WHO Drug Information · WHO Drug Information Vol 22, No. 4, 2008 International Harmonization Crisis management: safeguarding health In the course of their work, staff working in regulatory

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WHO Drug InformationContents

World Health Organization

International HarmonizationICDRA: medicines agencies decide

future action 253ICH–Q11 appears on the horizon:

development and manufacture ofdrug substances 268

Pharmacovigilance UpdateStrategies for developing pharmaco-

vigilance: an international focus 272Harmonization and pharmacovigilance 273Global markets and patient safety 273Pharmacovigilance and the Pan

American Network for DrugRegulatory Harmonization 274

Lessons learned from the developmentof pharmacovigilance in Spain 274

Counterfeit and substandard medicines 276Counterfeit and illegitimate medicines:

a view from the Americas 277Pan American Network for Drug

Regulatory Harmonization Anti-Counterfeiting Group 278

Argentine National InvestigationProgramme on Illegitimate Medicines 278

Administrative traceability requirementsin medicines purchasing 279

Industry commitment in the battle againstfraud and counterfeiting 281

Access to MedicinesBetter medicines for children: the way

forward 282

Safety and Efficacy IssuesErlotinib: hepatic failure and hepatorenal

syndrome 285Botulinum toxin type A and distant toxin

spread 285Safety review of bisphosphonates 286

Ergot-derived dopamine agonists:fibrotic reactions 286

Use of antibiotics in premature labour 287Intravenous immune globulin:

transfusion-related lung injury 288Alemtuzumab: infection-related deaths 288Theophylline: narrow therapeutic index

and potential for misuse 289Cesium chloride and ventricular

arrhythmias 289Drug-induced hyponatraemia 290Slimming health products adulterated

with sibutramine 291Phenytoin and fosphenytoin: serious

skin reactions 291Etoricoxib: hypertension risks 292Efalizumab: updated labelling 292Oseltamivir: hepatic and skin disorders 293

Regulatory Action and NewsRimonabant: suspension of marketing

authorization 296Vaccines for use in the 2009 influenza

season 296Australian Adverse Drug Reaction

Committee (ADRAC) to be replaced 29750th orphan medicine receives positive

opinion 297Televancin: withdrawal of marketing

authorization application 298Docetaxel: no extension of indication 298Ciclosporin eye drops: withdrawal of

marketing authorization application 298Positive opinions on paediatric investi-

gation plans 299Biosimilar products: a regulatory update 300

ATC/DDD ClassificationATC/DDD Classification: temporary list 302ATC/DDD Classification: final list 305

(Continued ...)

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Recent Publications,Information and EventsFIP and the future of hospital pharmacy 307Assessing, monitoring and evaluating

pharmaceutical situations 307European Pharmaceutical Forum

success 307Procurement and supply management

toolbox 308

Contents (... continued)

Report on essential medicines forchildren 309

Uganda’s antimalarials market 309Right to access to medicines 309New issue of WHO/HAI pricing bulletin 310

Proposed InternationalNonproprietary Names: List 100 311

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International Harmonization

The Thirteenth International Conference of Drug Regulatory Authorities (ICDRA) heldin Berne, Switzerland, from 16 to 19 September 2008 has once again provided drugregulators with a unique opportunity to meet and discuss the particular challenges ofmedicines regulation.

On this occasion, the ICDRA was hosted by the Swiss Agency for TherapeuticProducts, Swissmedic, in collaboration with the World Health Organization (WHO).The event was highly appreciated for its continuing role in fostering a regulatoryforum where matters of urgency and international relevance can be openly debatedamong regulatory officials from developed and developing countries. The ICDRA wasattended by over 300 participants from 96 countries and led to adoption of recom-mendations which regulators consider important in assuring the quality, safety andefficacy of medical products. The recommendations are set out below and on thefollowing pages.

ICDRA: medicines agencies decide future action

Building mutual trustas a key to access

Regulatory approval of medicines —evaluation, registration, and marketingauthorization — is based on scientificassessment. The approval process needsconsiderable resources and capacity if itis to be carried out properly. This plenarysession set out to show how mutual trustconstitutes a capacity building factor andleads to improved access to medicines.Potential public health gains can beharnessed from a harmonized under-standing of what is needed to ensure thequality, safety and efficacy of medicines.

This session addressed the many ques-tions faced by regulators in difficult,resource constrained environments,including:

• How can regulators best contribute topublic health with the resources theyhave?

• Should regulators assess and inspectevery innovative product that is pro-posed for their market?

• Can and should all regulators assessand inspect generic medicines?

• Does repetitive assessment and inspec-tion provide added value?

• How can confidence be built into scien-tific assessments carried out by otherparties?

ModeratorCanada: Meena Ballantyne

PresentationsWHO Intergovernmental Working Groupon Public Health, Innovation and Intellec-tual Property: Implications for regulators.Mandisa Hela, South Africa.

How to benefit from other regulators’work. A New Zealand view point .Stewart Jessamine, New Zealand.

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Building trust, enhancing competenceamong African medicines regulatoryauthorities: a WHO initiative. JonathanMartey, Ghana.

Recommendations

WHO should:

1. Promote, in a targeted and prioritizedway, adoption and implementation of theWHO Model Registration Package asminimum information requirements forproduct registration.

2. Produce a guidance and draft regula-tion for managing confidentiality issuesamong regulatory authorities.

3. Undertake joint assessments of se-lected applications, using the WHO ModelRegistration Package.

4. Foster the development of regional,collaborative post-market surveillanceand pharmacovigilance systems tomonitor the quality, safety and efficacy ofhealth products.

5. Explore the potential development ofan interagency e-governance workinggroup to harmonize electronic require-ments to assist in the development ofregulatory management systems and thesharing of information in accordance withestablished WHO international regulatorynorms and standards.

6. In partnership with well-resourcedregulatory authorities:

• establish formal mechanisms for theexchange and use of regulatory infor-mation among all authorities tostrengthen capacity and to maximizeefficiencies, and

• facilitate cooperation between small andmedium well-resourced regulatoryauthorities to develop systems for theabbreviated assessment, approval andmonitoring of health products.

Regulatory systems in achanging environmentRegulators are facing a rapidly changingenvironment including demographics andburden of disease, scientific progress,globalization of manufacturing and clinicalresearch, difficulties in availability of newand old drugs, and difficulties for indi-vidual agencies to meet challenges ontheir own.

ModeratorEuropean Union: Thomas Lönngren

PresentationsChanging environments and small regula-tory authorities. Ngawang Dema, Bhutan.

Implications of rapid socioeconomicchanges to the regulatory affairs.Cuong Truong Quoc, Viet Nam.

The changing environment and regulatorysystems. Björn Beermann, Sweden.

Regulatory paradigms for change:A Singapore perspective. John Lim,Singapore.

Regulatory systems: a Dutch viewpoint.Aginus Kalis, Netherlands.

Recommendations

Member States should:

1. Facilitate and speed up global regula-tory cooperation.

2. Support and stimulate their regulatoryauthorities to work with regional andglobal partners.

WHO should:

1. Continue to support and create newactivities that stimulate cooperation andbuild trust among regulatory agencies.

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Crisis management:safeguarding healthIn the course of their work, staff workingin regulatory authorities may often experi-ence crises with medicinal products.Some of these crises can lead to loss ofpublic confidence and can be deeplydamaging to the reputation and effective-ness of the regulation of medicines.

This session explored ways in which theInternational Health Regulations can beused as a mechanism for information-sharing during a medicinal product crisis.The Regulations stipulate that it is man-datory to notify WHO of ‘all events whichmay constitute a public health emergencyof international concern’ and coverserious international safety events due tomedicinal products.

The case study of nelfinavir, which hasbeen suspended due to contaminationwith a harmful substance, was presented.This case represents a complex exampleof an international problem involvingmultiple stakeholders and areas forimprovement in the communications area.Experience in two different countrieswhere the product had been withdrawncompletely from the market and wherethe product had been reinstated into thetreatment programmes were discussed.Finally, a few examples were discussedon how vaccine crises are handled. Thereare no substantial differences between amedicine crisis and a vaccine crisis.

It was agreed that there should always bea crisis management plan in place. Thisshould consist of a process through whichorganizations, in collaboration withexternal stakeholders, prevent or effec-tively manage crises. Key elements aresystematic and planned operation andinvolvement of all stakeholders is essen-tial in order to provide an efficient, rapidand effective response.

ModeratorsRepublic of Korea: Inkyu KimWHO: Bruce Plotkin

PresentationsMechanisms for information sharing andpublic health response under the Interna-tional Health Regulations (IHR).B. Plotkin, WHO.

Communication during a crisis: nelfinavircase study. Emer Cooke, EMEA, Euro-pean Union.

Nelfinavir: Where are we now? Experi-ence in Barbados. Maryam Hinds,Barbados.

Nelfinavir: Where are we now? Experi-ence in Ghana. Delese Darko, Ghana

Responding to vaccine safety events.Karen Midthun, USA.

Recommendations


1. Have in place a standard operatingprocedure (SOP) for communication intimes of crisis. Main initial communicationdifficulties which are linked to uncertaintyof toxicity implications could be avoidedby use of such SOPs.

2. Consider that many reports may berequired to generate a signal, dependingon the seriousness of the event and thequality of the information.

3. Through national health authorities,continue encouraging spontaneousreporting and vigilance systems andintroduce crisis management systems.

4. Play an important role in monitoring,analysing, and communication of vac-cines safety.

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5. Undertake passive and active surveil-lance after licensure including observa-tional studies needed to detect andevaluate medicine and vaccine safetyconcerns.

WHO and Member States should:

1. Work further to integrate and coordi-nate information and other requirementsin the International Health Regulations(IHR) (2005) with functions and activitiesof medicines regulatory authorities andrelated networks. Such integration couldinclude establishing links between medi-cines regulatory authorities and theirrespective national IHR focal points,including potential access to the WHOIHR Event Information Site.

Current topics

ModeratorsEuropean Union/Council of Europe:Susan KeitelArmenia: Emil Gabrielyan

Good Governance for MedicinesIn late 2004, WHO implemented theGood Governance for Medicines (GGM)programme in an attempt to curb corrup-tion in the pharmaceutical sector. Its goalis to increase transparency and promoteethical practices in national medicinesregulatory authorities and supply man-agement systems.

The GGM programme started with fourcountries in the WHO South-East AsiaRegion and has now extended to 27countries in all WHO regions. WHO hasnow a technical package to guide coun-tries in implementing the GGM pro-gramme and facilitates sharing of accu-mulated experiences within countries.

The programme is based on a three-phase model process:

Phase I: National assessment of trans-parency and vulnerability to corruption in

six functions of the medicines chainsupply (from registration to distribution).

Phase II: Development of a national GGMframework and its official adoption by theMinistry of Health.

Phase III: Implementation of a nationalGGM programme.

PresentationWHO Good Governance for MedicinesProgramme: the Zambian experience.Esnat Mwape, Zambia.

Recommendation

1. Develop, implement and monitor aGood Governance for Medicines imple-mentation framework, including:

• Establishment and implementation ofcodes of conduct.

• Enforcement of anticorruption laws.

• Provision of transparency and access toinformation.

• Protection of whistleblowers.

• Improvement of inter-institutional col-laboration and cooperation.

• Provision of guidelines to define andunderpin public-private partnerships.

Variations

PresentationNew proposal for the EU Variation Regu-lation – point of view of an EU NationalCompetent Authority. Christa Wirthumer-Hoche, Austria.

Recommendation

1. Create a robust and efficient variationsystem as it is vital for the quality of amedicine throughout its life-cycle.

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Radiopharmaceuticals

PresentationChallenges in regulating radiopharma-ceuticals: view of the International Con-sultancy Group affiliated to IAE.Kadariah Mohamed Ali, Malaysia.

Recommendations

1. Encourage better regulatory oversight.

2. Establish a prequalification system forradiopharmaceuticals.

3. Establish an international commonplatform (website and electronic data-base) for harmonized dossiers to pre-qualify radiopharmaceuticals.

4. Establish detailed mechanisms.

Involvement of consumers in medi-cines surveillance reporting

PresentationInvolving consumers in medicines surveil-lance reporting. Tan Lie Sie, Malaysia,and Cynthia Lim, Philippines.

Recommendation

1. Increase efforts to include consumersin medicines surveillance reporting byfostering consumer awareness, informingand educating the public and by promot-ing the programme to consumers.

WHO Stability Testing Guideline

PresentationRevision of WHO stability testing guide-lines. Tamás Paál, Hungary.

Recommendations

1. Finalize the revision of the guidelineand apply it in Member States.

2. Provide information about the nationallong-term conditions to WHO.

3. WHO to make the data available on itsweb site.

WHO Certification Scheme

PresentationWHO Certification Scheme for finishedpharmaceutical products, where are wetoday? Margareth Sigonda, Tanzania.

Recommendations

1. Review reports of recent meetings heldat WHO.

2. Give feedback to WHO for furtherdiscussion.

Adverse reactions

PresentationAdverse reactions related to change offormulation: thyroxine case. StewartJessamine, New Zealand.

Regulatory aspects ofpaediatric medicinesThis session was linked to the two daypre-ICDRA meeting “Better Medicines forChildren: the way forward”. The meetingwas unique in inviting, for the first time,regulators, industry, clinicians, civilsociety and academics to meet andidentify challenges and seek solutions toensuring better access to medicines forchildren. The pre-ICDRA meeting wasattended by more than 240 participantsfrom 75 countries. [A summary of themain themes to emerge from the meetingis presented on page 282.]

ModeratorEuropean Union: Agnès Saint-Raymond

PresentationsRecent legislative changes regardingpaediatric medicines in the EuropeanUnion. Agnès Saint-Raymond, EuropeanUnion.

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Clinical trials in neonates – challenges forall stakeholders? Irja Lutsar, Estonia.

Paediatric medicines: a viewpoint from anAfrican regulator. Richard Rukwata,Zimbabwe.

Report from the pre-ICDRA meeting“Better medicines for children – the wayforward”. Agnès Saint-Raymond, Euro-pean Union.

Recommendations from pre-conferencevaccines and biologicals track. DavidWood, WHO.

Recommendations


Assist WHO to form an ICDRA paediatricworking group to:

1. Ensure global collaboration.

• Agree on global regulatory standards.

• Streamlining paediatric clinical trials.

2. Implement efficient registration ofchildren’s medicines.

• Put children medicines as top priority.

• Fast track strategies: e.g., hybrid appli-cations, mutual recognition, cooperativereview, waivers, etc.

3. Develop consolidated views/advice ondosage forms and delivery devices.

• Guideline on dosage forms.

• Manipulations, extemporaneous formu-lations.

• Increase knowledge on paediatricexcipients.

4. Devise mechanisms for ensuring trans-parency and exchange of information ontrials, licensing, and children’s medicines(dose, adverse effects).

5. Improve information on safety ofmedicines used in children and buildinginfrastructure for pharmacovigilance.

Other parties

For industry: continue integrating paediat-ric dosage forms and delivery devicesearly in development of new medicines.

For industry: continue integrating paediat-ric needs, including developing countriesneeds in the development of new vac-cines.

For the generic industry: develop missingdosage forms of off-patent medicines(including necessary fixed-dose combina-tions).

To health professionals: engage activelyin sound, ethical research with children,with the aim of avoiding duplication ofresearch.

WHO should:

1. Convene a global paediatric workinggroup of regulators.

2. Work with civil society to mobilize andempower consumers, parents, patients’groups and health professionals toadvocate for better medicines for chil-dren.

3. Develop strategies for addressing highpriority needs with achievable resultsincluding: zinc for diarrhoea, Pneumoniaetreatment, neonatal sepsis, HIV, TB,malaria treatments, and analgesics.

4. Establish a drug development helplineto support new essential medicines forchildren.

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Vaccines and biologicals:

1. National regulatory authorities (NRAs)should prioritize evaluation of vaccines fordiseases of most importance to childsurvival.

Member States and WHO:

1. Networking among NRAs for the jointevaluation and oversight of clinical trialsof new vaccines is proving an effectiveprocess in Africa. NRAs are requested tocontinue to develop this type of collabora-tion and WHO is requested to facilitatethe long-term sustainability of this andother vaccine regulatory networkinginitiatives.

2. Post-marketing effectiveness data is animportant aspect of vaccine evaluation.WHO is requested to support capacitybuilding and NRAs are requested tostrengthen collaboration with publichealth agencies in this area.

3. Vaccine pharmacovigilance is a regula-tory function that needs to be strength-ened. NRAs are requested to prioritizecapacity building for this function andWHO is requested to support this activitythrough setting standard definitions,development of guidelines, training, anddevelopment of networks.

4. NRAs are requested to expeditenational-level approval of WHO prequali-fied vaccines. To facilitate this, WHO isrequested to provide more detailedinformation about the quality, safety andefficacy of prequalified vaccines.

5. Forty per cent of venomous snake bitevictims are children. There is a shortageof appropriate antivenoms globally.Improving the quality, quantity and distri-bution of antivenoms is essential. NRAsare requested to implement new WHOguidance on the quality, safety andefficacy of antivenoms and WHO isrequested to develop a prequalificationprogramme for antivenoms

Development of regulationfor herbal medicinesCurrently, around 110 countries regulateherbal medicines in response to a dra-matically increased use globally anddemand for more vigorous requirementsto ensure quality, safety and efficacy. Anumber of countries also review andstrengthen existing regulations for herbalmedicines in a continued effort to improvetheir use and efficacy. Regulation ofherbal medicines varies from country tocountry, reflecting national circumstancesand legislative frameworks. A globalnetwork of regulatory agencies responsi-ble for regulation of herbal medicines, the“International regulatory cooperation forherbal medicines (IRCH)” was estab-lished in 2006 under the coordination ofWHO and currently has 19 members.

ModeratorsSingapore: Shen Kuan Yee

Lao PDR: Somthavy Changvisommid

PresentationsRegulatory Framework: overview of theregulation of herbal medicines in Switzer-land. Karoline Mathys, Swissmedic,Switzerland.

Regulatory Framework: overview of theregulation of herbal medicines in BrazilBruno Rios, ANVISA, Brazil.

Overview of the regulation of herbalmedicines in Benin in supporting primaryhealth care needs. Regina Badet, Depart-ment of Traditional Medicine and pharma-copoeia, Ministry of Health, Benin.

Overview: revising the regulatory frame-work of herbal medicines in China.Zhang Wei, State Food and Drug Admin-istration, China.

Promotion of regulatory cooperation:perspectives from IRCH. Shen Kuan Yee,Deputy Director, Centre for Drug Adminis-

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tration, Health Products RegulationGroup, Health Sciences Authority, Singa-pore.

Recommendations


1. Promote and improve use of traditionalmedicine (TM) as an important therapeu-tic tool within health-care systems.

2. Provide well balanced prescribinginformation concerning TM includingpotential interactions with conventionalmedicines.

3. Promote research and use of TM as animportant therapeutic tool.

4. Raise awareness of cases of adultera-tion of TM with undeclared plants orconventional medicines, or syntheticsubstances.

5. Countries with resources shouldsupport developing countries to achieveaccess to better technology tools forevaluation of the therapeutic potential ofplants.

WHO should:

1. Provide policy and technical support tocountries to facilitate integration oftraditional medicine into the health-caresystem.

2. Support developing countries to accessmodern technologies to facilitate produc-tion and manufacturing of herbal medi-cines.

3. Support and coordinate North-Southcooperation to improve access to bettertechnology to evaluate the therapeuticpotential of plants.

4. Continue to support sub-regional groupcountries in developing monographs on

commonly used medicinal plants throughcooperation and in building nationalresearch capacity for traditional medi-cines.

5. Provide technical guidance to countrieson how to avoid interactions betweenconventional and herbal medicines.

6. Continue to play a coordinating role inInternational Regulatory Cooperation onHerbal Medicines (IRCH) functions bypromoting the network to involve othercountries while encouraging membercountries of IRCH to incorporate theirnational lists of registered herbal productsinto the IRCH library and to share thiswith IRCH non-member countries.

7. In cooperation with other relevantinternational organizations, promoteintroduction of intellectual property rights(“patent protection”) for all newly regis-tered herbal products.

Safety and pandemicpreparedness

Pandemics and epidemics are publichealth emergencies that put sudden andintense stress on all institutions involved.Regulatory authorities will be faced withseveral issues that need to be dealt withrapidly, efficiently and possibly withlimited resources as pandemics are likelyto disrupt many aspects of public life.

Medicines, vaccines and blood productswill have to be made available at shortnotice for large populations. This includeslarge scale quality control and intensemonitoring of therapeutic agents thatmight not have been previously adminis-tered outside clinical development set-tings.

In the case of an avian influenza pan-demic the safety of vaccines administeredduring the pre-pandemic phase needs tobe evaluated very rapidly.

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Adequate storage of therapeutic agentsand safe and rapid distribution channelsare further challenges to be taken on.

ModeratorsSwitzerland: Pia Carduff-Janosa

Indonesia: Lucky Slamet

PresentationsMedicines and associated regulatoryissues relevant in the pandemic context.Philip Bryan, United Kingdom.

Vaccines and associated regulatoryissues relevant in the pandemic context.Elwyn Griffiths, Canada.

PaniFlow tool for monitoring drug/vaccineadverse events during a pandemic.Andres Schneider, Switzerland.

Blood supply and blood products: regula-tory issues in the pandemic context.M. Heiden, Germany.

Convalescent plasmas during a pan-demic. Jay Epstein, USA.

Recommendations

WHO should:

1. Establish, facilitate and intensifyinternational collaboration in safetysurveillance of pandemic vaccines andantivirals.

2. Request the WHO CollaboratingCentre for International Drug Monitoring/Uppsala Monitoring Centre, to providefree access to PaniFlow (a simplifiedonline reporting form for primary report-ers) for all countries who wish to use it,and to develop and implement a tool forrapid signal detection on pooled data andkeep all countries informed on findings ina timely manner.

3. In recognition of the potential valueand availability of convalescent plasma

as a therapeutic in pandemic flu and itslikely empirical use, WHO should:

• Develop guidance on best practices forcollection and use of convalescentplasma in a flu pandemic

• Promote pre-pandemic research onconvalescent plasma

• Encourage rapid sharing of scientificand technical knowledge from both pre-pandemic and pandemic experience

National regulatory authorities (NRAs)should:

1. Develop and share business continuityplans to enable essential functions to beperformed during the pandemic.

2. Develop and share regulatory plans toenable rapid access to medicines, includ-ing vaccines, that may need to be im-ported to respond to the pandemic. Thisshould include emergency use provisions;information sharing agreements betweenNRAs and batch release procedures forvaccines to be implemented in the pan-demic context.

3. NRAs are encouraged to activelyparticipate in already existing networks(such as the pandemic influenza vaccineregulatory network, blood regulatorsnetwork).

Regulatory approaches toproving interchangeabilityExperience has demonstrated thatprescribers and other health-care profes-sionals as well as patients are reluctant tochange to generics unless there is a clearreason to do so and this reluctance is amajor hurdle for the introduction ofgenerics. Demonstrating qualitative andquantitative equality with the originator istherefore important for the introduction ofgenerics and subsequent drop in medi-cines prices and health-care costs.

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In light of knowledge gained in the lastforty years on pharmaceuticals, scientificevidence supports the need for regulatingthe interchangeability of medicinal prod-ucts. Many national competent authoritieshave issued guidelines on bioquequiva-lence studies and on the type of medici-nal product that can be exempted from invivo bioequivalence studies.

Interchangeability of medicinal products isregulated in most EU Member Countries,Japan, USA and other countries. Theregulation of interchangeability of medici-nal products requires a strong team withineach drug regulatory authority. Surveil-lance of performance and outcomes alsorequires expertise and resources.

ModeratorsSaudi Arabia: Salah Bawazir

Spain: Carlos Lens

PresentationsProof of interchangeability of pharmaceu-tical products and assurance of theirquality in Ukraine. Olga Baula, Ukraine.

Implementation of bioequivalence re-quirements: lessons learned. RodrigoChristofoletti, Brazil.

Interchangeability and registration ofmultisource (generic) products in Japan.Daisuke Koga, Japan.

WHO biowaiver guideline in regulatorypractice. Kamal Iddir, Tunisia.

Recommendations


1. Ensure that drug laws and regulatoryframeworks contain the required provi-sions to ensure submission of bioequiva-lence data to regulators.

2. Promote generic prescribing based onassurance that all mulltisource (generic)products are therapeutically equivalent.

3. Allocate more resources to medicinesregulatory authorities (MRAs) for trainingof assessors for evaluation of inter-changeability of multisource (generic)products.

4. Enable MRAs to certify the contractresearch organizations (CROs) conduct-ing bioequivalence studies

WHO should:

1. Promote mutual trust and internationalcooperation mechanisms in order torecognize MRA inspections of CROs thathave been conducted based on interna-tionally acceptable standards.

Strategies to fightcounterfeit medicinesCounterfeiting of medicines, including theentire range of activities from manufactur-ing to providing such products to patients,is a vile and serious criminal offence thatputs human lives at risk and underminesthe credibility of health systems. Becauseof its direct impact on health, counterfeit-ing of medicines should be combated andpunished accordingly.

Combating counterfeit medicines requiresthe coordinated effort of all the differentpublic and private stakeholders that areaffected and are competent to addressthe different aspects of the problem.

Counterfeiting medicines is widespreadand has escalated to such an extent thateffective coordination and cooperation atthe international level is essential forregional and national strategies to bemore effective.

The above principles have been the basisfor the establishment of the InternationalMedical Products Anti-CounterfeitingTaskforce (IMPACT). The Taskforce hasidentified five areas where action isneeded in order to combat counterfeitmedical products effectively. Accordingly,

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five working groups have been created,covering: legislative and regulatoryinfrastructure, regulatory implementation,enforcement, technology, and communi-cation.

ModeratorsNigeria: Dora Akunyili

Brazil: Bruno Rios

PresentationsNational Experience in combating coun-terfeit medical products:

Justina Molzon, USA.Eishah A. Rahman, MalaysiaDomenico Di Giorgio, ItalyDanny Lee-Frost, United Kingdom

Recommendations

1. Medicines regulatory agencies (MRAs)should be more proactive in providingother NRAs and the general public withappropriate information on the scope ofthe problem of counterfeit medical prod-ucts at the national level.

2. MRAs should ensure that all concernedgovernmental institutions are aware of thescope of the problems related to counter-feit medical products and of the activitiesthat are undertaken to address these atnational and international level.

3. MRAs should develop and adopt multi-pronged anti-counterfeiting strategiesaddressing at least: (a) ensuring properregulatory oversight, (b) securing thesupply chain, (c) increasing and applyingpenalties, (d) increasing public and healthprofessional vigilance and awareness, (e)developing and applying effective authen-tication and detection technologies, and(f) improving coordination with all con-cerned stakeholders at the national andinternational level.

4. MRAs should clearly define the respon-sibilities of manufacturers and operators

of the supply chain at all steps of thepharmaceutical supply system.

5. In developing track and trace method-ologies used to secure the supply chain,MRAs should take into account the needto ensure international compatibility inorder to improve their effectiveness intracking products that move acrossborders, whenever applicable.

6. WHO and MRAs should promote thedevelopment of collaborative networksbased on the principle of Single Points ofContact (SPOC).

7. WHO should further assist MRAs tostrengthen their capacity to detect andcombat counterfeit medical products andto exchange information at the interna-tional level.

8. WHO should further promote a harmo-nized definition of a counterfeit medicalproduct that is based on the 1992 defini-tion of counterfeit medicine, that focuseson the protection of public health, andtakes into account the need to safeguardlegitimate generic medicines.

9. WHO should develop and implementinitiatives aimed at disseminating aware-ness and triggering political will to combatcounterfeit medical products.

Emerging regulatory issuesconcerning biosimilars andbiologicalsDraft WHO guidance states that, incontrast to a generics approach, thedossier for a similar biological product willneed to contain information on the non-clinical and clinical data in addition to thequality data. However, the proposedguidance considers that a non-clinicaland clinical package could be abbrevi-ated; the extent of abbreviation willdepend on the level of similarity to the

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well established reference product with aproven record of quality, efficacy andsafety.

Experience gained by using a “biosimilarapproach” in the EU was considered inthe development of the WHO guidelinesand one abbreviated regulatory pathwayis proposed. However, during review ofthe document, a need for an alternativewas identified and an additional abbrevi-ated pathway is under development.

ModeratorsEuropean Union/EMEA: Nick GatesRepublic of Korea: Chung Keel Lee

PresentationsRegulation of copies of therapeuticbiological medicinal products: WHOguidelines. Elwyn Griffiths, Canada.

Regulatory considerations in Thailand.Prapassorn Thanaphollert, Thailand.

WHO guidelines: abbreviated licensingpathways for biological products. MartinaWeise, Germany.

Panel discussion: Experience with exist-ing regulatory pathways for copies oftherapeutic biological medicinal products.

Elwyn Griffiths, Canada.Prapassorn Thanaphollert, Thailand.Martina Weise, Germany.

Recommendations

WHO should:

1. Develop guidance for regulatoryevaluation of similar biological productsthat includes clarification of the scientificbasis for the reduction, wherever possi-ble, of non-clinical and clinical datarequirements for such products.

2. Assist regulators in implementingglobally agreed regulatory principles intonational regulations and, where appropri-ate and feasible, develop support mecha-

nisms such as regional centres of excel-lence in regulatory evaluation of similarbiological products.


1. Strengthen NRA functions for theevaluation, pharmacovigilance andoverall regulation of biotherapeutics.

Emerging diseases:regulating blood productsThis session recognized the need world-wide for blood product regulation toensure availability of safe blood andblood products in the face of known andemerging threats, including emerginginfectious diseases.

ModeratorsUSA: Jay Epstein

Indonesia: Lucky Slamet

PresentationsEmerging Diseases, blood safety andsupply: Chikungunya virus outbreak in2005/2006. Isabelle Sainte Marie, France.

Dengue outbreaks in Latin America.Clarice Lobo, Brazil.

Assessment criteria for blood regulatorysystems: effectiveness in risk manage-ment. Christian Schaerer, Switzerland.

Plasma Quality: How does it matter?Rainer Seitz, Germany.

Assessment criteria for blood regulatorysystems: effectiveness in risk manage-ment. Jay Epstein, USA (presenting forPeter Ganz, Canada).

Recommendations

WHO should:

1. Take steps to further develop andstrengthen national and regional blood


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regulatory authorities and promotecooperation among them.

2. Provide well-harmonized “AssessmentCriteria for Blood Regulatory Systems”building on work of the Blood RegulatorsNetwork

3. Take full account of existing assess-ment tools in use by NRAs by:

• Convening a consultation of NRAs toreview the draft assessment tool, and

• Ensuring coordination with related WHOguidance documents.

4. Prioritize development of guidelines ongood manufacturing practices (GMP) forBlood Establishments.

5. Promote introduction of WHO recom-mended plasma standards by NRAs.

Regulators contributionto accessModeratorHungary : Tamás Paál

PresentationsAvailability of human medicinal productsin Europe – how big is the problem andwhat can we do? View from the regulator.Kristin Raudsepp, Estonia.

Can regulators facilitate access? Aviewpoint from China. Zhang Wei, China.

Panel Discussion

Recommendations


1. Involve regulators in the formulation ofpolicies and measures assuring patientaccess to medicines. Regulators should,in addition to their traditional roles, takeresponsibility for facilitating availability ofmedicines.

2. Formulate policies and, as far aspossible, legislation to enable prioritymedicines availability according to localhealth care needs.

3. Direct drug regulatory authorities toreveal medicine availability problems bygiving priority to new applications forproducts answering locally unmet healthneeds.

WHO should:

1. Provide a forum to discuss and facili-tate both availability and affordability ofmedicines in all Member States.

Update on harmonizationinitiativesModeratorsTanzania: Margareth Sigonda

Canada: Mike Ward

PresentationsDevelopment of ICH Global CooperationGroup: a non-ICH regional harmonizationand country perspective. YuppadeeJavroongrit, Thailand.

Harmonization of drug regulation in EastAfrica: the way forward. Apollo Muhairwe,Uganda.

Harmonization of regulatory require-ments: a view point from an APECcountry. Mike Ward, Canada.

Update on Pan American Network forDrug Regulatory Harmonization. JamesFitzgerald, PAHO/WHO.

Recommendations

1. WHO should encourage and facilitateMember States’ use of the assessmenttool for drug regulatory authorities as animportant step in promoting effective


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regulatory strategies and harmonizationefforts.

2. WHO should promote the principle ofinterconnectivity by information sharingand cooperation between harmonizationinitiatives and enabling organizations tobuild synergies, leverage capacity andsustain efforts.

3. WHO and Member States shouldpromote effective mechanisms of harmo-nization through the establishment orstrengthening of secretariats or coordina-tion points, steering committees andprocedures respecting expert workinggroups, governance and transparency.

4. WHO should facilitate the adoption byMember States of a common format formarketing applications as a means ofpromoting a common regulatory languagethat supports the sharing of information,good review practices and access tomedicines.

5. The topic of harmonization should be astanding agenda item at each ICDRA.

Role of regulators in clinicaltrial approvalModeratorAustralia: Rohan Hammett

PresentationsRegistration of clinical trials in the na-tional registry or authorization by thenational DRA – what should come first?Surinder Singh, India.

Roles and responsibilities of nationalregulators and the ethics committees:ways for better cooperation and commu-nication. Lucky Slamet, Indonesia.

Interactions between manufacturing andtrial host country regulators. Pieter Neels,Belgium.

Recommendations


1. Promote national mechanisms forcommunication and collaboration be-tween ethics committees and regulatoryagencies regarding the oversight ofclinical trials.

2. Provide mechanisms that allow expertsfrom well resourced regulatory agenciesto assist in capacity building of regulationof clinical trials in less resourced regula-tory authorities. This may include expertsupport from regulators of the manufac-turing country to regulators of the trialhost country.

3. Promote a risk-based approach toregulatory oversight of clinical trials.

WHO should:

1. Promote regulation of clinical trials bysupporting countries to establish robustlegal and regulatory frameworks andsystems to register and publish ongoingtrials to achieve transparency.

2. Facilitate the establishment of confi-dentiality provisions that will allow com-munications and cooperation betweenregulatory agencies from manufacturingand trial host countries.

Building regulatory capacity:best practices for the futureModeratorsIndia: Debasish Panda

Japan: Takayuki Okubo

PresentationsBuilding regulatory capacity. DebasishPanda, India.

NRA assessment/benchmark system andinstitutional development plan (IDP).Rafael Perez Christia, Cuba.


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Building regulatory capacity in a regula-tory network: experience from twinningprojects and EU worksharing. DagmarStará, Slovak Republic.

Recommendations

WHO should:

1. Systematically inform ministries ofhealth of outcomes of NRA assessments.

2. Evaluate ways for improving bench-marking activities within the assess-ments.

3. Strengthen NRAs in regulatory self-assessment approaches.

Member States and NRAs should:

1. Use WHO tools for conducting selfevaluation as an adequate way forimproving regulatory performance.

2. Provide staff to support the WHOassessment process and take advantageof the experience resulting from thisprocess.

GMP inspections: impact ofinformation sharing and riskmanagementIncreasingly, strategies are discussed onhow best to cope with the increasingneed for inspections by national andregional bodies. This topic was alsodiscussed during several WHO consulta-tions and meetings of the WHO ExpertCommittee on Specifications for Pharma-ceutical Preparations, which suggestedthat this would be a good subject fordiscussion at the 13th ICDRA.

ModeratorsUSA: Justina Molzon

South Africa: Joey Gouws

PresentationsRisk management of GMP inspections:Australian approach. Tony Gould, Aus-tralia.

Coping with increasing need for inspec-tions: ASEAN initiatives. Abida Haq,Malaysia.

What is EMEA’s approach in GMP in-spections? Emer Cooke, EuropeanUnion.

Recommendations


1. Work towards ensuring quality, efficacyand safety of drugs while making effortsto contain escalating costs of drug pricesby minimizing duplication of inspectionactivities through:

• Better networking.

• Improved information sharing.

• Enhanced collaboration.

• Increased mutual trust/confidence.

2. Promote efficient use of inspectorateresources through use of a risk manage-ment approach in GMP inspections,especially for overseas manufacturers, bytaking advantage of information availablefrom other drug regulatory authorities.

3. Collaborate with WHO Member Statesand the WHO Medicines PrequalificationProgramme to share information aboutdates, purpose of inspection and majoroutcomes.

Manufacturers should:

1. Actively collaborate in informationsharing among national, regional andinternational bodies involved in inspec-tions.


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2. Increase availability of non-confidentialinformation on the web sites of interestedauthorities and on protected sites ac-cess-ed by national authorities.

WHO should:

1. Promote and enable networking andinformation sharing among national,

The US Food and Drug Administration(FDA) and the Pharmaceutical Researchand Manufacturers of America (PhRMA)hosted an ICH Quality satellite roundtable in Rockville, Maryland, USA 27– 28September 2007. The objectives of themeeting were:

• To discuss the technical and regionaldifferences and similarities in describingthe development and manufacturing ofdrug substances in the common techni-cal document (CTD).

• To determine how best to apply theprinciples of ICH Q8, Q9 and Q10guidelines for both small and largemolecules.

• To integrate these principles into devel-oping future quality guidances.

The conclusion of the meeting was thatthe quality by design (QbD) approach,including the design space, is applicableto both chemical and biotechnological (1)active pharmaceutical ingredients (APIs),although opportunities and challengesare different in the two groups of pharma-ceutical substances.

The business plan was approved by theICH Steering Committee (ICH SC) in

ICH-Q11 appears on the horizon:development and manufacture of drug substances

Yokohama in October 2007 and the FinalConcept Paper Q11: Development andManufacture of Drug Substances (chemi-cal entities and biotechnological / biologi-cal entities) was endorsed by the ICHSteering Committee in April 2008. A six-party expert working group (EWG) wasestablished, including observers from theEuropean Free Trade Association (EFTA),Health Canada and WHO. The EWGfollows the process used by the CTD-QEWG where biotechnological / biologicaland chemical experts work together.

The concept paper (2) summarizes thegoals of the guideline, as follows:

• Harmonize and encourage the submis-sion of relevant documents regardingthe manufacturing process informationand its justification.

• Outline the science-based conceptsrelevant to the design of a robustmanufacturing process that reliablydelivers a quality drug substance.

• Provide examples as appropriate ofacceptable approaches for demonstrat-ing process and product understanding.

• Facilitate the regulatory evaluationprocess for authorities.


Article submiited by János Pogány, Budapest. Comments to: [email protected]

regional and other relevant authoritiesinvolved in inspections.

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Organic active pharmaceutical ingredients (APIs) may be manufactured by isola-tion from herbal, animal or human sources, for example: The structure synthesizedfrom Artemisia annua has been modified by chemical synthesis to obtain a mol-ecule with improved pharmacological and pharmaceutical properties.

Artemisinin Artesunate

The majority of (small-molecule) APIs are manufactured by chemical synthesis.

Biotechnological methods are used to produce “large molecules”, e.g., antibiotics.

The three groups of manufacturing methods, including the use of (geneticallyengineered) micro-organisms in fermentation, are frequently combined in thepharmaceutical industries.


Streptomycin

Nevirapine

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• Recommend approaches for demon-strating process and product under-standing.

• Address the complexity of differentmanufacturing processes and products.

• Accommodate variable approaches todevelopment and corresponding infor-mation to be provided as described inQ8 and Q8R.

• Address enhanced approaches tomanufacturing that can also create abasis for alternative approaches tocontrol the quality of a product and forthe application of innovative technolo-gies for the manufacture of APIs (e.g.continuous manufacture).

• Address systematic approaches to drugsubstance development, application ofquality risk management, and conceptssuch as design space, control strategies(including real-time release) over thelifecycle of the product.

Topics already covered by other ICHguidelines such as analytical procedurevalidation (Q2), quality of biotechnologicalproducts (Q5 series), and GMP activities(Q7) will be cross-referenced in the newguideline, as appropriate.

Step 1: Consensus building stage beganwith the first meeting of the Q11-EWG inPortland, Oregon (USA) in June 2008,where the guideline topic/definitions wereaccepted. Draft No.0 was tabled fordiscussion in Brussels in November 2008.Initial discussions have revealed thatICH-Q11 may become the hardest everdocument to elaborate because it willbecome a stand-alone document to covera wide scope of not-yet-harmonizedissues:

• Information on development and manu-facture of drug substances in regulatorysubmissions;

• Chemical and biotechnological molecu-lar entities;

• New chemical entities opposed togeneric APIs;

• Current practice versus quality bydesign (QbD) approach

Many quality topics have not yet been thesubject of ICH guidelines (e.g. drugsubstance synthesis) and the content ofCommon Technical Document (CTD) forthe Registration of Pharmaceuticals forHuman Use: Quality – M4Q(R1) is nottotally harmonized.

Innovator pharmaceutical industriesalways develop a new chemical entityconcurrently with the finished pharmaceu-tical product (FPP), while generic APIindustries are often isolated from the drugproduct manufacturers and the open partof the drug master file (DMF) is thetechnical link between them. The CTD –Quality Questions and Answers/ LocationIssues (3) states that “Since the DMFsystems differ in the three regions, ICHdoes not address this issue.”

A control strategy has always existed inthe drug-substance industries but Q8initiated a new way of thinking and manycompanies have adopted risk assess-ment (impact of process on safety andefficacy of API) and aim at more processunderstanding and the associated designspace as well as process analyticaltechnology (PAT) monitoring of criticalmanufacturing process parameters.

These illustrative examples intend todemonstrate that ICH Q11 is an importantdocument both for industry and regulatoryagencies and its impact goes beyond theICH regions.


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Notes and references

1. Biotech drug substances were defined asactive pharmaceutical ingredients manufac-tured by biotechnological processes including,but not limited to, macromolecules (such asproteins, peptides and nucleic acids) andexcluding vaccines.


2. The full text of the ICH-Q11 concept papercan be found at http://www.ich.org/LOB/media/MEDIA4523.pdf

3. http://www.ich.org/LOB/media/MEDIA620.pdf

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Pharmacovigilance Update

Strategies for developingpharmacovigilance: aninternational focusThe 8th International Society of Pharma-covigilance (ISoP) conference, Strategiesfor developing Pharmacovigilance, held inBuenos Aires, Argentina, in October 2008was hosted by the Argentine Society ofPharmacovigilance. This was the firstISoP meeting to be held in Latin America,which is a geopolitical region mainlycomposed of developing countries with atotal population of more than 450 millionpeople. Although political, economic andeven ethnic conditions vary in the differ-ent Latin American countries, they are allaffected in different degrees by similarproblems concerning production, distribu-tion and utilization of medicines.

The conference was attended by morethan 350 participants from more than 50countries. Among the audience weremany medicines regulatory authorities,health professionals, and representativesof academia and pharmaceutical labora-tories, student and patient organizations.Thirty participants were also sponsored toattend a pre-conference course Pharma-covigilance: from fundamental basics topractice. This course was organized bythe Argentine Ministry of Health to allowhealth professionals from Argentina’sprovinces to attend the 8th ISoP confer-ence.

The 8th ISoP conference was organizedas a bilingual event in English and Span-ish. Spanish is one of the most widelyspoken languages in the world. Besides

Spain, with 40 million inhabitants, thereare nineteen Spanish-speaking countriesin Central and South America and agrowing Spanish-speaking population,around 45 million, in the USA.

The Scientific Programme includedissues concerning pharmacovigilance andpresented differences in organization,complexity and effectiveness in differentregions. Harmonization in pharmacovigi-lance was approached in such a way asto discuss and compare the regulations ofdeveloped and developing regions. Twosessions were devoted to enhancingmethodology and one to improving theefficacy of systems to prevent the circula-tion of counterfeit and substandardmedicines (a summary of which is set outon page 276). The need to enhancepharmacovigilance in pregnant women,children and older people was alsostressed.

Different approaches to pharmacovigi-lance in vaccines and a round-tablediscussion on strategies of risk manage-ment from a regulatory perspective dealtwith two main topics in internationalpharmacovigilance. The need for monitor-ing of a relatively new group of medicineswas the basis for the session aboutbiological products and advanced thera-pies. The crucial role of communication inpharmacovigilance was also approachedfrom different perspectives and focusedon public and media communication. Theevaluation of medicines for marketingauthorization and the impact of thiscomplex process on patient safety weretackled in three plenary lectures dealing

This article was prepared by Raquel Herrera Comoglio on behalf of the Argentine Society ofPharmacovigilance (www.safv.org.ar). Speaker authorization for publishing the summaries andreviews of lectures is kindly acknowledged.

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with benefit/risk balance, off-label use,and the non-commercial sponsorship ofclinical research.

Summaries of two sessions and a plenarylecture that have special importance forthe Latin-American region are providedbelow and on the following pages.

The programme from the 8th ISoP confer-ence is available at http://www.isop2008.org/isop2008-final programme3.pdf.

Harmonization andpharmacovigilance*The international harmonization of phar-macovigilance has an impact on druglicensing and utilization and on the healthand disease burden worldwide, but itsimpact is greatest within trade alliances,like Mercosur or the European Union. Thecomplex issue of pharmacovigilanceharmonization has become a growingconcern for regulators and presentsconsiderable challenges.

Global markets and patient safety**In the context of market globalization, theacceptance and perception of risk andbenefit of drugs is influenced by social,structural and legal factors in differentcountries. The key question is whetherharmonization of pharmacovigilance andregulatory action can be consolidatedgiven the varying degrees of pharma-covigilance development observed in thedifferent regions.

Pharmaceutical manufacturers actglobally in an unequal world where not allcountries have the opportunity to benefitfrom medical progress or access to health

care and where medicines are oftenlacking. Many countries trading in com-mon markets often have varying prioritiesin their fight against different diseases.Depending on the situation, these mayfocus on treating lifestyle diseases or onbattling diseases of poverty and underde-velopment. There is also a broad diversityin the structure and quality of pharmaceu-tical markets, in the number of differentproducts licensed, in the active ingredi-ents and in sales figures. Advertising andpromotion of medicinal products to healthprofessionals and direct-to-consumer ad-vertising are just a few of the challengesfacing societies within a context of vary-ing financial and human resources, socialsecurity systems and infrastructure.

Regulators have a responsibility toensure patient health and safety and theyare required to act within existing nationalstructures and environments. However,their power to act decisively may also beinfluenced or hindered by overridingpublic health needs or politics.

The role of harmonizationHarmonization should use the bestevidence of favourable or unfavourabledrug effects to assess the benefit-to-harmrelationship. Likewise, it should promoteequal and fundamental rights for popula-tions and the proper use of drugs in allsettings in order to achieve high stand-ards of safety.

The main preconditions for harmonizationare availability of high quality informationand transparency. It is necessary todefine different levels of information inorder to make appropriate decisions. Forunderdeveloped countries with difficultInternet access, WHO’s role should bereinforced to achieve effective coverageof essential information.

In conclusion, harmonization shouldreflect and respect differences betweencountries and societies, but patient safetymust have the highest priority. Full access

* Session chaired by Ulrich Hagemann,Pharmacovigilance Department, FederalInstitute for Drugs and Medical Devices -BfArM, Germany and Pedro Lipszyc, BuenosAires National University, Argentina.** Presentation by Ulrich Hagemann.


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to data and exchange of information arekey elements for collaboration andinterchange between all stakeholders.Regulators should also be supportedthrough international or regional networksand action tending to improve pharma-covigilance in poor or under resourcedcountries should continue to be strength-ened by support from independentorganizations.

Pharmacovigilance and the PanAmerican Network for DrugRegulatory Harmonization*

The objective of the Pan AmericanNetwork for Drug Regulatory Harmoniza-tion (PANDRH) is to offer a forum toidentify common activities among mem-bers. It aims to establish priorities in drugregulatory harmonization processes,facilitate continuity of technical agree-ments and encourage convergence ofdrug regulatory systems within theAmericas.

PANDRH is made up of representativesfrom drug regulatory authorities of the 35countries in the region, organisms foreconomic integration such as CARICOMand MERCOSUR, associations of thepharmaceutical industry, academia andnongovernmental organizations. Its maintargets are:

• To strengthen drug regulatory agenciesat country level.

• To promote constructive participation ofall partners.

• To facilitate the establishment of anetwork of regulatory authorities.

Key concerns are to improve the accessto safe and effective medicines of goodquality in all countries of the region and toreduce unnecessary, duplicate require-

ments for drug registration. The group isworking for the harmonization of interna-tional standards of quality, safety andefficacy and a pharmacovigilance workinggroup was established in 2006 in order to:

• Develop and strengthen pharmaco-vigilance through activities and harmo-nized regulatory action that promotesthe safe and rational use of medicinesas a necessary component of publichealth policies in the WHO Region ofthe Americas.

• Promote the development and dis-semination of knowledge, criteria andmethodologies used in pharmaco-vigilance for training and educationactivities directed to all stakeholders.

• Develop, analyse and propose the useof tools to support harmonization ofpharmacovigilance in the Region.

In order to improve adverse drug reactionreporting, there must be strong politicalcommitment from each component of thehealth-care system. As an example,experience in Cuba has shown thatappointing a focal point responsible forpharmacovigilance in each district hospi-tal has led to a considerable increase inthe number of adverse drug reactionreports.

Lessons learned from the develop-ment of pharmacovigilance in Spain*

Spontaneous reporting started in Catalo-nia in the 1980s, when pharmacovigi-lance was almost completely unknown tohealth authorities or health professionalsin Spain. Establishment of the Cataloniapharmacovigilance system and researchwas mainly the result of development of adynamic Clinical Pharmacology Unit atthe University Hospital in Catalonia.

*Lecture presented by Joan-Ramon Laporte,Universidad Autonòma de Barcelona, Spain.

* Presented by Julian Pérez Peña, NationalPharmacoepidemiology Development Center,Ministry of Public Health, Cuba.


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Examples of signals leading to marketwithdrawals:agranulocytosis – cinepacidehepatitis – bendazacGuillain Barré syndrome – gangliosideshepatitis – droxicamhypersensitivity and hepatotoxicity – glafenineagranulocytosis – pyrithyldionehepatotoxicity – ebrotidinerhabdomyolysis – cerivastatinliver toxicity – nimesulidehepatitis – green tea extractextrapyramidal and psychiatric reactions – veralipride.

Examples of signals leading tochanges in approved indicationsand conditions of use:Parkinsonism and depression – cinnarizine and flunarizinetaste disorders – citioloneacute dystonic disorders – cleboprideTB infection – infliximab(This last signal was generated by a SaoPaulo University Hospital, where aPharmacovigilance system was set upwith the collaboration of the CatalanInstitute of Pharmacology.)

Of note, many of the drugs involved hadno evidence of efficacy, and this benefit-risk assessment was straightforward. Inaddition, many of the adverse reactionswere type B (not related to the expectedpharmacological effect, not dose-related,etc.).

Traditionally, monitoring of medicinessafety has mainly relied on spontaneousreporting, especially for detecting type Beffects. In Spain, spontaneous reportingalso proved to be helpful in clearing themarket of irrational and useless medi-cines – and even harmful and ineffectivedrugs. However, although spontaneousreporting has proved to be useful indetecting these type B reactions andsome type A effects, the surveillance ofmedicines safety should include other

In Catalonia, spontaneous reporting wasestablished, and continues to be devel-oped, as part of a broader communica-tions strategy of drug monitoring betweenthe Clinical Pharmacology Unit andprescribers. It also encompasses acontinuous education activity, mainly forhealth professionals, health managers,policy makers, and politicians working inthe health sector. A major contribution ofthe clinical pharmacology unit to publichealth was a change in prescriptionpatterns in Catalonia. In 1984, many ofthe most highly prescribed pharmaceuti-cal products in the health system lackedevidence of therapeutic efficacy, or weresimply irrational fixed-dose combinations.In comparison, the most highly prescribedmedicines in 2007 had better evidence ofefficacy.

The initial pharmacovigilance systemreceived very strong institutional supportfrom the Ministry of Health, which under-stood the need for collaboration withhealth professionals independent fromthe Ministry of Health and public adminis-tration, and of communication and makingalliances with people working in Universi-ties and hospital structures because oftheir closer access to prescribers. Spain’sintegration into the European Union wasalso positive in establishing regulatorymeasures for the licensing of new drugsand safety monitoring

The programme was then extended toother Spanish regions and the SpanishAgency for Medicines and Health Prod-ucts (AEMPS) now maintains a centraldatabase, FEDRA, containing 140 000reports. All the 17 PharmacovigilanceRegional Centres regularly publishbulletins with information on their findingsand on drug safety issues.

In all these twenty-seven to twenty-eightyears since its establishment, the Span-ish pharmacovigilance system hasproduced many important results in thefield of public health.


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pharmacoepidemiological methods. Sincethe drug-induced disease burden consistsmainly of type A effects, the challenge is arisk evaluation of these, not only inrelative terms but in the amount of deathsor hospitalizations caused by drugs in oursocieties.

The following represent examples ofpharmacoepidemiological methods usedin recent years to asses some importantdrug safety problems:

1. Randomized clinical trials (RCTs) andmeta-analysis of randomized clinical trialsfor assessing the relationship between:

• Hormone replacement therapy andbreast cancer, myocardial infarction,thromboembolic disease, cerebro-vascular accidents.

• SSRI antidepressants and suicide inchildren.

• Epoetins and hypertension and cardio-vascular risk.

2. Longitudinal follow-up of unselectedpatients for assessing the relationshipbetween risk of haemorrhage and use oforal anticoagulants.

3. Observational studies, meta-analysis ofobservational studies and meta-analysisof RCTs for assessing the risk of myocar-dial infarction with rofecoxib, other COX-2and other NSAIDs.

4. Spontaneous reporting, observationalstudies, and meta-analysis of RCTs forgastrointestinal bleeding and NSAIDs andantiplatelet drugs.

5. Meta-analysis of RCTs for assessingthe risk of myocardial infarction and deathwith inhaled anticholinergic drugs.

Special attention must also be paid todrug utilization patterns; not only howmuch medicine is consumed, but how it isconsumed in real practice.

Reporting and publication of adversedrug reactions is a responsibility ofregulatory agencies. However, adverseeffects of medicines are experienced firsthand in clinical practice, and thereforepharmacovigilance is mainly a matter ofcollaboration and communication withinthe health system and health care pro-vider organizations and among all otherpartners of the health care system.

The Spanish pharmacovigilance systemwas conceived not only for regulatorypurposes but also as part of a broadercommunication strategy between theuniversity and prescribers.

Counterfeit andsubstandard medicines*The ISoP session Counterfeit Medicinesand Illegitimate Drugs tackled the grow-ing problem of counterfeit and substand-ard medicines.

The World Health Organization defines acounterfeit medicine as “a medicine whichis deliberately and fraudulently misla-belled with respect to identity and/orsource. Counterfeiting can apply to bothbranded and generic products andcounterfeit products may include productswith the correct ingredients or with thewrong ingredients, without active ingredi-ents, with insufficient active ingredients orwith fake packaging.”

Although an accurate estimate of counter-feit medicines available in markets isdifficult to obtain, the number may bemore than 10% of the global medicinesmarket, with a probable worth estimate of75 billion dollars in 2010. Medicines

* Session chaired and presented by LuisAlesso, Córdoba National University andMaria José Sánchez, Argentine Institute ofMedicines (INaMe), National Administration ofFood, Drug and Medical Technology(ANMAT), Argentina.


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counterfeiting affects individuals fromboth developing and developed countries.In Latin America, the extent of this prob-lem is still unknown and weak bordersbetween countries make appropriatecontrols even more difficult to establish.

Developing countries are more affectedby this threat because they have, ingeneral, weaker medicines regulatorysystems, scarcity and/or erratic supply ofbasic medicines, unregulated marketsand unaffordable prices. An estimated25% of the medicines consumed indeveloping countries are believed to becounterfeit; and in some underdevelopedcountries, the figure is thought to be ashigh as 50%.

Because it is a global, serious publichealth problem, medicines counterfeitingshould be considered as a crime and notonly as an intellectual property issue orcommercial fraud. As a potential cause ofserious risk to health which may be life-threatening, the battle against medicinescounterfeiting demands the involvementof all social and economic actors from thepublic and private sectors.

Counterfeit medicines are part of abroader phenomenon of substandardproducts which can threaten the popula-tion’s health. Altogether, counterfeit,adulterated medicines, stolen medicinalproducts, smuggled medicines, unregis-tered medicines, and expired medicinesare generally considered “illegitimatemedicines”. The definition illegitimatemedicines is a legal term, rather than onereferring to the quality of a product. Allillegitimate medicines are considered assubstandard, even when they may havebeen legally and properly produced (i.e.stolen medicines), because it is impossi-ble to know if they have been correctlystored and transported. It should benoted that some legitimate medicines canalso be considered substandard if testsprove that they do not have the appropri-

ate strength, pH, excipients or otherchemical properties.

In countries where governments supplymedicines for the treatment of specificdiseases (such as haemophilia andAIDS), some high-priced medicines areprovided free of charge to patients by thestate health insurance systems. Theseproducts may sometimes be sold bypatients to wholesalers and then reintro-duced into the market (a process called“revolving”).

During this ISoP session, an urgent needwas identified for exhaustive and manda-tory guidance for medicines purchase, aswell as national laws punishing drugcounterfeiting or adulteration and market-ing of illegitimate, counterfeit and adulter-ated medicinal products.

Counterfeit and illegitimate medicines:a view from the Americas*

The WHO/Pan American Health Organi-zation (PAHO) states that a counterfeitproduct cannot be considered a medicalproduct because it has been manufac-tured and sold by withholding its realorigin, evading regulatory controls with anarbitrary and, above all, unpredictablecomposition. Social and political condi-tions which help medicines counterfeitingto flourish include:

• Inadequate legislation.

• Weak regulatory oversight and enforce-ment.

• Inadequate cooperation between drugregulators, police, customs, prosecu-tors, health professionals, manufactur-ers, wholesalers, and retailers.

* Presentation made by José Luis Castro, PanAmerican Health Organization/World HealthOrganization, Argentina.


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• Trading through several intermediaries/brokers, wholesalers and the distribu-tion chain.

• Unregulated trade, Internet-based sales,transit through free zones.

• No or limited patient access to reliablehealth care and medicines supply.

• Lack of control over medicines destinedfor export.

• The high price of legal medicines.

• Illiteracy and poverty and lack of infor-mation or lack of access to information.

WHO/PAHO have undertaken manyactivities to help prevent and fight medi-cines counterfeiting: they support coun-tries with technical advice to establishpharmaceutical policies and regulationsand by developing guidelines for qualityassurance, good manufacturing practices,purchasing, and distribution of medicines.WHO/PAHO coordinates the InternationalMedical Products Anti-CounterfeitingTaskforce (IMPACT) launched to gatherall actors in the fight against counterfeit-ing and target global action against thispublic health threat.

Adequate information exchange betweengovernments and adviser groups is apriority and PAHO has set up an externalquality control programme for nationallaboratories in the Americas and hasdeveloped a regional medicines prequali-fication system which is now beingharmonized with the WHO MedicinesPrequalification Programme.

Pan American Network forDrug Regulation HarmonizationAnti-Counterfeiting Group

The Pan American Network for DrugRegulation Harmonization (PANDRH)Anti-Counterfeiting Group was created topromote the development of strategies toprevent and fight counterfeit medicalproducts in the Americas. Representa-

tives of national regulatory agencies fromArgentina, Brazil, Canada, Colombia,Dominican Republic, Paraguay, St. Lucia,and USA participate in this Group. Thepharmaceutical industry is represented bythe Federación Latinoamericana de laIndustria Farmacéutica (FIFARMA) andthe Asociación Latinoamericana deindustrias Farmacéuticas (ALIFAR).

The PANDRH Anti-Counterfeiting Groupis working on defining indicators forcounterfeit medicines and on a proposal,with a standardized procedure, for struc-tural strengthening of national regulatoryauthorities (NRAs) through a specificexecutive unit. It is also working on aroadmap which would allow counterfeitmedicines structured follow-up and onupdating diagnostic studies and recom-mendations for industry, NRAs andgovernments in general.

In September 2007, with support from theMinistry of Health in Panama, the PAN-DRH Anti-Counterfeiting Group held aworkshop to establish national andmultisectorial task forces and launchcoordinated action against counterfeiting.The Group is also working to define andestablish a network of vital focal points ofcommunication within and among coun-tries and to draft an inspection guideline.This document was presented at thePANDRH Meeting in Buenos Aires inNovember 2007.

Argentine National InvestigationProgramme on Illegitimate Medicines*

In Argentina, the first case of a counterfeitmedicine (quinine sulfate) was docu-mented in 1858 but it was not until 1997that the National Institute of MedicinesProgramme for the Investigation ofIllegitimate Medicines was created. Theprimary aim of the Programme is tocounteract the commerce of counterfeit

* Presentation made by Maria José Sánchez,Argentina


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drugs in order to guarantee quality,effectiveness and security of pharmaceu-tical products. It acts in joint action withthe National Administration for Medicines,Food and Medical Technology (ANMAT),government prosecutors and the FederalPolice. The pharmaceutical Industry andAcademia also provide valuable collabo-ration.

The Programme is based on a strictcontrol of the legal medicines marketingchain: it covers community and hospitalpharmacies, wholesalers, distributors,and both private and public health-careinstitutions. The methodology is primarilybased on:

• Visual inspection of pharmaceuticalproducts.

• Request for documents proving productpurchase.

• Medicines sampling throughout thenational distribution chain.

The analysis of products discovered atsites manufacturing counterfeit medicinesshowed that there was no uniformity inthe characteristics of batches, and thequantity of active ingredient variedbetween zero and 200% of the amountstated on the label. Both primary andsecondary packaging were, in general,different from the original. Holograms alsodemonstrated differences with the origi-nals.

All 12 inspectors of the Argentine Pro-gramme for the Investigation of Illegiti-mate Medicines are pharmacists and aresupported by technical, administrativeand legal staff. Since Argentina is afederal country, inspectors work in col-laboration with the authorities from 23provinces. In the 1990s, the main prob-lem involved counterfeiting of inexpensivemedicines with a high consumption rate.Nowadays, counterfeit or adulteratedproducts are mainly high priced medi-

cines for specific diseases (antiretrovirals,anticancer drugs, products for haemo-philia).

In Argentina, there is no law specificallypunishing medicines counterfeiting ormarketing of illegitimate medicines andthe current legislation considers trade insubstandard medicines as a commercialoffence. Currently, legislation has beenproposed against medicines counterfeit-ing and adulteration and, also, a proposalhas been made setting out the adminis-trative requirements for purchase ofmedicines.

Administrative traceability require-ments in medicines purchasing*

In Argentina, the only legislation coveringpurchasing by public health administrationsystems and public hospitals refers to thesupplier’s fiscal status. There is no specificlegal rule for medicines purchasing.

In December 2004, at least 19 patientssuffered iron poisoning and one of themdied following the administration of acounterfeit iron product in a public hospi-tal in Argentina. This product, containingiron citrate instead of iron sorbitex, had3.5 times more iron than the brandedproduct. The switch in active ingredientwas apparently made to obtain the samecolour as the original. The product waspurchased from a third-party wholesalebroker who had no links with the manu-facturer. The wholesaler was prosecutedand the Argentine Medicines Agency,ANMAT, immediately published a list ofrecommendations to avoid the purchaseof counterfeit products. But in May 2005,a pregnant woman suffered serious liverfailure and premature labour because ofthe administration of the same counterfeitproduct in the same public hospital.

Presentation made by Rodolfo Rodriguez,Córdoba Provincial Administration HealthInsurance (AProSS), Córdoba, Argentina.


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Before and since then, many otherillegitimate products have been foundboth in public and private health-careinstitutions, some of them with a soundreputation. In 2008, ANMAT published,among others, 15 legal resolutionswithdrawing highly priced products basedon laboratory, health care professional orpatient reports (see table above).

Marketing authorization holders (MAH) ofbranded marks add identification devices

and traceability systems. However, thefight against the sale of illegitimatemedicines also needs concurrent ap-proaches from all partners involved.Health insurance systems have a key rolein avoiding counterfeit or illegitimatemedicines purchasing.

According to international and Nationalrecommendations, Córdoba ProvinceHealth Insurance Administration(AProSS) has established a mandatory

• Rituximab: A physician reported adulteration in a vial; no active principle was foundat all.

• Riluzol: Following an adverse drug reaction report. Packaging was adulterated.

• Two rHu-eritropoyetin products: Adulterated products were found in a dialysiscentre during an INaMe inspection.

• Epoetin alfa recombinant: Following a physician’s report; adulterated packaging.

• Erlotinib: Following a patient report. Adulterated packaging and blister pack withcapsules instead of coated tablets. Capsules did contain erlotinib 100 mg.

• Rituximab: A wholesaler reported adulteration in packaging. Reported products hadnot been legally imported and belonged to batches marketed in other Latin-Ameri-can countries.

• Trastuzumab: A nurse reported a different color in the vial content. Both packagingand vial had been adulterated; no active principle was found at all.

• Interferon Beta 1-A, Rituximab, parenteral Vitamins: Reported products had notbeen imported and belonged to batches marketed in other Latin-American coun-tries (Interferon and rituximab) and Spain (Cervenit®).

• Six batches of Concentrated VIII Factor, manufactured in Germany. Followingpatients’ reports (with samples). Samples showed adulteration (pierced stopper,manipulated top, content different from the original in quantity) and fungal develop-ment when reconstituted. Original ampoules had been re-utilized.

• Efavirenz: Blisters did not show the expiration date, with ink traces saying “not forsale”. Blisters are believed to come from AIDS programmes providing free medi-cines (community pharmacy).

• One batch of ritonavir, identified in a community pharmacy because of adulteratedpackaging.

* www.anmat.gov.ar: National Administration of Food, Drugs and Medical Technology (ANMAT),Argentine Health Minister, legal rules N˚ 193/08, 1185/08, 1416/08, 1943/08, 2599/08, 2831/08,3307/08, 3351/08, 4125/08, 4143/08, 4244/08, 4543/08, 5647/08, 5650/08, 6110/08

Table: illegitimate medicines identified in Argentina in 2008*


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list of requirements for wholesalers. Itdemands wholesalers to supply proof ofmarketing authorization, wholesalerlicensure, inspection results, and a list ofany disciplinary action against the whole-saler. Packing lists and invoices are alsorequested in order to ensure legitimacy ofmedicines. This is an inexpensive andeffective traceability system to avoid thepurchase of adulterated or illegitimatemedicines.

Industry commitment in the battleagainst fraud and counterfeiting*

For many years, medicines manufactur-ers’ associations have participated inWHO and PAHO Working Groups againstmedicines counterfeiting, and the phar-maceutical industry is actively engaged inthis battle worldwide. The ArgentineNational Investigation Programme onIllegitimate medicines has been sup-ported by manufacturers’ associationsand significant outcomes in terms ofdeactivation of clandestine laboratories,impounding medicines and prosecutingindividuals have been achieved.

Argentine medicines manufacturers haveidentified a need to improve proceduresfor the public acquisition of medicines,and to identify more funds for the controland monitoring of pharmaceutical whole-salers and pharmacies in provinces. Theoutstanding role of the PANDRH Networkand PAHO in promoting preventiveeffective action, which are being under-

taken and executed by national regula-tory authorities in the region, especiallyANMAT (Argentina), ANVISA (Brazil),INVIMA (Colombia) and COFEPRIS(Mexico) are recognized.

With regard to measures to preventcounterfeiting and illegal trade of medi-cines, a stricter authorization process formarketing and approval of facilities andregular audits along the commercializa-tion chain (manufacturing laboratories,pharmaceutical wholesalers and distribu-tion companies, pharmacies and hospi-tals and health institutions) are essential.An accurate system of medicines trace-ability and legal rules and procedures toremove manufacturing machines andequipment is also needed. In the searchand detection of illegal medicines inunauthorized facilities, it is necessary tocollaborate jointly and synchronizeactions among the health authorities,police and judicial system.

Manufacturers are involved in intensifyingthe communication network and providingtraining to the highest possible number ofregulatory agencies in the region. Manu-facturers support and are committed toactions of vigilance and control of medi-cines marketing, the distribution chain,and of unauthorized marketing premises/facilities. It is also essential to improvethe education of patients and consumersand to pass clear and strict laws andregulations in order to track down andsanction this crime against public health.

* Presented by Miguel Maito, Cilfa, Industrial Chamber of Argentine Pharmaceutical Labora-tories.


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Access to Medicines

Better medicines forchildren: the way forwardEvery second year, the World HealthOrganization (WHO) convenes theInternational Conference of Drug Regula-tory Authorities (ICDRA). The ICDRAsprovide drug regulatory authorities with aregulators-only forum to meet and dis-cuss ways to strengthen collaboration.ICDRA pre-meetings are organized todiscuss selected topics of interest linkedto regulatory affairs for which participationof regulators and other interested stake-holders gives added value.

The theme of the two day pre-meetinglinked to this year’s 13th ICDRA in Berne,14-15 September 2008, was “BetterMedicines for Children: the way forward”.The meeting was unique in being the firsttime that regulators, industry, clinicians,civil society and academics worldwidewere invited to meet and discuss chal-lenges and seek solutions to ensuringbetter access to medicines for children.The meeting involved more than 240participants from 75 countries.

Presentations were given by members ofacademia, industry and regulatory agen-cies. They offered perspectives on issuesinvolving the safety, quality and dosing ofmedicines for children, and the ethicalchallenges of conducting trials, particu-larly in children of the developing world.The conference was divided overall intotwo tracks with presentations focusing onmedicines, and biologicals and vaccines.

Discussion included strategies for devel-oping fixed dose combinations for chil-dren, alternate dosage forms for children(both liquid and non-liquid formulations).

Additionally, it identified gaps and chal-lenges in paediatric research, gave anupdate on clinical trials in neonates, andpresented issues from the WHO Medi-cines Prequalification Programme. Otherpresentations focused on challenges inthe development, regulation and supplyof vaccines and biologicals, as well asissues surrounding safety and pharmaco-vigilance of vaccines in children.

A summary of the main themes to emergefrom the presentations is outlined below.A series of recommendations that havearisen as a result of these discussions ispresented on page 257. Detailed informa-tion on each of the presentations can beaccessed through the following link: http://www.who.int/medicines/

The current situation

• The global mortality rate in childrenunder five years remains inequitableand a significant problem.

• Children’s medicines are an identifiedpriority, as stated in the World HealthAssembly Resolution on Better Medi-cines for Children (WHA60.20), and asexpressed in the Millennium Develop-ment Goals.

• Advances in knowledge and technologyhave led to:

- better understanding of paediatricgrowth and development and theassociated changes in paediatricphysiology;

- methodological advances in clinicaltrials and population health, includingadaptive and bridging trials;

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- pharmacokinetic modelling techniques; and

- databases of information on medicines safety.

• Positive achievements and develop-ments have been made in regulatorystructures with incentives to promotethe development of medicines forchildren, with some additional advancesin innovative technology for age appro-priate dosage forms.

• Although clinical evidence on how bestto use medicines effectively and safelyin children has started to be collated,many gaps in knowledge, particularlyabout the safety of medicines in childrenand optimal doses remain.

For vaccines and biological products

• Many potential future vaccines forpriority diseases are currently in devel-opment. However, despite advances inthe field, barriers to research anddevelopment — including increasedtechnological complexity and safetyrequirements, high clinical researchcosts, and ongoing public concerns overvaccine safety — mean that vaccinesstill occupy only a small portion of thepharmaceutical market.

• Post marketing efficacy data and vac-cine pharmacovigilance is an importantaspect of vaccine development. Ap-proaches to post marketing surveillanceinclude passive (vaccine adverse eventreporting system) and active ap-proaches (phase IV studies, FDAsentinel initiative and CDC’s VaccineSafety Datalink), as well as the use ofelectronic databases. Advantages andlimitations are present with all methods.

• Forty per cent of venomous snake bitevictims are children and there is ashortage of appropriate antivenomsthroughout world. Improving the quality,quantity and distribution of antivenoms,

through support of manufacturers,preclinical and clinical testing, commu-nity education, and training of medicalpersonnel is essential.

• Integrating immunization and other childhealth interventions in a campaign styledelivery such as child health days forhigh-priority health services has provensuccessful if adequately supported bylogistics, distribution, storage systems,supply chain management, tracking andmonitoring of supplies.

First stepsThe following actions were identified asessential in order to ensure availabilityand affordable access to appropriatemedicines for children:

• Strengthening political commitment toensure that childhood survival remainsa high topic of priority on the agenda.

• Movement towards primary health care,up-scaling high impact interventions atcommunity level, strengthening ofhealth systems, and continued advo-cacy.

• A global collaborative stakeholderapproach – to include patients andcarers, health professionals, academicsand manufacturers, as well as regula-tors and policy makers is needed.

• Optimal age-appropriate dosage formsshould be developed as a priority.

• Better quality research involving chil-dren is required. Capacity building tostrengthen ethical and high qualityclinical trials globally and increasing thecapacity and capability of ethics com-mittees to review and monitor clinicaltrials is essential. Global standards forclinical trials in children need to beagreed and implemented.

• Unnecessary duplication of researchshould be avoided. Existing literature,including clinical trials and pharmaco-kinetic studies in relevant populations

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needs to be collated and synthesized.Methods for ensuring transparency ofinformation about existing clinical trialsand licensed products need to bedeveloped and implemented globally.

• Strengthening of manufacturing capacityand health systems infrastructure,particularly for vaccines is needed.

• Global strategies need to be developedto promote efficient and effective regis-tration/licensing of medicine for children,with due consideration of risks andbenefits.

• Methods to ensure increased safety ofmedicines for children need to bedeveloped, in particular through moni-toring of adverse drug reactions.

In conclusion, the pre-ICDRA meetingdedicated to children’s medicines hassuccessfully achieved its objectives andthe recommendations will lead to follow-up activities. It is expected that a prog-ress report will be presented to the 14th

ICDRA to be held in Singapore in 2010.

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Safety and Efficacy IssuesErlotinib: hepatic failureand hepatorenal syndromeUnited States of America — Healthcareprofessionals have been informed ofcases of hepatic failure and hepatorenalsyndrome, including fatalities, reportedduring use of erlotinib (Tarceva®), par-ticularly in patients with baseline hepaticimpairment. Patients with hepatic impair-ment receiving erlotinib should be closelymonitored during therapy and the productshould be used with extra caution inpatients with total bilirubin >3x ULN.

Dosing should be interrupted or discontin-ued if changes in liver function aresevere, such as doubling of total bilirubinand/or tripling of transaminases in thesetting of pretreatment values outside thenormal range. New information from apharmacokinetic study in patients withmoderate hepatic impairment associatedwith significant liver tumour burden hasbeen provided in the revised prescribinginformation.

Reference: Communication from OSI Phar-maceuticals and Genentech. September 2008and information from FDA, 14 November2008, at http://www.fda. gov/medwatch

Botulinum toxin type Aand distant toxin spreadCanada — Botulinum toxin health prod-ucts have recently been the subject ofsafety notices because of their suspectedassociation with the potential spread ofthe toxin to sites in the body distant fromthe sites of administration (distant orsystemic toxin spread) (1, 2). In Canada,botulinum toxin type A is marketed asBotox® and Botox Cosmetic®. Botox® isindicated for the treatment of cervical

dystonia, blepharospasm associated withdystonia, strabismus, dynamic equinusdue to spasticity in paediatric cerebralpalsy patients, hyperhidrosis of the axillaand focal spasticity (3). Botox Cosmetic®is indicated for the treatment of facialwrinkling (4).

Toxin spread may occur locally, whenbotulinum toxin disperses to surroundingtissues, as in the case of dysphagiareported with the use of botulinum toxintype A in patients with cervical dystonia(3). In addition, adverse reactions (ARs)suggestive of botulism have also beenreported and may occur as the result ofsystemic toxin spread beyond the site ofinjection (2). Symptoms of botulism caninclude muscle weakness or paralysis,dysarthria, dysphagia and dysphonia (5).Serious complications of botulism includerespiratory depression and dysphagiawhich may lead to aspiration pneumonia.These manifestations may be fatal ifuntreated (5,6).

Extracted from the Canadian Adverse Reac-tions Newsletter, Volume 18, Issue 4, October2008.

References

1. Health Canada reviewing issue of distanttoxin spread potentially associated withBotox® and Botox Cosmetic®. Ottawa: HealthCanada; 20 February 2008.

2. Early communication about an ongoingsafety review - Botox and Botox Cosmetic(botulinum toxin type A) and Myobloc (botuli-num toxin type B). Rockville (MD): US Foodand Drug Administration, 2008.

3. Botox (botulinum toxin type A for injection)[product monograph]. Markham (ON): AllerganInc.; 2007.

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4. Botox Cosmetic (botulinum toxin type A forinjection) [product monograph]. Markham(ON): Allergan Inc.; 2007.

5. Brook I. Botulism: the challenge of diagno-sis and treatment. Rev Neurol Dis 2006;3(4):182–9.

6. Palmer JL, Metheny NA. Preventingaspiration pneumonia in older adults withdysphagia. Am J Nurs 2008;108(2):40–8.

Safety review ofbisphosphonatesUnited States of America — On 1October 2007, the Food and Drug Admin-istration (FDA) announced that it wasreviewing safety data on a potentialincreased risk for atrial fibrillation inpatients treated with a bisphosphonatedrug (1).

Bisphosphonates are a class of drugsused primarily to increase bone mass andreduce the risk for fracture in patients withosteoporosis. Bisphosphonates are alsoused to slow bone turnover in patientswith Paget disease of the bone and totreat bone metastases and lower elevatedlevels of blood calcium in patients withcancer. Bisphosphonate products include:alendronate (Fosamax®, Fosamax PlusD®), etidronate (Didronel®), ibandronate(Boniva®), pamidronate (Aredia®),risedronate (Actonel®, Actonel W/Cal-cium®), tiludronate (Skelid®), andzoledronic acid (Reclast®, Zometa®).

An article and an accompanying letter tothe editor in the 3 May 2007 issue of TheNew England Journal of Medicine de-scribed increased rates of serious atrialfibrillation in two different studies ofwomen ages 65 to 89 years old withosteoporosis treated with the bisphos-phonates, Reclast® and Fosamax®. Datashowed an increased risk of serious atrialfibrillation and this risk was reflected inthe Reclast® labelling.

On 1 October 2007, FDA began request-ing placebo-controlled clinical trial infor-mation from the sponsors of alendronate,ibandronate, risedronate, and zoledronicacid in order to explore the potential riskfor atrial fibrillation in male and femalepatients treated with these bisphos-phonate drugs.

The data submitted by the four sponsorsincluded data on 19 687 bisphosphonate-treated patients and 18 358 placebo-treated patients who were followed for 6months to 3 years. The occurrence ofatrial fibrillation was rare within eachstudy, with most studies containing 2 orfewer events. The absolute difference inevent rates between each of the bisphos-phonate and placebo arms varied from0–3 per 1000.

One large study of zoledronic acidshowed a statistically significant increasein the rate of serious atrial fibrillationevents. However, across all studies, noclear association between overall bis-phosphonate exposure and the rate ofserious or non-serious atrial fibrillationwas observed. Increasing dose or dura-tion of bisphosphonate therapy was alsonot associated with an increased rate ofatrial fibrillation.

References:

1. http://www.fda.gov/cder/drug/early_comm/bisphosphonates.htm

2. FDA Information at www.fda.gov/medwatch/12 November 2008

Ergot-derived dopamineagonists: fibrotic reactionsUnited Kingdom/European Union —The European Medicines Agency (EMEA)has recommended new warnings andcontraindications for ergot-deriveddopamine agonists as a result of the riskof fibrosis, particularly cardiac fibrosis,associated with chronic use. The risk of

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cardiac fibrosis is higher with cabergolineand pergolide than with the other ergot-derived dopamine agonists. Cabergoline,pergolide, and bromocriptine are indi-cated for the treatment of Parkinsondisease.

Cabergoline (brand leader Dostinex®) isused in hyperprolactinaemia. Bromo-criptine (brand leader Parlodel®) isindicated for chronic endocrine disorderssuch as hyperprolactinaemia and ac-romegaly. This new advice applies only totreatment of chronic endocrine disorderswith these agents — it does not apply tothe inhibition of lactation.

Cabergoline and bromocriptine

• Exclude cardiac valvulopathy as deter-mined by echocardiography beforetreatment.

• Monitor patients for signs or symptomsof pleuropulmonary disease (e.g., dys-pnoea, shortness of breath, persistentcough, or chest pain) and retroperito-neal disorders during treatment. Renalinsufficiency or ureteral or abdominalvascular obstruction might occur, withpain in the loin or flank and leg oedema.Abdominal masses or tenderness couldsuggest retroperitoneal fibrosis.

Cabergoline

• Monitor patients for signs of cardiacfibrosis during treatment.

• Echocardiography should be donewithin 3–6 months of starting treatmentand subsequently at 6–12-monthintervals.

• Stop treatment if echocardiographyshows new or worsened valvular regur-gitation, valvular restriction, or valveleaflet thickening.

• Pregnancy should be excluded beforeadministration of cabergoline.

• Women who are planning pregnancyshould stop taking cabergoline onemonth before they try to conceive.

References

1. MHRA Drug Safety Update. Volume 2,Issue 3, October 2008 at http://www.mhra.gov.uk/mhra/drugsafetyupdate.

2. http://www.emea.europa.eu/pdfs/human/press/pr/32239508en.pdf.

3. Zanettini R et al. Valvular Heart Diseaseand the Use of Dopamine Agonists for Parkin-son’s Disease. N Engl J Med 2007; 356–39.

4. Schade R et al. Dopamine Agonists and theRisk of Cardiac-Valve Regurgitation. N Engl JMed, 2007; 356–29.

Use of antibioticsin premature labourUnited Kingdom —In the ORACLEChildren Study (a 7-year follow-up of alarge randomized, placebo controlledtrial to investigate the effects of erythro-mycin and co-amoxiclav in prematurelabour) parents reported small increasesin the number of children with mildfunctional impairment or cerebral palsyborn to mothers whose membranes wereintact and who had received antibiotics.

In women who presented with spontane-ous premature labour without rupture ofthe membranes, prophylactic antibioticshad neither beneficial nor harmful short-term effects for babies.

Advice for healthcare professionals

• This research was conducted in a veryspecific group of women and so theresults do not mean that antibiotics aregenerally unsafe for use in pregnancy.Untreated infections can be dangerousand potentially life threatening forpregnant women and their unbornbabies, and antibiotics should continueto be prescribed in line with currentguidance and the product licence.

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• The study confirms existing practice thatantibiotics should not be given routinelyto women who are in premature labourwith intact membranes and who haveno obvious infection.

• These results were unexpected and themechanism by which this reportedassociation occurred in women withintact membranes is unclear, particularlyas no increase in functional impairmentor cerebral palsy was reported in thechildren of mothers who received thesame antibiotics but whose membraneshad ruptured. Additional research isrequired to shed light on these findings.

References

1. MHRA Drug Safety Update. Volume 2,Issue 3, October 2008 at http://www.mhra.gov.uk/mhra/drugsafetyupdate.

2. Oracle Children Study website athttp://www.le.ac.uk/cm/rs/oracle/

Intravenous immune globulin:transfusion-related lunginjuryCanada — Transfusion-related acutelung injury (TRALI) is a clinical syndromethat presents as acute hypoxaemia andnoncardiogenic pulmonary oedemaduring or within 6 hours after bloodtransfusion (1, 2). TRALI is an importantcause of transfusion-associated death,even though it is probably still under-diagnosed and underreported (2). Therehave been few literature reports of TRALIin patients administered intravenousimmune globulin (IVIG) (3). The Canadianproduct monograph for Gamunex®(human IVIG 10%) recommends that IVIGrecipients be monitored for pulmonaryadverse reactions (4).

Health Canada has received a report of a38-year-old man who had receivedGamunex® for the treatment of strepto-coccal thoracic cellulitis, which had also

required débridement. Subsequently, thepatient experienced hypotension anddyspnoea and the infusion was stopped.The results of a chest radiograph werecompatible with a diagnosis of TRALI.The patient was transferred to the inten-sive care unit, where he required intuba-tion. The result of an anti-humanleukocyte antigen test was pending at thetime of reporting.


References

1. Kleinman S, Caulfield T, Chan P et al.Toward an understanding of transfusion-related acute lung injury: statement of aconsensus panel. Transfusion 2004;44(12):1774–89.

2. Toy P, Popovsky MA, Abraham E et al.Transfusion-related acute lung injury: defini-tion and review. Crit Care Med 2005;33(4):721–6.

3. Rizk A, Gorson KC, Kenney L, et al.Transfusion-related acute lung injury after theinfusion of IVIG. Transfusion 2001; 41(2):264–8.

4. Gamunex® (immune globulin intravenoushuman 10%) [product monograph]. Toronto:Bayer Inc; 2005.

Alemtuzumab: infection-related deathsCanada — Health Canada has informedhealth-care professionals of importantsafety information regarding the use ofalemtuzumab (Mabcampath®) as consoli-dation therapy following combinationtreatment with other chemotherapeutic orbiologic agents.

Alemtuzumab is a recombinant human-ized monoclonal antibody and is currentlyauthorized for the treatment of B-cellchronic lymphocytic leukaemia (B-CLL) in

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patients treated with alkylating agentsand who have failed fludarabine therapy.Alemtuzumab is not authorized for use asconsolidation therapy.

Preliminary safety information from theCALGB10101 clinical trial conducted inthe United States, reported 6infection-related deaths out of 51 patients whoreceived 3 chemotherapeutic agentsfollowed by consolidation therapy withMabcampath®). The potential for anincreased risk of infection-related compli-cations may exist following treatment withmultiple chemotherapeutic or biologicalagents.

The phase II CALGB10101 clinical trialreported six infection-related deaths outof 51 patients who received the threechemotherapeutic agents. The six fatalinfections were reported as: Viral menin-gitis, Listeria meningitis, Legionella pneu-monia, cytomegalovirus infection, Pneu-mocystis jiroveci pneumonia, and EpsteinBarr virus associated lympho-proliferativedisorder.

Reference: Health Canada. MedEffect Alert,18 November 2008 at http://www.hc-sc.gc.ca/dhp-mps/medeff/advisories-avis/prof/_2008/mabcampath_nth-aah-eng.php

Theophylline: narrowtherapeutic index andpotential for misuseUnited Kingdom — Several productsthat contain theophylline or aminophyllineare available as pharmacy medicines thatcan be dispensed without a prescription.Theophylline—a bronchodilator—inter-acts with several medicines and has anarrow margin of safety between thera-peutic and toxic doses. Therefore, com-munity pharmacists are reminded tocheck whether patients who buy theo-phylline without a prescription are alsotaking any other medicines (includingtheophylline on prescription).

Reference: MHRA Drug Safety Update.Volume 2, Issue 3, October 2008 at http://www.mhra.gov.uk/mhra/drugsafetyupdate.

Cesium chloride andventricular arrhythmiasCanada — Nonradioactive cesiumchloride (CsCl) is used orally as a naturalhealth product. Although not authorizedfor therapeutic use in Canada, unauthor-ized cesium products are accessible forpurchase (e.g., on the Internet) and areused for the self-treatment of cancer. Asof 28 May 2008, Health Canada received3 reports of prolonged QT interval andventricular tachyarrhythmia suspected ofbeing associated with the oral use ofCsCl.

CsCl’s effects on cardiac rhythm havebeen demonstrated in animal studies,where it has been used to experimentallyinduce ventricular arrhythmias (3). Al-though the mechanism is not fully under-stood, CsCl is known to block a variety ofpotassium channels, including many ofthose involved in the cardiac actionpotential (4,5).


References

1. Lyon AW, Mayhew WJ. Cesium toxicity: acase of self-treatment by alternative therapygone awry. Ther Drug Monit 2003;25(1):114-6.

2. Pinter A, Dorian P, Newman D. Cesium-induced torsades de pointes. N Engl J Med2002;346(5):383-4.

3. Jones DL, Petrie JP, Li HG. Spontaneous,electrically, and cesium chloride inducedarrhythmia and afterdepolarizations in therapidly paced dog heart. Pacing Clin Electro-physiol 2001;24(4 pt 1):474-85.

4. Vyas H, Johnson K, Houlihan R, et al.Acquired long QT syndrome secondary tocesium chloride supplement. J Altern Comple-ment Med 2006;12(10):1011-4.

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5. Zhang S. Isolation and characterization ofIKr in cardiac myocytes by Cs+ permeation.Am J Physiol Heart Circ Physiol 2006;290(3):H1038-49.

Drug-induced hyponatraemiaAustralia — The Australian Adverse DrugReactions Committee (ADRAC) continuesto receive reports of hyponatraemia (1) inassociation with various medicines.Severe hyponatraemia is a potentiallydevastating condition that can developrapidly and without obvious prior symp-toms, particularly in the elderly. Oncesevere hyponatraemia develops, special-ist management is required to achieve afavourable outcome (2).

Since May 2005, ADRAC has received307 reports of hyponatraemia, several ofwhich also described syndrome of inap-propriate antidiuretic hormone secretion.227 (74%) of the reports implicate asingle drug as the suspected cause:mainly diuretics (126 reports) and antide-pressants (78 reports, 33 of which werewith an SSRI or SNRI).

Severe hyponatraemia, which can causesignificant and permanent neurologicalinjury or death (1), was documented in101 of the reports. Individual drugs mostcommonly associated with the severeform were hydrochlorothiazide, indapa-mide, carbamazepine, paroxetine, venla-faxine and sertraline.

Eighty of the 307 reports describe hypo-natraemia in association with more thanone agent; virtually all of these involvedthe combined use of a diuretic (hydro-chlorothiazide or indapamide) with anACE inhibitor or an angiotensin II receptorblocker or with an SSRI or SNRI. Thecombination of carbamazepine with anantihypertensive agent and a diuretic orwith an antidepressant was also de-scribed.

Older age is generally acknowledged tobe a risk factor for hyponatraemia. Two-thirds of the reports received since 2005describe patients aged over 70 years andover 70% involved women. Onset ofhyponatraemia occurred within the firstmonth in 74% of cases that provided thisinformation (median, 11 days).

The clinical presentation varied greatlybut the most commonly described disor-ders were: neurological (including convul-sions, postural hypotension, syncope,altered consciousness or coma, somno-lence, headache, ataxia, tremor, abnor-mal gait, visual disturbances and cerebraloedema), psychiatric (including confu-sion, delirium, agitation and hallucina-tions) and gastrointestinal (includinganorexia, nausea and vomiting).

This series of reports included two deathswhich were considered attributable tohyponatraemia.

Although a few reports described hy-ponatraemia as an incidental finding onroutine laboratory testing in asymptomaticpatients, there is evidence that even mildlevels of chronic hyponatraemia maycontribute to an increased rate of falls (3).In fact, nine falls were documented in thisseries of reports.

Extracted from the Australian Adverse DrugReactions Bulletin, Volume 27, Number 5,October 2008 at http//www.tga.gov.au/adr

References

1. Androgué HJ, Madias NE. Hyponatraemia.NEJM 2000; 342:1581–1589.

2. Douglas I. Hyponatraemia: why it matters,how it presents, how we can manage it.Cleveland Clinic J Med 2006; 73 (Suppl3):S4–S12.

3. Decaux G. Is asymptomatic hyponatraemiareally asymptomatic? Am J Med 2006; 119(7A):S79–S82.

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Slimming health productsadulterated with sibutramineSingapore — In recent months, thePharmacovigilance Branch of the HealthSciences Agency (HSA) has receivedthree reports of adverse drug reactions(ADR) associated with two slimminghealth products. On further investigation,the products namely, Relacore® andLami®, were found to containsibutramine, an undeclared western drugingredient used as an appetite suppres-sant in the management of obesity.

In June 2008, HSA issued a press state-ment to alert the public of the adulteratedproduct labelled as Relacore®. This wasprompted by two ADR reports involvingtwo adult patients (a male and female) intheir early twenties. Both patients admit-ted to purchasing the slimming productover the Internet from a Chinese website.The product was subsequently tested byHSA’s analytical laboratory and found tocontain 12.22 mg of sibutramine in eachcapsule.

The adulterated product labelled asRelacore® (which could be a counterfeitof the product sold in the USA) waspromoted as a dietary supplement.

Sibutramine-induced psychosisSibutramine is a noradrenaline andserotonin reuptake inhibitor indicated forweight loss. Commonly reported ADRsinclude insomnia, headache and anxiety.Tachycardia and hypertension have alsobeen reported in some patients.

Sibutramine is also known to exhibitsignificant dopamine reuptake inhibitionand some authors have postulated thatthis could possibly lead to the develop-ment of psychotic symptoms, especiallyin the event of an overdose (1). This isbased on the postulation that the dopa-mine reuptake inhibition could result inexcess dopamine in the synaptic clefts

and a consequent increased dopaminer-gic neurotransmission, in line with thedopamine hypothesis of psychosis (2, 3).

Be mindful of Internet purchaseof drug & health productsGiven the increasing trend of consumersturning to the Internet for purchase ofhealth products, health-care professionalsare encouraged to ask patients about theconsumption of such complementarymedicines or health supplements. Veryoften, patients may not regard theseproducts as medicines and not mentionthem to doctors. The information may beimportant to physicians in making adifferential diagnosis of the adverseevents experienced by patients.

References

1. J Psychosom Res. 2008 Jan;64(1): 107–9.

2. Am J Psychiatry. 2000 Dec; 157(12):2057–8.

3. J Clin Psychopharmacol. 2007 Jun;27(3):315–7.

4. Product safety alert. Slimming healthproducts (Relacore & Lami) adulterated withsibutramine. 1 December 2008. athttp://www.hsa.gov.sg

Phenytoin and fosphenytoin:serious skin reactionsUnited States of America — The Foodand Drug Administration (FDA) is investi-gating new preliminary data regarding apotential increased risk of serious skinreactions including Stevens Johnsonsyndrome (SJS) and toxic epidermalnecrolysis (TEN) from phenytoin(Dilantin®, Phenytek®) therapy in Asianpatients positive for a particular humanleukocyte antigen (HLA) allele, HLA-B*1502. This allele occurs almost exclu-sively in patients with ancestry acrossbroad areas of Asia, including HanChinese, Filipinos, Malaysians, SouthAsian Indians, and Thais. Because

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fosphenytoin is a prodrug and is con-verted to phenytoin after administration,any concern regarding this associationis also applicable to fosphenytoin(Cerebyx®). Phenytoin and fosphenytoinare used to control tonic-clonic (grandmal) and complex-partial seizures inepilepsy. A recent FDA information sheet(12/12/2007), described an increased riskof SJS/TEN with another anti-epilepticdrug, carbamazepine, in Asian ancestrypatients with the HLA-B*1502 allele.

The FDA is working to identify additionalinformation to evaluate the possible riskof SJS/TEN from phenytoin and fos-phenytoin in patients with HLA-B*1502.Until the evaluation is completed, health-care providers who are considering theuse of phenytoin or fosphenytoin shouldbe aware of the risks and benefits de-scribed in the current prescribing informa-tion for this drug.

Because this new data suggests apossible association between HLA-B*1502 and phenytoin or fosphenytoin-induced SJS/TEN, and because of theknown association between phenytoinand SJS/TEN, health-care providersshould consider avoiding phenytoin andfosphenytoin as alternatives for car-bamazepine in patients who test positivefor HLA-B*1502.

Reference: FDA Alert, 24 November 2008 atwww.fda.gov/medwatch/

Etoricoxib: hypertension risksUnited Kingdom/European Union —Health-care professionals have previouslybeen informed of the risk of hypertension-related adverse events associated withuse of etoricoxib, and of the contraindica-tion for use of etoricoxib in patients withhypertension whose blood pressure (BP)is not adequately controlled.

The European Medicines Agency (EMEA)has recently completed a review of the

benefits and risks of 90 mg etoricoxib(Arcoxia®) in the treatment of rheumatoidarthritis and in ankylosing spondylitis. Thereview included analyses from an obser-vational database (General PracticeResearch Database) study, which sug-gest that a substantial number of patientswith systolic BP >150mmHg and/ordiastolic BP >90mmHg have been initi-ated on etoricoxib despite earlier recom-mendations.

Prescribers are therefore asked to notethe following updated and strengthenedsafety recommendations:

• Etoricoxib should not be used in pa-tients with hypertension whose BP ispersistently elevated above 140/90mmHg and has not been adequatelycontrolled.

• In all patients starting treatment withetoricoxib, BP should be monitoredwithin two weeks after initiation, andperiodically thereafter.

Reference: Medicines and HealthcareProducts Regulatory Agency, September2008, at http://www.mhra.gov.uk/mhra.

Efalizumab: updated labellingUnited States of America — The Foodand Drug Administration (FDA) hasannounced labelling changes to highlightthe risks of life-threatening infections,including progressive multifocal leuko-encephalopathy (PML), with the use ofefalizumab (Raptiva ®). The FDA is alsorequiring the submission of a Risk Evalu-ation and Mitigation Strategy (REMS),which will include a Medication Guide forpatients and a timetable for assessmentof the REMS.

Efalizumab is a once-weekly injectionapproved for adults with moderate tosevere plaque psoriasis who are candi-dates for systemic (whole body) therapyor phototherapy to control their psoriasis.

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The FDA has received reports of seriousinfections leading to hospitalization anddeath. The Boxed Warning will highlightthe risk of bacterial sepsis, viral meningi-tis, invasive fungal disease, progressivemultifocal leukoencephalopathy and otheropportunistic infections.

Additionally, labelling will be updated toinclude data from juvenile animal studiesin mice (age equivalent to a 1–14 year oldhuman). These data indicate a potentialrisk for the permanent suppression of theimmune system with repeat administra-tion of efalizumab in this age group.Raptiva® is not approved for childrenunder 18 years of age.

Efalizumab works by suppressing theimmune system to reduce psoriasis flare-ups. However by suppressing the body’snatural defence system, it can alsoincrease the risk of serious infections andmalignancies in patients.

Patients identified to begin therapy withRaptiva® should have received all theirage-appropriate vaccinations beforestarting the drug. Vaccinations should notbe administered to patients takingRaptiva® because immunity to thevaccination virus may not be conferred.

Reference: FDA News, 16 October 2008 athttp://www.fda. gov/medwatch/

Oseltamivir: hepaticand skin disordersWorld Health Organization —Theantiviral agent oseltamivir is a selectiveinhibitor of influenza virus A and B neu-raminidase. It is indicated for the treat-ment and prophylaxis of influenza virusinfection types A and B although vaccina-tion is preferred for prophylaxis. It shouldbe commenced early in the course ofillness to achieve maximum benefit.

WHO has recommended its use fortreating avian influenza A (H5N1) (1).

In 2007 the Uppsala Monitoring Centre(UMC) undertook a review of the interna-tional adverse reaction reports attributedto oseltamivir in the WHO Global Indi-vidual Case Safety Report Database,Vigibase, as well as the relevant literatureand product information. This review didnot identify any clearly defined signals ofunsuspected serious adverse reactionsnot already in the product information orregulatory authority alerts, the latterconcerning neuropsychiatric reactions.

Reports of serious skin disordersReports of Stevens Johnson syndromeand toxic epidermal necrolysis have beenreported in Vigibase. These disorders arelisted under adverse reactions in productinformation for Tamiflu® (oseltamivir) butcausality has not been established (2).The Vigibase reports did not provideadditional information on causality.

Oseltamivir and hepatic disordersDespite the lack of a clear signal, reportsin Vigibase of serious hepatic disordersoccurring in association with oseltamiviruse were of concern. Reports of hepaticfailure, hepatic necrosis, hepato-renalsyndrome, jaundice and bilirubinaemiawere statistically disproportionate to thebackground data. Product information foroseltamivir (Tamiflu®) indicated thathepatitis and abnormal liver function testshad been identified during post-marketingexperience but that it was not possible toestablish a causal relationship withoseltamivir exposure.

Patient characteristicsAt the time of the review, Vigibase held770 reports for oseltamivir. There were 46non-duplicated reports of hepatic reac-tions including reports of hepatic failureand necrosis. Numbers of males andfemales affected were similar and the agerange was 18 to 88 years apart from twoinfants aged 12 months.

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Duration of oseltamivir useData provided in 25 reports showedpatterns of use, duration and reactiononset. Overall, oseltamivir was used forone to five days in 17 patients. Thelongest periods of use were 8 days and19 days. In 16 patients, onset of hepaticmanifestations occurred up to one weekafter oseltamivir was discontinued.Hepatic reactions to medicines usuallybecome evident between five and ninetydays after first exposure (3). For thisreason eight patients with onset one totwo days after first exposure and onepatient for whom onset was 120 daysafter exposure were excluded fromfurther analysis.

Dechallenge and rechallengeNo reports had valid dechallenge orrechallenge data.

Hepatic failure, hepatic necrosis andserious hepatocellular reactionsFive reports of hepatic failure and/orhepatic necrosis were identified thatcontained information on time to onsetfrom first exposure that was appropriatefor drug-induced hepatotoxicity. Oseltami-vir was the only medicine consideredsuspect in two of these reports. Therewere no reports of cholestatic hepatitisoccurring within five and ninety days ofoseltamivir use. There were five reportsof hepatocellular damage but these werepoorly documented in terms of exposureduration and other medicines were oftenco-suspect.

The original copies of eight reports ofjaundice and/or bilirubinaemia togetherwith elevated hepatic enzymes or hepati-tis were requested from the countries oforigin in order to identify serious hepato-cellular reactions that are likely to pro-gress to hepatic failure (4). Three suchreports were obtained. Two of thesepatients progressed to the hepatic failuregroup described above. The third patienthad not taken other suspect medicinesapart from low dose paracetamol.

Thus oseltamivir appeared to be the mostlikely causal medicine in two reports ofhepatic failure and one serious hepato-cellular reaction. It is of note that onepatient with hepatic failure had pre-existing renal failure and was taking themaximum recommended daily dose ofoseltamivir.

CausalityWhile oseltamivir appeared to be themost likely causal medicine in threereports of the most serious suspectedhepatic reactions, no details of investiga-tions for other potential causes, e.g., viralstudies, were provided. The other reportsof serious hepatic disorders could notreadily be assigned a causality classifica-tion. There are difficulties in assigningcausality to hepatic reports with oseltami-vir for the following reasons:

1. Prodromal symptoms of hepaticdisorders may mimic influenza symptoms.

2. Dechallenge data is largely unhelpfulas oseltamivir has usually been discontin-ued before the reaction is evident.

3. If patients have influenza symptomsthey are likely to take other medicinesthat can be hepatotoxic e.g., nonsteroidalanti-inflammatory medicines and para-cetamol.

4. A number of patients were also takingantibiotics as well as oseltamivir andmany of these are also potentially hepato-toxic.

Items (1) and (2) describe problems thatmake it almost impossible to assign a“probable” rather than “possible” causalityto hepatic reactions attributed to oseltami-vir. However, one advantage is that theusual short duration of oseltamivir treat-ment means that more serious injury maybe avoided in many cases, if the associa-tion is causal. Most of these difficultiesalso apply when assessing causality ofserious skin disorders following exposureto oseltamivir.

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Summary and recommendationsThere are reports of hepatic reactionsattributed to oseltamivir in Vigibase thatare more serious than those described inthe product information. Where identifi-able, the reports appeared to be predomi-nantly of hepatocellular disorders. Thereis no clear evidence of causality becauseit is difficult to discriminate influenza andearly symptoms of hepatic disease,because of common concurrent use ofother hepatotoxic medicines and becauseof the usual short duration of oseltamiviruse.

There is a strong argument for alternativeexplanations (described above) for thesereports, particularly the likelihood thatoseltamivir was used to treat prodromalsymptoms of hepatic disease rather thaninfluenza. However, given the potentialwidespread and unsupervised use ofoseltamivir a cautious approach shouldbe considered. This could involve:

1. Alerting patients to the possibility ofhepatic and serious skin reactions as wellas other documented adverse effects, atthe time of prescription.

2. Discontinuation of oseltamivir withhepatic function testing where patientsare slow to recover from presumedinfluenza, or relapse. Such testing wouldidentify both those patients whose

Spontaneous monitoring systems are useful in detecting signals of relatively rare, serious and unexpected adversedrug reactions. A signal is defined as "reported information on a possible causal relationship between an adverse eventand a drug, the relationship being unknown or incompletely documented previously. Usually, more than a single reportis required to generate a signal, depending upon the seriousness of the event and the quality of the information". Allsignals must be validated before any regulatory decision can be made.

hepatic disorder had not been diagnosedearlier because they were presumed tohave influenza and those who are devel-oping an adverse reaction to oseltamivir.Oseltamivir will not provide any benefit atthis stage and discontinuation may avoidmore serious outcomes.

3. Prompt discontinuation of oseltamivir ifa serious skin disorder occurs. Patientsshould also be advised to consult theirmedical attendant prior to taking thismedicine if they have renal impairment,as they may need to take a reduceddose.

References

1. World Health Organization: Clinical man-agement of human infection with avianinfluenza A (H5N1) virus, at http://www.who.int/csr/disease/avian_influenza/guidelines/Clinical Management07.pdf

2. Tamiflu capsules® (Roche). Physician’sDesk Reference. Revised January 2008.

3. Lee WM. Drug-induced hepatotoxicity. NEngl J Med 2003;349(5): 474-485.

4. Reuben A. Landmarks in Hepatology. Hy‘sLaw. Hepatology 2004;39(2): 574–578.

5. Report from Vigibase at the WHO Collabo-rating Centre for International Drug Monitor-ing, Uppsala, Sweden.

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Regulatory Action and NewsRimonabant: suspension ofmarketing authorizationUnited Kingdom/European Union —The European Medicines Agency (EMEA)has completed a review of rimonabant(Acomplia®), a treatment for obesity, afterconcerns about its psychiatric safety. Thereview has found that the benefits ofrimonabant do not outweigh the risks ofpsychiatric reactions in clinical use. Themarketing authorization for this medicinewill be suspended across the EuropeanUnion.

Prescribers should not issue any pre-scriptions for rimonabant and shouldreview the treatment of those who arecurrently taking this medicine.

Patients who are currently enrolled inclinical trials of rimonabant may wish tocontact the trial investigator for moreinformation.

References

1. MHRA Drug Alert, DDL/001/23Oct08 athttps://www.cas.dh.gov.uk/ and http://www.mhra.gov.uk/Safetyinformation/ [email protected]

2. EMEA Press Release, Doc. Ref. EMEA/CHMP/537777/2008. 23 October 2008. http://www.emea.europa.eu

Vaccines for use in the 2009influenza seasonWorld Health Organization — It isrecommended that vaccines for use in the2009 influenza season (southern hemi-sphere winter) contain the following:

• an A/Brisbane/59/2007 (H1N1)-like virus[A/South Dakota/6/2007 (an A/Brisbane/

59/2007-like virus) is a current vaccinevirus used in live attenuated vaccines].

• an A/Brisbane/10/2007 (H3N2)-like virus[A/Brisbane/10/2007 and A/Uruguay/716/2007 (an A/Brisbane/10/2007-likevirus) are current vaccine viruses].

• a B/Florida/4/2006-like virus [B/Florida/4/2006 and B/Brisbane/3/2007 (a B/Florida/4/2006-like virus) are currentvaccine viruses].

Vaccine viruses (including reassortants)and reagents for use in the laboratorystandardization of inactivated vaccinemay be obtained from: ImmunobiologySection, Office of Laboratory and Scien-tific Services, Therapeutic Goods Admin-istration, P.O. Box 100, Woden ACT,2606 Australia (fax: +61 2 6232 8564,web site: http://www.tga.gov.au); Divisionof Virology, National Institute for Biologi-cal Standards and Control, BlancheLane, South Mimms, Potters Bar, Hert-fordshire, EN6 3QG England (fax:+44 1707 641050, e-mail: [email protected], web site: http://www.nibsc.ac.uk/flu_site/index.html); or Division ofProduct Quality, Center for BiologicsEvaluation and Research, Food and DrugAdministration, 1401 Rockville Pike,Rockville, MD 20892, United States (fax:+1 301 480 9748).

Requests for reference strains for anti-genic analysis should be addressed tothe WHO Collaborating Centre for Refer-ence and Research on Influenza, 45Poplar Road, Parkville, Victoria 3052,Australia (fax: +61 3 9389 1881, web site:http://www.influenzacentre.org); the WHOCollaborating Centre for Reference andResearch on Influenza, National Instituteof Infectious Diseases, Gakuen 4-7-1,

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information about listed drugs and invitingconsumers to sit on all its committees. Aspart of this effort, the TGA says it will bepublishing consumer medicines informa-tion for all drugs and make this availableon the TGA web site.

The legislative amendments needed areexpected to be introduced in the autumn2009 sitting of the Australian Parliament.

References:

1. http://www.tga.gov.au/docs/html/tganews/news57/tganews57.htm

2. http://www.tga.gov.au/regreform/common.htm

3. http://www.6minutes.com.au/dirplus/images/6minutes/newspluspharma/13_11_2008.pdf

50th orphan medicinereceives positive opinionEuropean Union — Efforts in combatingrare diseases reached a new milestonethis October, with the 50th positiveopinion on an orphan medicine beingadopted by the EMEA’s Committee forMedicinal Products for Human Use(CHMP).

To date, a total of 569 medicines havebeen awarded orphan-designationstatus by the European Commission,based on recommendations of theEMEA’s Committee for Orphan MedicinalProducts (COMP).

Developed specifically for the diagnosis,treatment or prevention of rare diseases,these medicines have the potential tooffer relief to many thousands of Euro-pean citizens suffering from chronic andoften debilitating diseases who wouldotherwise have few treatment optionsavailable.

A listing of the 50 orphan medicines tohave received a positive CHMP opinion isavailable at http://www.emea.europa.eu/

Musashi-Murayama, Tokyo 208-0011,Japan (fax: +81 42 561 0812 or +81 42565 2498, web site: http://www.nih.go.jp/niid/index.html); the WHO CollaboratingCenter for Surveillance, Epidemiologyand Control of Influenza, Centers forDisease Control and Prevention, 1600Clifton Road, Mail Stop G16, Atlanta, GA30333, United States (fax: +1 404 6390080, web site: http://www.cdc. gov/flu/);or the WHO Collaborating Centre forReference and Research on Influenza,National Institute for Medical Research,The Ridgeway, Mill Hill, London NW71AA, England (fax: +44 208 906 4477,web site: http:/ www.nimr. mrc.ac.uk/wic).Updated epidemiological information isavailable on the WHO website at http://www.who.int/influenza.

Reference: Weekly Epidemiological Record(WER), 83(41) 365–372, 10 October 2008.

Australian Adverse DrugReaction Committee (ADRAC)to be replacedAustralia — The Australian AdverseDrug Reaction Committee (ADRAC) is tobe abolished and a new committee set upto take a more pro-active approach todrug safety and post-marketing surveil-lance of medicines.

ADRAC will be replaced by a MedicinesSafety Committee as part of a ‘whole-of-lifecycle’ approach to pharmacovigilancefor prescription medicines. The newapproach will also bring in drug audits,the appointment of an individual ‘drugmonitor’ to oversee safety of specificdrugs and a more flexible protocol thatwill allow drugs to be suspended ratherthan withdrawn or recalled when safetyissues arise.

In the reforms planned for next year, theTherapeutic Goods Administration (TGA)says it will also improve access to drugdata and increase transparency, with theregulatory body pledging to release more

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pdfs/human/comp/56357508en.pdf andOrphan drugs and rare diseases at aglance http://www.emea.europa.eu/pdfs/human/comp/29007207en.pdf

Reference: EMEA website http://www.emea.europa.eu/htms/human/orphans/intro.htm

Telavancin: withdrawal ofmarketing authorizationapplicationEuropean Union — The EuropeanMedicines Agency (EMEA) has beenformally notified of the decision to with-draw the application for a centralizedmarketing authorization for the medicinalproduct telavancin (Vibativ®) 15 mg/mlpowder for concentrate for solution forinfusion.

Vibativ® was expected to be used for thetreatment of complicated skin and softtissue infections in adults. In its officialletter, the company stated that the with-drawal was based on the CHMP’s com-munication that the data provided werenot sufficient to allow it to conclude apositive benefit-risk balance for Vibativ®for the applied indication at that time.

Reference: Press Release, Doc. Ref. EMEA/562428/2008 24 October 2008. http://www.emea.europa.eu

Docetaxel: no extensionof indicationEuropean Union —The EuropeanMedicines Agency (EMEA) has beennotified by the manufacturer of its deci-sion to withdraw the application for anextension of indication for the centrallyauthorized medicines containing do-cetaxel (Taxotere® 20 mg/0.5 ml and 80mg/2 ml, concentrate and solvent forsolution for infusion and DocetaxelWinthrop® 20 mg/0.5 ml and 80 mg/2 ml,concentrate and solvent for solution forinfusion).

Taxotere® and Docetaxel Winthrop®were expected to be used for theadjuvant treatment of patients withoperable breast cancer whose tumoursoverexpress HER2 in the followingcombinations:

• in combination (given simultaneously)with trastuzumab following a chemo-therapy regimen based on doxorubicinand cyclophosphamide.

• in combination with trastuzumab andcarboplatin.

Taxotere® and Docetaxel Winthrop® arecurrently indicated for the treatment ofbreast cancer, non-small cell lung cancerand prostate cancer, gastric adenocarci-noma and head and neck cancer.

Withdrawal is based on the CHMP’sopinion that the study design did notadequately define the contribution ofTaxotere® and Docetaxel Winthrop®.

Reference: Press Release, Doc. Ref. EMEA/610719/2008 17 November 2008. http://www.emea.europa.eu

Ciclosporin eye drops:withdrawal of marketingauthorization applicationEuropean Union — The EuropeanMedicines Agency (EMEA) has beenformally notified by the manufacturer ofwithdrawal of the application for acentralized marketing authorization forthe medicine ciclosporin 0.05% eye drops(Vekacia®). Vekacia® was expected tobe used for the treatment of vernalkeratoconjunctivitis and was designatedas an orphan medicine on 6 April 2006.

Withdrawal of the application was basedon the CHMP’s view that the data pro-vided did not allow the Committee toconclude on a positive benefit-risk bal-ance for Vekacia® at that time.

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Reference: Press Release. Doc. Ref. EMEA/610677/2008. 17 November 2008. http://www.emea.europa.eu

Positive opinions onpaediatric investigation plansEuropean Union — A paediatric investi-gation plan (PIP) sets out a programmefor the development of a medicine in thepaediatric population. The PIP aims togenerate the necessary quality, safetyand efficacy data through studies tosupport the authorization of the medicinefor use in children of all ages. These datahave to be submitted to the EMEA as partof an application for a marketing authori-zation for new medicinal products orproducts covered by a patent. In somecases, a PIP may include a waiver tostudy one or more age groups of children,or a deferral when it is appropriate toconduct studies in adults prior to initiatingstudies in the paediatric population, orwhen studies in the paediatric populationwould take longer to conduct than studiesin adults.

The Paediatric Committee (PDCO)adopted positive opinions on PIPs for thefollowing medicines:

• Everolimus (oncology); TGplPTH1-34(Osteogenic Gel I-040302) (endo-crinology, gynaecology, fertility andmetabolism); AEB0713-(1H-indol-3-yl)-4-(2-(4-methyl-1-piperazinyl)-4-quinazolinyl)-1H-pyrrole-2,5-dioneacetate(1:1), (dermatology); Alipogenetiparvovec (cardiovascular diseases);Human Normal Immunoglobulin (immu-nology and rheumatology); Telbivudine(gastroenterology); Maraviroc (infec-tious diseases); Tigecycline (infectiousdiseases).

The PDCO adopted a negative opinionon a PIP for sitagliptin phosphate mono-hydrate-metformin hydrochloride (endo-crinology, gynaecology, fertility and

metabolism). The PDCO subsequentlyadopted on its own motion a positiveopinion on full waiver for this medicine inall subsets of the paediatric population,on the grounds that the specific medicinalproduct does not represent a significanttherapeutic benefit over existing treat-ments for paediatric patients.

The PDCO adopted an opinion on themodification of an agreed PIP for Clopi-dogrel in the therapeutic area ofcardiovascular diseases. Modifications toan agreed PIP can be requested by theapplicant when the plan is no longerappropriate or there are difficulties thatrender the plan unworkable.

The PDCO adopted positive opinions forproduct-specific waivers recommendingthat the obligation to submit data ob-tained through clinical studies withchildren be waived in all subsets of thepaediatric population for the followingmedicines:

• Lenalidomide (oncology); Ibuprofen -diphenhydramine hydrochloride, from(pain); HIN1, H3N2, and B vaccine;Omega-3-acid (ethyl esters of eico-sapentaenoic acid (EPA) - docosa-hexaenoic acid (DHA)) - simvastatin(cardiology, endocrinology and metabo-lism).

Waivers can be issued if there is evi-dence showing that the medicinalproduct concerned is likely to be ineffec-tive or unsafe in the paediatric population,or that the disease or condition targetedoccurs only in adult populations, or thatthe medicinal product does not representa significant therapeutic benefit overexisting treatments for paediatric patients.

Guideline on neonatesThe PDCO reviewed comments madeduring the public consultation on theguideline on the investigation of medicinalproducts in preterm and term neonates.

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The guideline aims to provide guidancefor the development of medicines for usein neonates. It is based on severalconcept papers released by the Paediat-ric Working Party (PEG) — the Agency’sformer expert working party on paediatricmedicines, which addressed the impactof immaturity of different organ systemswhen investigating medicines inneonates.

Neonates represent a particularly vulner-able subgroup of the paediatric popula-tion. Whilst they account for a low per-centage of the total use of medicines inchildhood, up to 90% of medicines areused without a marketing authorization oroff-label in this population.

Reference: Press Release, Meeting highlightsfrom the Paediatric Committee, 15-17 October2008. Doc. Ref. EMEA/PDCO/552811/2008.24 October 2008. http://www.emea.europa.eu

Biosimilar products:a regulatory updateSingapore — A biosimilar medicine is amedicinal product which is similar to abiological medicine that has already beenregistered with a drug regulatory authorityand is submitted for medicinal productregistration by an independent applicantafter the patent period for the originalproduct has expired.

As the cost of innovative biologicalproducts is generally high, therebylimiting use, the expiration of patents onmany biological products such as humangrowth hormone and erythropoietin hasprompted the development and licensingof biosimilar products. A biosimilar prod-uct would have an abbreviated nonclinicaland clinical development programmeleveraging on the existing information ofthe original product and focusing ondemonstration of similarity with theoriginal product, also knownas the reference product.

Biosimilar products such as Valtropin®and Omnitrope® (both are somatropins)and Binocrit® (which contains epoetinalpha) are registered in the EuropeanUnion. There are no biosimilar productsregistered in Singapore as yet but suchproducts will eventually enter the market,subject to approval by HSA.

How are biosimilar products differentfrom generic chemical products?Biosimilar products may commonly bemistaken for generic versions of thereference biological product. Unlikegeneric chemical drugs, whereby thechemical structure is identical to that ofthe reference chemical product, abiosimilar product does not usually havean identical structure to the referencebiological product. Hence, even thoughthese biological/biotechnology-derivedproteins may be approved by regulatoryauthorities to be similar in terms of quality,safety and efficacy to a reference biologi-cal medicine to which it has been com-pared, there is a chance that theseproducts may cause adverse reactionswhich may be different from that of theirreference products. One such adversereaction may be differing immunologicalresponse of the patient.

How are biosimilarproducts assessed?Biosimilar products are assessed basedon comparability data between thebiosimilar product and the referenceproduct in terms of quality of product,nonclinical studies (e.g. animal pharma-codynamic studies and toxicity studies)and clinical studies (e.g. pharmacokineticand pharmacodynamic studies in humansubjects). The eventual approval for thebiosimilar product may be for the sameindication and patient group as that of thecorresponding reference product regis-tered in Singapore, or it may be for morerestricted indications and patient groups.

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How should a biosimilar product beprescribed and dispensed?The decision by a doctor whether toprescribe a biosimlar product or theinnovator biological product is dependenton factors relevant to the patient and theinstitution in which he practises. Howeverwhen prescribing such products, it isimportant to use the brand name of theselected product. A biosimilar productmay have the same international nonpro-prietary name (INN) as the referencebiological product but they should not bepresumed to be identical. Using the brandname will help avoid the issue of auto-matic substitution of the product whendispensed in the pharmacy, or duringadministration of the product.

How are adverse drug reactions(ADRs) to biosimilars reported?In view of the complexity of biologicalmolecules and for the reasons mentionedabove, it is pertinent to report the brandname of the biosimilar which is suspectedto cause an ADR rather than the nameof the substance (e.g. Genotropin®instead of somatropin), together with thebatch number of the product used.

References

1. http://www3.niaid.nih.gov/research/re-sources/DAIDSClinRsrch/Glossary.htm

2. Drug Safety Update Vol. 1, Issue 7February 2008 from MHRA and CHM

3. Adverse Drug Reaction News, Vol. 10No. 3, December 2008. http://www.hsa.gov.sg

Important information concerning biosimilar products

Biosimilar products are similar but NOT identical to an existing biological product.

A biosimilar product may have the same or a more restricted indication for usecompared to the existing biological product.

When prescribing a biosimilar product, the brand name of the product should beclearly stated on the prescription.

When dispensing/administering a biosimilar product, only the product with thecorrect brand name should be dispensed/administered. There should NOTbe any substitution with another product with the same international nonproprietaryname (INN) without seeking clarification from the prescribing doctor.

When reporting an adverse reaction, the brand name and batch number of theproduct should be clearly stated.

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New ATC level codes (other than 5th levels):Agents for atopic dermatitis, excluding corticosteroids D11AGPeripheral opioid receptor antagonists A06AH

New ATC 5th level codes:Aciclovir, combinations D06BB53Alvimopan A06AH02Asenepine N05AH05Bacitracin J01XX10Bazedoxifene G03XC02Becaplermin A01AD08Benzethonium chloride D08AJ08Bromfenac S01BC11Casopitant A04AD13Cefcapene J01DD17Cevimeline N07AX03Cilostazol C04AX33Corifollitropin alfa G03GA09Dalbavancin J01XA04Dapsone D10AX05Dexmethylphenidate N06BA11Doxercalciferol H05BX03Eltrombopag B02BX05Eperisone M03BX09Everolimus L01XE10Fluocinolone acetonide S02BA08Golimumab L04AB06Iclaprim J01EA03Lansoprazole, amoxicillin and clarithromycin A02BD07

ATC/DDD Classification

The following anatomical therapeutic chemical (ATC) classifications and defined dailydoses (DDDs) were agreed by the WHO International Working Group for Drug Statis-tics Methodology in 27–28 October 2008. Comments or objections to the decisionsfrom the meeting should be forwarded to the WHO Collaborating Centre for DrugStatistics Methodology at [email protected]. If no objections are received, the new ATCcodes and DDDs will be considered final and included in the January 2010 issue ofthe ATC index.The inclusion of a substance in the lists does not imply any recommen-dation of use in medicine or pharmacy.

ATC/DDD Classification (Temporary)

ATC level INN/Common name ATC code

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Lisinopril and amlodipine C09BB03Meningococcus, tetravalent purified polysaccharide antigen conjugated J07AH08Meptazinol N02AX05Methylnaltrexone bromide A06AH01Mitiglinide A10BX08Nabiximols N02BG10Nalfurafine V03AX01Oritavancin J01XA05Pazopanib L01XE11Pegloticase M04AX02Phenazone S02DA03Potassium acetate B05XA17Pralatrexate L01BA05Regadenoson C01EB21Saxagliptin A10BH03Silodosin G04CA04Sodium fluoride (18F) V09IX06Sodium levofolinate V03AF10Stavudine, lamivudine and nevirapine J05AR07Tamsulosin and dutasteride G04CA52Valsartan, amlodipine and hydrochlorothiazide C09DB03Vinflunine L01CA05

INN/Common name Previous ATC code New ATC code

ATC code changes:Alitretinoin D11AX19 D11AG04Clotiapine N05AX09 N05AH06Cromoglicic acid D11AX17 D11AG03Paricalcitol A11CC07 H05BX02Pimecrolimus D11AX15 D11AG02Tacrolimus D11AX14 D11AG01

Previous name New name New ATC code

ATC name changes:Angiotensin II antagonists and calcium Angiotensin II antagonists channel blockers and calcium channel blockers,

including combinations with diuretics C09DB

Diazepines, oxazepines and Diazepines, oxazepines, thiaze- thiazepines pines and oxepines N05AH



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New DDDs:

INN/common name DDD Unit Adm.R ATC code

Cefcapene 0.45 g O J01DD17Cefotiam 1.2 g O J01DC07Cevimeline 90 mg O N07AX03Cilostazol 0.2 g O C04AX33Dabigatran etexilate 0.22 g O B01AE07Doripenem 1.5 g P J01DH04Eperisone 0.15 g O M03BX09Febuxostat 80 mg O M04AA03Icatibant 30 mg P C01EB19Meptazinol 1.2 g O,P N02AX05Methylnaltrexone bromide 6 mg P A06AH01Micafungin 0.1 g P J02AX05Mitiglinide 30 mg O A10BX08Polymyxin B 0.3 MU O A07AA05Rilonacept 23 mg P L04AC04Romiplostim 30 mcg P B02BX04Sodium levofolinate 30 mg (1) P V03AF10Tafluprost 0.3 ml (2) S01EE05

(1) Expressed as levofolinic acid(2) Single dose package

Change of DDDs

INN/common name Previous DDD New temporary DDD ATC Code

Risperidone* 1.8 mg P depot 2.7 mg P depot N05AX08

*Please note that the changes will not be implemented before January 2010


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New ATC 5th level codes:Alipogene tiparvovec C10AX10Arbekacin J01GB12Capsaicin M02AB01Catumaxomab L01XC09Ciclosporin S01XA18Decitabine L01BC08Degarelix L02BX02Doripenem J01DH04Eslicarbazepine N03AF04Icatibant C01EB19Liraglutide A10BX07Mepolizumab L04AC06Oxycodone, combinations N02AA55Panipenem and betamipron J01DH55Peginterferon alfa-2a, combinations L03AB61Perindopril and amlodipine C09BB04Plerixafor L03AX16Pneumococcus purified polysaccharide antigen and Haemophilus influenzae, conjugated J07AL52Prucalopride A03AE04Rilonacept L04AC04Romiplostim B02BX04Tocilizumab L04AC07Tocofersolan A11HA08Ustekinumab L04AC05Zucapsaicin M02AB02

The following anatomical therapeutic chemical (ATC) classifications and defined dailydoses (DDDs) were agreed by the WHO International Working Group for Drug Sta-tistics Methodology in March 2008. They will be included in the January 2009 issueof the ATC index. The inclusion of a substance in the lists does not imply any recom-mendation of use in medicine or pharmacy. The WHO Collaborating Centre for DrugStatistics Methodology can be contacted at [email protected]


ATC/DDD Classification (Final)

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Previous name New name New ATC code

ATC name changes:Capsicum preparations and similar Capsaicin and similar agents M02AB agentsClostridiopeptidase Collagenase D03BA02*Clostridiopeptidase, combinations Collagenase, combinations D03BA52*House dust House dust mites V01AA03*

* Correction of names to be decided at the Working Group meeting in October 2009

New DDDs:

INN/common name DDD Unit Adm.R ATC code

Anidulafungin 0.1 g P J02AX06Arbekacin 0.2 g P J01GB12Cefmetazole 4 g P J01DC09Cerolizumab pegol 14 mg P L04AB05Clevudine 30 mg O J05AF12Eculizumab 64 mg P L04AA25Fluticasone furoate 0.11 mg N R01AD12Fosaprepitant 95 mg (1) P A04AD12Raltegravir 0.8 g O J05AX08Rivastigmine 9.5 mg TD N06DA03Tiotropium bromide 5 mcg Inhal solution R03BB04Vildagliptin 0.1 g O A10BH02

(1) Expressed as fosaprepitant.


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FIP and the futureof hospital pharmacy

The Global Conference on the Future ofHospital Pharmacy was convened as partof the 68th Annual Congress of theInternational Pharmaceutical Federation(FIP). Hospital pharmacists from aroundthe world met 30–31 August 2008 inBasel, Switzerland and successfullydeveloped 74 consensus statementsreflecting the profession’s preferred visionof practice in the hospital setting.

The FIP Global Conference on the Futureof Hospital Pharmacy has been inplanning for nearly three years, duringwhich time a survey of hospital pharmacypractice was conducted. The survey,describing the nature and scope ofpharmacy practice worldwide, includedresponses from 85 nations representing86% of the world’s population.

All of the approved consensus state-ments, along with evidence-basedliterature reviews that support the state-ments, will be published in early2009 in a special supplement of theAmerican Journal of Health-SystemPharmacy. Free access to the full pro-ceedings will be made possiblethrough the Journal web site.

Reference: http://www.fip.org/globalhosp

Assessing, monitoring andevaluating pharmaceuticalsituationsPharmaceutical sector assessment allowsthe monitoring and evaluation of accessto essential medicines, safety, effective-ness and good quality, and proper use.

The WHO Operational package forassessing, monitoring and evaluatingcountry pharmaceutical situations isintended as a useful tool for researchers,policy-makers, planners and others whoneed to use standardized measurementtools to gather data and other information.The tools presented have already beenused for several years at global andcountry levels. In addition, the operationalpackage can be used by internationalagencies and donors, by professionalgroups and nongovernmental organiza-tions.

Reference: WHO Operational package forassessing, monitoring and evaluating countrypharmaceutical situations. Guide for coordina-tors and data collectors. WHO/TCM/2007.2 athttp://www.who.int/entity/medicines/publica-tions/WHO_TCM_ 2007.2.pdf

European PharmaceuticalForum successThe final report of the PharmaceuticalForum was presented on 18 October2008 in Brussels setting out principlesand recommendations on three keychallenges in the pharmaceutical sector.Firstly, how to improve information ondiseases and treatments, secondly, howto compare medicines and identify themost effective ones, and thirdly, how tobalance access and reward for innovationwithin limited health-care budgets.

The Pharmaceutical Forum broughttogether European Union countries andstakeholders, including patient organiza-tions, health professionals, industry andinsurers. The final report comprises a setof principles and recommendations toincrease cooperation in three key areas.

Recent Publications,Information and Events

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The Forum adopted the following recom-mendations:

Enhance quality of informationCore quality principles for the develop-ment of information to patients will im-prove the quality of information by provid-ing a clear and defined framework andalso identify information of poor quality.The Forum invites all health actors torefer to the agreed principles. The ban onadvertising of prescription medicinesshould continue.

Increase accessibilityMore information to citizens in effectivecommunication formats should be pro-vided (by electronic and non-electronicmeans), taking account of local traditions,health-care systems and languages.

Generation of information by makingthe best use of all actorsThe Forum recommends that MemberStates, the Commission and health actorsconsider strengthened collaboration inthe field of information to patients. Suchcollaboration should respect the minimumethical requirements of transparency,disclosure of financial and other supportand a definition of responsibilities.

Relative effectivenessMember States, payers and patients facethe common challenge of containinghealth care budgets, including pharma-ceutical costs, while promoting andsustaining innovation. They thereforeneed to recognize the value of identifyingthe most effective medicines.

Pricing and reimbursementFinal pricing and reimbursement deci-sions are usually required before patientscan access new health solutions andinnovative companies can obtain rewardfor their research. Although pricing andreimbursement decisions are made byindividual Member States, they share theconcern on balancing access and rewardwith limited resources.

Optimal use of resourcesA toolbox of knowledge should help touse limited resources optimally andaddress specific mechanisms like risk-sharing/conditional pricing and tenderingand adopted Guiding Principles to helpnational authorities find a balance be-tween expenditure, access and innova-tion.

Reward for innovationThe expected value of innovation andpotential reward mechanisms for innova-tive medicines have been analysed inorder to better match public health needsand long-term investments in researchand development.

Follow-upMember States and stakeholders areinvited to implement the recommenda-tions of the Forum. The Commission willprovide support to the strengthening ofthe cooperation tools.

Reference: Report of the European Pharma-ceutical Forum, Brussels, 2 October 2008 athttp://ec.europa.eu/pharmaforum

Procurement and supplymanagement toolboxSince the Procurement & Supply Man-agement Toolbox web site went live inDecember 2007, 27 new tools have beenadded making a total of 116 English tools.

A separate toolbox has now been devel-oped in French and contains 27 tools.The tool categories are:

1. Policy2. Selection3. Quantification4. Procurement5. Inventory Management6. Use7. Monitoring & Evaluation8. Pricing9. Capacity Building

Recent Publications, Information and Events

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The web site now also contains demovideos, which illustrate how to use thedifferent features of the web site (http://www.psmtoolbox.org/demos.php).

Reference: Vincent Habiyambere at WHO/AMDS [email protected] and IDASolutions [email protected]. Websiteat http://www.psmtoolbox.org

Report on essentialmedicines for childrenA draft report of the meeting of theSecond Subcommittee on Selection andUse of Essential Medicines for Children,including the draft second Model List ofEssential Medicines for Children has nowbeen published as an agenda paper forthe March 2009 Expert CommitteeMeeting.

Reference: Information from World HealthOrganization at http://www.who.int/selection_medicines/committees/expert/17/en/index.html

Uganda’s antimalarials marketThe Medicines for Malaria Venture (MMV)has just released a new report mappingthe antimalarials market in Uganda. Thereport highlights a new focus in gatheringan evidence base about the structure andsize of the antimalarials market in order toguide new initiatives to increase accessto high quality malaria medicines.

Understanding the Antimalarials Market:Uganda 2007 — An Overview of theSupply Side provides a wealth of interest-ing facts about the structure of theantimalarials market in rural Uganda. Thestudy identifies the types of antimalarialsavailable on the market, availability ofproduct by outlet type, range of prices,affordability, supply chain structure, andprice mark-ups.

By mapping a detailed record of therange of antimalarials available, where

people can access them, and how muchthey pay, this study provides an evidencebase for policy makers in Uganda andinternationally to guide initiatives toreplace older, ineffective medicines withaffordable high quality ACTs.

Reference: Understanding the AntimalarialsMarket: Uganda 2007 — An Overview of theSupply Side http://www.mmv.org [email protected]

Right to access to medicinesA resolution calling on the African Com-mission on Human and Peoples’Rights to recognize the human right toaccess for needed medicines was passedat a meeting of African Human Rightsorganizations in Abuja, Nigeria,on 10 November 2008.

The NGO forum is composed of approxi-mately 100 human rights organizations inAfrica with observer status before theAfrican Human Rights Commission. Theresolution will now be transmitted to theAfrican Commission for consideration inits biannual meeting.

The resolution adopted by the Forumcalls on the African Commission torecognize “access to needed medicinesas a fundamental component of theright to health ...”. It specifically calls onthe Commission to recognize duties torespect, protect and fulfil rights to accessto medicines, including by taking “fulladvantage of all flexibilities in the WTOAgreement on Trade Related Aspects ofIntellectual Property that promote accessto affordable medicines.” A full copy of theresolution is available at http://wcl.american.edu/pijip/go/humanrights andhttp://www.wcl. american.edu/pijip/go/resolution-abuja

Reference: African NGO Forum Resolution onRight to Access to Needed Medicines at http://www.wcl.american.edu/pijip/go/resolution-abuja.


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New issue of WHO/HAIpricing bulletinIn September, the United Nations Millen-nium Development Goals (MDG) GapTask Force reported that medicines aretoo costly and availability is often poor.The lead article in the WHO/HAI PricingBulletin outlines key findings in the UNreport, and lists national and globaltargets to reduce prices and improveavailability.

Other articles in the bulletin:

• New legislation aimed at making medi-cines more affordable in the Philippines.

• Actions taken by the Lebanese Govern-ment to lower prices and improvetransparency.

• The improved availability of artemether/lumefantrine in Kenya.

• What’s new in the 2nd edition of thesurvey manual.

• Key findings from a medicine price andavailability survey in Thailand.

Reference: Health Action Internationalwebsite http://www.haiweb.org and http://www.haiweb.org/GlobalDatabase/Main.htm


Documents

WHO Drug Information · WHO Drug Information Vol 22, No. 4, 2008 International Harmonization Crisis management: safeguarding health In the course of their work, staff working in regulatory