european Industrial Pharmacy Issue 25 (June 2015)

ISSUE 25 • JUNE 2015www.industrialpharmacy.eu

www.eipg.eu

features4 RAISING THE BAR ON PHARMA IT SECURITY

Reduce risk and better protect business-criticalpharma IT applications and data by leveragingstrong authentication and identity hubs to controlinternal and external user access.by Vijay Takanti

8 THE OFFICE OF PHARMACEUTICALQUALITY: FDA’S NEW “ONE QUALITY VOICE”The new Office of Pharmaceutical Quality at the US-FDA promises to become FDA’s “One QualityVoice”, a fully functioning source of information forall things related to quality for US drug products.by Gary Bird

12 NEXT IN LINE: PERSONALISED HEALTHCAREFinding, validating and commercialising new andpowerful biomarkers and bringing these togetherin syndromic panels will push the personalisedhealthcare model forward, research that will bedriven by the introduction of new and innovatingtechnologies.by Wouter Laroy

15 TECHNOLOGICAL ADVANCES IN RATIONALDRUG DESIGNHybrid photon counting pixel detectors can leadto better X-ray structures more quickly and provideoptimised starting points for drug design.by Andreas Förster and Clemens Schulze-Briese

17 THE PHARMACEUTICAL PIPELINE FOR NON-SMALL CELL LUNG CANCERThis article discusses diversity and innovation in theNSCLC treatment pipeline, as pharmaceuticalcompanies seek to meet the needs of anincreasingly segmented market.by Joshua Libberton

20 CURING THE AILING CLINICAL TRIALIt can be a costly business for a clinical trial to fail,but several indicators have been identified whichcan lead to early intervention and recovery.by Dirk Meijer

regulars3 EDITORIAL COMMENT24 REGULATORY REVIEW26 BOTTLED BROWN27 NEWS FROM THE EIPG29 EVENTS

europeanINDUSTRIALPHARMACY

2 european INDUSTRIAL PHARMACY June 2015 • Issue 25

europeanINDUSTRIALPHARMACY

June 2015ISSN 1759-202X

MANAGING EDITORSue Briggs

PRODUCTIONDave Johnson

SUBSCRIPTIONSJill Monk

EDITORIAL BOARDMichael AnisfeldClaude FarrugiaMichael Gamlen

Linda HakesJohn Jolley

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european INDUSTRIAL PHARMACYis the official publication of the European IndustrialPharmacists Group (Groupement des Pharmaciens del’Industrie en Europe) www.eipg.eu

Cover photo: Pharma IT security (see Raising the Bar on Pharma IT Securityon page 4).

associate editors

Belgium: Philippe Bollen

Bulgaria: Valentina Belcheva

Czech Republic: Ales Franc

Finland: Anni Svala

France: Jean-Pierre Paccioni

Germany: Armin Hoffmann

Great Britain: Shilpa Gohil, Janet Halliday

Greece: Ioannis Nikolakakis

Hungary: Sylvia Marton

Ireland: Stan O'Neill

Italy: Piero Iamartino

Latvia: Inta Saprovska, Anita Senberga

Malta: Claude Farrugia

Netherlands: Amon Wafelman

Norway: Wenche Gordon

Spain: Beatriz Artalejo

Sweden: Marianne Andersson

Switzerland: Valter Gianesello, Maurizio Battistini

A patient in every boxDuring a recent symposium on drug shortages, acommunity pharmacist colleague pleaded for moreinformation from his industrial pharmacist colleagues.“We have to face the patients, and explain to thepatients why their medicine is not available”, he said.He was right, of course, but the point is another,more fundamental one. Down at the coalface ofpharmacist–patient interaction, a single box isdispensed to a single patient, a very personalinteraction at the core of our profession that issometimes denied to industrial pharmacists. This isnot to diminish for a single moment industrialpharmacists’ constant commitment to quality, safetyand efficacy of medicinal products, but our dailypractice is centred around batch releases, marketauthorisations, pharmacovigilance, quality assurance– all of which are certainly a commitment aspharmacists to patients. However, it takes a momentof deliberate pause to stop and try to visualise theindividual patient to whom the single box ofmedicine is destined, and, even then, how does onevalorise the significance of that box of medicines tothat patient, what it means to him or her to be ableto get through the day with that much less pain, or tohave the hope of another day of life without the fearof remission?

This “patient-centric” approach is a new conceptthat the pharmaceutical industry must embrace, andwe feel that as industrial pharmacists, gatheredthrough our national associations under the banner ofEIPG, we must lead the way. Already, we can seeelements of this approach in the new provisions ofthe Unique Identifier, which will seek to provide anassurance that each and every box of medicinedelivered to each and every patient is not a falsifiedproduct. This is but the tip of the iceberg. Advancesin technology have inculcated discussions of“personalised medicine”, and it is already evidentthat this will pose challenges and paradigm shifts inour daily practice of industrial pharmacy. We must beprepared for these challenges and look forward to afuture where we see a patient in every box, where ourdaily activities of ensuring quality, safety, efficacy,accessability and availability are evermore aguarantee to each and every individual patient.

With this in mind, we would like to reflect on ourrecent Scientific Symposium and General Assembly inEdinburgh. We must thank the Royal PharmaceuticalSociety for having put together an excellent three

days where our discussions centred on newtechnologies in pharmaceutical manufacturing, andthe seeds of the challenges that these pose in theevaluation of the risk-benefit analysis of theseproducts, the release of these products, and thetraining of future industrial pharmacists to beprepared to be active professionals in these newfields, as well as current challenges in drug shortagesthat we must necessarily solve in order not to letthese existing problems undermine the benefits thatfuture advances in health technology can bring topatients. We must also thank the delegates from theMember States as well as the representatives oforganisations that so readily lent their views to ourdiscussion to ensure that we have all come awayenriched by the experience and better armed tocontinue forwards on our road as industrialpharmacists.

We would like to conclude with a look to the futurewith no small sense of anticipation as this road willlead next year to Paris to celebrate the 50thanniversary of the EIPG. We will have good reason tocelebrate for we have come a long way in these 50years. However, we will celebrate even more theadvances in the industry that will enable us, every dayin our professional lives, to see with greater clarity thepatient in every box.

We wish you all well.

Jean-Pierre Paccioni and Claude Farrugia

3european INDUSTRIAL PHARMACY June 2015 • Issue 25

editorial

Information is perhaps our mostprecious resource. Those of us of acertain age remember when hardcopies and manual processes werethe sole means to document, storeand share information. Today, welive in the Information Age. The vastmajority of information ismaintained digitally, and powerfulsystems and applications allow us toanalyse and exchange informationin less than the blink of an eye.Technologies like the cloud andmobility mean we can accessinformation virtually anytime,anywhere. Looking ahead, theInternet of Things will put evenmore information at our fingertips.

IT and the emerging field ofOperations Technology clearlyimprove our lives. We can workmore productively than ever.

Information is far more difficult tomisplace or lose. We can morequickly and accurately track sensitiveinformation, such as an individual’smedical records and history, toensure we safely prescribe theoptimal treatments and therapiesthat lead to improved outcomes.

With all of these advances andbenefits comes a challenge –security. Physical security – lockedbuildings, rooms and file cabinets –is woefully insufficient in theInformation Age. IT security is farmore vast, complex and important.Think about the IT security breachesthat have occurred in just the pastseveral months, including Target,Home Depot and Sony. Now,consider that IT systems areresponsible for the electric grid, thewater supply, and even our personal

identities. There’s little doubt thatthe wars of tomorrow will be foughtin cyberspace, which makes ITsecurity a top priority in virtuallyevery industry.

Pharma IT systems inmanufacturing and distribution arehigh-value targets for hackers andcriminals. After all, these systemsmaintain information about all ofthe following.

• Drugs – what is in the researchpipeline, how clinical trials areprogressing, and what’s in stockat the point of purchase.

• Healthcare providers – names,addresses, licenses, roles inclinical trials and more.

• Suppliers – contracts, points-of-contact, payments and more.

• Patients – personally identifiableinformation (name, birth date,social security number) andmedical information (insurancecompany, insurance number,prescribed medications).

Protecting and securing thesesystems, information and assets isessential. In fact, it has become soimportant that it is no longervoluntary. Regulatory authorities,such as the Drug EnforcementAdministration (DEA) in the UnitedStates, are issuing compliancemandates to mitigate the risks ofsecurity breaches and theirdevastating consequences.

Collectively, we have to raise thebar on pharma IT security. A May2014 report from BitSightTechnologies found the healthcareand pharmaceuticals sector laggingbehind other S&P 500 sectors(finance, utilities and retail) insecurity performance, with a highvolume of security incidents andslow response times1.

Access to IT resources and theassets they manage requiresstronger controls to better confirmthe identities of users. The mostbasic form of authentication, theusername/password combination, issimply too vulnerable. This data istoo easily forgotten, shared orcompromised. As a result, we nolonger can take for granted thatindividuals are who they claim to bewhen they enter a valid username

european INDUSTRIAL PHARMACY June 2015 • Issue 25

RAISING THE BAR ONPHARMA IT SECURITYby Vijay Takanti

Pharma information technology (IT) systems areresponsible for sensitive information that cannot be

allowed to fall into the wrong hands. Intellectualproperty on drug formulations and research results,targeted research including key relationships with theresearch community, preclinical studies, and analysis andproduct distribution control codes/systems are allbecoming targets for global attackers interested inaccelerating their competitive position in drugdevelopment and distribution. In order to protect thisinformation, we must more tightly control access topharma applications and data by more conclusivelyauthenticating identities with strong credentials. Ascommunities of engaged organisations and individualsbecome larger, more dispersed and more complex,identity hub providers can perform the critical identityand access management function – raising the bar onsecurity while easing the burden on valuable ITresources.

Vijay Takanti brings over 25 years of experience to his role as Vice President of Securityand Collaboration Solutions at Exostar. He is responsible for the strategy and productroadmap, design, development, and customer delivery of the company’s cloud-basedsolutions for the life science and healthcare industries. Exostar’s Life Sciences Identity Hubbrings together over 700 organisations, 15,000 individuals, and dozens of applications sopharmaceutical companies and healthcare providers can collaborate securely andproductively.

4

RAISING THE BAR ON PHARMA IT SECURITY continued


and password. Nor should we – thestakes are too high.

Improving pharma IT securityrequires implementing a two-factorauthentication solution to moreconclusively validate identities andcontrol access to business-criticalresources. The username/password,something an individual knows, canserve as the first factor. However, itmust be augmented by a secondfactor, a strong credential, which issomething an individual only canpossess upon successful completionof an identity proofing event.

The second factor credential cantake on a variety of hardware orsoftware formats. It can be a one-time password delivered to anindividual via a token, a textmessage, a voice message, or amobile app. It can be a mediumlevel of assurance public keyinfrastructure hardware or softwarecertificate. Or it can be a commonaccess card that also controls accessto physical locations.

Regardless, the credential isissued and maintained by anidentity provider. The identityprovider can be the individual’semployer or a trusted, certifiedthird-party organisation with a trackrecord of success in the field. Forexample, the SAFE-BioPharmaAssociation certifies identityproviders to the pharma industry asfull-service Credential ServiceProviders. To receive thiscertification from SAFE-BioPharma,an identity provider must prove that

it meets regulatory compliancerequirements. In the United States,the identity provider must complywith the National Institute ofStandards and Technology’s 800-63standards mandated by the DEA.

The identity proofing event that isa precursor to issuing the secondfactor credential can be executedeither in person or remotely viawebcam or other form ofcommunication. Remote proofing isan attractive option when there is alarge, globally-distributed, multi-organisation user community.

In either case, the proofingactivity should be conducted by atrusted party, such as a notary, or acredit bureau, like Experian, thathas access to a wealth of personalinformation. The trusted partyexamines government-issueddocuments, including a passport,birth certificate or driver’s license,and/or asks individuals questionsthat they should be able to answerquickly, confidently and accuratelyto substantiate their identity. Thetrusted party confirms the results ofits analysis and informs the identityprovider that the individual canreceive the desired credential.

Once an individual completes theidentity proofing process, theidentity provider works with theindividual to deliver and activatethe credential. When individualssubsequently wish to access ITresources, they enter theirusername and password andpresent their second factor

credential by typing a one-timepassword alphanumeric string orinserting a common access card orother hardware device into theirlaptop.

In this scenario, the end userexperience is streamlined andstraightforward. But how does ITensure that system and informationprivileges and permissions areproperly enforced now that bothaccounts and credentials must bemanaged? IT could take on the jobitself, which is fine for small, stablegroups of users. What happenswhen the user community includespharmacists, suppliers, healthcareproviders and even patients? Howdoes IT keep up with a dynamic,dispersed community that extendsbeyond its enterprise boundaries?The task quickly becomes toocomplex, too resource intensiveand too risky – potentiallydetracting from security rather thanenhancing it.

An April 2015 report from Gartnerconfirms the challenge2. Accordingto Gartner’s research, since theHealth Insurance Portability andAccountability Act breachnotification requirement took effectin the USA in 2009, nearly 31.4million people have had theirprotected health informationcompromised in privacy andsecurity breaches. In the UK, therewere 7255 recorded incidents ofbreaches of confidentiality by theNational Health Service betweenApril 2011 and April 20142.

One answer is to turn to a third-party identity hub provider. Theidentity hub provider interacts withapplication, information andresource owners to gather theinformation about users,permissions and credentials. Theidentity hub provider creates andmaintains a master repository of allsecurity-related data. Asset ownerssend updates to this data to theidentity hub provider. In turn, theidentity hub provider acceptscredentials issued by identityproviders and enforces the rules foraccess developed by the assetowners. Figure 1 illustrates how theprocess works.Figure 1: Illustration of access approval workflow

When an individual enters ausername/password and presents acredential to access an application,the identity hub providerauthenticates the individual andgrants access based on theprivileges for that user supplied bythe application owner. IT security isstrengthened withoutoverburdening the IT organisation.

Electronic prescribing ofcontrolled substances (EPCS) offersan excellent use case to illustratethe relevance and value ofstrengthening pharma IT throughidentity proofing and second factorcredentials issued, administered,maintained, and enforced byidentity providers and identity hubproviders. Because of the dangerscontrolled substances pose ifabused, healthcare providers andpharmacies must incorporatestringent processes and specialforms and documentation into their

operations to manually issue and fillprescriptions. These requirementscreate time, cost, training, andother pains that can be eased bytransitioning to secure EPCSsolutions delivered via pharma ITsolution vendors.

Security is the key. A studypublished in the Journal of theAmerican Medical InformaticsAssociation showed that over 75%of providers surveyed believedEPCS would lead to fewer medicalerrors and improved managementof therapy by pharmacists, butnearly 15% were concerned EPCSwould cause system breaches ofpatient confidentiality3.

Pharma IT vendors mustovercome two challenges to makeEPCS a reality. First, they mustextend their electronic healthrecords product suites in a mannerthat ensures a seamless, consistentuser experience for physicians and

pharmacists who use the softwarefor other functions. Second, theymust mitigate the risk of abuse bycontrolling access to the EPCSsolution in compliance with the DEAor other regulatory body standards,which brings identity proofing, two-factor authentication and strongcredentials into play.

For the former challenge, pharmaIT vendors must implement anEPCS extension that encapsulatesthe relevant business processes intheir product’s user interface. Forthe latter, they should outsource toa service provider that specialises inthese capabilities. In this scenario,when individuals initially requestaccess to EPCS functionality, theywill be directed to an identityprovider who can conduct theidentity proofing event and createand send a SAFE-BioPharma orsimilarly compliant credential. Whenindividuals are ready to execute



Figure 2: Identity hubs bring together users, identity providers, and applications for secure access to pharma IT assets.

EPCS functionality, they will presenttheir second-factor credential forauthentication by an identity hubprovider, who, in turn, will enforceaccess privileges and allowindividuals to proceed with writing,viewing or filling the digitally-signedprescription.

Note that the identity providerand the identity hub provider canbe one and the same organisation,simplifying the underlyingintegration requirements and theburden on the pharma ITorganisation. Figure 2 shows howExostar fills both roles with ourcloud-based Life Sciences Identity

Hub and ProviderPass serviceofferings, which are being usedtoday to promote EPCS by pharmaIT vendors, including eClinicalWorksand Cerner.

Making the move to two-factorauthentication to more effectivelycontrol access to pharma IT systemsand mitigate the risk of informationcompromise must be a top priority.We invest enormous sums of moneyin the research, development anddistribution of vital drugs andtherapies. We must protect thoseinvestments, along with the privacyand well-being of providers,pharmacies and patients, by

committing the resources necessaryto raise the bar on pharma ITsecurity.

References1 BitSight Insights. BitSight Technologies

Industry Report – Will Healthcare Be theNext Retail? Cambridge, MA, USA:BitSight Technologies; May 2014.

2 Chaudry Z, Runyon B. Healthcare DeliveryOrganizations will Need Stronger Securityto Participate in Digital Business.Stamford, CT, USA: Gartner, Inc.; 2 April2015.

3 Parks Thomas C, Kim M, McDonald A etal. Prescribers’ expectations and barriersto electronic prescribing of controlledsubstances. J Am Med Inform Assoc2012;19(3):375–381.



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Dr Janet Woodcock will carry thetitles of Director of CDER as well asthe Director of the newly formedoffice for the immediate futurewhile Dr Lawrence Yu, PhD, will beacting Deputy Director. Now,responsibility for all things quality;including chemistry, manufacturing,and controls (CMC) components ofsubmissions, lifecycle management,investigations, etc. as related tonew molecular entities (NMEs), i.e.new drug applications (NDAs) andbiological license applications(BLAs), and non-NMEs (abbreviatednew drug applications (ANDAs) and505(b)2); will reside in the newoffice. The formation of the OPQ isover a decade in the making. In2004, the FDA announced its goodmanufacturing practices (GMPs) forthe 21st century initiative. This wasfollowed in 2012 with the approvalof the FDA Safety and InnovationAct (FDASIA) of 2012 which furtherenforced the direction the FDA washeading by stipulating, amongother requirements, that the Agencyimprove its risk-based surveillanceinspection schedule for

manufacturing facilities. Toimplement this approach, the FDAwas to use performance measuresto assess a facility’s quality systemto assure product quality. TheFDASIA also required that acommon language be establishedto gauge progress related to qualityallowing the Agency “to identifyand respond to quality issues atmanufacturing facilities beforethose issues become major,systemic problems”.

The stated purpose of the OPQ isto bring together all of the qualityand CMC-related activitiespreviously residing in multipleoffices within the CDER. Byconsolidating them into a singlesuper office, the FDA intends toestablish a system for quality-related issues as robust as theAgency’s current programs for drugsafety and efficacy. The resultingorganisation has responsibility formonitoring drug quality throughoutthe products lifecycle, includingdrug application review, post-approval improvements, andsurveillance and inspections of

global manufacturing facilities. Withthis recent development, the FDAseems determined to achieve itsmore than 10-year goal of having“One Quality Voice”.

A refined focusOn 14 April 2015, the FDApublished a white paper thatdescribes the general expectationsfor this new organisation. The paperdiscusses the organisationalstructure, the expected processesthat will be implemented, themechanisms by whichimprovements will occur andprovides significant context for thenew organisation2. Since its primaryfocus is on patient safety andproduct quality, the Agency intendsthe new structure to encouragemodernisation of manufacturingprocesses within the companies itregulates. This will necessarilyrequire the FDA to modernise itsown regulatory processes. Thefocus on quality goes beyond thetraditional interpretation of theGMPs related to the manufacturingof the drug product. For the OPQ,this will include the following.

• The quality of products given topatients.

• The continuing improvementand modernisation of themanufacturing processes.

• Establishing clear review andinvestigational standards withclearly defined enforcementoptions.

• Establishing and implementinga patient-focus firmly linked toclinically relevant specifications.

• Confirming that risk-baseddecisions are linked to qualityrisk to confirm productavailability.

The new organisationThe OPQ was created to bear thebrunt of the FDA CDER’s QualityInitiative to achieve the following.

• Integrate regulatory reviews andinspectional activities.

• Establish standards andspecifications that are clinicallyrelated and provide clearexpectations for industry.

• Address the requirements for


THE OFFICE OFPHARMACEUTICAL QUALITY:FDA’S NEW “ONE QUALITYVOICE”by Gary Bird

The Center for Drug Evaluation and Research (CDER)in the US Food and Drug Administration (FDA)

signalled its intentions to address the significant issuesof drug product quality on 14 April when it announcedthe establishment of its new super office, the Office ofPharmaceutical Quality (OPQ)1.

Thomas Gary Bird is President, PharmaConsult-US LLC and Managing Partner,PharmaConsult Global Ltd., an international cooperative supplying GXP qualityconsulting services. He served as Director of Corporate Quality for GTx, Inc. from 2003until 2013 and was responsible for confirming all non-clinical (GLP), manufacturing(GMP) and clinical trial (GCP) activities were compliant with appropriate laws andregulations. He has held previous positions with Eli Lilly and the FDA. He representedboth PhRMA and the FDA in the International Conference on Harmonizationnegotiations on four different agreed guidances. Dr. Bird holds a Ph.D. inBiochemistry/Entomology from Mississippi State University and is a PharmaceuticalScience Member of the Royal Pharmaceutical Society.

drug products from earlydevelopment through all stagesof post-approval for innovatorand generic drugs.

• Evaluate risks with clinicalrelevance that may impact thedrug’s safety and efficacyprofiles.

• Encourage continuingmanufacturing process andtechnology improvements.

• Encourage robust data andsurveillance techniques tomonitor the state ofmanufacturing in thepharmaceutical industry.

To achieve these goals, the OPQhas an “Immediate Office” thatincludes a Program ManagementAnalysis Staff, providingadministrative services, and aScience and Research Staff (SRS),coordinating scientific activitieswithin the OPQ. Additionally, sixother sub-offices, all charged with asignificant component of the overallmission, were created as shown inFigure 1.

The Office of Program andRegulatory Operations (OPRO) takeson the formidable task of leadingand coordinating the regulatoryreview processes of the new OPQ. Itwill facilitate the development andintegration of a quality management

system by which all of the OPQ’sstaff and related FDA personnel willbe able to exchange information.Further, as owner of the regulatoryreview processes, it is accountablefor leading and coordinating theregulatory review processes andestablishing the professionaldevelopment programs required toharmonise review processes and toreinforce the use of the newsystems.

The Office of Policy forPharmaceutical Quality (OPPQ) willassume responsibility for allscientific activities of the OPQ withrespect to policies, standards, andguidance documents which includeCMC guidances, review processesand inspectional standards,including current GMP regulationsfor all drugs, including largemolecules. The OPPQ is intendedto create an umbrella of consistencyand collaboration under which theentirety of the OPQ will operate topromote a consistent interpretationand application of drug productquality policies and programs,including collaboration withinternational regulatory authorities.

The Office of BiotechnologyProducts (OBP), Office of New DrugProducts (ONDP) and Office ofLifecycle Drug Products (OLDP)within the OPQ will assume primary

quality (CMC) review of drugsubstances, drug products, andbiopharmaceutics. These three sub-offices will combine knowledge andexperts to ensure that marketeddrug products meet appropriatestandards, provide the necessarydata to support claims, and confirmthat drug substance, drug productformulation and specifications foreach maintain clinical relevance anddata from exhibit or clinical batchesare consistent and within acceptablelimits. The depth of the combinedknowledge will ensure that theapproved drug products maintaintheir clinically defined efficacy andsafety profiles and minimise risk tothe patients. The offices will attemptto establish widely applicableevaluation and acceptance criteriafor drug products in such relatedareas as impurity control, dissolution(where applicable), instead of usingprocess capability or manufacturingcontrols as previous.

The Office of Process and Facilities(OPF) is assigned the responsibilityof reviewing facility, process designsand controls to confirm that drugsubstances and drug productsundergoing, for example, processscale-up and change activities,maintain their clinical safety, quality,and efficacy profiles throughouttheir lifecycles. Reviewers willparticipate in pre-approval

THE OFFICE OF PHARMACEUTICAL QUALITY: FDA’S NEW “ONE QUALITY VOICE” continued

european INDUSTRIAL PHARMACY June 2015 • Issue 25 9

Immediate Office

Office of Program andRegulatory Operations

Office of Surveillance

Office of Processand Facilities

Office of Policy forPharmaceutical Quality

Office of Testingand Research

Office of LifecycleDrug Products

Office of NewDrug Products

Office of Biotechnology Products

Figure 1: Organisation of the OPQ.

inspections, thereby linking thereview process to the inspectionalprocess. The restated job functionof microbiology reviewers willinclude full evaluation of drugsubstances, drug products, andmanufacturing processes to confirmthey are sufficiently controlled formicrobiological contamination toassure quality standards are met.

A key component of the newreview paradigm will include aformalised communication processto share risk assessments with otherreviewers and investigators to assistin pre-approval inspection, qualitysurveillance and decision-making.Additionally, a close relationship willbe encouraged and fosteredbetween the OPQ, the SRS and theFDA’s research laboratories tofurther develop new manufacturingtechnologies and clarify regulatoryexpectations, process and facilitieswith implementation and regulatoryrequirements.

The Office of Surveillance will beresponsible for the oversight ofapproved and marketed products to

enhance the Agency’s ability torespond to identified process trendsprior to occurrence of seriousproblems. Key to this proactiveactivity will be the establishment ofa viable set of quality metrics, suchas those that capture product,facility and process-relatedknowledge in a centraliseddatabase. This centralised data setwill be at both the product-specificand site-specific level. It will allowrapid and thorough review ofspecific issues and circumstancesthat may affect product quality andthe supply chain to strengthen theFDA’s ability to both apply andmake risk-based regulatoryjudgements related to, for example,inspection frequency, coverage,manufacturer reliability, and theneed for greater oversight of aparticular company or facility.

The Office of Testing and Research(OTR) and the OBP laboratorycomponent, included in the OPQ’sdrug product quality laboratories,are tasked with performing theresearch required to develop

scientific standards and policieswhich are foundational for thequality, safety and effectiveness ofhuman drug products. While it isrecognised by the OTR and OBPthat considerable information isalready present, the key focus of theresearch efforts will be tounderstand new technologies,modernise current regulatorypathways and explore newregulatory pathways. These researchfunctions will act as advisors,collaborators, trainers andresearchers for review staff involvedin pharmaceutical quality andbioavailability/bioequivalenceissues, including formulation,analytical testing, manufacturingand modelling. Additionally, thelaboratories will continue their“research on the development,manufacture, testing, and molecularmechanisms of therapeuticbiotechnology products, assuring ascientific basis for establishingstandards for safety, purity, potency,and effectiveness; they alsoanticipate emerging technologiesand enable the timely provision ofbiotechnology products to meetpatient needs”.

Teams: cornerstone to theOPQ and the new processesIn the initial roll-out, the OPQ haschosen to devote considerableenergy to confirm that the teamconcept becomes part of the neworganisation’s DNA. Because of thevaried nature of the functions forwhich the OPQ will be assumingresponsibility, the leadership teamcreated the team-based structure toemphasise the cooperativerelationships required to fulfil thelofty goals set for the organisation.In the white paper published on 14April, the FDA includes a diagramto illustrate the intent of the teamactivities (see Figure 2).

For the OPQ, the use of team-based integrated qualityassessments (IQAs) is themechanism chosen by the Office toachieve its regulatory charge. Iteffectively places team membersfrom each of the relevant sub-officesand the Office of Regulatory Affairs


european INDUSTRIAL PHARMACY June 2015 • Issue 2510

DrugSubstance

ProductDesignInspection

ProcessMicrobiology

SurveillanceTeam-based

Integrated QualityAssessment

Biopharm

Facility

Figure 2: Team-based integrated quality assessment.



(ORA; the “field” investigators) intoa formalised working relationship. Inthis arrangement, patient-focusedand risk-based drug product qualityassessments will be developed andcommunicated as the consensusreview for the drug substance ordrug product. The IQA teams willevaluate BLAs, NDAs and ANDAsand is inclusive of drug substance,drug product, manufacturing andfacilities.

Formally, the make-up of the IQAteams will include the following.

• An application technical leadwho oversees the scientificcomponent of the review.

• A regulatory business processmanager who manages thereview process to confirmadherence to the establishedproduct-specific timelines.

• Discipline reviewers. • Additional technical advisors as

needed.

Review disciplines may includedrug substance, drug product,process, facility, microbiology,biopharmaceutics and ORAinvestigators. The IQA teams will callupon technical advisors from OPQlaboratories, policy, surveillance andother offices as needed.

FinallyThe effort to create the OPQ ischallenging in both intent andoutcome. By placing the motto ofthe organisation “One QualityVoice” into the forefront, the FDA isstating unequivocally that the OPQwill speak to industry on all issues ofquality. As the OPQ matures, it isexpected that its processes willimpact all of the areas involved inquality-related activities. Forexample, CDER-OPQ reviewers willlikely participate in inspections, justas the ORA investigators will beIQA team members. These strongeralliances and relationships between

the historic reviewer and “the field”are expected to enhance and speedup the quality assessment ofproduct, ultimately leading to moreeffective and efficient regulatorydecisions regarding facilities andthe overall approvability ofapplications. Only time will tell if theeffect will be worth the effort, butthe initial response from industryhas been generally hopeful that itwill be.

References1 FDA. FDA Center for Drug Evaluation and

Research strengthens its quality initiativeby launching a new office. Silver Spring,MD, USA: FDA; January 2015.http://www.fda.gov/drugs/drugsafety/ucm429866.htm

2 FDA. Office of Pharmaceutical Quality.FDA Pharmaceutical Quality Oversight –One Quality Voice. Silver Spring, MD,USA: FDA; 14 April 2015.http://www.fda.gov/downloads/AboutFDA/CentersOffices/OfficeofMedicalProductsandTobacco/CDER/UCM442666.pdf

For full details and to order, please go to:www.euromedcommunications.comor tel: +44 (0)1428 75 22 22

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IntroductionEach person on this planet shouldbe considered equal. However, all ofus are unique from a molecular pointof view. For sure, this has itsinfluence on how humans should bemedically treated. The era of ‘onesize fits all’ medicine is over and anapproach where tailored diagnosticsand therapy go hand in hand shouldtake that place1. Doctors have alwaystaken into account the status of theirpatient. Hippocrates (460 BC)already mentioned the importanceof balancing the four humours (blackand yellow bile, phlegm and blood)for better health. In the modernconcept of personalised medicine,prescription of therapy is based onactionable information on anindividual, provided by differenttypes of biomarkers. With today’sadvanced tools and technologies,most diseases are now consideredmultifactorial, meaning that multiplechanges are at the origin of thedisease itself or of the comorbiditiesassociated with the disease. From abiomarker point of view this meansthat not one but rather a ‘syndromic’panel of biomarkers will provide theclinician the information needed to

initiate or adapt proper therapy. Tocome to a truly personalisedmedicine, some hurdles still need tobe overcome. For one,comprehensive technologies tomeasure these syndromic panels arecrucial in making such modelssuccessful.

The evolving healthcaremodelMost healthcare models that areapplied today are based on thetreatment of the diseased. Onecould argue using the term sickcarerather than healthcare here. Theultimate goal of personalisedmedicine is to not only treat thesick people but to also take bettercare of the healthy and improve theoverall wellness in life. The currenttrial-and-error strategy in therapydecision taking should make wayfor a more informed and timelytreatment strategy where theinformation comes from acomprehensive syndromic panel(see Figure 1). Undoubtedly, thiswill have a positive influence on thepatient’s health and itsenvironment. Besides that, theenormous current burden on social

security systems should be greatlyrelieved.

The single biomarkers versusthe syndromic panelA biomarker is a characteristic thatcan be objectively measured andevaluated as an indicator of specificbiological processes or conditions.This information is consideredactionable if a specific treatment canbe linked to it. Different types ofbiomarkers exist, providinginformation on the geneticbackground (e.g. in targeted cancertherapy), the protein expressionpattern (e.g. to assess theinflammation status), the metaboliccontent (e.g. in kidney function) oreven the pathogenic content (e.g.human papilloma virus profiling incervical cancer) of a person.

Rarely, one single biomarkerprovides the clinician sufficientinformation to treat his patient inthe most optimal way. It is rather asyndromic biomarker panel that willprovide the physician thisinformation. The result of the panelcan be interpreted in different ways.Through an algorithm, results from amulti-biomarker panel can becombined into one or multipleactionable outputs. On the otherend of the spectrum, all biomarkerscan be considered independentlyand guide the clinician through atherapy decision tree. In any case, tomake syndromic panels work inpractice, some major technologicalchallenges still need to beovercome. Some examples areprovided where the personalisedapproach has already proven itssuccess or where a syndromicapproach would show helpful.

Genetic profiles are becominghugely important in anti-cancertherapy, where targeted therapy istaking a major position because ofseveral advantages. Mutatedpathways in cancer cells are thecause of uncontrolled growth intotumours. Targeted drugs specificallyattack these mutated pathways.Assessing the genetic profile of atumour is thus of prime importancein deciding on the right therapy2.Moreover, it has been shown thatremission of tumour load after orduring treatment is mostly due to an


NEXT IN LINE:PERSONALISEDHEALTHCAREby Wouter Laroy

Personalised medicine is considered the new model foran optimised healthcare system. Trial-and-error

therapy approaches will make way for models wheretailored diagnostics and fit-for-purpose therapy go handin hand, providing clear advantages for both patientsand social security systems. Innovative technologies willneed to bridge the gap between biomarker discovery,and their commercialisation and use as ‘syndromic’biomarker panels.

Wouter Laroy ([email protected]) is VP Scientific Marketing at MyCartis and hasover 15 years of experience in biotech and life science research and industry. He helda management position at Pronota where he developed and applied state-of-the-arttechnologies for the discovery and validation of biomarkers in multiple disease areas.He has authored over 25 peer-reviewed publications during his academic researchperiod, mainly on the involvement of carbohydrates in diseases.


altered genetic profile, making thetumour resistant against the drugused. Continued follow-up profilingis thus important to maximisetherapy success. Tumour mutationprofiles can be obtained from biopsymaterial. More recently, there hasbeen a growing interest in gettingthe profile from tumour DNA shed inthe blood. Especially for therapymonitoring, where the tumour wasfirst removed, this is an importantbut challenging progression in thispersonalised approach.

Cervical cancer is the fourth mostcommon cancer in women. Whendiagnosed early, treatment hasshown to be very successful. For that

reason, large screening campaignshave been set up, leading to muchreduced mortality rates. The widelyused Pap screening test (over 50million of these cytology tests are runper year in the US alone) is limited bya high false-positive rate, leading tomany unnecessary and expensivecolposcopies and biopsies. Theinfection with certain high-risk strainsof human papilloma virus is known tocause cervical cancer and amolecular test to identify thesestrains has, therefore, been added tomost screening protocols.

However, this still results in a largeover-diagnosis rate. Currently, newpromising oncoprotein tests are

under development to solve thisissue3. Clearly, a syndromic panel forscreening and diagnosis of cervicalcancer will cover different types ofbiomarkers.

Heart failure, a condition in whichthe heart is unable to pump enoughblood to support physiologicalcirculation, is one of the majorcauses of hospitalisation worldwide,only beaten by normal babydelivery. Disease cures are not yetavailable but correct diseasemanagement helps in improvingquality of life of the patients4. Heartfailure is truly considered asyndrome as it can be triggered bydifferent conditions, such as

NEXT IN LINE: PERSONALISED HEALTHCARE continued

Figure 1: The current ‘trial-end-error’ approach to medical practice will make place for personalised medicine wheretailored diagnostics and fit-for-purpose therapy go hand in hand. In the former approach, the drug is central. In thelatter, the syndromic panel outcome provides the information for the clinician to make an informed decision ontherapy.

NEXT IN LINE: PERSONALISED HEALTHCARE continued


damaged heart tissue, lung disease,infections or even life style.Moreover, the disease is typicallyassociated with major comorbiditieslike kidney dysfunction. Diseasemanagement is mainly focused onreducing symptoms and treatingcomorbidities. Although theblockbuster biomarker b-typenatriuretic peptide is used fordiagnosing patients presenting inthe emergency department withshortness of breath, it provides noor limited information on otherimportant aspects of the disease.Again, in this area, a syndromicpanel approach would dramaticallyimprove patient wellness andreduce healthcare cost.

Technological challengesand solutionsThe understanding that personalisedmedicine is the future of healthcarehas driven the biomarker marketlately. Market reports differ a bit ontheir predictions, but with anexpected compound annual growthrate of 12–18% through 2018, theglobal biomarker market is expectedto reach $40–50 billion by then.Nevertheless, only few newbiomarkers hit the market yearly,despite the ever growing number ofscientific publications describingnew ones. Commercialisingbiomarkers is not only a long,tedious and costly process,technological limitations have alsoslowed down or halted their paththrough regulations at differentstages of validation and assaydevelopment. Besides, mostbiomarker in vitro diagnosticstechnologies allow the measurementof only one biomarker per analysisor, at most, a panel of biomarkers ofthe same type. Within the conceptof the syndromic panels, theseestablished technologies haveserious limitations. Both examplesillustrate the current need forinnovative technology to bridge thegap between discovery,commercialisation and use in apersonalised clinical setting. Robustand reliable results as well as easyworkflows are some of the major keyfeatures for such technology.

Ideally, a ‘one technology fits all’solution enables researchers andassay developers to validate all theirbiomarkers, to utilise and tocommercialise them, all in anaccurate and robust way. Today,recording syndromic biomarkerpanels is still a time-consuming andlabour-intensive process, puttingadditional pressure on thetechnology developers to makethem fast and easy to operate. Notechnology that fits all criteria is yetavailable, but several are trying totake their share in the research andclinical market. Some advancedtechnologies allow the simultaneousmeasurement of different biomarkersof the same kind. The Idylla platform(Biocartis, Belgium), for example,seamlessly integrates sample work-up and measurement of molecularbiomarker panels to enable rapidand high-quality care of cancerpatients. To measure syndromicprotein panels, automated multipleximmunoassay approaches like theMESO QuickPlex (Mesoscale, USA)have been developed. Rarely,multiple biomarker types can bemeasured using the sametechnology. Examples that canmeasure multiple biomolecules arethe bead array approaches (Luminex,USA) or the recently launchedmicrofluidics Evalution (MyCartis,Belgium) platform5–6. Differentchemistries and assay conceptsenable the real-time measurement ofproteins, nucleic acids and other(bio)molecules on a single device,which is a clear advantage within thesyndromic panel idea. Moreover, thelatter systems have an open designalso allowing researchers to buildcustom assays, enabling them tovalidate their biomarkers.

ConclusionsFor a lot of diseases, goodprevention methods or appropriatetherapies are still lacking. Looking atthese diseases as being amultifactorial syndrome and findingout the underlying biology is of keyimportance to finding solutions. Inhis latest State of the Union, USpresident Obama announced hisPrecision Medicine Initiative which

should pioneer this new patient-centred healthcare concept7. Theinitiative is associated with an initial$215 million investment, clearlydemonstrating its importance. Onecan argue the benefit of introducinga new term or discussing theirmeaning and differences, but‘personalised’ and ‘precision’medicine are essentially the same.Both put the patient in a centralposition and from there sciencedrives decision taking. Finding,validating and commercialising newand powerful biomarkers andbringing these together insyndromic panels should be themajor focus of future research,research that will be driven by newand innovating technologies.

References1 Personalized Medicine Coalition. The case

for Personalized Medicine 2014.Washington, DC, USA: PersonalizedMedicine Coalition.http://www.personalizedmedicinecoalition.org/Userfiles/PMC-Corporate/file/pmc_case_for_personalized_medicine.pdf

2 Febbo PG, Ladanyi M, Aldape KD et al.NCCN Task Force report: evaluating theclinical utility of tumor markers inonclology. J Natl Compr Canc Netw2011;9(suppl. 5):S1–S32.http://www.jnccn.org/content/9/Suppl_6/S-1.full.pdf

3 Tornesello ML, Buonaguro L, Giorgi-Rossi P,Buonaguro FM. Viral and cellularbiomarkers in the diagnosis of cervicalintraepithelial neoplasia and cancer. BiomedRes Intl 2013;2013:Art ID 51619, 10 pp.http://downloads.hindawi.com/journals/bmri/2013/519619.pdf

4 Heart failure today: a paradigm shift.Medicographia 2011;33(4).http://www.medicographia.com/wp-content/pdf/Medicographia109.pdf

5 Laroy W, Ladestein P. Company profile:MyCartis NV. Biomarkers Med2015;9(2):85–88.http://www.futuremedicine.com/doi/abs/10.2217/bmm.14.109?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub%3dpubmed

6 Falconnet D, She J, Tornay R et al. Rapid,sensitive and real-time multiplexingplatform for the analysis of protein andnucleic-acid biomarkers. Anal Chem 2015;87(3):1582–1589.http://pubs.acs.org/doi/ipdf/10.1021/ac502741c

7 FACT SHEET: President Obama’s PrecisionMedicine Initiative. Washington, DC, USA:The White House, Office of the PressSecretary; 30 January 2015.https://www.whitehouse.gov/the-press-office/2015/01/30/fact-sheet-president-obama-s-precision-medicine-initiative


Rational drug design depends onthe quality of protein structures thatserve as the basis for fragmentsearches. Protein structures areusually obtained by X-raycrystallography, which involvescrystallising purified proteins-of-interest and then exposing theobtained crystals to X-rays. Crystalsdiffract X-rays, and if the proteincrystals are of sufficient quality, adiffraction pattern can be obtainedthat will permit the determination ofthe three-dimensional structure ofthe protein, at atomic resolution inbest cases.

The availability of high-resolution

structures allows the interpretationof biochemical experiments, likeactivity assays and binding studies.At the end of this process, an activesite is described and chemicallyunderstood, which can then be usedfor fragment screening or ligandoptimisation (Figures 1A and B)1,2. In this way, inhibitors are beingdeveloped against oncogenes3, Gprotein-coupled receptors4 and �ß-lactamase5, to name just a few.

Structural information helps duringthe prioritisation of targets,potentially increasing the efficiency oftargeting itself. Embarking on a drugdesign process is most promising and

should be pursued preferentially ifthe active site forms a deep pocketwith multiple contact points on thesurface of the target protein that adrug could bind to with high avidity.The level of detail provided by acrystal structure is often beyond whatother experiments allow one to see.For example, the crystal structure ofthe human P2Y1 receptor, animportant target for antithromboticdrugs, showed not just one but twoligand-binding sites6. Without acrystal structure as a starting point,designing a drug is like building ahouse with closed eyes. One mightarrive at something useable, but itwill, in many respects, be deeplyflawed.

To obtain a crystal structure, onecritical step is protein crystallisation,which is poorly understood andlargely random in its success. Mosteffort in industry and academia goesinto growing better crystals – orgetting crystals at all, but theapproach is entirely stochastic.Specialised robots perform high-throughput crystallisationexperiments in ways that minimisesample input and time expended,while maximising chemical space.Once conditions that yield crystals ofsufficient quality have been found,these can usually be reproduced andscaled to whatever quantities areneeded for structure determinationor ligand-binding studies.

The other critical step is datacollection, which also dependsheavily on technology. In recentyears, equipment has beenimproved at all levels to amelioratethe quality of the data that can beobtained. At one end of thediffraction experiment, this meantupgrading the radiation sources.Synchrotron beams are now morebrilliant, more tightly focused andmore coherent than ever before. Atthe other end, detector technologyhas made it possible to count everydiffracted photon with minimalnoise and high accuracy.

Hybrid Photon CountingdetectorsThe greatest step forward indetector technology was theintroduction of Hybrid PhotonCounting (HPC) detectors.

TECHNOLOGICALADVANCES IN RATIONALDRUG DESIGNby Andreas Förster and Clemens Schulze-Briese

Rational drug design depends on structuralinformation of the biological target to model ligands

and optimise interactions. Recent advances in detectordesign, exemplified by the EIGER family of X-raydetectors, have dramatically improved the quality ofdata that can be obtained from protein crystals.

Andreas Förster ([email protected]) is Application ScientistMacromolecular Crystallography and Clemens Schulze-Briese is Chief ScientificOfficer at DECTRIS Ltd., Baden, Switzerland (www.dectris.com).

Figure 1: Structure-based drug design applied to tRNA-guanine-transglycosylase, a target for the treatment of shigellosis. (A) The X-raystructure of lin-benzoguanine bound to the active site of the enzyme2

(binding affinity 58nM) was used to design ligands with higher affinity. (B)Addition of a cyclohexyl moiety designed to fill the active site increasedthe binding affinity of the ligand (2nM). The protein is shown cut open toreveal the deep binding pocket as a blue surface. The ligand is shown as astick model, with yellow carbons, blue nitrogens and red oxygens. Orderedwater molecules are shown as red spheres. The atomic coordinates for bothcomplexes are available from the Protein Data Bank (pdb codes 2z7k and3eos, respectively).

TECHNOLOGICAL ADVANCES IN RATIONAL DRUG DESIGN continued

Traditional X-ray detectors (imageplates and charge-coupled devices(CCDs)) first convert X-ray photonsinto visible light, which is thendetected. The detection is indirectby design, with associatedproblems, like leakage and peakbroadening. In addition, duringintegration of the photonintensities, readout noise and darkcurrents are added to the recordeddata. Traditional X-ray detectorsthus degrade the data that iscollected from protein crystals, astate of affairs that was onlyacceptable because of the lack ofalternative technologies.

HPC detectors count eachabsorbed photon directly anddiscretely. When a photon isabsorbed by the sensor material,normally a layer of silicon, a largenumber of electron-hole pairs arecreated. The application of anelectrical field across the sensorallows the collection of the chargeby a readout chip. As each sensorpixel is directly bump-bonded to itsown dedicated readout pixel (fromwhich the term hybrid in the nameof the detectors derives), extremelyshort readout times can beachieved. Where image plates tookminutes to read out and CCDsseconds, HPC detectors can beread out in milliseconds or faster.Correspondingly, high frame ratesare possible in experiments where acrystal is rotated while hundreds oreven thousands of successivediffraction images are collected.These experiments can now bedone without closing the shutterbetween measurements, which notonly further accelerates the processbut also averts shutter jitter as asource of error.

In the readout chip, a thresholdenergy is set to suppress any low-energy signal and, thus, any noisepresent in the electronics. Thismakes HPC detectors effectivelynoise-free and leads to excellentsignal-to-noise ratios. The directdetection of photons results in apoint spread function of one pixel.Peak broadening is non-existentwith HPC detectors, and diffractionlattices can be resolved for even the

largest unit cells. Combined, thefeatures of HPC detectors haveallowed the formulation of noveldata collection strategies that yielddata in unprecedented quality7.

The primary practical consequenceof HPC detectors is the improveddata quality, which means that thepharmaceutical target can bedescribed more accurately and,therefore, targeted more precisely.Ligands or inhibitors developedagainst a well-understood target areobviously more likely to bind exsilico. Furthermore, the high speedof data acquisition increases theefficiency with which limited and, forthat reason, pricey beamtime atsynchrotron radiation facilities can beused, and enhances theeffectiveness of more readilyavailable time at laboratory X-raysources.

HPC detectors in industriallaboratoriesThe technology of laboratory X-raysources has been optimised overyears, even decades. Commerciallyavailable systems are mature andreliable. The strength of the beamapproaches that of second-generation synchrotrons. Thegoniometer and the entire dataacquisition process can becontrolled by powerful software,even by an operator at a remotelocation (an office in the simplestcase). Robotic sample changershave turned the cumbersomeprocess of mounting samples intoan efficient operation that does notrequire the presence of personnelonsite. Thanks to the stability of thebeam and the automation ofsample mounting and experimentalcontrol, laboratory X-ray sourcescan provide unattended operationovernight and collect data 24/7 withminimal downtime.

The only class of laboratory X-rayequipment that has notexperienced a comparable degreeof technological progress has, untilrecently, been detectors. Imageplates and CCDs prevail and –arguably – hinder rather than helpscientific research. This is nowchanging with the arrival of fast and

noise-free HPC detectorsspecifically designed for therequirements of industrialapplications. These detectorsbenefit from affordability, smallfootprints, low maintenance, andoperation at room temperature,while exhibiting all the attractiveproperties of their larger cousins atthe synchrotron. It is likely thatlaboratory X-ray crystallography isabout to enjoy a period ofrenaissance now that fullydeveloped equipment is available.

In the long and unpredictableprocess of designing a drug andbringing it to the market, every stepis under constant scrutiny. Fragmentsearch algorithms, the prediction ofbinding affinity from structuralcomplementarity, the bioavailabilityof the designed ligand, the exclusionof cross-reactivity, and clinical trialswith all their uncertainties – all needto be persistently monitored andimproved. With latest-generationHPC detectors, the pharmaceuticalindustry now has the option tooptimise the quality of the structureof the underlying biological target aswell.

References1 Lounnas V, Ritschel T, Kelder J et al.

Current progress in structure-basedrational drug design marks a new mindsetin drug discovery. Comput StructBiotechnol J 2013;5: e201302011.

2 Ritschel T, Hoertner S, Heine A et al.Crystal structure analysis and in silico pKacalculations suggest strong pKa shifts ofligands as driving force for high-affinitybinding to TGT. Chembiochem2009;10:716–727.

3 Hedvat M, Emdad L, Das SK et al.Selected approaches for rational drugdesign and high throughput screening toidentify anti-cancer molecules. AnticancerAgents Med Chem 2012;12:1143–1155.

4 Kellici T F, Tzakos AG, Mavromoustakos T.Rational drug design and synthesis ofmolecules targeting the angiotensin IItype 1 and type 2 receptors. Molecules2015;20:3868–3897.

5 Nichols DA, Renslo AR, Chen Y.Fragment-based inhibitor discoveryagainst �b-lactamase. Future Med Chem2014;6:413–427.

6 Zhang D, Gao ZG, Zhang K et al. Twodisparate ligand-binding sites in the humanP2Y1 receptor. Nature 2015;520:317–321.

7 Mueller, M, Wang M, Schulze-Briese C.Optimal fine-slicing for single-photon-counting pixel detectors. Acta CrystallogrSection D: Biol Crystallogr 2012;68:42–56.


NSCLC has the second highestincidence of all cancers globally andis associated with a very poorprognosis and a 5-year survival rateof 14%, making it the leading causeof cancer-related mortalityworldwide. Approximately 70% ofpatients are ineligible for surgery atthe point of diagnosis, necessitatingpharmaceutical intervention to delaydisease progression1.

The NSCLC market is large,comprising 458 products; however,most lack diversity in terms ofmolecular target and activepharmaceutical ingredient (API). Asa result, the market predominantlycomprises generic chemotherapiesthat often have serious side-effectsand that offer only minorimprovements to overall survival.Targeted therapies are slowlyemerging onto the NSCLC marketand are having a significant impact,although generic chemotherapiesretain dominance.

The NSCLC pipeline provides adrastic contrast to the market, with amuch greater diversity and aplethora of novel therapies indevelopment that are aligned toknown disease-causing pathways.Furthermore, a significant portion ofthis pipeline diversity has emergedfrom high levels of first-in-class

innovation within this indication,defined as products acting onmolecular targets not yet present inany market industry-wide.

A major driving force behindinnovation and increased diversity inNSCLC drug development is theincreasingly segmented market,which is beginning to alter thetherapeutic landscape. Over recentdecades, NSCLC has transitionedfrom a singular entity into a diseasethat encompasses multiple distinctsubtypes. It is currentlypredominantly differentiated byhistology, with adenocarcinoma,squamous cell carcinoma and largecell carcinoma being the mostfrequently occurring subtypes. Dueto differing characteristics, certaintargeted therapies, such as Avastin(bevacizumab) have been approvedonly in particular subtypes, therebyaltering the treatment algorithm forpatients depending on theirhistological subtype2,3.

In addition to histologicalcharacterisation, recent advances inthe understanding of NSCLCtumour pathophysiology haveallowed tumours to be characterisedbased on molecular aberrations4.The identification of mutated,amplified or overexpressed proteinsin NSCLC tissue is one of the

primary reasons that the pipeline isso diverse, as new and novel targetshave been identified that drugdevelopers are now aiming toconvert into clinically andcommercially viable therapeutics.The launch of mutation-specifictherapies commonly targetingmutations to epidermal growthfactor receptor (EGFR) furtherexacerbated the difference betweenNSCLC subpopulations and theirtreatment algorithms. As themutation frequency of key proteinsdiffers significantly betweenhistological subtypes, treatmentoptions will become morepersonalised in the future, providingthe industry continues to developtherapies that target thesemolecular aberrations.

In terms of molecular targets, asmall portion of the current marketis devoted to receptor tyrosinekinase (RTK) inhibitors, which act onsome of the most commonmolecular aberrations in theadenocarcinoma subtype,predominantly EGFR and anaplasticlymphoma kinase (ALK) mutations.In total, there are eight unique APIson the market; however, there is alarge generic presence for manychemotherapies. The remainder ofthe market is oriented aroundvarious DNA targets and tubulin,which are targets commonlyassociated with chemotherapies.

Analysis by GBI Researchidentified 389 products in activedevelopment for NSCLC5. In adrastic contrast to the market, thereis a much wider range of productsand target families in the pipeline,as shown in Figure 1. The largesttarget family is now RTKs, with 30%of pipeline products modulatingthese receptors in some way. Fortypercent of the RTK target family isdevoted to the ErbB family ofreceptors. Following on from theachievements of therapeutics, suchas Tarceva (erlotinib) which targetsEGFR, drug developers are seekingto build on the established successof this molecular target and providetreatment options that overcomeresistance to current treatments orthat improve upon the safety andefficacy profile. EGFR remains thefavoured target of the ErbB family;


THE PHARMACEUTICALPIPELINE FOR NON-SMALLCELL LUNG CANCERby Joshua Libberton

The non-small cell lung cancer (NSCLC) pipeline isshowing great diversity and innovation, in an effort

to solve some of the most pressing issues facing NSCLCtreatment. Following improvements to tumourcharacterisation and classification, treatment is stilltrying to meet the needs of an increasingly segmentedmarket. The pipeline has a large first-in-class component,meaning that there are many therapies with inventiveand interesting methods of treating this malignancy.

Joshua Libberton is an Analyst at GBI Research. He is part of a team developing theFrontier Pharma module of market forecast reports, which focus on promising first-in-class, early-stage products in various disease markets. In recent years, he hasspecialised in oncology markets.

however, targeting other receptorshas shown promise as combinationtherapies or methods of overcomingEGFR inhibitor resistance.

A significant number ofcombination inhibitors have arelatively broad-acting effect byinhibiting multiple RTKs. This caninduce a larger response and can besafer in some instances as theyrequire a lower dose of each specificinhibitor. ALK, hepatocyte growthfactor and Axl-targeted therapies alloccupy approximately 7% of theRTK target family. Both ALK andhepatocyte growth factor receptorare methods of targeting underlyingmolecular aberrations in NSCLC,whereas targeting Axl may haveimplications in overcoming EGFRinhibitor resistance.

The second largest category issignal transduction antagonists,which is a category that is absentfrom the market and comprises 21%of pipeline products. Productstargeting signal transductionpredominantly interfere withintermediates in common signallingcascades associated with cancerprogression. The mitogen-activated

protein kinases/extracellular signal-regulated kinases andphosphatidylinositide 3-kinasessignalling pathways are the mostfrequently targeted, at 28% and 17%of this particular target family,respectively. They are also wellestablished in cancer pathology andoften promote aberrant cell survival,proliferation, growth and migrationin NSCLC cells. Such signallingpathways are often dysfunctional inNSCLC cells due to overexpressionof pathway components orupstream mutations. Other targetfamilies that appear in the pipelinebut not in the market includecytokines and growth factors,tumour-associated antigens,immune signalling, and epigeneticregulation.

The diversity in the NSCLCpipeline outlined above is apromising sign, as new therapies willoffer opportunities to treat specifichistological and molecular subtypeswith higher safety or efficacy thanoffered by current therapeuticoptions. Innovation is an importantaspect of drug development, withthe industry constantly seeking to

improve on marketed products withaddition-to-class or advance-in-classproducts. However, first-in-classdrug development can be a sign oftrue innovation in a developmentalpipeline and is associated with agreater chance of yieldingbreakthrough therapies, despite theriskier development strategy. GBIResearch’s analysis also revealedthat, on average, first-in-classproducts generate higher annualrevenue 4 years after market launchcompared to non-first-in-classproducts. First-in-class developmentis especially apt in NSCLC, whereadvances in molecularcharacterisation of tumours haveprovided ample molecular targets.

Of the 389 pipeline products, 122are first-in-class products,comprising 96 first-in-class targets5.This represents 38% of the pipelinetherapies with a disclosed moleculartarget: greater than thepharmaceutical industry average of36% but smaller than the oncologyaverage of 43%.

The greatest amount of first-in-class development was in the signaltransducer antagonist target

THE PHARMACEUTICAL PIPELINE FOR NON-SMALL CELL LUNG CANCER continued


Figure 1: Pipeline molecular targets. Source: GBI Research, Proprietary Pipeline Products Database.

category, with almost 40 first-in-classproducts, as shown in Figure 2.However, the number of establishedtargets within this category is almostequal to the number of first-in-classtargets. Therefore, antigen-targetedcytotoxicity could be considered themost innovative target family, having18 first-in-class products and fourwith established targets, equating to82% of this category being focusedon first-in-class development.Targets in this category areincredibly diverse, including Mucin-1and cancer testis antigen.

Using an array of parameters,including mutation frequency andalignment to disease-causingpathways, GBI Research hasdetermined the most promisingfirst-in-class targets in the earlystages of the pipeline andsubstantiated them by reviewingpublished literature.

Literature on each of thediscussed targets has, for the mostpart, justified the pharmaceuticalindustry’s pursuit. It is, therefore,highly likely that several of thesetargets, such as focal adhesion

kinase and human epidermal growthfactor receptor 3, provide a glimpseinto NSCLC’s distant future.However, whether there is thepotential for a blockbuster therapyto develop from these targets is adifferent matter. The benefit of manyof the targets derives from thembeing able to enhance currenttherapeutic options, whetherenhancing chemotherapy orcombating resistance to the EGFRinhibitors. While these areundeniably importantimprovements, they are notrevolutionary.

The NSCLC developmentalpipeline comprises an array ofmolecular targets with variablealignment to disease-causingpathways. The importance placedon signal transduction and aberrantgrowth factor signalling pathways isseen across many oncologyindications; however, this is ofparticular importance in NSCLC interms of further segmenting themarket based on histological andmolecular tumour characterisation,with many of the therapies showing

greater efficacy in particularsubpopulations. A large proportionof the NSCLC pipeline diversity isdue to the high degree of first-in-class innovation. While a significantportion of these molecular targetshas clinical potential, currentevidence suggests that they will bemost effective as adjuncts, ratherthan replacements, ofchemotherapy.

Further reading1 Daniels MG, Bowman RV, Yang IA et al.

An emerging place for lung cancergenomics in 2013. J Thorac Dis2013;5:S491–S497.

2 Forde PM, Ettinger DS. Targeted therapyfor non-small cell lung cancer: past,present and future. Expert Rev AnticancerTher 2013;13(6):745–758.

3 Perez-Moreno P, Brambilla E, Thomas R,Soria J-C. Squamous cell carcinoma of thelung: molecular subtypes and therapeuticopportunities. Clin Cancer Res2012;18(9):2443–2451.

4 Shtivelman E, Hensing T, Simon GR et al.Molecular pathways and therapeutictargets in lung cancer. Oncotarget2014;5(6):1392–1433.

5 GBI Research. Frontier pharma: non-smallcell lung cancer – identifying andcommercializing first-in-class innovation.Report code: GBIHC341MR. London, UK:

THE PHARMACEUTICAL PIPELINE FOR NON-SMALL CELL LUNG CANCER continued


Figure 2: Distribution of first-in-class development in NSCLC. Source: GBI Research, Proprietary Pipeline ProductsDatabase.

Figure 1 shows success rates ofpharmaceutical clinical trials at eachphase of drug development. Forexample, 64% of preclinical studiessucceed and progress into Phase 1trials, 44% of Phase 1 studiessuccessfully proceed into Phase 2trials and 22% of Phase 2 studiescontinue on into Phase 3 trials.Furthermore, it is estimated that just3% of preclinical studies, 5% ofPhase 1 studies, 12% of Phase 2studies and 54% of Phase 3 studieslead to one new drug product.

There are a number of reasonswhy so few clinical trials make it tothe next stage. Two of the more

frequent reasons are that theproduct actually isn’t any good atdoing what it was being tested foror that the product hasunacceptable side effects. However,a clinical trial that proves that aproduct has not achieved what itwas meant to is not necessarily afailure, but rather could beconsidered a success because it hasfulfilled the purpose of the trial.Many clinical trials, however, fail intheir purpose; according to onesource1, almost 80% of clinical trialsfail to meet enrolment timelines.This can result in high costs, forexample, a study2 published in 2011

found that at a leading academicmedical centre in the US, one-thirdof all the studies terminatedbetween 2005 and 2009 had eitherno or only one participant, whichcost the centre almost US$1 millionannually.

The medical device sector is evenmore prone than the pharmaceuticalindustry to flawed studies. This isbecause the medical device industryattracts more start-up companieswith novel device ideas. Thesestudies are frequently poorlydesigned and managed or based onincorrect assumptions, therebyincreasing the chances that thestudy will be rejected by regulatoryauthorities. As the companiesconducting such trials are oftensmall, the cost of a failed clinical trialcan bankrupt them.

The question then arises as towhat can be done about it; and theadage that prevention is better thancure is as applicable to clinical trialsas it is to the conditions they aredesigned to treat. There are someestablished assumptions that canput a trial in jeopardy. For example,when recruiting the study team, it isobviously important to attempt torecruit the best team possible; butthe “famous” investigator may notbe the ideal investigator, becausethey could be involved in a numberof projects which will restrict themfrom fully committing to the trial.This is a very common problem andcan occur particularly in situationswhere the Chief Investigator isgiven the freedom to recruit theother Principal Investigators, whoare often colleagues involved intheir other trials. The sponsor orcontract research organisationshould, therefore, ensure that theprocesses illustrated in Figure 2 areconducted in evaluating potentialinvestigators.

In preparing the study design, thefirst question to ask is “What is thegoal of the clinical investigation?”For example, is it to prove safetyand efficacy or superioreffectiveness to competitivetechnologies? The relevantendpoints should then beidentified, for example, is itnecessary to demonstrate 90%revascularisation by a stent at 6


CURING THE AILINGCLINICAL TRIALby Dirk Meijer

Clinical trials are expensive and time consuming. It isoften cited that only 50% of late stage and 25% of

early stage trials succeed, so there is a very good chancethat a clinical trial will be a waste of time and money.Fortunately, several early warning signs have beenidentified which can help to rescue them providing theintervention is swift.

Dirk Meijer is the CEO and co-founder of Factory CRO, based in The Netherlands.Factory CRO is a Clinical Research Organisation that has been conducting medicaldevice clinical trials for the FDA and CE Mark since 1994. With over 70 clinical trialspecialists operating in 30 countries around the world, Factory CRO offers guidanceand facilities to manufacturers of medical devices for preclinical and GCP clinicalresearch.

Figure 1: Drug development success rates.

months or a 50% decrease inreadmission after 1 year? Whendeciding the goal and endpointsalong with the rest of the trialdesign, information and opinionsshould be sought from a number ofsources, including the manufacturer,the clinicians, and the users. Factorsthat should be covered include thefollowing.

• The hypothesis behind the trial.• The aims and objectives of the

trial (endpoints).• Randomised or comparative. • Inclusion and exclusion criteria

of patients – not only what arethe physical requirements(concomitant treatments, etc.),but what are the ethicalrequirements (the use ofterminally ill patients, etc.).

• Sample size of subjects toenable statistical significance tobe calculated or to be clinicallymeaningful. Examiningsuccessful investigations ofsimilar technologies/products isuseful in this respect.

• Minimal data sets required persubject – both in budgetaryterms and in terms ofmaintaining subject compliance.Fewer data points incurs lesscost, but there needs to be

enough data points to allow forcalculations of statisticalsignificance. Procedures alsohave to be in place to followwhen data points are missed.

• Duration of investigation – whatis the minimum period neededfor recruitment and follow up.

• Number of study sites – this hasto be considered in terms of therate of patient recruitment andthe budget required to monitordifferent sites.

• Safety and performance criteria– these must be clearly definedand understood by all so thatappropriate information can bedisseminated as requiredthroughout the trial.

• Data collection and monitoringprocedures – again this shouldbe well documented andunderstood and efficientdissemination of the informationorganised.

If the above procedures are notfollowed, the clinical trial can beginto fail and signs that sponsorsshould look out for are illustrated inFigure 3.

In circumstances where a failingstudy site has been identified,Factory CRO has developed arescue assessment program, which

can be implemented in as little as 3weeks, that effectively helps realignthe failing study with best practice.

The process starts with an auditof the study that involves thecooperation of the sponsor and allof the investigation sites toexamine such items as thescreening logs, case report forms,enrolment logs, delegation logsand protocol. From thisexamination, many factors can beascertained, including whichcentres are recruiting best, whatfactors are causing screeningfailures and which investigators aretaking most personal responsibilityfor the study and are mostproactive.

Site staff will also be contacted todiscuss if they have noted anyconflicts between the trialprocesses and the site’s standardclinical practice, which could hinderthe efficiency of the trial. On thebasis of all these findings, thesenior management of the clinicaltrial will be contacted to review theprotocol; discuss problem areas,including those of enrolment andregulatory compliance; anddevelop a recovery plan. Althoughit may be unpalatable to somesponsors and Chief Investigators,such actions can include thefollowing.

CURING THE AILING CLINICAL TRIAL continued


Assess whether good clinicalpractice training is already inplace or whether it needs to besupplied

Review the study requirementswith the investigator and makesure they are capable of carryingout all of them

Ensure that the facility iscapable of supplying thesupport the investigationrequires or whether support willneed to be given by thesponsor

Formulate a comprehensive agreement with the investigator andthe site that covers all financial, legal and functional requirements

Gain references for theinvestigator

Make a personal visit to facilityto ensure it meets requirements

Assess any staff that theinvestigator may use to supportthem and their qualifications

Assess their currentcommitments and ensure thatthere is nothing that wouldconflict with the investigation,either in terms of time or interms of conflicting research

Figure 2: Feasibility checks on potential investigators and sites.

• Closing down failing sites andcreating feasibility forms toassess new sites.

• Removing and addinginvestigators to the delegationlogs at sites.

• Reviewing delegated duties inthe study as a whole and on asite-specific basis.

• Changing endpoints.• Streamlining case report forms.• Modifying overly strict inclusion

and exclusion criteria.

• Conducting a statistical check tosee if the sample size can bemodified.

• Creating and submittingamendments to the protocol.

Although many companies maybe concerned about the financialcosts and time implications withmodifying protocols and adjustinginvestigational site dynamics, suchearly-stage diagnosis and re-alignment can mean the difference

between success and failure of theclinical trial; a factor that issignificant to both medical deviceand pharmaceutical companies.

References1 Hess J. Web-Based Patient Recruitment.

North Carolina, USA: Cutting Edgeinformation.http://www.cuttingedgeinfo.com/process/?ref=122

2 Kitterman DR, Cheng SK, Dilts DM,Orwoll ES. The prevalence and economicimpact of low-enrolling clinical studies atan academic medical center. Acad Med2011;86(11):1360–1366.

CURING THE AILING CLINICAL TRIAL continued


Figure 3: Signs of a failing site.

Increased negativefindings compared

to other sites orrequested corrective

actions notcompleted by return

Serious auditfindings

Low or zero Incomplete Not completed orreturned on time

Recruitment Returned data Case report forms Monitoring External audit

Industrial

Pharmaceutical

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regulatory reviewThe current review periodhas seen a number ofchanges in the regulation ofmedicines and regulatoryguidance in the EU,international markets andthe USA

USA

Development and Submissionof Near Infrared AnalyticalProcedures This Draft Guidance providesrecommendations to applicantsregarding the development andsubmission of near infraredanalytical procedures used duringthe manufacture and analysis ofpharmaceuticals.

Final guidance onreprocessing of reusablemedical devicesThe food and drug administration(FDA) has announced new actions toenhance the safety of reusablemedical devices and address thepossible spread of infectious agentsbetween uses.

FDA requires label warnings toprohibit sharing of multi-dosediabetes pen devices amongpatientsThis initiative is intended to reducethe serious risk of infection spreadthrough sharing of multi-dosediabetes pen devices intended forsingle patient use only.

Europe

Reverse osmosis in EuropeanPharmacopoeia (Ph. Eur.)monograph for water forinjections bulkThis monograph has been revisedto include, in addition to distillation,reverse osmosis coupled withsuitable techniques for theproduction of water for injection; arequirement for regular totalorganic carbon monitoring hasbeen added to emphasise furtherthe specific test controls required in

the production section. As a result,the monograph water, highlypurified (1927), will be maderedundant and will be deleted fromthe Ph. Eur.

The European Directorate for theQuality of Medicines and Healthcare(EDQM) organised a free webinarexplaining the context of therevision and the steps taken towardsrevising the water for injectionmonograph.

Identification of medicines: EUtask force to implement newinternational standardsThe European Medicines Agency(EMA) is establishing this task forceand has invited interested parties toexpress their interest in taking part.

Prospective pharmacopoeialharmonisation pilot project(US Pharmacopeia andEDQM/Ph.Eur.)Four monographs were elaboratedvia this project and eleven referencestandards established to support themonographs. Subsequently the USPharmacopeia and the EDQMdecided to officially conclude thepilot project. Both remain fullycommitted to pharmacopoeialharmonisation and will continue tocollaborate on prospectivelyharmonised monographs in a lessformal manner.

Specification for sub-visibleparticles in eye drops and eyelotionsThe Ph. Eur. Commission is currentlyconsidering updating thismonograph to add a specificationfor particulate contamination.Accordingly, it invites responses tothe following questions.

• Is such a specificationnecessary?

• If not, why not?• If so, why, and what should the

specification be?

EU Good ManufacturingPractice (GMP) GuidelinesConcept Paper on the

Revision of Annex 1 of theGuidelines on GoodManufacturing Practice –Manufacture of SterileMedicinal ProductsThis Concept Paper (jointly issuedby the Pharmaceutical InspectionCo-operation Scheme (PIC/S))states that the revised guideline willclarify to what extent Q9 and Q10should be followed in the designand implementation of facilities,equipment and processes for themanufacture of sterile medicinalproducts. Other changes that mayrequire new GMP guidance includethose for the revision to the Ph. Eur.monograph on methods other thandistillation for the production ofwater for injection.

Annex 15 – Qualification andValidationThis revision, effective 1 October2015, is considerably longer thanthe previous version. Retrospectivevalidation is no longer allowed.Newer (than 3 batch validation)approaches or hybrid approachesto validation are discussed. Therewill be significant impact in thearea of cleaning validation where atoxicological approach is required.The revision takes into accountchanges to other sections of theEudraLex Volume 4, Part I,relationship to Part II, Annex 11,ICH Q8, Q9, Q10 and Q11, QualityWorking Party guidance on processvalidation, and changes inmanufacturing technology. Thedocument has also been adoptedby PIC/S with the same operationaldate.

Good distribution practice(GDP) of active substancesfor medicinal products forhuman useThe European Commission (EC) haspublished new guidelines, effective21 September 2015, on GDP foractive substances for medicinalproducts for human use.

Distribution of active substancescomprise activities of procuring,importing, holding, supplying orexporting active substances.


MHRAGMP Data Integrity Definitionsand Guidance for IndustryFollowing initial publication of thisguidance in January 2015, theMHRA has responded to questionsfrom stakeholders by providingadditional clarifications to the text.

Certificates of Free Sale to beissued by the MHRA The MHRA took over responsibility

for issuing Certificates of Free Salefor medicines from the Departmentof Health from 1 April 2015.

InternationalCanadaInspections databaseHealth Canada has made availableaccess to its inspection databasesfor both foreign and domesticfacilities.

For further information on these

and other topics we suggest you

refer to the websites of relevant

regulatory bodies and to current

and past editions of “GMP Review

News” published by Euromed

Communications. To subscribe to

this monthly news service contact

[email protected]

REGULATORY REVIEW continued

CALL FOR ARTICLESDear Colleague

We hope you enjoy the European Industrial Pharmacy and find it both useful and informative.

We are currently seeking new articles for future issues of the journal and would like to inviteyou to contribute an article or review paper on any aspect of industrial pharmacy to thejournal. All issues of European Industrial Pharmacy are indexed by both Scopus and Embaseand thus are available through the listings for any other industrial pharmacist internationally.

Please contact the Managing Editor, Sue Briggs ([email protected]) for further informationor submissions.

In over 600 pages and twelvechapters this unique book providesa focussed account of regulatoryissues from pre-approvalinspections and the inspectionitself to post-inspection andmaintaining compliance. This is abook that every pharmaceuticalcompany will wish to study beforeand during any inspection processto ensure a successful outcome.

Complete Remit

The book is a fully detailed andpractical guide containingpragmatic and up-to-date adviceand insight to help anypharmaceutical organisation

prepare for GMPInspections, understand keyregulatory issues and reviewinspectorate trends andfindings.

Expert Advice

The authors, with a wealth ofregulatory experience behind them,express their views and provideuseful tips for succeeding in vitalregulatory inspections

International Applications

For a full list of the chapters andauthors see further details on theEuromed website

order online at www.euromedcommunications.comOr contact the publishers: email: [email protected];

Tel: +44 (0)1428 752222; Fax: +44 (0)1428 752223.

PHARMACEUTICAL

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A unique and comprehensive guide to ensureregulatory compliance and success inpharmaceutical regulatory inspections


The mother of allbattlesThe critical economic battle of thefirst half of the 21st century is nigh.It will hurt. At least, so arguesJeremy Rifkin in “The Zero MarginalCost Society the Internet of Things,the Collaborative Commons and theEclipse of Capitalism”. What is theconnection with industrialpharmacy?

Three industrial revolutions eachtook (or are taking) 30 years tointroduce and 20 to mature. The mid-19th century saw the first industrialrevolution. Its power was coal,communication was the telegraph,and transport (logistics) was therailway. The early 20th century sawthe second revolution. Power wasfrom oil (e.g. petrol), communicationthe telephone, transport, vehicles onroads. The third revolution started inthe late 20th century. Power is“green” (e.g. solar), communication,the internet, and the need fortransport has almost vanished.Sustainable micro generators feedelectricity into local co-operativenetworks; that avoids the high lossesin long-distance transmission. Smartmachines/robots communicatewithout humans. Most software isfree; friendly, collaborative global“geeks” write. They despiseintellectual property protection.“Prosumers” (consumers andproducers) print most desired objectsfrom, for example, glass, metal,plastic or proteins. Artefacts rangefrom bulldozers to skin prosthetics tonew printers. Many already are. ThinkStar Trek replicator.

Death of capitalism?However, capitalism works byproducing things more efficiently, so

cheaper, so customers buy more, soprofits increase. When marginalcosts fall to near zero, capitalismdies. It will fight: that is thebattleground.

It may not happen. It is crystal ballterritory. Even future orbits of justthree inanimate bodies cannot, ingeneral, be accurately predicted.Add humans, cultures, globalwarming and cyber terrorism andanything could happen. But if theinternet of things looks likely, braceyourself against three blows.

First, the pharmaceutical industry,as we know it, may vanish — nomatter how gargantuan the efficientfactories in the developing world.Goodbye mass production ofmeticulously quality-assuredbatches of medicines andassociated expensive distribution.Hello 3-D printing of medicines,within health professionals’premises or even patients’ homes,tailored for individual patients. Massproduction continues but locally.The number of dose forms requiredis smaller because (assumingcompatible) medicines are mixedinto a single medicament. Thatincreases compliance. Industrialpharmacists merely supply, forexample, stable concentratedliquids. Arguably, a signaturepharmaceutical material from thefirst (“smoke-stack”) industrialrevolution was paracetamol tablets;from the second (oil), plasticpackaging. The third (replenishableenergy, internet/computers, localfabrication), tailored, in exact dose— not one-size-fits-all —biopharmaceuticals for thatpatient’s genetics. Already, the costof gene-testing has tumbled toalmost zero.

Secondly, patent protection,

however strong, may vanish. Thereason is that the ideologicalpassion of the internet, that open-source software programmers and3-D modelling hobbyists inhabit,globally, firmly favourscollaboration. The internet isincreasingly a “commons” like otherlong-accepted shared publicspaces, such as Swiss mountainpastures or public squares of cities.Clearly, some governance (e.g.pharmaceutical regulation) isnecessary.

But discontented citizens willswarm. Tanks might prevail, short-term; long term, probably not.Ghandi said that the Earth providesenough for every (wo)man’s needbut not every (wo)man’s greed.

Industrialpharmacist aswarriorFinally, pharmaceutical capitalistsmay enlist you. Brainstorm: how canwe stop this? How can our model ofinvesting in research anddevelopment, claiming patent rightsand recouping costs (plus a bit,including your salary) during patentlife, continue? Brown suggests: turnthreat into opportunity. Buy the“pipes”: expensive webinfrastructure and industrial printers.Lease out with your research/development expertise. Re-structure management from verticalto horizontal. Co-operate, notcompete, with rival companies.

Diversify, preferably intopharmacies, but otherwise doctors’/dentists’/vetinarians’ surgeriesand/or patients’ homes. I alreadyhear howls.

Malcolm E Brown

bottled brown


General Assembly 18–19AprilDuring the April General Assembly,Dr Piero Iamartino, AFI, Italy, was re-elected as Vice- President ofTechnical Affairs and Dr MaurizioBattistini, AFTI, Switzerland, waselected as Vice-President ofEuropean Affairs for the next 3years. The chairman, Jean-PierrePaccioni, described his vision for theEIPG, and the Bureau reported onthe progress of the Road Map. Awide range of “hot topics” werepresented by delegations. Annualreports of Member Associations canbe found on the EIPG website under“Member States”.

Working Group on NewTasks and Responsibilitiesof the Qualified Person (QP)resulting from revisedAnnex 16The aim of this group was to discussthe impact of revised Annex 16 onthe professional duties of theindustrial pharmacist, especiallywhen acting as a QP. It was also thescope of this Working Group toidentify any necessary actions to betaken by the EIPG to supportindustrial pharmacists in their roleas QPs.

Tracy Lovatt, MHRA Inspectorate,joined the meeting and the maincontents of the published revisedAnnex 16 were presented, focusingin particular on the responsibilitiesfor batch certification and release,recalling difficulties due to thecomplexity of the supply chain andin case of conflicts within thecompany. It was observed thatamong the duties assigned to a QP,as reported in the Annex, 21 ofthem can be delegated. However, itwas agreed that a QP needs to bevery confident with an appropriatequality management system.

The auditing performed by thirdparties was highlighted as a criticalissue as a QP has to count onreliable professionals in order tomaintain his/her responsibility forthis essential duty.

On the discretion in evaluatingunexpected deviations from theMarketing Authorisation dossier, itwas observed that there is still alarge discrepancy in the position oflocal regulatory authorities, allowinga margin of interpretation on thisissue.

After further discussion, the grouppointed out that, apart from a fewchallenges (such as increasedknowledge), opportunities can befound in the development andmanufacture of biotechnologyproducts and personalisedmedicines.

Among the actions the EIPG willtake to support industrialpharmacists in their QP role, it wasagreed to promote continuingprofessional development (CPD)initiatives, to keep on track with ourSpecial Interest Group (SIG)initiative, to maintain the currentprompt circulation of technicalinformation via the website and toconsider the introduction of a freeforum for an open discussion onprofessional issues.

Working Group on Shortagesof MedicinesThis group, which includedcommunity pharmacist Ash Soni,President of the RoyalPharmaceutical Society, and PatriciaMunoz, Pharmaceutical Group of theEuropean Union (PGEU), noted thatthere is an urgent need forimproved communications. Productsin the European Medicines Agency(EMA) drug shortages cataloguegive an "ongoing" description withno reason for the shortage or re-supply date, and most nationalauthority shortage lists do notindicate when supplies will beresumed.

The General Assembly agreedthat it was appropriate to re-engagethe Commission in discussion onthis topic, emphasising that if theCommission truly believes thatmedicines are not ordinary items ofcommerce, then in current scenarioit has a duty and responsibility to

intervene more effectively, and,amongst other actions, reviewtender-driven purchasing modelsand the improvement of standardsin giving value to robust supplychains. The Assembly alsorecommended joining otherpartners in renewed publicstatements on shortages, andparticipating in the PGEU-drivenstakeholder roundtable on drugshortages. It was also agreed that allorganisations should work towardsan integrated shortage informationsystem to provide a pan-Europeanpicture and hence mitigate theimpact on effects of potential andactual drug shortages.

Communications ReportProfessor Claude Farrugia presentedthe website improvements includingthe new Education Section with thePharmaConsult e-learning coursesavailable on a wide range of topics.He discussed the wide choice ofsocial media fora, a line-up whichnow includes Paper.li, Slideshareand YouTube, as well as the originalfora Twitter, LinkedIn and Facebook.Amongst various items of interest,the sites cover regulatory round upsof Commission/EMA publishedguidelines, directives andregulations, their enforcement datesand the final dates for comment ondrafts.

EIPG SIGsOnce the revised Annex 16 ispublished, the Production SIGproposes to update the EIPG Codeof Practice for Qualified Persons andincorporate the EIPG Guidance onCPD. The PHAR-IN courses on themanufacture of biopharmaceuticals,prepared in response tocompetencies requested by staff inthe pharmaceutical industry, will beadvertised on our website.

The Regulatory Affairs SIG aims toupdate the EIPG Guide to GoodRegulatory Practice and the Guideto CPD for Regulatory Affairs. The

news from the EIPG

Continued on page 28

potential for webinars on hot topicsin regulatory affairs was discussed.

EFPIA Code on Disclosure ofTransfers of Value fromPharmaceutical Companiesto Healthcare Professionalsand HealthcareOrganisationsIn his presentation on the EuropeanFederation of PharmaceuticalIndustries and Associations (EFPIA)Disclosure Code, Andrew Powrie-Smith, Director of Communications,noted that nine EFPIA members willdisclose information via a centralwebsite and the other 24 memberswill use their company websites.Payments from industry to themedical profession must bedisclosed to the public by the endof June 2016 for the first reportingperiod which is the calendar year2015. The EFPIA guide explainswhat is to be disclosed whilstnational bodies are responsible forimplementation. Most companies

have sensible in-house minimumlimits for disclosed monies whichthe EFPIA considers should becapped at about 75 Euros.Disclosure varies from one countryto another and if there is noconsent from the medicalprofession there can be nodisclosure and no payments made.EFPIA company heads have allcontributed to the production ofthe Code so that there should beconsensus. Generic and medicaldevice companies are laggingbehind on disclosure but therequirements will be implementedby them.

European CommissionThe Commission’s proposed updateto Annex A of the ProfessionalQualifications Directive was referredto by the PGEU, as was theEuropean Medicines VerificationSystem resulting from the FalsifiedMedicines Directive. TheCommission-funded survey on CPD

for health professionals providing acomparative account of CPD modelsin the European Free TradeAssociation and European EconomicArea countries can be found on thefollowing websitehttp://ec.europa.eu/health/workforce/docs/ev_20141124_co01_en.pdf

SymposiumA scientific symposium on“Technology Advances Impactingthe Pharmaceutical Industry” washeld at the University of Strathclydeon the day before the GeneralAssembly. It was chaired byProfessor Jayne Lawrence, ChiefScientist to the RoyalPharmaceutical Society, and wasattended by about 75 participants,including EIPG delegates. Slidesfrom the presentations are availableon the EIPG website.

Jane Nicholson, Executive Director EIPG, [email protected]

EIPG NEWS continued


PharmacoVigilanceRevıew

Journal on drugsafety issues

Editor – Rob Begnett

This quarterly journal providesinformed comment and analysis ofinternational pharmaceuticalregulations relating to the safe use ofmedicines and medicinal devices. It

also carries reviews of current methods of pharmacovigilance.

Order online at www.euromedcommunications.com

Or email: [email protected]

Tel: +44 (0)1428 752222 Fax: +44 (0)1428 752223

PharmacoVigilanceRevıewSupporting the safe use of

medicines and medical devices

Managing Reference SafetyInformation

The EU centralised applicationfrom a pharmacovigilance andrisk management prospective

Post-authorisation aggregatesafety reporting: the new PSUR

New European pharmacovigilancelegislation – an adequateresponse to current challenges?

Volume 7 Number 3/4 Nov 2013


eventsJUNE 20152–3 June 2015 – Amsterdam, TheNetherlandsAdvanced Therapy MedicinalProductshttps://europe.pda.org

9–10 June 2015 – Heidelberg,Germany6th European GMP Conferencewww.gmp-conference.org

10–12 June 2015 – Boston, MA, USA14th Annual World PharmaCongresswww.worldpharmacongress.com

15–17 June 2015 – Geneva,SwitzerlandEUFEPS Annual Meeting 2015 –Systems Approaches for BetterMedicines and Healthwww.eufeps.org

16–17 June 2015 – SwitzerlandPharmaceutical Packaging andLabelling Summitwww.pharmapackaginglabelling.com

23–24 June 2015 – Brussels,BelgiumQuality and Regulation Conferencehttps://europe.pda.org

23–24 June 2015 – Brussels, BelgiumPublication & Clinical TrialDisclosure www.cbinet.com

25 June 2015 – London, UKChallenges in Current GMPwww.jpag.org

AUGUST 201510–12 August 2015 – Philadelphia,PA, USAGlobal Pharma Summithttp://american.pharmaceuticalconferences.com/

17–19 August 2015 – Washington,DC, USA9th Annual TransparencyReporting Congress www.cbinet.com

SEPTEMBER 20151–3 September 2015 –Nottingham, UKAPS PharmaSci 2015www.ukpharmsci.org

7–9 September 2015 – The Hague,The Netherlands1st Annual GMP by the Sea –Europewww.pharmaconference.com

7–9 September 2015 –Nottingham, UKAPS 5th International PharmSciConference 2015www.apsgb.co.uk

8–9 September 2015 – Berlin,GermanyWorld Drug Safety CongressEurope 2015www.healthnetworkcommunications.com

13–14 September 2015 –Birmingham, UKRoyal Pharmaceutical SocietyAnnual Conference 2015www.rpharms.com

15–16 June 2015 – Munich,GermanyPharmaceutical Freeze DryingTechnologyhttps://europe.pda.org

28–30 September 2015 – LasVegas, NV, USA2015 Pharma EXPOwww.ispe.org

29 September–3 October 2015 –Düsseldorf, Germany75th FIP World Congress ofPharmacy and PharmaceuticalSciences 2015www.fip.org

OCTOBER 20155 October 2015 – Loughborough,UKAPS PharmaceuticalPhotostability 2015www.apsgb.co.uk

6–7 October 2015 – Amsterdam,The NetherlandsPharmaceutical Cold & SupplyChain Logisticshttps://europe.pda.org

7–8 October 2015 – London, UKPharma Compliance Europe 2015www.terrapinn.com

8 October 2015 – London, UKWhat’s New in the Approval andConduct of Clinical Trials in Europe?www.jpag.org

13–15 October 2015 – Madrid,SpainCPhI Worldwidewww.cphi.com

14–15 October 2015 – Dublin,IrelandBioProduction 2015www.informa-ls.com

21–23 October 2015 – Washington,DC, USA16th Annual PharmaceuticalRegulatory and ComplianceCongresshttp://pharmacongress.com

26–28 October 2015 – Hyderabad,India4th International Summit onGMP, GCP & Quality Controlhttp://gmp-gcp-quality-control.pharmaceuticalconferences.com

NOVEMBER 20154–6 November 2015 – Amsterdam,The Netherlands18th APIC/CEFIC EuropeanConference on ActivePharmaceutical Ingredientswww.gmp-compliance.org

8–11 November 2015 – Philadelphia,PA, USA2015 ISPE Annual Meetingwww.ispe.orge

9–10 November 2015 – Basel,SwitzerlandWorld Biosimilar Conferencewww.terrapinn.com

european Industrial Pharmacy Issue 25 (June 2015)

Documents

Transcript of european Industrial Pharmacy Issue 25 (June 2015)