intracellular targets willrequire passage across the cellmembrane, favouring NCEs as NBEssuch as mAbs have yet to be reliablyused to target intracellular targets.However should a long biological effectbe required, an NBE such as a mAbmay be chosen given its likely half-lifespanning days to weeks. Understandingthe target, its location and down-stream

signalling pathway effects are thereforecrucial.

ISSUES RELATING TO NCESChemical starting pointsWhen little is known about the target, afragment screening approach may beconsidered. Large libraries of lowmolecular weight compounds can beassessed through using high throughputscreening assays. Virtual screeningutilising the computer simulation ofknown target and compound structuresmay help reduce the number of likelyfragments for further consideration frommillions to thousands. One majorhurdle for fragment screening is thesensitivity of the associated screeningassay; given the low potency of anyfragment, will the effect be readily

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| FIGURE 2: Key stages in drug discovery

Figure 2: Key stages in drug discovery

Target identification/

validation

Hitidentification

Leadidentification

Leadoptimisation

Candidate selection

detected and could the effects be off-target related?

Structural biology and chemistry Structural based drug design usingsoftware modelling in association withX-ray Crystallography and NuclearMagnetic Resonance Spectroscopy canpredict likely docking patterns of NCEsto binding sites. When combined withassays, the development of NCEs can beguided through functional readouts andcomputer predictions. This approachdoes however require detailedknowledge of the target as well as targetprotein synthesis; the availability ofwhich can be a major stumbling blockwhen it is difficult to synthesize.

Is it druggable? Traditional NCEs have often obeyed anumber of key principles including theLipinski rule of five:

• Molecular weight of < 500 Daltons

• CLogP < 5 an assessment of watersolubility (octanol - water partitioncoefficient)

• Hydrogen-bond donors <5

• Hydrogen-bond acceptors <10

These basic rules help assess the ADME(Absorption, Distribution, Metabolism,Excretion) of the compound. Theliberation of the therapeutic entity fromdifferent formulations will also beassessed. In-vitro and In-vivo assaysassessing the PK/PD properties ofcompounds are essential to enableinitial predications of dosingrequirements for early clinicaldevelopment. Compounds with adversePK/PD profiles such as lowbioavailability (essentially the amount ofcompound within the systemic systemfollowing ingestion, gastrointestinalabsorption and first pass metabolism),poor distribution in target organ (e.g.crossing the blood-brain-barrier to targetthe central nervous system) or toxiceffects (liver or other organs) need to beidentified so that this series/class of

compound within the program can beterminated as soon as the data becomesavailable.

Simplifying synthesisOften chemists will use inefficient routesto quickly synthesize compounds ofinterest. Once a number of likelycandidates are shortlisted, work needsto be initiated to design the mostefficient and stable synthetic routes tosupport both clinical development andeventually commercial production ofapproved therapeutics. One criticalaspect will be to decide upon the formand delivery of the drug; confirmationof the likely indication is thereforeneeded.

ISSUES RELATING TO NBESNBEs encompass a number of differentcomplex natural and synthetic proteinssuch as insulin, erythropoietin andsomatotropin. Since the pioneering workof Kohler and Milstein which led to theiraward of the Nobel Prize in Physiologyor Medicine[2] the development of mAbshas revolutionised medicine as well asthe biopharmaceutical therapeutic field.Following identification of a target, thereare a number of technical issues thatrequire consideration for developing amAb.

Antibody generation and format A number of different recombinanttechnologies exist for identifying andacquiring antibodies. Hybridomaspioneered the production of mAbs usingmyeloma cell lines and animalimmunisation techniques. Phage displaytechnology also enables the screening ofDNA libraries for millions of differentantibodies through the incorporation ofdifferent specific antigen bindingdomains into phage DNA that are thenexpressed through bacterial cultureconditions. One critical issue thatrequires some thought is the exactformat of the antibody therapeutic.Should the antibody be conjugated witha cytotoxic agent for a possible tumourtarget; will the recruitment of the hostimmune response confer a benefitthrough interaction with the Fc region

and will the therapeutic benefit from ashorter half-life? These decisions willconfirm whether a full construct or Fab(fragment antigen binding) will be theconstruct of choice.

Protein engineering and humanisation Following screening of suitableantibodies, selected antibodies can beisolated and sequenced. Usingadvances in molecular biology, bothhuman and murine constructs (whichcan be humanised to reduceimmunogenicity and improve PK/PDproperties) form the basis of numeroustreatments for chronic disease andcancer. Protein engineering enables theintroduction of subtle changes in theconstruct; amino acid substitution maymodify some of the biopharmaceuticalproperties.

Protein expression Following protein engineering, efficientprocesses for antibody production arerequired to allow for sufficient quantitiesof reliably expressed and stable productto be synthesised in order to supportpreclinical and clinical studies. Extensiveanalysis using technologies such as HighPerformance Liquid Chromatography(HPLC) ensures the stability and purity

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of the product. Both bacterial andmammalian cell lines can be used toproduce the final therapeutic (dependingupon the construct and other desiredproperties), often initially in small 1Lflasks that can then be ultimately scaledup to produce quantities for productregistration / market approval.

DON'T FORGET THEPHARMACOLOGY Following the identification of severallead compounds or antibody formats,pharmacological studies are required toassess therapeutic binding and effect.These extend from the development ofscreening assays that help determine theselectivity of the therapeutic through tothose assessing changes in downstreamsignalling in cells derived from celllines, animals and ultimately humandonors / patients. The close (and early)collaboration with KOLs with an interestin the target / field is therefore essentialin developing assays requiring patientderived samples.

The public debate over the use ofanimals in therapeutic research stillremains a controversial issue; despitemany advances in in-vitro and in-silicoassay development, positive results inanimal models of disease still provideconfidence in both the target and thetherapeutic being developed. Data fromanimal models is extremely important tohelp explore the full effects ofpharmacological intervention and toidentify pharmacological dosingregimens. One must be aware ofinterspecies differences in potency andpharmacokinetics which must be takeninto account when determining FIHdoses.

Numerous in-vitro and in-vivo studiesare also performed to assess the safetyof the therapeutic; often organised bycolleagues working in pre-clinicaldevelopment who specialise intoxicology. Exploratory studies will beperformed early on to attain confidencein the safety profile. However, in

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| FIGURE 3: The drug discovery process (Reproduced with kind permissionfrom reference[3])

Research team formed and objectives set

Novel ChemicalsSynthesised

Preclinical studies

Clinical studies

CH3

HgC

HN

N

O

S

Chemicals tested for efficiency and safety in test tubes and animals.Results used to choose drug candidates

Formulation, stability scale-up synthesis, chronic safety in animals

Company files Investigations New Drug (IND) application with FDA

Phase I: Studies in healthy humans (Toleration)

Phase II: Studies in patients (Efficacy)

Phase III: Large clinical trials in many patients

Company files New Drug Application (NDA)

FDA reviews NDA

Drug is approved for marketing

FDA

support of late stage research and inpreparation for Investigation New Drug(IND: USA) applications, a range ofstudies will be performed under GoodLaboratory Practice (GLP) conditionsthat are required for regulatoryapproval. In brief, these studies includethose for genotoxicity, safetypharmacology as well as single dose,multiple dose and chronic toxicitystudies that are performed at differentstages of research and development,depending upon the risk profile of thetherapeutic in question.

PRECLINICALPHARMACEUTICALDEVELOPMENTIn parallel to candidate NCE or NBECandidate selection activities,preparation for manufacture in sufficientquantities to support both preclinicalsafety studies and ultimately early phaseclinical development should beunderway. When and how colleagues inpharmaceutical development areinvolved in the project can be debatedat length, my personal view would beas early as possible. A 'drug in a bottle'approach is often the simplest andquickest approach as it requires theleast amount of development for earlyclinical studies. Essentially this is wherethe active compound is suspended in anoral solution. This will require specialistpharmacy support at the clinical site andfurther formulation resource will berequired later on to support pivotal trialsand ultimately product registration. Howthe therapeutic is to be delivered willdepend upon the disease indication andtarget population, the choice ofexcipient (carrier substance) will also bedecided once the delivery mechanism ischosen. One will have to consider themost efficient manufacturing process aswell as assess chemical stability andconsistency in physical, chiral andbiopharmaceutical properties. Getting itwrong may mean more delays andwasted resource for completingadditional bioequivalent studies that arerequired following an unexpectedchange in manufacturing process. GoodManufacturing Practice (GMP) will have

to be implemented when preparing forclinical development.

WHEN TO PATENT? Extensive research into the literature aswell as searches for patent applicationswill define the scope for work in aparticular class of compounds, whetherNCE or NBE. A crowded patentlandscape may well 'kill' projects even ifthere is a positive scientific andcommercial view on the target. Timingthe patent filing is also crucial; giventhat patents in all commerciallyimportant territories are nowadaysgranted for 20 years. Filing the patentapplication too early when followed bymany years of post filing developmentleads to a shorter time frame for marketexclusivity and therefore loss in revenuefollowing product approval.Alternatively filing too late may allowcompetitors an inside track on a noveltarget or compound. Often patentapplications will be filed once severallead compounds have demonstratedpromising results in a range of relevantin-vitro and in-vivo studies. Althoughseen as being a complex process tomany, the basic principles are quitestraightforward. Generally, for a patentapplication to succeed, the innovatorshould be able to demonstrate novelty(i.e. the molecule has never beenpublished anywhere before) andinventive step (i.e. the structure orproperties of the molecule are notobvious relative to the structurallyclosest ‘prior art’ molecule), as well asindustrial applicability (although this is

usually taken as read for apharmaceutical molecule).

CONCLUSIONThe drug discovery process is subject tomany scientific, commercial andcorporate challenges. Medical research isa highly dynamic and competitive fieldthat demands innovation, determinationand some luck to enable the successfuldelivery of a new therapeutic into clinicaldevelopment on time, within budget andof course before the competition!

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| REFERENCES1. Adams C, Brantner V (2006). "Estimating the cost of new drug development: is it really

802 million dollars?". Health Aff (Millwood) 25 (2): 420–8. [online article] Available fromURL: http://content.healthaffairs.org/cgi/content/abstract/25/2/420 [accessed 9 Nov2009]

2. Presentation Speech for The Nobel Prize in Physiology or Medicine 1984. Professor HansWigzell [online article] Available from URL:http://nobelprize.org/nobel_prizes/medicine/laureates/1984/presentation-speech.html[accessed 27 Oct 2009]

3. Joseph G. Lombardino and John A. Lowe III. The role of the medicinal chemist in drugdiscovery – then and now. Nature Reviews Drug Discovery 2004; 3: 853-862

PERSONAL VIEW: Tackling the Diabetes Epidemic: with Digital Therapeutics

By Dr. Matthew Goodman

Matthew Goodman

January 2017

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28PHARMACEUTICAL PHYSICIAN

AS THE GLOBAL leading cause of heartattacks, stroke, blindness andamputations, it’s no exaggeration to saythat diabetes threatens the lives of thepeople it affects. But it may surpriseyou to learn that the relentless rise ofdiabetes single-handedly has thepotential to destroy healthcare systemsand even undermine whole countryeconomies if left to continue unabated.

The proportion of people now livingwith diabetes in the UK may be as highas 4 million, of which nearly all are type2 diabetics. That number is set to rise to5 million by 2025. The costs of this arestaggering - estimates suggest that £10billion per year is spent on diabetes inthe NHS alone – that's £1 million anhour. Every hour. Of every hour of theyear. And that number doesn’t eventouch on the indirect costs of diabetes -social care, time off work, family carersand a variety of other economicallydamaging effects.

With expenditure increasing every yearto cover the rising numbers of diabetics,this is not just a huge burden to thehealthcare systems, but a substantial riskto the already fragile wider economy ofthe UK overall. This isn’t a healthcareissue anymore, but one of widerrelevance to the entire country.

For an audience working inpharmaceuticals, you’ll be disappointedto hear that it’s widely accepted that themajor part of the solution depends onimproving ‘self-management’ – that iscultivating the skills in patients to bettermanage their lifestyle, and therebyimprove the outcomes of their illness.Clinical studies support this notion –that better-informed, better-equipped

patients tend to live longer, healthierlives, and suffer from fewer of thecomplications that diabetes can cause.

Innovators have recognized that thereare opportunities to use technology tohelp manage diabetes. Indeed,affordable, portable devices let usorganize all parts of our lives, fromsocializing to banking, conveniently andsecurely. These technologies offer theopportunity for us to transform the waywe support self-management too. Thebenefits for patients are clear – theconvenience of accessible support thatcan be relied upon at any time of theday, resulting in improved health andbetter outcomes. Equally, for healthcareproviders, the unparalleled scalabilityand ability of technology to touch hard-to-reach populations, is attractive, not tomention the potential for tremendouscost-savings.

However this is not without itschallenges. If it were as simple ascreating ‘demand-driven’ technologyproducts aimed at the healthcaremarket, then, like other consumer areas,this problem would have been solved adecade ago. Ironically this isn’t aboutthe technology at all, but aboutmanaging the integration of these newservices into current healthcare systems,understanding the benefits and ensuringappropriate reimbursement, andnavigating a nascent, but increasinglycomplex regulatory environment,including that of privacy and securityconcerns amongst users.

There’s still a long way to go before wesee the widespread use of digitaltherapeutics to improve health. But the‘push factor’ of rapidly depleting NHS

healthcare budgets in the face of anational epidemic of diabetes, and the‘pull factors’ of potentially huge andcost effective patient benefits are toostrong to ignore.

The current way of delivering care issimply no longer sustainable – andwithout doubt technology willrevolutionize healthcare. We havereached the tipping point where digitaltherapeutics move from being afuturistic showcase platform to anintegrated healthcare solution used bypatients and doctors alike.

Dr. Matthew Goodman is a physicianwith a special interest in the applicationof technology to long-term conditions. Heis Medical Director of Mapmyhealth, anOxford, UK-based healthcare company

that specializes in the delivery of digitaltherapeutics to healthcare providers inthe NHS and beyond.

He also has experience as apharmaceutical physician.

PERSONAL VIEW: Tackling the Diabetes Epidemic:

with Digital Therapeutics

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PHARMACEUTICAL PHYSICIAN CONTACT: Liz Langley

Info@brapp.org 0118 934 1943

Advertiseyourrecruitmentopportunitieshere or on theBrAPP website.

NEWS

From: Medicines and Healthcare products Regulatory Agency

January 2017

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30PHARMACEUTICAL PHYSICIAN

MHRA leading European action to

reinforce market surveillance of

medical devices to protect public

health

The Medicines and Healthcare productsRegulatory Agency (MHRA) has officiallylaunched the Joint Action on MarketSurveillance of Medical Devices.

Medical devices cover a wide range ofproducts – from sticking plasters to hipreplacements, from contact lenses topersonal oxygen tanks and implantedpacemakers. These devices and otherslike them, can be found in everyhousehold across Europe, once theyhave been CE marked.

To make sure devices like these areacceptably safe and perform asintended, Competent Authorities needto have a strong programme of marketsurveillance.

On 19 October 2016, at the 39thmeeting of the Competent Authoritiesfor Medical Devices in Bratislava,Slovakia, MHRA officially launched theJoint Action on Market Surveillance ofMedical Devices.

The project aims to reinforce the marketsurveillance system for medical devicesby improving the coordination ofactivities by all member states of theEuropean Union, and ensuring adequatecommunications and cooperation. Theseare crucial for success and effectivenessof the market surveillance in the field ofmedical devices.

The Joint Action supports theConsumers, Health, Agriculture andFood Executive Agency’s (Chafea)programme of community action in the

field of health to deliver against one ofits objectives: to contribute toinnovative, efficient and sustainablehealth systems.

Chafea is entrusted by the EuropeanCommission to implement the healthprogramme and EU Members Statesinvolved in the programme – in January2016.

John Wilkinson, MHRA’s Director ofMedical Devices, said:

We are pleased to be leading thisimportant activity and look forward toworking with our colleagues across theEU in delivering improvements toreinforce market surveillance.

BACKGROUND1. The Joint Action will be implemented

through five work packages: MHRAleads on three (Coordinationdissemination and evaluation), whiletwo will be implemented anddelivered by EU Member Statepartners: the Netherlands(manufacturers’ inspection) andIreland (clinical process and resourcedevelopment). More informationabout the Joint Action can be foundon the CAMD website

2. To report a suspected problem orincident with a medical device pleasevisit the Yellow Card Scheme website.

3. MHRA is responsible for regulating allmedicines and medical devices in theUK. All our work is underpinned byrobust and fact-based judgements toensure that the benefits justify anyrisks. MHRA is a centre of theMedicines and Healthcare products

Regulatory Agency which alsoincludes the National Institute forBiological Standards and Control(NIBSC) and the Clinical PracticeResearch Datalink (CPRD). TheAgency is an executive agency of theDepartment of Health.www.mhra.gov.uk

17 November 2016

NEWS

January 2017

volume 27 | No 1PHARMACEUTICAL PHYSICIAN 31

PHARMACEUTICAL PHYSICIAN CONTACT: Liz Langley

Info@brapp.org 0118 934 1943

Advertise your recruitment opportunitieshere or on the BrAPP website.

Capture theright

candidate

PEOPLE

January 2017

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32PHARMACEUTICAL PHYSICIAN

New ICHP Managing Director

appointed

IMPERIAL COLLEGE HEALTH Partners(ICHP) is delighted to announce that DrAxel Heitmueller, who is currentlyacting Managing Director, has beenappointed to the substantive positionwith immediate effect.

Axel was appointed by the PartnershipBoard following a robust search andselection process which attracted anumber of high calibre candidates. Axelhas an impressive track record spanningboth senior positions in the NHS andgovernment. In 2011 he was asked tolead the establishment of ICHP workingalongside Lord Ara Darzi. He took upthe substantive role of Director ofStrategy and Commerce of ICHP insummer 2013.

As you know, ICHP, which is alsolicensed as one of the 15 AcademicHealth Science Networks in England,works with its partners to identify newinnovations and best practice solutions

to address system wide challenges andensure safe, high quality and efficientservices for patients.

In his new role at ICHP, Axel will leadthe Partnership in helping to addresssome of the biggest health challengesfacing the region. His focus will be onfostering collaboration and systemleadership, and supporting thesystematic uptake of best practice andinnovation.

He will have a key role to play in NorthWest London’s health economy,working with our NHS and academicpartners, industry, third sector, localgovernment and patients and the publicto deliver transformational change.

Axel takes over from Dr Adrian Bullwho left the Partnership earlier this yearto take up the role of CEO at EastSussex Healthcare NHS Trust.

Please join us in welcoming Axel intohis new role.

Dr Axel Heitmueller