WHO drug information 2000

W H O DRUG

INFORMATION V O L U M E 14 • N U M B E R 3 • 2 0 0 0

R E C O M M E N D E D I N N L I S T 44 I N T E R N A T I O N A L N O N P R O P R I E T A R Y N A M E S F O R P H A R M A C E U T I C A L S U B S T A N C E S

W O R L D H E A L T H O R G A N I Z A T I O N • G E N E V A

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WHO Drug Information Vol. 14, No. 3, 2000

General Policy Issues

International harmonization of regulatory activities: future optionsThe World Health Organization (WHO) has traditionally supported the process of international harmoniza-tion by directing and coordinating health work and in encouraging technical cooperation. The Organizationhas been involved in a number of important harmonization activities having a major impact on thedevelopment, production and regulatory control of pharmaceutical products. Among these, the preparationof specifications and guidelines for the quality assurance, safety and efficacy of pharmaceutical substanceshas been carried out in close collaboration and consultation with Member States.

New regional and interregional harmonization activities related to drug regulation are now under way inmany parts of the world and, as this situation unfolds, it is clear that the establishment of internationalstandards needs more than ever to be focused on interests of public health. Possible options for thecontinued involvement of WHO in the international harmonization of drug regulatory activities were recentlyevaluated in a report developed by a WHO independent review team*. The report highlights the urgent needfor WHO to sustain regional and international harmonization efforts through greater participation inactivities under development.

The report discusses two main areas of harmonization. The first concerns regional harmonization currentlyin progress throughout the world. The second, which is summarized below, addresses the respective rolesof WHO and the International Conference on Harmonization of Technical Requirements for Registrationof Pharmaceuticals for Human Use (ICH) involving the harmonization efforts of regulatory requirements ofpharmaceuticals in the European Union, Japan and the United States of America. The report proposesoptions for the future role of WHO.

*The report of the WHO independent review team is available from Quality Assurance and Safety: Medicines, Departmentof Essential Drugs and Medicines, World Health Organization, Geneva. The Team comprised: Dr Susan Alder, Australia,Professor Ali Haggag, Egypt, Dr Helen Rees, South Africa, and Professor Witold Wieniawski, Poland (Team Leader). Thefinal draft of the report has been extensively circulated for comment, including the Expert Committee on Specficiations forPharmaceutical Preparations.

Global harmonization and the ICHHarmonization of various elements of drug regula-tory activities has taken place in the last decadeand has involved intergovernmental initiatives atregional and interregional levels. The driving forcebehind the harmonization effort is the need toimprove availability of pharmaceutical products andrespond to the forces of international trade withadequate standardized technical regulations onsafety, quality and efficacy. By reducing unneces-sary duplication of regulatory requirements, it isproposed that therapeutic advances will be mademore rapidly and at a lower developmental cost.

A prerequisite to any harmonized approach tointernational drug regulation is the existence ineach of the participating countries of a functional

drug regulatory system. This is understood as fulldrug registration processes, pharmaceutical inspec-tion services and certified compliance with goodmanufacturing practice.

The International Conference on Harmonization ofTechnical Requirements for Registration of Phar-maceuticals for Human Use (ICH) was establishedin 1990 by the drug regulatory authorities andresearch-based pharmaceutical industries of theEuropean Union, Japan and USA to focus on newdrug development requirements. ICH is a tripartiteventure of 17 high-income countries. To date, ICHhas produced over 45 guidelines describing techni-cal requirements related to specific components ofthe drug registration process drawn up by groups ofspecialists from drug regulatory authorities and the

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pharmaceutical industry of the ICH countries. Thescientific level of each guideline is high and reflectsstate-of-the-art technology. The cost related to fullimplementation of the guidelines may in somecases be considerable but, it is argued, this is offsetby more rapid registration of new drugs in the ICHcountries.

The ICH initiative was established to harmonize thedocumentation needed for drug development andsubsequent regulatory evaluation of productscontaining new chemical entities or products ob-tained by biotechnology. WHO is accorded ob-server status within the ICH Steering Committee,but is not directly involved in the process of draftingor developing ICH guidelines and has no controlover their approval.

History of ICHThe International Conference on Harmonization ofTechnical Requirements for the Registration ofPharmaceuticals for Human Use (ICH) was estab-lished in 1990 as a tripartite regulatory/research-based industry venture. The major aim of the ICH isto provide a forum for constructive discussion onthe real and perceived differences in technicalrequirements for the registration of new chemicalentities. Other objectives are to achieve greaterharmonization in the interpretation and applicationof technical guidelines for the registration of newchemical entities or products obtained by biotech-nology by its members, to improve the efficiency ofglobal drug development, and to reduce redundantstudies.

The co-sponsors of ICH comprise the EuropeanCommission and the European Federation ofPharmaceutical Industries and Associations(EFPIA); the Japanese Ministry of Health andWelfare (JMHW) and the Japanese PharmaceuticalManufacturers Association (JPMA); and the USFood and Drug Administration (FDA) and thePharmaceutical Research and Manufacturers ofAmerica (PhRMA). These six co-sponsors repre-sent the voting members of the ICH Steering Com-mittee.

The ICH thus represents 17 countries comprising15% of the world's population and accounting for90% of the US$ 200 billion annual sales made bythe multinational research-based pharmaceuticalindustry. ICH regulatory authorities are among thefirst to evaluate new chemical entities and newproducts obtained from biotechnology. The Secre-tariat is provided by the International Federation

of Pharmaceutical Manufacturers Associations(IFPMA).

WHO, Health Canada and the European FreeTrade Association (EFTA) hold observer status inthe ICH Steering Committee.

Expanded ICH initiativesFollowing the completion of the majority of harmo-nized ICH objectives in 1997, it was agreed that afurther phase of harmonization activities should becontinued. The terms of reference of ICH wereamended to include provisions for updating existingguidelines and global harmonization. The revisedterms of reference are:

• To maintain a forum for constructive dialoguebetween regulatory authorities and the pharma-ceutical industry on the real and perceived differ-ences in the technical requirements for productregistration in the European Union, USA andJapan in order to ensure a more timely introduc-tion of new medicinal products, and their availabil-ity to patients.

• To monitor and update harmonized technicalrequirements leading to a greater mutual accept-ance of research and development data.

• To avoid divergent future requirements throughharmonization of selected topics needed as aresult of therapeutic advances and the develop-ment of new technologies for the production ofmedicinal products.

• To facilitate the adoption of new or improvedtechnical research and development approacheswhich update or replace current practices, wherethese permit a more economical use of human,animal or material resources, without compromis-ing safety.

• To facilitate the dissemination and communicationof information on harmonized guidelines and theiruse to encourage the implementation and integra-tion of common standards.

As part of the expanded phase of ICH activities, theICH Steering Committee has established a GlobalCooperation Group. Its stated purpose is to "makeinformation available on ICH, ICH activities and ICHguidelines to any country or company that requeststhe information." The principles and terms ofreference for this group were finalized recently anda formal approach has been made to WHO to jointhe Group. The aim of the Global Cooperation


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Group is to disseminate finalized ICH guidelineswith an anticipated goal of acceptance and adop-tion of ICH guidelines in non-ICH countries.

The implications of the establishment of the GlobalCooperation Group are discussed below.

Globalization of ICH guidelinesAlthough countries excluded from the ICH processare free to attend some ICH meetings and confer-ences, they do not make up part of the decision-making process. It is therefore estimated that theinterests of approximately 85% of the world’spopulation are not directly represented within theICH process.

While laudable in its support of ICH members,some countries and nongovernmental organizationsexcluded from the process have become vocalabout perceived shortcomings of the ICH. Thecomposition of the ICH has been a cause for con-cern from a range of interested parties, includingpatients and consumer groups. For example, theICH has produced Guidelines on Good ClinicalPractice which include reference to ethics commit-tees and to informed consent. Some consumergroups have argued that while these are central toconsumer protection, there has been little consulta-tion with patient or consumer groups in the develop-ment of these guidelines. It has also been pointedout that while many clinical trials are conducted indeveloping countries, there has been no consulta-tion between ICH and key officials from thesecountries.

While it is fair to assume that the partners withinICH are satisfied with the infrastructure and proc-ess, commentators outside have questioned theappropriateness of having the IFPMA coordinatethe process and provide the Secretariat. Somecritics have stated that this structure has led to anindustry driven agenda, with the regulators tendingto accept this as the status quo. Similar commentshave been made about a perceived lack of suffi-cient consultation with academics, scientists andthe medical profession. While these concerns maybe theoretical, specific examples given below tendto support this view.

Over the years, ICH has grown to rely more onadvanced pharmaceutical technology in its stand-ard setting on the assumption that this technologywill lead to increased safety of new drugs. Anexample is the ICH Guidelines for Impurities in NewDrug Substances (Q3A). The additional safety

benefits from these rigorous standards have not yetbeen demonstrated but the costs incurred by manu-facturers in meeting these requirements are signifi-cant. Setting such norms allows only the well-resourced pharmaceutical companies to achievethe necessary standards. This will become a con-cern if the guidelines are intended for global appli-cation. Smaller pharmaceutical companies, genericcompanies and many larger companies responsiblefor essential drug production in developing coun-tries may be effectively squeezed out of the drugmanufacturing picture if ICH guidelines start to beinterpreted as the only global standard. For exam-ple, the application of the ICH Guideline on Impuri-ties – Residual Solvents (Q3C) was developed fornew products but is being extended to cover allproducts registered in the European Union. Anotherexample is the ICH Guideline on Stability Testing(Q1) which covers only stability requirements inClimatic Zones I and II (temperate climates), anddoes not yet cover Climatic Zones III and IV (stabil-ity requirements for hot/dry and hot/humid cli-mates).

The public health implications of the application ofthese guidelines in developing countries may be farreaching. In many countries, essential drugs re-quired for the prevention and treatment of locallyendemic conditions are not supplied by the majormultinationals, but by local industry or by genericmanufacturers. If they are unable to meet what maybe unsubstantiated quality standards, the adverseimpact of the withdrawal of these drugs on thehealth of the population would be far more dramaticthan that of any hypothetical risk posed by failing toachieve the ICH standards.

Another element of some ICH guidelines is thatthey describe high safety requirements as appropri-ate for drugs which are marketed in the high-income countries but many of these products areintended to improve the quality of life of the popula-tion. Since the ICH guidelines do not addressspecific requirements for any category of productsthey do not cover neglected diseases, includingdebilitating tropical diseases.

It might be argued that the above scenarios areirrelevant, since the initial aims of the ICH were notto set global standards for drug development andevaluation. Further, ICH has no legal mandate fromthe international community on which to base suchan assumption. However, recent developmentsconcerning the ICH Global Cooperation Groupwould suggest that ICH activities are set to gain


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wider international acceptance. During the initialphase of ICH activities, it was made clear that theintentions of the ICH had relevance only to the co-sponsors, to the extent that approaches from otherindividual countries seeking membership wererefused by the Steering Committee as unnecessaryand a potential cause of confusion. It should, how-ever, be stressed that ICH advocacy seminars havealready been held in different regions of the world,and participating countries look on the ICH guide-lines as the international “norm”.

This interpretation of the ICH process is a particularchallenge for WHO as reflected in the recommen-dation of the Ninth International Conference of DrugRegulatory Authorities (ICDRA) held in Berlin in1999 which requests WHO to take into account thefull implications for non-ICH countries when partici-pating as an observer in the ICH process.

Benefits of the ICH processThe establishment of ICH ten years ago reflected aneed felt by the research-based industry and cer-tain governments to streamline the approval proc-ess for the registration of new drugs. The tendencyof many countries to regard ICH guidelines asinternational standards further supports the argu-ment that there was a need for such a process. Thewidespread reference to ICH guidelines by coun-tries attests to the quality of their technical content.Indeed, many of the scientists involved in the ICHworking groups responsible for developing thedifferent guidelines have contributed to the highcalibre of technical and scientific content in therecommendations. They argue that while recogniz-ing serious omissions in some of the guidelines,this should not detract from the quality of the con-tent of those already approved.

While the structure of the ICH was clearly exclusivefrom the outset, this position continues to be de-fended by its supporters as an appropriate partner-ship to achieve ICH aims and objectives. Theomission of other participants, such as the genericsindustry, was not seen as a barrier to ICH work, asthe original aim was not to harmonize the approvalof generic drugs. Similarly, the ICH partners wouldargue that before countries implement the guide-lines, regulatory authorities are able to involveconsumer groups who can give comments. Addi-tionally, in all the countries represented within ICH,there are appropriate mechanisms which allowpublic comment on the guidelines before they arefinally adopted.

One of the most important criticisms of the ICHprocess is that its guidelines have been increas-ingly perceived as the ‘gold standard’ for interna-tional harmonization. The ICH has never claimedto have formal international authority to produceglobal standards and it further indicates that it is inno position to compel national drug regulatoryauthorities to adopt these standards. Neverthelessmany countries consider adoption of the guidelinesas a necessary move. ICH proponents arguefurther that the intention of involving WHO as anobserver in ICH was to ensure that internationalconcerns about the protection of public healthinterests are met.

Challenges for WHORecommendations about the future role of WHOwith respect to ICH must take into account both thecurrent high status achieved by ICH internationally,the applicability of ICH products in non-ICH coun-tries, and valid criticisms of the ICH process. WHOis the only international organization that has alegal international mandate from 191 MemberStates to set global standards for the promotion andprotection of public health. The ICH, in contrast,has been established to harmonize standards forcomponents of specific drug regulatory activitiesfrom 17 countries that are economically developedand where multinational research-based pharma-ceutical companies involved in new drug develop-ment are situated.

Conversely, there is no proof that ICH guidelineswill produce additional public safety benefits. In-deed, in replacing existing standards, there may bean impact on the availability of essential drugs indeveloping countries. This could also disrupt thegenerics industry and pharmaceutical manufactur-ers from countries outside the ICH tripartite, particu-larly with regard to increased costs as a result ofimplementation of ICH guidelines.

Currently, WHO attends ICH Steering Committeemeetings as an observer and WHO has also beenasked to become an observer to the work of theGlobal Cooperation Group. While the Group ex-presses the desire for the globalization process tobe consultative and open, this initiative could giverise to concern for WHO and countries outside theICH process since WHO, although not a full partnerin the decision-making process of ICH, would belooked on as endorsing the globalization of ICHguidelines. Although the terms of reference of ICHare expanding into a wider international arena,there are no indications that ICH intends to broaden


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its membership base or change its process ofguideline development to reflect these new globalambitions.

A concern commonly voiced in this complex de-bate, is that the setting of different standards for theprocess of drug regulatory harmonization by ICHand by WHO will effectively produce a dual stand-ard — a higher one for the more affluent countriesand a lower one for poorer countries. This concernis untested. However, the raising of standards tosuch a level that essential drugs cannot be pro-duced would be of tremendous concern. Further-more, the rationale for introducing new expensivetechnologies to increase safety in drug productionhas yet to be proven in many situations.

Present developments in the international harmoni-zation of drug regulation should be seen as achallenge to WHO to revisit the standards andguidelines that it has already set. In the opinion ofthe Review Team the setting of international stand-ards should rightly remain within the domain ofWHO and should be protected from interests be-yond those of public health.

The fact that ICH guidelines have increasingly beenperceived within countries as a global standardshould seriously concern WHO. Before any discus-sion of global recognition, it is imperative thatguidelines should be subjected to an internationalreview for their global applicability. The consultativeprocesses utilized by WHO are necessary in orderto promote the public health interests of populationsin all countries. In some instances, this may alsoresult in a need for WHO to develop standards forthe quality, safety and efficacy of generic productsto ensure that supplies of essential drugs are notsqueezed off the market by standards that areunrealistic for the settings in which generic andessential drugs are produced and traded.

Recommendations to WHOThe ICH has made clear that it is committed tomaintaining the status quo to achieve full effective-ness of the ICH process. However, other groupshave influenced the ICH to change some of itsprocedures. Although it is considered unlikely thatthe ICH would accept a significant change in eitherthe membership of its Steering Committee orcurrent guideline modification or development,

WHO should be encouraged to find ways to workmore closely with ICH to engage and seek inputfrom other countries.

The following recommendations are proposed forimplementation by WHO. They are dependent onresources being made available for implementation.

• WHO continues to play an observer role within theICH Steering Committee.

• The review team proposes that observer statustakes on a more critical role within ICH. This couldtake the form of proposals of topics for guidelinedevelopment and opinions on the potential publichealth implications of some of the guidelinesproposed.

• WHO accepts observer status within the ICHGlobal Cooperation Group. However, measuresshould be taken for this not to be considered asan endorsement of ICH guidelines or proceduresby WHO Member States.

• WHO establishes a mechanism to review, modifyand/or adopt ICH guidelines as WHO internationalguidelines for drug regulatory activities, as rel-evant.

Within this mechanism, a series of consultationsand meetings should be convened to review theexisting ICH guidelines. These meetings shouldinclude national representatives, selected expertsand academics other than those involved in ICH,as well as senior policy staff and scientific advis-ers from ICH and non-ICH countries encompass-ing all levels of regulatory activity.

As part of the process, endorsement could beachieved through WHO governing bodies orsimilar mechanisms.

• WHO should include the recommendations of thereview group as topics for discussion at the TenthICDRA which will be held in Hong Kong in Novem-ber 2001.

The review team also considered that a more activeinvolvement of WHO as a full partner to the ICHprocess would be beneficial in allowing develop-ment of guidelines which would take public healthissues fully into account. However, this wouldrepresent a significant structural change for theICH.


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International Conference on Harmonization (ICH) Guidelines

ICH guideline developmentA total of 45 guidelines were produced during the first phase of ICH under quality, safety, efficacy andmultidisciplinary topics. It soon became clear that updating of the guidelines is an ongoing activity. Aselected listing of the guidelines is set out on the following pages and complete copies are availablefrom http://www.ifpma.org.

Harmonization initiatives that are undertaken under the auspices of ICH are guided and overseen bythe ICH Steering Committee, which is composed of representatives of the six co-sponsors and ob-servers. The Committee meets on average 2–3 times a year.

ICH Expert Working Groups (EWGs) are responsible for the drafting of individual guidelines. EWGsare made up of representatives from the six co-sponsors, according to the topic under discussion.Participation has also been extended recently to observers, the pharmacopoeial authorities, genericindustry associations and representatives of the non-prescription pharmaceutical industry.

Each ICH guideline proceeds through the following stages:

Step 1: The development of a consensus among scientists working in industry and regulatory agen-cies who discuss the topic in Expert Working Group meetings and exchange views on successivedraft documents. The drafting process is conducted by a Rapporteur.

Step 2: Is reached when the Steering Committee accepts the consensus draft and it is transmitted tothe three regional regulatory agencies for formal consultation in accordance with normal internal andor external procedures.

Step 3: The draft guideline leaves the ICH process and is treated in the three ICH regions as a regula-tory draft for consultation. In the European Union it is circulated as a CPMP draft guideline, in Japan itis translated and circulated internally and externally for consultation, and in the USA it is published asa consultation document in the Federal Register. Comments are collected by the regulatory agenciesin the three regions and are consolidated by a Regulatory Rapporteur in order that a single, harmo-nized text can be adopted for implementation.

Step 4: Is reached when the final consolidated draft is accepted by the Steering Committee and“signed off” by the six co-sponsors.

Step 5: Is reached when the guideline has been adopted by the three regulatory authorities andincorporated into their appropriate administrative procedures. Simultaneous public announcementsare made by regulatory authorities.

ICH documents currently available

The following summaries describe ICH Guidelines produced so far and are provided as information.An update of those Guidelines discussed during the recent International Conference on Harmonizationheld in November 2000 follows on page 159.

Efficacy testing guidelinesTo date, the ICH has produced 11 guidelines addressing the efficacy assessment of new chemical andbiological entities.

E1A The Extent of Population Exposure to Assess Clinical Safety (Adopted at Step 4 – 1994)This is a brief guideline which establishes the number of patients to be treated and minimum duration of


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treatment periods for the safety evaluation of drugs intended for the long-term treatment of non-lifethreatening diseases.

E2A Clinical Safety Data Management: Definitions and Standards for Expedited Reporting(Adopted at Step 4 – 1994)Definitions for adverse event (or experience) terms and adverse reactions. The guideline also gives therecommended timeframe for reporting to regulatory agencies adverse drug reactions which occur duringclinical development. Attachment 1 sets out the Key Data Elements for inclusion in expedited reports ofserious adverse drug reactions.

E2B Clinical Safety Data Management: Data Elements for Transmission of Individual Case SafetyReports (Adopted at Step 4 – 1997)This guideline extends E2A to give details of the data elements required for reporting individual cases ofsafety events (adverse drug reactions or adverse drug events) for both pre and post approval periods. Theguideline covers reporting of adverse drug reactions and events from all sources and to any destinations,including reporting from authorities to the WHO Collaborating Centre for International Drug Monitoring.

E2C Periodic Safety Update Reports for Marketed Drugs (Adopted at Step 4 – 1996)This guideline sets out the format and content for comprehensive periodic safety updates of marketeddrugs for reporting to regulatory authorities. The PSUR presents the worldwide safety experience of amedicinal product at defined times (6-monthly or in multiples of 6-monthly reports) after the date of the firstmarketing authorization for the product granted to any company in any country in the world (internationalbirthdate). The guideline also provides a sample model for a periodic safety update report.

E3 Structure and Content of Clinical Study Reports (Adopted at Step 4 – 1995)This guideline sets out the structure and content of a report to allow for the compilation of a single integratedfull report of any clinical study which will be acceptable to all regulatory authorities of the ICH. The reportconsists of the clinical and statistical description, presentations, and analysis integrated into a single reporttext and with appendices containing the protocol, sample case report forms, investigator relatedinformation, information related to the test drugs/investigational products including active control/comparators, technical statistical documentation, related publications, patient data listings and technicalstatistical details such as deviations, computations, analysis and computer output, etc. Appendices areintended to be additional information required by only some regulatory authorities and may be requestedas needed.

E4 Dose Response Information to Support Drug Registration (Adopted at Step 4 –1994)This guideline sets out the purpose, principles and study design for the determination of the relationshipamong dose, drug-concentration in blood, and clinical response (effectiveness and undesirable effects).

E5 Ethnic Factors in the Acceptability of Foreign Clinical Data (Adopted Step 4 – 1998)This guideline recommends a framework for evaluating the impact of ethnic factors upon a medicine'seffect (its efficacy and safety at a particular dosage and dose regimen) in order to facilitate the registrationof medicines among the ICH regions. Ethnic factors are defined as those factors relating to the geneticand physiological (intrinsic) and the cultural and environmental (extrinsic) characteristics of a population.The guideline also provides on outline of the properties of a compound which makes it more or less likelyto be sensitive to ethnic factors. It also defines the circumstances when additional data (called bridgingstudies) may be needed in order to allow extrapolation of the foreign data to a new region.

E6 Good Clinical Practice: Consolidated Guideline (Adopted at Step 4 –1996)This guideline sets out the principles and procedures to be followed when designing, conducting, recordingand reporting clinical trial data that are intended to be submitted to regulatory authorities. It also providesdetails on the information which should be included in the Investigator's Brochure, the clinical trial protocoland the essential documentation to be collected during the course of a clinical trial.


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E7 Studies in Support of Special Populations: Geriatrics (Adopted at Step 4 – 1993)This guideline sets out the principles required for the development of new drugs, new formulations andnew combinations of established medicinal products which are likely to have significant use in theelderly, either because the disease intended to be treated is characteristically a disease of ageing orbecause the population to be treated is known to include substantial numbers of geriatric patients. Theguideline defines the geriatric population and details the pharmacokinetic, pharmacodynamic (dose/response studies) and drug interaction studies which should be undertaken.

E8 General Considerations for Clinical Trials (Adopted at Step 4 — 1997)This guideline provides an overview of the principles and practices in undertaking clinical trials for thedevelopment of new medicinal products. It illustrates the relationship between the phases of clinicaldevelopment and types of study by objective and the general principles of design, conduct and analysisof trials.

E9 Statistical Principles for Clinical Trials (Adopted at Step 4 — 1998)This guideline sets out the principles of statistical methodology to be applied to clinical trials for medicinalproducts being developed for marketing applications in the ICH regions.

E10 Choice of Control Group and Related Issues in Clinical Trials (Adopted at Step 4 – 2000)The purpose of this guideline is to describe the general principles involved in choosing a control groupfor clinical trials intended to demonstrate the efficacy of a treatment and to discuss related trial designand conduct issues. This guideline does not address the regulatory requirements in any region, butdescribes what trials using each design can demonstrate.

E11 Clinical Investigation of Medicinal Products in the Paediatric Population(Adopted at Step 4 – 2000)The goal of this guideline is to encourage and facilitate timely paediatric medicinal product develop-ment internationally. The guideline provides an outline of critical issues in paediatric drug develop-ment and approaches to the safe, efficient, and ethical study of medicinal products in the paediatricpopulation.

Quality testing guidelinesQ1A Stability Testing of New Drug Substances and Products (Adopted at Step 4 – 1993)The scope of the guideline is confined to new molecular entities and associated drug products. Well-established active substances and associated products (generics ) are not included.

Stability testing conditions:Long-term testing: for both drug substances and drug products: 25 °C ± 2 °C / 60% RH ± 5% for 12months. Accelerated testing: for both drug substances and drug products: 40 °C ± 2 ºC /75% RH ± 5%for 6 months. The long-term testing is continued for a sufficient period of time beyond 12 months to coverall appropriate re-test periods (for drug substances). Where “significant change” occurs during 6 monthsstorage under conditions accelerated testing, additional testing at intermediate conditions of 30 °C ±2 °C /60% RH ± 5% is carried out. “Significant change” at 40 °C /75%RH or 30 °C/60%RH is defined asfailure to meet the specifications. Mutual acceptability of information generated on stability in any oneof the areas has been established, provided it meets the appropriate requirements of the guideline andthe labelling is in accordance with national / regional requirements.

The ICH Harmonized Tripartite Guideline on stability testing of new drug substances and products (Q1A)notes that light testing should be an integral part of stress testing.

(Note: The WHO Stability Guideline covers the four climatic zones, whereas the ICH guideline coversonly two climatic zones.


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Furthermore, the WHO guidelines cover multisource products, whereas the ICH Guideline is confined tonew molecular entities and associated drug products.)

Q1B Photostability Testing of New Drug Substances and Products (adopted at Step 4 – 1996)The Guideline on Photostability Testing Q1B is an annex to guideline Q1A. The Q1B guideline addressesthe generation of photostability information for submission of Registration Applications for New MolecularEntities and associated drug products. The guideline does not cover photostability of drugs afteradministration (i.e. under conditions of use).

A systematic approach to photostability testing is recommended in the guideline covering studies such as:(i) Tests on the drug substance; (ii) Tests on the exposed drug product outside the immediate pack; (iii)Tests on the drug product in the immediate pack (if necessary); and (iv) Tests on the drug product in themarketing pack (if necessary). A detailed Decision Flow Chart is established which describes how theextent of drug product testing can be established by assessing the change that has occurred at the endof the light exposure testing. Acceptable change is change within limits justified by the applicant. Theguideline gives detailed information on light sources, procedure, presentation of samples, analysis ofsamples and judgement of results.

Q1C Stability Testing: Requirements for New Dosage Forms (adopted at Step 4 – 1996)This guideline is an annex to guideline Q1A. The Q1C guideline addresses the recommendations on whatshould be submitted regarding stability of new dosage forms by the owner of the original application afterthe original submission of new drug substances and products. Stability protocols for new dosage formsshould follow the Q1A guideline in principle. However, a reduced stability data base at submission time(e.g. 6 months accelerated and 6 months long-term data from ongoing studies) may be acceptable incertain cases.

Q2A Text on Validation of Analytical Procedures (adopted at Step 4 -–1994)The guideline discusses the characteristics to be considered during the validation of analytical proceduresincluded in the Registration Application submitted to drug regulatory authorities (DRA) in the EU, Japanand USA. The guideline contains a collection of terms and their definitions with the object of bridging thedifferences that often exist between various compendia and DRAs in the EU, Japan and USA. The typesof analytical procedures to be validated are included in the guideline besides a tabular summation of thecharacteristics applicable to these different types: identification tests, control of impurities (i.e. quantitativetests for impurities content, limit tests for the control of impurities) as well as assay procedures (i.e.quantitative tests of the active moiety in samples of drug substance or drug product, or other selectedcomponents of the drug product). The validation characteristics of an analytical procedure (Accuracy,Precision, Repeatability, Intermediate Precision, Specificity, Detection Limit, Quantitation Limit, Linearityand Range) are defined in a glossary at the end of the guideline. Although robustness is not included inthe table of typical validation characteristics, it is stated that it should be considered at an appropriate stagein the development of the analytical procedure. Revalidation should be carried out in case of changes inthe synthesis of drug substance, in the composition of the finished product or in the analytical procedure.

Q2B Validation of Analytical Procedure — Methodology (adopted at Step 4 – 1996)The guideline is complementary to the parent guideline Q2A on Validation of Analytical Procedures. Thepurpose of the guideline is to provide some guidance and recommendations on how to consider variousvalidation characteristics for each analytical procedure. The guideline states that different approachesmay be applicable for the validation, provided that they demonstrate that the procedure is suitable for itsintended use. Also analytical procedures for biological and biotechnological products may be approacheddifferently. The guideline considers the various validation characteristics in distinct sections: Specificity(identification and assay as well as impurity tests), Linearity, Range, Accuracy (assay, quantitation ofimpurities), Precision (repeatability, intermediate precision, reproducibility), Detection limit (based onvisual evaluation, based on signal-to-noise, based on standard deviation of the response and the slope),Quantitation limit (based on visual evaluation, based on signal-to-noise, based on standard deviation ofthe response and the slope), Robustness, System suitability testing.


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Q3A Impurities in New Drug Substances (Adopted at Step 4 –1995)The guideline provides guidance for Registration Applications on the content and qualification ofimpurities in new drug substances produced by chemical synthesis. It is not intended to apply to new drugsubstances used in clinical trials. It does not cover biological/biotechnological peptides, oligonucleotides,radiopharmaceuticals, fermentation products, herbal products, and crude products of animal or plantorigin. The guideline addresses chemistry aspects and safety aspects of impurities which are classifiedinto the three following categories: organic impurities, inorganic impurities, residual solvents. Regardingorganic impurities, the new drug substance specifications should include, where applicable, limits for: (i)Each Specified Identified Impurity; (ii) Each Specified Unidentified Impurity at or above 0.1%; (iii) AnyUnspecified Impurity, with a limit of not more than 0.1%; and (iv) Total Impurities. Significant emphasisis placed on the qualification of impurities, i.e. establishing the safety of impurities at the levels specified.The applicant should provide a rationale for selecting impurity limits based on safety considerations.Qualification threshold is 0.05% in case the maximum daily dose exceeds 2g/day. The guideline includesa glossary and a decision tree for safety studies.

Q3B Impurities in New Drug Products (Adopted at Step 4 – 1996)The guideline provides guidance recommendations for registration or marketing applications on thecontent and qualification of impurities in new drug products produced from chemically synthesized newdrug substances. The guideline is an annex to the guideline on Impurities in New Drug Substances (Q3A).The scope of the guideline is confined to degradation products of the active ingredients or reactionproducts of the active ingredients with an excipient and/or immediate container/closure system. Theguideline does not cover impurities arising from excipients present in the drug product. The guideline doesnot apply during clinical research stages of development. Biological/biotechnological products, peptides,oligonucleotides, radiopharmaceuticals, fermentation products and semisynthetic products, herbalproducts, and crude products of animal or plant origin are not covered. Also excluded from the guidelineare: extraneous contaminants which are more appropriately addressed as GMP issues, polymorphicforms, and enantiomeric impurities. Impurities present in the new drug substance need not be monitoredin drug products unless they are also degradation products. The guideline deals with the analyticalprocedures to be used and the necessity that they are validated and the specification limits for impuritiesas well as the qualification of impurities. The guideline includes a glossary, thresholds for reporting,thresholds for identification and thresholds for qualification of degradation products in New Drug Products.A decision tree for safety studies is included.

Q3C Impurities: Guideline for Residual Solvents (Adopted at Step 4 – 1997)The guideline recommends acceptable amounts for residual solvents in pharmaceuticals for the safetyof the patient. The solvents are classified in the guideline into three classes: Class 1: solvents to beavoided; Class 2: solvents to be limited; Class 3: solvents with low toxic potential. The guideline describestwo options for describing limits of class 2 solvents. Also concentration limits for solvents to be avoidedare given. The guideline includes a glossary and an appendix listing solvents included in the guideline inaddition to a second appendix giving additional background and a third appendix describing methods forestablishing exposure limits.

Q4 Pharmacopoeial HarmonizationAlready at the start of the ICH process, it was realized that the harmonization of drug quality requirementsand test methods presented in pharmacopoeia monographs would not be possible through elaborationof specific guidelines, but should be treated differently, because harmonization has to affect separatelyeach method and each individual substance. For that reason, a Pharmacopoeia Discussion Group (PDG)was established by representatives of three pharmacopoeias from the ICH group of countries: theEuropean Pharmacopoeia, the Japanese Pharmacopoeia and the United States Pharmacopeia. Theactivity of PDG has proceeded in parallel to the work of ICH and in close involvement with its harmonizationefforts. In the period 1992 –1999 the efforts of the PDG were directed toward harmonization of a numberof general methods of drug analysis, including methods used for the analysis of biotechnology products,and towards harmonization of quality requirements contained in pharmacopoeia monographs for a


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considerable number of excipients and several products obtained by biotechnology. In the process ofharmonization, the PDG has established a list of 45 excipients that were most widely used in preparationof dosage forms or were considered critical for their quality. By mid-1999 the PDG has achievedharmonization of some 70% of the relevant monographs between the 3 pharmacopoeias. Considerableprogress has also been achieved towards harmonization of important general methods and apparatusused in quality testing of dosage forms. Further efforts in this area are continuing in connection with thework on Q6A guideline where a number of pharmacopoeial test methods which previously differedbetween the 3 pharmacopoeias has been now harmonized. The harmonization of pharmacopoeialrequirements through the PDG activities results in practice in the elevation of quality standards throughthe use of more sophisticated test methods but this requires the use of highly special apparatus and costlyreagents. Also the requirement to use in the tests of only official reference materials of high unit cost,which is now quite frequent in the case of testing drug impurities, tends to increase further the expensesfor the testing of drug quality according to harmonized methods.

Q5A Viral Safety Evaluation of Biotechnology Products (Adopted at Step 4 – 1997)The guideline is concerned with testing and evaluation of the viral safety of biotechnology productsderived from characterized cell lines of human or animal origin (i.e. mammalian, avian, insect). The termvirus in this guideline excludes non-conventional transmissible agents such as those associated withBovine Spongiform Encephalopathy (BSE) and scrapie. The scope of the guideline covers productsderived from cell cultures initiated from characterized cell banks. It covers products derived from in-vitrocell culture, such as interferons, monoclonal antibodies and recombinant DNA-derived productsincluding recombinant subunit vaccines, and also includes products derived from hybridoma cells grownin vivo as ascites. Excluded from the scope of this guideline are inactivated vaccines, all live vaccinescontaining self-replicating agents, and genetically engineered live vectors.

The guideline describes potential sources of virus contamination. It states that viral contamination ofbiotechnology products may arise from the original source of the cell line or from adventitious introductionof viruses during production processes. The guideline describes cell line qualification: Testing forviruses; Tests for Master Cell Bank (MCB), for Working Cell Bank (WCB), and cells at the limit of in vitrocell age used for production and recommended viral detection and identification assays such as: testsfor retroviruses, in-vitro assays, in-vivo assays, antibody production tests. The guideline describes theacceptability of cell lines used for the manufacture of product on a risk-benefit basis. Also testing forviruses in unprocessed bulk is described. Inactivating or removing viruses is described in the guidelineon the basis of viral clearance studies. The guideline includes specific precautions to be observed as wellas a glossary. In summary, the guideline suggests approaches for the evaluation of the risk of viralcontamination and for the removal of virus from the product, thus contributing to the production of safebiotechnology products derived from animal or human cell lines.

Q5B Quality of Biotechnological Products: Analysis of the Expression Construct in Cells Usedfor Production of rDNA derived protein products (Adopted at Step 4 – 1995)The guideline presents guidance for the characterization of the expression construct for the productionof recombinant DNA protein products in eukaryotic and prokaryotic cells. This is important to ensure theconsistent production of a recombinant DNA derived product. Nucleic acid analysis data and theevaluation of the final purified protein serve to ensure the quality of a recombinant protein product.

Q5C Quality of Biotechnological Products: Stability Testing of Biotechnological/BiologicalProducts (Adopted at Step 4 – 1995)The guideline is considered an annex to the parent guideline Q1A, “Stability Testing of New DrugSubstances and Products” (1993), whose content applies to biotechnological/biological products.However, because of the distinguishing characteristics of the biotechnological/ biological products, theseshould be given special consideration in stability testing. Being proteins and/or polypeptides, mainte-nance of molecular conformation is dependent on covalent and non-covalent forces. They areparticularly sensitive to temperature change, oxidation, light, ionic contents and shear. Stringent storage


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conditions are usually necessary to ensure maintenance of biological activity. For stability studiescomplex analytical methodologies may be necessary. Assays for biological activity, where applicable,should be part of the stability studies. Biochemical, physicochemical and immunochemical methods forthe analysis of the molecular entity and the quantitative detection of degradation products should be partof the stability studies. The scope of the guideline covers products such as cytokines (interferons,interleukins, colony stimulating factors, tumour necrosis factors), erythropoietins, plasminogen activa-tors, blood plasma factors, growth hormones and growth factors, insulin, monoclonal antibodies andvaccines consisting of well-characterized proteins or polypeptides, i.e. well-characterized proteins andpolypeptides, their derivatives and products of which they are components, and which are isolated fromtissues, body fluids, cell cultures or produced using rDNA technology. The guideline does not coverantibiotics, allergenic extracts, heparins, vitamins, whole blood, or cellular components. The guidelinehandles selection of batches of bulk materials, intermediates and final container product as well as sampleselection. Validated methods should be used to assess potency, purity and molecular characteristics. Theguideline describes further storage conditions, testing frequency, specification and labelling of biotech-nology products. A glossary is included.

Q5D Quality of Biotechnological Products: Derivation and Characterization of Cell Substratesused for Production of Biotechnological/Biological Products (Adopted at Step 4 – 1997)The guideline provides broad guidance on standards for the derivation of human and animal cells andmicrobial cells to be used to prepare biotechnological/biological products and for the preparation andcharacterization of cell banks to be used for production. The guideline covers cell substrates having a cellbanking system, i.e. microbial cells or cell lines derived from human or animal sources that possess thefull potential for the generation of the desired biotechnological/biological products for human in vivo or exvivo use. Reagents for in vitro diagnostic use are outside the scope of this guideline. Animal sources ofcell lines include all those of metazoan origin. Microbial sources include bacteria, fungi, yeast, and otherunicellular life forms. Biotechnological/biological products in the guideline are any products prepared fromcells cultivated from cell banks with the exception of microbial metabolites, such as antibiotics, aminoacids, carbohydrates, and other low molecular weight substances. Included in the guideline are cell banksused to prepare gene therapy products or vaccines. Also certain viral vaccines are prepared in primarycell cultures derived directly from animal tissues or organs. Primary cells are not banked and thereforenot addressed by this guideline. However, other considerations which may apply to primary cells arediscussed further in the Appendix. The guideline handles generation of cell substrates, origin, sources andhistory of cells, cell banking, cell banking procedures as well as principles of characterisation and testingof cell banks, such as tests of identity, tests of purity for both microbial and metazoan cells. The guidelinedescribes further how cell substrate stability is tested. Also tests for karyology and tumourigenicity areused for characterization. A glossary is included.

Q6A Specifications for New Drug Substances and New Drug Products: Chemical Substances(Adopted at Step 4 – 1999)The guideline is intended to assist in the establishment of a single set of global specifications for new drugsubstances and new drug products. It provides guidance on the setting and justification of acceptancecriteria and the selection of test procedures for new drug substances of synthetic chemical origin and newdrug products produced from them. The guideline addresses specifications, i.e. those tests, proceduresand acceptance criteria used to assure the quality of the new drug substance and new drug product atrelease and during shelf-life. Specifications are an important component of quality assurance, but are notits only component. Other components are design, development, in-process controls, GMP controls, andprocess validation. Guidance is provided with regard to universal acceptance criteria, which should beestablished for all new substances and drug products and those which are considered specific toindividual drug substances and/or dosage forms. The guideline gives a definition for general conceptswhich are important in setting harmonized specifications. These concepts are not universal, but can beconsidered in particular circumstances. They include: periodic/skip testing, release vs. shelf-life accept-ance criteria, in-process tests, design and development considerations, limited data available at filing,parametric release, alternative procedures, pharmacopoeial tests and acceptance criteria, evolvingtechnologies, impact of drug substance on drug product specifications, reference standards.


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The guideline does not address drug substances or drug products during clinical research stages ofdrug development. Biological/biotechnological products, high molecular weight peptides,oligonucleotides, fermentation products, radiopharmaceuticals, herbal products, and crude productsof animal or plant origin are not covered by the guideline. The full utility of this guideline is dependenton the successful completion of harmonization of pharmacopoeial procedures for several attributescommonly considered in the specifications for new drug substances or new drug products.

Q6B Specifications: Test Procedures and Acceptance Criteria for Biotechnological/BiologicalProducts (Adopted at Step 4 – 1999)The guideline contains the requirements for the testing of products obtained by biotechnology. Theguideline provides general principles on the setting and justification of a uniform set of internationalspecifications for biotechnological and biological products to support marketing applications. Thescope of the guideline covers proteins and polypeptides, their derivatives, and products of which theyare components, e.g. conjugates. These proteins and polypeptides are produced from recombinant ornonrecombinant cell-culture expression systems and can be highly purified and characterised usingan appropriate set of analytical procedures. The principles outlined in this guideline apply also toproteins and polypeptides isolated from tissues and body fluids. The following are not covered:antibiotics, synthetic peptides and polypeptides, heparins, vitamins, cell metabolites, DNA products,allergenic extracts, conventional vaccines, cells, whole blood and cellular blood components. Theprinciples to be considered in setting specifications are described in detail as: • characterization(physicochemical properties, biological activity, immunochemical properties, purity, quantity) • analyti-cal considerations: (reference standards and reference materials, validation of analytical procedures)• process control (process-related considerations, in-process acceptance criteria and action limits, rawmaterials and excipient specifications) • pharmacopoeial specifications • release limits versus shelf-lifelimits • statistical concepts. A justification of the specifications is handled in detail. A glossary is includedin the guideline.

Safety testing guidelinesS1A Guideline on the Need for Carcinogenicity Studies of Pharmaceuticals(Adopted Step 4 – 1995)This guideline sets out the definitions of the circumstances under which it is necessary to undertakecarcinogenicity studies on new drugs, taking account of known risk factors and the intended indicationsand duration of exposure.

S1B Testing for Carcinogenicity of Pharmaceuticals (Adopted Step 4 – 1997)This guideline outlines the scientific approach to testing pharmaceuticals for carcinogenicity in bothmice and rats, and provides guidance on alternative testing procedures which may be applied withoutjeopardizing safety.

S1C Dose Selection for Carcinogenicity Studies of Pharmaceuticals (Adopted Step 4 – 1995)This guideline sets out the criteria for the selection of the high dose to be used in carcinogenicity studiesfor new therapeutic agents.

S2A Genotoxicity: Guidance on Specific Aspects of Regulatory Genotoxicity Tests for Pharma-ceuticals (Adopted Step 4 – 1995)This guideline gives specific guidance and recommendations for in vitro and in vivo tests and on theevaluation of test results. It also includes a glossary of terms related to genotoxicity tests.

S2B Genotoxicity – A Standard Battery for Standard Genotoxicity Testing of Pharmaceuticals(Adopted Step 4 – 1997)This guideline sets out a standard set of assays to be conducted for registration of new medicinalproducts and the extent of confirmatory experimentation in any particular genotoxicity assay in thestandard battery.


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S3A Note for Guidance on Toxicokinetics: the Assessment of Systemic Exposure in ToxicityStudies (Adopted Step 4 – 1994)This guideline gives guidance on developing test strategies in toxicokinetics and the need to integratepharmacokinetics into toxicity tests in order to aid in the interpretation of the toxicity findings and promoterational study design development.

S3B Pharmacokinetics: Guidance for Repeated Dose Tissue Distribution Studies(Adopted Step 4 – 1994)This guideline gives guidance on the circumstances when repeated dose tissue distribution studiesshould be considered (i.e. when appropriate data cannot be derived from other sources). It also givesrecommendations on the conduct of such studies.

S4 Single Dose Toxicity Tests (Adopted at ICH-1, 1991)Agreement was made in 1991 that the LD50 determination should be abandoned on pharmaceuticals.

S4 Duration of Chronic Toxicity Testing in Animals (Rodent and Non-Rodent Toxicity Testing)(Adopted Step 4 – 1998)Sets out guidance for repeated dose toxicity tests.

S5A Detection of Toxicity to Reproduction for Medicinal Products (Adopted Step 4 – 1993)This guideline gives guidance on the tests required for reproductive toxicity, in which animals are treatedduring defined stages of reproduction, in order to better reflect human exposure to medicinal productsand allow more specific identification of stages of risk.

S5B Reproductive Toxicology: Male Fertility Studies (an Addendum to S5A)(Adopted Step 4 – 1995)This guideline is an Addendum to S5A to provide a better description of the testing concept andrecommendations for male fertility studies, especially those addressing flexibility, pre-mating treatmentduration and observations.

S6 Preclinical Safety Evaluation of Biotechnology-Derived Pharmaceuticals(Adopted at Step 4 – 1997)This guideline gives guidance on the preclinical safety testing requirements for biotechnology products.It covers the use of animal models of disease, determination of when genotoxicity assays andcarcinogenicity studies should be performed and the impact of antibody formation on the duration oftoxicology studies.

Multidisciplinary guidelinesIn this group of guidelines only guideline M3 has reached the implementation stage although M1, M2 andM3, discussed on page 159, are nearing implementation.

M3 Non-Clinical Safety Studies for the Conduct of Human Clinical Trials for Pharmaceuticals(Adopted at Step 4 – 1997)The guideline addresses the principles of developing pre-clinical strategies on the timing of toxicitystudies in relation to the conduct of clinical trials. It covers the timing of single dose and repeated dosetoxicity studies, reproduction toxicity studies, genotoxicity studies, local tolerance studies and carcino-genicity studies as well as studies for safety pharmacology and pharmacokinetic studies in relation todifferent phases of human clinical trials.

ICH documents currently under discussion (2000)The main ICH documents that are at present at the development stage include the M4 guideline onCommon Technical Document and the Q7A guideline on GMP for Active Pharmaceutical Ingredients.Other guidelines that are still under development include guidelines in the drug efficacy and drug safety


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areas as well as a revision of several quality guidelines. At the International Conference on Harmonizationheld in November 2000 further progress in preparation of the guidelines was achieved and several otherguidelines proposed for development.

Efficacy GuidelinesGuidelines that are under development include:• E2B(M) – Data Elements for Transmission of Individual Case Safety Reports.• E12A – Principles for Clinical Evaluation of New Antihypertensive Drugs. It is intended that this guideline

should serve as an example for a whole series of guidelines on clinical trials of specific groups of drugs.

Quality guidelinesSeveral important guidelines related to this area are still at various stages of development including:• Q1Ar – Guideline on Stability Testing of New Drug Substances and Products.• Q3Ar – Guideline on Impurities in New Drug Substances.• Q3Br – Guideline on Impurities in New Drug Products.• Q3C(M) – Impurities: Residual Solvents – (PDE for tetrahydrofuran) (PDE for N-methylpyrrolidone).• Q7A – Good Manufacturing Practice Guide for Active Pharmaceutical Ingredients. The guideline is

intended to produce a common text for good practices in the manufacture of pharmaceutical substancesused as active ingredients. It will describe all elements of control required in process during productionof active pharmaceutical ingredients, as well as requirements for all wholesalers (agents, brokers,distributors, etc.) trading in these products.

Safety Guidelines• S7 – Safety Pharmacology Studies for Human Pharmaceuticals. The guideline will describe the core

battery of safety pharmacology studies, the necessity of such studies and the application of GoodLaboratory Practices to safety pharmacology.

Multidisciplinary Guidelines• M1 Medical Terminology

The guideline will describe a single medical terminology for drug regulatory purposes, including adversedrug reaction reporting. After discussing medical terminologies that currently exist and are in extensiveuse it was decided to select the MEDDRA terminology developed by the Medicines Control Agency in UKas suitable for the needs of the electronic transfer of data. The MEDDRA dictionary has taken intoconsideration the terms of several widely used terminologies, including WHOART (WHO AdverseReaction Terminology), COSTART (used by US FDA) and ICD 9. Future modifications may includeadditional terms, such as those in the ICD 10.

• M2 Electronic Standards for the Transfer of Information and DataThe guideline will define electronic communication standards for direct communication of applications fordrug registration, and drug safety data in a way that ensures the integrity of information. It should facilitatethe exchange of data between pharmaceutical companies and drug regulatory authorities.

• M4 Common Technical DocumentThe Common technical document should serve as a standard document for submission of applicationsto drug regulatory authorities for registration of a new product. The document would consist of a generalpart (M4) and 3 specialized parts for sub-topics M4Q, M4S and M4E. The latter deal with the elementsrelated to quality, safety and efficacy issues. Various parts of the document have now been completedand it was finalized during the International Conference on Harmonization in November 2000.


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Current Topics

Ethical Principles for MedicalResearch Involving Human Subjects

A. Introduction1. The World Medical Association has developedthe Declaration of Helsinki as a statement of ethicalprinciples to provide guidance to physicians andother participants in medical research involvinghuman subjects. Medical research involving humansubjects includes research on identifiable humanmaterial or identifiable data.

2. It is the duty of the physician to promote andsafeguard the health of the people. The physician’sknowledge and conscience are dedicated to thefulfilment of this duty.

3. The Declaration of Geneva of the World MedicalAssociation binds the physician with the words,“The health of my patient will be my first considera-tion,” and the International Code of Medical Ethics

declares that, “A physician shall act only in thepatient’s interest when providing medical carewhich might have the effect of weakening thephysical and mental condition of the patient.”

4. Medical progress is based on research whichultimately must rest in part on experimentationinvolving human subjects.

5. In medical research on human subjects, consid-erations related to the well-being of the humansubject should take precedence over the interestsof science and society.

6. The primary purpose of medical research involv-ing human subjects is to improve prophylactic,diagnostic and therapeutic procedures and theunderstanding of the aetiology and pathogenesis ofdisease. Even the best proven prophylactic, diag-nostic, and therapeutic methods must continuouslybe challenged through research for their effective-ness, efficiency, accessibility and quality.

7. In current medical practice and in medical re-search, most prophylactic, diagnostic and therapeu-tic procedures involve risks and burdens.

8. Medical research is subject to ethical standardsthat promote respect for all human beings andprotect their health and rights. Some researchpopulations are vulnerable and need special protec-

Adopted by the 18th WMA General Assembly, Helsinki,Finland, June 1964 and amended by the 29th WMAGeneral Assembly, Tokyo, Japan, October 1975; 35thWMA General Assembly, Venice, Italy, October 1983;41st WMA General Assembly, Hong Kong, September1989; 48th WMA General Assembly, Somerset West,Republic of South Africa, October 1996; and the 52ndWMA General Assembly, Edinburgh, Scotland, October2000

Declaration of Helsinki

The World Medical Association (WMA) General Assembly has recently revised the Declaration of Helsinki,the most widely accepted guideline on medical research involving human subjects. This set of principlesforms the basis for the CIOMS International Guidelines for Biomedical Research Involving HumanSubjects, and the ethical components of both the WHO and the ICH Good Clinical Practice Guidelines.

The Declaration sets out the obligations and responsibilities of doctors and physicians to subjects takingpart in medical research and makes clear that research is justified only if the populations to be studiedstand to benefit from the intervention. Individuals enrolled in trials must be given full information beforeconsenting and the benefits, risks, burdens and effectiveness of any new trial method should be testedagainst those of the best current treatment, whenever this exists, rather than placebo. The same ethicalrules need to be applied wherever research is being conducted and developing countries should not betargetted for clinical trial research because it is cheaper or because laws are not enforced to the sameextent as developed countries.

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tion. The particular needs of the economically andmedically disadvantaged must be recognized.Special attention is also required for those whocannot give or refuse consent for themselves, forthose who may be subject to giving consent underduress, for those who will not benefit personallyfrom the research and for those for whom theresearch is combined with care.

9. Research Investigators should be aware of theethical, legal and regulatory requirements for re-search on human subjects in their own countries aswell as applicable international requirements. Nonational ethical, legal or regulatory requirementshould be allowed to reduce or eliminate any of theprotections for human subjects set forth in thisDeclaration.

B. Basic principles for all medical research10. It is the duty of the physician in medical re-search to protect the life, health, privacy, anddignity of the human subject.

11. Medical research involving human subjectsmust conform to generally accepted scientificprinciples, be based on a thorough knowledge ofthe scientific literature, other relevant sources ofinformation, and on adequate laboratory and, whereappropriate, animal experimentation.

12. Appropriate caution must be exercised in theconduct of research which may affect the environ-ment, and the welfare of animals used for researchmust be respected.

13. The design and performance of each experi-mental procedure involving human subjects shouldbe clearly formulated in an experimental protocol.This protocol should be submitted for consideration,comment, guidance, and where appropriate, ap-proval to a specially appointed ethical review com-mittee, which must be independent of the investiga-tor, the sponsor or any other kind of undue influ-ence. This independent committee should be inconformity with the laws and regulations of thecountry in which the research experiment is per-formed. The committee has the right to monitorongoing trials. The researcher has the obligation toprovide monitoring information to the committee,especially any serious adverse events. The re-searcher should also submit to the committee, forreview, information regarding funding, sponsors,institutional affiliations, other potential conflicts ofinterest and incentives for subjects.

14. The research protocol should always contain astatement of the ethical considerations involved andshould indicate that there is compliance with theprinciples enunciated in this Declaration.

15. Medical research involving human subjectsshould be conducted only by scientifically qualifiedpersons and under the supervision of a clinicallycompetent medical person. The responsibility forthe human subject must always rest with a medi-cally qualified person and never rest on the subjectof the research, even though the subject has givenconsent.

16. Every medical research project involving humansubjects should be preceded by careful assessmentof predictable risks and burdens in comparison withforeseeable benefits to the subject or to others.This does not preclude the participation of healthyvolunteers in medical research. The design of allstudies should be publicly available.

17. Physicians should abstain from engaging inresearch projects involving human subjects unlessthey are confident that the risks involved have beenadequately assessed and can be satisfactorilymanaged. Physicians should cease any investiga-tion if the risks are found to outweigh the potentialbenefits or if there is conclusive proof of positiveand beneficial results.

18. Medical research involving human subjectsshould only be conducted if the importance of theobjective outweighs the inherent risks and burdensto the subject. This is especially important when thehuman subjects are healthy volunteers.

19. Medical research is only justified if there is areasonable likelihood that the populations in whichthe research is carried out stand to benefit from theresults of the research.

20. The subjects must be volunteers and informedparticipants in the research project.

21. The right of research subjects to safeguard theirintegrity must always be respected. Every precau-tion should be taken to respect the privacy of thesubject, the confidentiality of the patient’s informa-tion and to minimize the impact of the study on thesubject’s physical and mental integrity and on thepersonality of the subject.

22. In any research on human beings, each poten-tial subject must be adequately informed of the

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aims, methods, sources of funding, any possibleconflicts of interest, institutional affiliations of theresearcher, the anticipated benefits and potentialrisks of the study and the discomfort it may entail.The subject should be informed of the right toabstain from participation in the study or to with-draw consent to participate at any time withoutreprisal. After ensuring that the subject has under-stood the information, the physician should thenobtain the subject’s freely-given informed consent,preferably in writing. If the consent cannot beobtained in writing, the non-written consent must beformally documented and witnessed.

23. When obtaining informed consent for the re-search project the physician should be particularlycautious if the subject is in a dependent relationshipwith the physician or may consent under duress. Inthat case the informed consent should be obtainedby a well-informed physician who is not engaged inthe investigation and who is completely independ-ent of this relationship.

24. For a research subject who is legally incompe-tent, physically or mentally incapable of givingconsent or is a legally incompetent minor, theinvestigator must obtain informed consent from thelegally authorized representative in accordance withapplicable law. These groups should not be in-cluded in research unless the research is neces-sary to promote the health of the population repre-sented and this research cannot instead be per-formed on legally competent persons.

25. When a subject deemed legally incompetent,such as a minor child, is able to give assent todecisions about participation in research, the inves-tigator must obtain that assent in addition to theconsent of the legally authorized representative.

26. Research on individuals from whom it is notpossible to obtain consent, including proxy oradvance consent, should be done only if the physi-cal/mental condition that prevents obtaining in-formed consent is a necessary characteristic of theresearch population. The specific reasons forinvolving research subjects with a condition thatrenders them unable to give informed consentshould be stated in the experimental protocol forconsideration and approval of the review commit-tee. The protocol should state that consent toremain in the research should be obtained as soonas possible from the individual or a legally author-ized surrogate.

27. Both authors and publishers have ethical obli-gations. In publication of the results of research, theinvestigators are obliged to preserve the accuracyof the results. Negative as well as positive resultsshould be published or otherwise publicly available.Sources of funding, institutional affiliations and anypossible conflicts of interest should be declared inthe publication. Reports of experimentation not inaccordance with the principles laid down in thisDeclaration should not be accepted for publication.

C. Additional principles for medical re-search combined with medical care28. The physician may combine medical researchwith medical care, only to the extent that the re-search is justified by its potential prophylactic,diagnostic or therapeutic value. When medicalresearch is combined with medical care, additionalstandards apply to protect the patients who areresearch subjects.

29. The benefits, risks, burdens and effectivenessof a new method should be tested against those ofthe best current prophylactic, diagnostic, andtherapeutic methods. This does not exclude the useof placebo, or no treatment, in studies where noproven prophylactic, diagnostic or therapeuticmethod exists.

30. At the conclusion of the study, every patiententered into the study should be assured of accessto the best proven prophylactic, diagnostic andtherapeutic methods identified by the study.

31. The physician should fully inform the patientwhich aspects of the care are related to the re-search. The refusal of a patient to participate in astudy must never interfere with the patient-physi-cian relationship.

32. In the treatment of a patient, where provenprophylactic, diagnostic and therapeutic methodsdo not exist or have been ineffective, the physician,with informed consent from the patient, must befree to use unproven or new prophylactic, diagnos-tic and therapeutic measures, if in the physician’sjudgement it offers hope of saving life, re-establish-ing health or alleviating suffering. Where possible,these measures should be made the object ofresearch, designed to evaluate their safety andefficacy. In all cases, new information should berecorded and, where appropriate, published. Theother relevant guidelines of this Declaration shouldbe followed.

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Regulatory and Safety Matters

Misoprostol and pregnancy:reminder of dangersA letter has been circulated by the manufacturer ofmisoprostol (Cytotec®) to remind health careproviders that misoprostol administration by anyroute is contraindicated in women who are preg-nant because it can cause abortion.

Misoprostol is indicated for the prevention ofgastric ulcers induced by use of nonsteroidal anti-inflammatory drugs (NSAIDs) in patients at highrisk of complications from gastric ulcer.

The uterotonic effect of misoprostol is an inherentproperty of prostaglandin E1, of which misoprostolis a stable, orally active, synthetic analogue. Seri-ous adverse events reported following off-label usein pregnant women include maternal or foetaldeath, uterine hyperstimulation, rupture or perfora-tion requiring uterine surgical repair, hysterectomyor salpingo-oophorectomy, amniotic fluid embo-lism, severe vaginal bleeding, retained placenta,shock, foetal bradycardia and pelvic pain.

Reference: Letter from Searle, USA, dated 23 August2000. http://www.fda.gov/medwatch

Southern hemisphere influenzavaccine compositionWorld Health Organization — The compositionfor the southern hemisphere influenza season(2001) has been decided and communicated tovaccine manufacturers. It is recommended that theinfluenza vaccine will contain the following threecomponents:

• An A/Moscow/10/99 (H3N2)-like virus (A/Panama/20007/99 is this kind of virus).

• An A/New Caledonia/20/99 (H1N1)-like virus.

• A B/Sichuan/379/99-like virus.

WHO strongly recommends the use of vaccine asan effective preventive measure against this poten-tially fatal disease. About 50 – 80% of vaccine

recipients will be protected against the diseasewhen there is a good match between the vaccineand strains of circulating influenza virus. However,in those cases where the vaccine does not fullyprotect against influenza, severity of illness andfrequency of complications are reduced.

Most populations have been previously exposed toinfluenza A(H3N2), influenza A(H1N1) and Bviruses and are known to have some degree ofresidual immunity. One dose of influenza vaccineshould therefore be sufficient for all ages exceptyoung children. Previously unimmunized childrenshould receive two doses of vaccine at an intervalof at least four weeks.

The specific vaccine viruses used in each countryshould be approved by the national control authori-ties who are responsible for making recommenda-tions on their use.

Reference: Weekly Epidemiological Record, 75: 330–333(2000).

Zafirlukast: labelling changesWith increased use over the past three years,additional events have been reported for zafirlukast(Accolate®), a leukotriene receptor antagonistindicated for the prophylaxis and chronic treatmentof asthma in adults and children 7 years of age andolder. As a result, the precautions and adversereactions sections of the package insert have beenupdated.

Based on reports of liver dysfunction, more specificrecommendations are made for patient manage-ment, as follows. Hepatic events have occurredpredominantly in females.

• If liver dysfunction is suspected based uponclinical signs, zafirlukast should be discontinued.

• If liver function tests are consistent with hepaticdysfunction, zafirlukast therapy should not beresumed and patients should not be re-exposed ifno other attributable cause is identified.

In addition to the above changes, the adversereactions section now also includes the information

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that reports have been received of patients experi-encing arthralgia and myalgia in association withzafirlukast therapy.

Reference: Letter from AstraZeneca, USA, dated Sep-tember 2000. http://www.fda.gov/medwatch

Thioridazine: majorlabelling modificationsImportant labelling changes have been made for alldosage forms of thioridazine hydrochloride(Mellaril®) by the manufacturer.

A boxed warning has been added to prominentlyadvise clinicians that thioridazine has been shownto prolong the QTc interval in a dose-related man-ner and drugs with this potential have been associ-ated with torsade de pointes-type arrhythmias andsudden death. Mesoridazine is the major activemetabolite of thioridazine and appears to have thecapacity to prolong the QTc interval.

Thioridazine hydrochloride is now indicated only forschizophrenic patients who fail to show an accept-able response to adequate courses of treatmentwith other antipsychotic drugs. It is contraindicatedwith certain other drugs, including fluvoxamine,propranolol, pindalol, any drug that inhibits P4502D6 isozyme, e.g. fluoxetine and paroxetine, andagents known to prolong the QTc interval such asdisopyramide, procainamide and quinidine. Thiori-dazine hydrochloride is also contraindicated inpatients know to have reduced levels of the P4502D6 isozyme as well as in patients with congenitallong QT syndrome or a history of cardiac arrhyth-mias.

Before being considered for treatment, patientsshould have a baseline electrocardiogram (ECG)performed and serum potassium levels measured.Periodic ECGs and serum potassium levels may beuseful. Thioridazine should be discontinued inpatients who are found to have a QTc interval over500 m/sec.

Patients currently being treated with thioridazinehydrochloride should be fully informed of this infor-mation. Switching to a different antipsychotic agentshould be considered and continuation ofthioridazine hydrochloride treatment should bebased on a careful assessment of the potentialbenefits and risks.

Reference: Letter from Novartis, USA, dated 7 July 2000and letter from Novartis Pharmaceuticals Canada Inc.,Canada, dated, 31 July 2000.

Mesoridazine besylate:new warningThe manufacturer of mesoridazine besylate(Serentil®) has advised doctors and pharmacists ofimportant prescribing information changes to the 25mg and 50 mg tablets. Mesoridazine besylate hasbeen shown to prolong the QTc interval in a dose-related manner and drugs with this potential havebeen associated with torsade de pointes and sud-den death. The following major modificationsshould be implemented immediately:

• Mesoridazine besylate is now indicated only forschizophrenic patients who fail to show an accept-able response to other antipsychotic drugs. Effi-cacy of mesoridazine besylate in treatment refrac-tory schizophrenic patients is unknown.

• Mesoridazine besylate is contraindicated withother drugs known to prolong the QTc interval, inpatients with congenital long QT syndrome or ahistory of cardiac arrhythmias.

• Patients considered for treatment with mesorid-azine besylate should have a baseline ECGperformed and serum potassium levels measured.

Patients currently being treated with mesoridazinebesylate should be fully informed of these informa-tion changes and switching to a different antipsy-chotic agent should be considered. Thioridazine, ametabolic precursor of mesoridazine also appearsto have the capacity to prolong the QTc interval.

Reference: Communication from Novartis Pharmaceuti-cals Canada Inc., Canada, dated 22 September 2000.

Lopinavir and ritonavirfor HIV infectionUnited States of America — An acceleratedapproval has been issued for Kaletra®, a combina-tion of the protease inhibitors lopinavir and ritonavirfor HIV infection in adults and children over 6months of age. Lopinavir's antiviral properties arecombined with a low dose of ritonavir that inhibits

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lopinavir's metabolism. This results in blood levelsof lopinavir that enhance effectiveness.

Side effects associated with Kaletra® are diar-rhoea, fatigue, headache, and nausea. It alsoproduces increases in blood lipid levels which insome patients may be large enough to requiretreatment. Infrequent cases of pancreatitis havebeen observed among patients receiving antiretro-viral regimens that included Kaletra® and, asobserved with other protease inhibitors, may alsobe associated with adverse events including in-crease in blood glucose, redistribution of body fat,and potentially serious drug interactions.

Reference: FDA Talk Paper, T00-43 (2000).

Arsenic trioxide for leukaemiaUnited States of America — The Food and DrugAdministration has approved arsenic trioxide(Trisenox®) for the treatment of patients with acutepromyelocytic leukaemia who have not respondedto first-line therapy with transretinoic acid andanthracycline-based chemotherapy.

Acute promyelocytic leukaemia is a cancer of thewhite blood cells characterized by a rapid accumu-lation of abnormal white blood cells in the bonemarrow and blood resulting in anaemia, susceptibil-ity to infections, bleeding and haemorrhage.

Arsenic-containing preparations have been inmedical use for more than 2000 years and interestin arsenic-based therapy was revived by reports ofanti-leukaemia activity of some traditional Chinesepreparations.

Arsenic trioxide can cause an increase in the QTinterval and lead to arrhythmia. Other adverseeffects include abdominal discomfort, nausea,vomiting, headache, fatigue, skin changes, and fluidaccumulation. These were considered mild andresolved after therapy was completed.

Reference: FDA Talk Paper, T00-47 (2000).

International plasma traffickingWorld Health Organization — Several newspaperarticles have reported on international trafficking ofcontaminated human plasma emanating fromsouthern Africa.

The articles refer to investigations under way since1996 when the Austrian authorities seized a con-signment of illegally imported plasma. The trial ofplasma brokers involved in this trafficking is due totake place soon in Austria. The Austrian healthauthorities as well as the Swiss authorities, whohave been investigating the same issue, haveconfirmed that countries identified during the inves-tigation as having received potentially dangerousblood products have been notified (1).

Exchange of information between national controlauthorities is essential. In line with Regulation andLicensing of Biological Products in Countries withNewly-developing Regulatory Authorities (2), thenational control authority is able to request informa-tion on the quality of products from the authority inthe exporting country.

References

1. Weekly Epidemiological Record, 75: 289–290 (2000).

2. Regulation and Licensing of Biological Products inCountries with Newly-developing Regulatory Authorities.WHO Technical Report Series, No. 858 (1995).

Cardiac failure andpioglitazone hydrochlorideJapan — Pioglitazone hydrochloride (Actos®) wasapproved for marketing in 1999 for the treatment ofdiabetes and is considered to improve resistance toinsulin. The Ministry of Health and Welfare in Japanhas received five case reports of cardiac failure,four out of five serious, associated with the use ofthe drug, and instructed the manufacturer to revisethe labelling and to issue a letter to health profes-sionals to draw their attention to cardiac failureduring treatment.

Case reports show that oedema and rapid weightgain — potentially due to plasma volume expansion— have occurred in patients during the use ofpioglitazone and this has triggered cardiac failure.

As reflected in the revised labelling, pioglitazone isnow contraindicated in patients with cardiac failureor a medical history of cardiac failure. Specialattention should be paid to oedema and rapidweight gain during the treatment of patients andpatients should consult their physician immediatelyin the event of any symptoms occurring.

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References

1. MHW Emergent Safety Information dated 5 October athttp://www.mhw.go.jp

2. Dear Doctor letter from Takeda Chemical Industries,Ltd. at http://www.pharmasys.gr.jp

New dosing for didanosineThe manufacturer of the nucleoside analoguereverse transcriptase inhibitor, didanosine (Videx®),has advised health care providers of a change inprescribing information. The results of a recentclinical trial have demonstrated that the treatmentresponse rate of once-daily didanosine was signifi-cantly lower than in the comparator arm. Althoughonce daily dosing is available, it should only beconsidered for adult patients whose managementrequires this administration.

It is therefore recommended that the more effectivedosing frequency of didanosine is twice-daily.

Reference: Letter from Bristol-Myers Squibb Company,USA, dated 1 August 2000.

Alosetron: guide and labellingimprove risk detectionUnited States of America — The Food and DrugAdministration (FDA) has developed a MedicationGuide for distribution by pharmacists to help ensurethat patients using the prescription drug alosetronhydrochloride (Lotronex®) for treatment of thediarrhoea-predominant form of irritable bowelsyndrome will understand the rare but serious risksand how they can take action. Risks include compli-cations from constipation and the risk of ischemiccolitis, caused by reduced blood flow to the intes-tines.

Irritable bowel syndrome is a functional abnormalityof the gastrointestinal tract that is estimated toaffect up to 15% of the US population. People withthis condition experience chronic or recurrentabdominal pain and irregular bowel movements.This condition is two to three times more commonin women than men.

Prescribing information has also been updated.This states that treatment should not be startedwhen women are constipated and it informs pre-

scribers that alosetron hydrochloride is now con-traindicated in women with:

• A history of intestinal obstruction, stricture, toxicmegacolon, gastrointestinal perforations, and/oradhesions or ischemic colitis;

• Active diverticulitis; or

• Current Crohn's Disease or ulcerative colitis, or ahistory of such a disease.

Reference: HHS News, P00-17 (2000).

Meningitis C vaccinesUnited Kingdom — In November 1999, a massnational immunization campaign to vaccinate allchildren under 18 years of age with the new menin-gococcal group C conjugate vaccine commenced.Two vaccines were used (Meningotec® andMenjugate®). Before licensing, the vaccines weretested in approximately 8000 children and adoles-cents in the United Kingdom and over 20 000children and adults in other countries. To date over15 million doses have been distributed in the UnitedKingdom.

Recent press reports of death following MeningitisC vaccination are based on misinterpretation ofdata which have not been linked to fatal outcomes.By 1 June 2000 the Committee on Safety of Medi-cine had received 4764 reports of patients experi-encing adverse reactions to the vaccine. Thiscorresponds to a reporting rate of 1 per 2875 dosesdistributed. The adverse reactions reported mostfrequently include dizziness, pyrexia, headache,nausea, vomiting and fainting. Patients normallyrecover rapidly.

After reviewing the data, the Committee on Safetyof Medicines has recommended that the followingadverse reactions should be added to the productinformation: nausea, vomiting, rash, malaise,lymphadenopathy, headache, myalgia and allergicreactions, including anaphylactic reactions whichwere reported once in 500 000 doses distributed.The Committee considers that the risk/benefit ratiois overwhelmingly favourable and there is no sug-gestion that the vaccine has led to any deaths.

References

1. The Pharmaceutical Journal, 265: 353 (2000).

2. Message from the Chairman of the Committee onSafety of Medicines, 30 August 2000.

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Mifepristone approvallinked to stringent conditionsUnited States of America — The Food and DrugAdministration has approved mifepristone(Mifeprix®) for the termination of early pregnancy,defined as 49 days or less from the beginning of thelast menstrual period.

Under the approved treatment regimen, 600 mg ofmifepristone is followed two days later with 400micrograms of misoprostol, a prostaglandin. Afollow-up visit should be scheduled 14 days afteradministration to determine whether pregnancy hasbeen terminated.

A medication guide will be provided to each womanreceiving mifepristone explaining how to take thedrug, when to avoid taking it and possible sideeffects.

Mifepristone should not be used on women with thefollowing conditions:

• Confirmed or suspected ectopic pregnancy.

• Intrauterine device (IUD) in place.

• Chronic failure of the adrenal glands.

• History of allergy to mifepristone, misoprostol orother prostaglandins.

• Bleeding disorders or current anticoagulanttherapy.

Physicians allowed to administer mifepristone mustbe part of a national registry and must be qualifiedto perform surgical intervention in cases of incom-plete abortion or severe bleeding, or they musthave made plans in advance to provide such carethrough others.

Mifepristone was first approved for use in France in1988. Since then 620 000 European women havetaken mifepristone in combination with a prostag-landin to terminate pregnancy.

Reference: HHS News, P00-19 (2000).

Proposed withdrawal ofenrofloxacin in poultryUnited States of America — The Food and DrugAdministration has proposed to withdraw use of thefluoroquinolone antimicrobial enrofloxacin for use inpoultry on the grounds that it has not be shown tobe safe. This action is put forward by the Center forVeterinary Medicine in consideration that:

• Use of fluoroquinolones in poultry causes thedevelopment of fluoroquinolone-resistant Cam-pylobacter.

• Campylobacter is transferred to humans and is asignificant cause of fluoroquinolone-resistantCampylobacter infections in humans; and

• Such infections are a hazard to human health.

Fluoroquinolones are considered to be one of themost valuable antimicrobial drug classes availablefor human infections because of their spectrum ofactivity, safety and ease of administration. They areused both in the treatment and prophylaxis ofbacterial infections in hospitals and for the treat-ment of foodborne diseases.

Data from the National Antimicrobial ResistanceMonitoring surveillance programme were used todetermine that poultry carrying fluoroquinolone-resistant Campylobacter are the predominantsource of campylobacteriosis in humans.

Fluoroquinolones have been available for humanuse since 1986, yet resistance did not increaseamong Campylobacter until 1997, soon after theapproval and use of these drugs in poultry. Fluoro-quinolone-resistant Campylobacter infections inhumans had risen in the USA to 17.6% by 1999.

Reference: CVM Update, 26 October 2000.

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Consultative Document

The importance ofprocurement proceduresProcurement staff are typically given little training ortechnical support to help them evaluate the prod-ucts they are buying or verify the sources of thoseproducts adequately. More often than not, thedecision to buy is based on cost alone, with as-sumptions about quality necessarily being left totrust rather than evidence. Given the distances thatseparate most procurement activities from the enduser of the products, feedback mechanisms areoften unavailable when problems occur.

To be effective, any health care project will dependon a whole series of procedures concerned withplanning, evaluation, management and implemen-tation. Most health care providers place a greatdeal of emphasis on quality when considering theirinterventions yet they appear not to give the samedegree of attention to their procedures when pur-chasing pharmaceuticals and medical supplies.

When considering the use of a medical supplier,buyers should always make sure that they aresatisfied with the information being provided withthe products including the measures being taken toensure the quality of the products. A basic overviewof the major issues is presented on the following

pages and suggestions are made for some reason-able demands which can be made in order toconfirm the quality and appropriateness of themedical products being purchased.

There are over 100 000 different pharmaceuticalpreparations available on the world market. Compo-sition, presentation and quality control, as well asprice, can vary enormously between manufacturersand countries, with implications for product perform-ance, appropriateness and potential harm to humanhealth. Even when regulations are in place togovern manufacturing practices and the manufac-turing chain, there can be considerable differencesin the application of such standards.

Terms and definitionsA number of regulations exist to ensure that prod-ucts supplied are fit for intended use. The followingterms are used in procurement practice.

Brand-name product: refers to a novel productwith patent protection. Other terms commonly usedare proprietary or ethical product.

Generic product: In pharmaceutical supply termsthe word generic implies that the product is free ofpatent restrictions. The pharmaceutical manufac-turer will use a generic or International Nonpropri-

Operational issues in the procurementof essential drugs and medical suppliesMedical supply is a complex and competitive area. A buyer is not only expected to obtain the right goodsat the right price but to be aware of the many other key factors impacting on the procurement process.It is therefore important to acquire as much information as possible on basic requirements and toconsider these in relation to other operational issues affecting the purchase of medical goods andpharmaceuticals. The following text has been prepared by Dr Bonface Fundafunda at ECHO Interna-tional Health Services Limited in the United Kingdom and does not yet represent the views of WHOnor reflect current WHO terms and definitions . It sets out to provide an aide memoire of theprocedures to be followed and standards which can be expected of suppliers of pharmaceuticals andmedical devices.

Comments are invited on the text with a view to its further development. These should be addressed to:Quality Assurance and Safety: Medicines, Essential Drugs and Medicines Policy, World HealthOrganization, Geneva, Switzerland, or by e-mail to: [email protected].

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etary Name (INN) or can market such a productunder the company’s brand name as long as it isregistered as a generic product (i.e. off-patent). Thegeneric product should be manufactured accordingto internationally accepted standards.

International Nonproprietary Name (INN) is theinternationally accepted descriptive name for thepharmaceutical substance, i.e. active ingredient. Anexample of an INN would be paracetamol, ibupro-fen, diazepam, etc.

It is important to have information on the relation-ship between the generic product and a brandproduct: with respect to clinical effect, efficacy andsafety there must be no difference between thegeneric product and the original (comparator)patented product. If a difference is present, thencompliance with the international standard has notbeen achieved. Many regulatory procedures are inplace to ensure that generic products are fit for theirintended use.

There is usually a marked difference in the cost ofgeneric products and the price of the brand-nameproduct may be more than the generic. Therefore,when buying, it is wise to enquire whether there is ageneric product, unless you specifically require thebrand-name product.

Pharmacopoeial standards: The most commonlyaccepted standards for pharmaceutical productmanufacture and quality control are the BritishPharmacopoeia (BP), the United States Pharmaco-peia (USP), and the European Pharmacopoeia(EP). WHO publishes The International Pharmaco-poeia, which includes specifications for drugs in theModel List of Essential Drugs, for use by countrieswithout a national pharmacopoeia. When buying aproduct, ensure that a product's standard is ac-cepted by the importing regulatory authority.

Essential drugs : Many countries have acceptedthe WHO Model List of Essential Drugs, a list ofmedicinal and related products that are essential totreating the majority of health needs within a coun-try.

National essential drugs list: In many cases, theWHO Model List has been adapted to local require-ments and a national list of essential drugs isavailable. The majority of products on an essentialdrugs list are generic products, although brand-name products may also be included if these areused widely in the health sector.

One objective served by the essential drugs list isto ensure that planning and expenditure for phar-maceuticals is transparent. When purchasingproducts for use in a country, first ensure that theproducts are on the national essential drugs list. Ifthe products are not listed, they may not be madeavailable in the public sector.

National regulatory requirementsThe following are some of the general regulationsaffecting pharmaceutical supply which will need tobe addressed before undertaking pharmaceuticalprocurement.

License to procure, hold and supply medicinalproducts: This requirement applies to any institu-tion outside a Ministry of Health structure. If you area nongovernmental organization (NGO), a charity,or agency working in health care, you will need toapply for a licence to the authority responsible fordrug regulation.

License to import medicinal products: Yourorganization will need to receive an import licence ifit is supporting the health authority in health careprovision. Therefore, before importing drugs, en-sure that licenses have been granted.

Responsible person: In many cases, the regula-tory authority will require that you have the neces-sary qualified staff and a health professional onyour team who will serve as the responsible personfor procurement, stock control, use and advice aswell as the supervision and monitoring of medicinalproduct supply. Depending on the country regula-tions, this is normally a qualified and registeredpharmacist. Alternatively, the authorities mayappoint another health professional (e.g. pharmacytechnician, nurse, doctor or medical assistant) totake on this role. The responsibility of this person isto ensure that all legal aspects of the practice,including procurement, storage, dispensing, use,professional advice to other health care staff andpatients is not compromised.

National drug formulary: The national healthauthorities may have developed a guideline onrecommended indications and therapeutic uses ofthe medicinal products listed according to its essen-tial drugs list. One of the objectives served by thedrug formulary is to provide common information forall health care providers in the country. Whenpurchasing, it is preferable to buy products whichare included in the formulary since treatment infor-mation will be readily available to prescribers.

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National product registration: The national healthauthorities will maintain a register of all pharmaceu-tical products on the market in the approved dos-age form in order to ensure safety, efficacy andquality.

The product licence holder is legally responsible foran application to register its products in a recipientcountry. The process of registration opens up thatmarket to the product licence holder. Given thecosts associated with this process, the productlicence holder has to assess the viability of thatmarket before proceeding to register itself and itsproducts. This process can be done through arepresentative office (an agent) resident in therecipient country, or through another authorizedbody (such as a wholesaler or distributor). It isimportant to stress that wholesale distributorscannot register products unless they have authorityfrom the product licence holder.

Always ensure that the products you are purchas-ing are registered in the recipient country.

Manufacturer registration: As a further step toensure the control of pharmaceutical products incirculation, drug regulators also license manufactur-ers and providers of medicinal products. There aremany pharmaceutical manufacturers making ge-neric products. Given the highly competitive natureof the generic market, care should be taken thatmanufacturers have followed WHO guidelines forgood manufacturing practice (GMP).

Manufacturers are inspected by national inspectorsor inspectors approved by other internationallyrecognized bodies or accredited commercial firms.The main focus of inspection is to ensure that amanufacturer is producing pharmaceutical productsmanufactured to quality standards and in accord-ance with GMP. When purchasing, ensure thatproducts are from manufacturers registered in thecountry and inspected to GMP standards.

Secondary manufacture: Business opportunities,economies of scale, and cutting operational costsare all elements and realities of business. Theresult of such strategies may be that some manu-facturers subcontract, or outsource production ofregistered products to another manufacturer (sec-ondary manufacture). The secondary manufacturermay or may not be a marketing establishment or itmay concentrate only on contract manufacture.

While national regulators want to know who is theactual manufacturer, it is important to note that it isnot illegal for a primary manufacturer to have itsproducts manufactured elsewhere. The primarymanufacturer will have declared this part of thebusiness under its Manufacturing Licence. How-ever, it is the primary manufacturer's responsibilityto demonstrate that secondary manufacture iscarried out under identical production conditions asat the primary manufacturing premises.

Wholesaler registration: As with manufacturers,wholesalers fall under the same degree of regula-tory control to ensure that they abide by principlesof good storage and distribution practice and fol-lows requirements for the handling of pharmaceuti-cal products. Since distribution involves less capitalinvestment, it has attracted a large number ofentrepreneurs who may not necessarily havesufficient knowledge or show enough responsibilitytowards the quality handling and safety of pharma-ceutical products.

However, among these are the so-called ‘suitcasemerchants’, who operate by seeking out thosecountries where regulation and enforcement isweak or nonexistent. They offer a source of cheapgoods, but cannot guarantee the quality of supplies.

When buying from wholesalers, ensure that theyare reliable, are known by the regulatory body, andthat they can guarantee the required quality ofproducts. Many international wholesalers conductextensive evaluation and inspection of manufactur-ers, which reduces the need for inspection by thebuyer. Request documentary evidence from thewholesaler which demonstrates inspection by acompetent body. You may also request referencesfrom other sources such as bank institutions, theChamber of Commerce, or fellow overseas buyers.

Public tender: Buyers announcing their require-ments by public tender often attract suppliers whorecognize that many buyers tend to focus on pricealone rather than the quality of the product. Oneway of avoiding this problem is to develop long-term relationships with known wholesalers andmanufacturers. By doing this, the buyer can alsobenefit from significant price discounts or pricefreezing, which may reduce the costs of annualtendering.

National quality control laboratory: Most coun-tries will have an appointed institution such as anational quality control laboratory that is responsi-

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ble for testing the claimed quality of the product.The role of this institution is to ensure that all phar-maceutical products for use in both the public andprivate sectors and in animal health care (veterinaryproducts), as well as the agricultural sector (agro-chemicals), are fit for intended use. All importersand suppliers of these products must be aware ofthe regulations and samples of product batchesmust be supplied for analysis.

Inspection of manufacturers: Most national healthauthorities require that the original source of medi-cal products including drugs, chemicals, diagnosticagents and sterile disposable items is inspectedbefore approval for use. The objective of theseinspections is to ensure that the manufacturerabides by and complies with all licensing, GMP,quality control, and good distribution practices(GDP) requirements as stated in the businessprofile (drug master file). Further, these inspectionsaim to ensure that the products they intend tomarket conform to the stated standards. One of thekey elements of inspection is the demonstration bythe manufacturer that in-house or independentvalidation of all processes affecting the manufac-ture of their licensed products is conducted.

For a manufacturer, the main objective of an in-spection is the demonstration of manufacturinglegitimacy and ability to meet relevant national and/or WHO GMP. The first step for the manufacturer,therefore, is to call for inspection of its premises,processes, procedures and management. Thenational regulatory authorities responsible for thequality of medicinal products for use in human andanimal health conduct such GMP inspections.

Where the manufacturer seeks to market its prod-ucts on the international market, it will call forinspection by an internationally recognized inspec-torate. The results of these inspections are madeavailable to authorities responsible for registeringproducts from that source. The number of times aninspection is conducted will vary depending onnational legal requirements, observations andrecommendations from previous inspections, etc.Inspections tend to be performed once a year, oronce every two years.

It is important to note that inspections can be veryexpensive and most countries, organizations andagencies cannot afford to conduct full inspections.However, these inspections are required to beperformed routinely and a manufacturer must showthat he is inspected independently. Consequently,

manufacturer evaluation may be performed at twolevels. The first will ensure that the manufacturercan provide minimum requirements for manufactureand product quality assurance. Preliminary in-formed and professional judgement on whether ornot to proceed in accepting that manufacturer canthen be made. The second level is to instituteindependent inspection of the manufacturer eitherfully (total infrastructure inspection), or limited toprocesses leading to the manufacture and supply ofthe product of interest.

Inspection of manufacturers’ premises is a legalrequirement, and not an imposition on the manufac-turer and a buyer may request a copy of the inspec-tion report. Additionally, a buyer may undertake anindependent inspection at his own cost. Suchreports tend to be the confidential and privateproperty of the buyer and cannot be used by otherswithout their permission. In view of the costs ofthese inspections, mutual recognition of inspections— whereby two or more purchasers perform oneinspection — may be acceptable to the regulatoryauthorities.

A buyer should purchase from selected manufactur-ers that are inspected routinely by the nationalauthority or, if you buy from a wholesaler, you mustensure that you provide the wholesaler with infor-mation on how products are regulated in the coun-try of import.

Checking qualityWith regard to quality assurance, all factors relatingto the manufacture and supply of finished productsshould be in place and functioning according torequired quality standards. Efforts should be madeto ensure that products in the supply system aresafe, and will not need to be replaced due to failurein quality.

A. About the manufacturerGood manufacturing practice (GMP) certificate:Applies to manufacturers of all medicinal products(drugs and medical devices). This certificate en-sures that products are consistently manufacturedand controlled to quality standards necessary forintended use, and as established by the ‘country oforigin’ regulatory authority. The certificate is issuedfollowing inspection of the premises, manufacturingequipment, personnel, product and marketingdocumentation, in-house quality control, in-houseprocess validation, etc. and is valid for a certainperiod of time. Its usefulness in assessing quality is

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debatable, largely due to the differing rigour withwhich assessments are carried out in differentcountries. None the less, lack of a GMP certificatefrom a manufacturer should be a cause for concern.

ISO Standards: These are standards of generalquality assurance issued by the International Or-ganization for Standardization (ISO), a nongovern-mental organization. The standards are not officialstandards and may be seen as voluntary, unless agovernment adopts them as part of regulatorylegislation. ISO standards apply to manufacturingsystems, or the creation and provision of a service,with a view to assuring customer satisfaction.

The following is information relating to the supply ofpharmaceutical products that must be requestedfrom the manufacturer or the wholesaler:

Country of origin: Regulatory authorities in theend-user’s country may have a list of countries (aswell as of manufacturers) whose regulatory andlicensing procedures are not approved because thequality and safety of the products cannot be guar-anteed. Products from these countries will not beauthorized for importation.

Manufacturer’s name: Information will need to beprovided on whether the name of the manufacturerappearing on the product is that of the actual manu-facturer, whether the product is made by a sub-contractor, and what the implications for productquality, safety and efficacy are.

Current manufacturing licence: Shows that themanufacturer is legally licensed to produce thelisted pharmaceutical products.

Good distribution practice (GDP) certificate:This measure ensures that the quality of products ismaintained during internal and external transportand distribution of goods.

Certificate of a pharmaceutical product (CPP):This certificate is part of the WHO CertificationScheme on the Quality of Pharmaceutical ProductsMoving in International Commerce. The regulatoryauthority in the country of manufacture (exportingcountry) issues this certificate to the regulatoryauthority of the importing country. The certificatecontains all the relevant information on a statedproduct (its manufacture, quality, etc.) that would berequired by regulatory authorities in the importingcountry. A CPP can contain a list of products to besupplied with individual information for each prod-uct.

A CPP relating to one product cannot be taken asacceptable evidence of licensing for another prod-uct not mentioned in the document. As well asindicating that a manufacturer has been licensed toproduce a particular pharmaceutical substance, theCPP also states whether the product is for exportonly, or if it is authorized for use in the country ofmanufacture (issuing country). Finally, it gives anindication of whether the manufacturer is routinelyinspected by the relevant authority.

Free sale certificate: The regulatory authoritiesmay wish to know whether the products beingoffered for sale by the manufacturer or wholesalerare in fact registered for use in the country ofmanufacture. This certificate is supported by aproduct licence (PL) issued by regulatory authori-ties in the manufacturing country; the PL is issuedfor the purpose of marketing and free distribution.However, the WHO certificate of a pharmaceuticalproduct (CPP) is increasingly superseding thisdocument, since many manufacturers tend toproduce for export.

Certificate of analysis (COA): This documentapplies to a specific batch of product being offeredfor sale. It shows whether the product in questionhas been manufactured according to a statedinternational standard by comparing actual chemi-cal analysis of a sample from the batch in questionwith the minimum requirements set out by thestandard chosen. A buyer will generally look forequivalence of British Pharmacopoeia (BP), Euro-pean Pharmacopoeia (EP) or US Pharmacopeia(USP) standards.

It should be noted that in the absence of othersupporting evidence these documents alone do notconstitute guarantees of product quality. However,the inability of a manufacturer or supplier to providesuch basic information should alert you as a buyer.

B. About the wholesalerWhile manufacturers will supply directly to thelarger customers, such as a government centralmedical stores, they tend not to supply to low valuebuyers.

The wholesaler is not a manufacturer, but offers theflexibility to deal with a large number of customers,and has the expertise to source from a wide geo-graphical area and offer goods at affordable cost.Due to low overheads, the wholesaler is also ableto entertain a variation in order sizes, unlike amanufacturer. And this is the advantage wholesal-ers offer.

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As a buyer, you may request the wholesaler toprovide any information normally available from amanufacturer. In addition, a Letter of authoriza-tion to supply can be requested which ensuresthat the wholesaler is legitimately offering productswhich he has the authority to sell.

C. About the agent or representativeMany manufacturers and some wholesalers will nothave offices in the recipient country for businessreasons. In order to effectively market their goods,they normally appoint an agent or representative tolook after their business interests. Increasingly, onefinds that there is a regulatory obligation for anoverseas supplier (manufacturer or wholesaler) tohave such representation in the recipient country.The advantage is that the regulatory authorities andpotential clients have someone to whom they canaddress their concerns and needs. If such an agentis not exclusively representing one supplier, he orshe may be a source of valuable product-relatedinformation (e.g., cost, alternatives, product litera-ture, research papers, brochure, etc.). There aredisadvantages, however. For example, the cost ofthe goods procured through the agent will includecommission. Further, and more worrying, in placeswhere laws and regulations affecting the supply ofmedicinal products are weak, one finds that anyonewith capital can work as an agent. In this case,professionalism or a concern for safety and qualityof the product may be lacking.

D. About the productOriginal manufacturer: As mentioned above, itmay be important to know who is the original manu-facturer of the product. Many manufacturers arenow able to subcontract production of licensedproducts to other local or international manufactur-ers. This is acceptable practice which is necessaryfor economies of scale to be achieved in produc-tion. In this case, the original manufacturer isconsidered to be the contractor. However, thesubcontractor's identity must appear on the docu-ments relating to the product. Further, the subcon-tractor must be inspected with the same rigour asfor the contractor.

Manufacturing date: This date must appear on thelabel and all documents relating to the product.

Expiry date: This date must appear on the labeland all documents relating to the product.

Expected shelf life upon sight or receipt by thebuyer: You may set a standard requirement that allpharmaceutical and other date-related productssuch as consumable items and sterile items musthave a minimum life span once opened. In somecases, the national regulatory authority will have setthis limit, which you must follow.

The supplier must state these dates, or state thatthey will supply goods according to your require-ments, demonstrating that you will receive productsthat meet the shelf life requirements. Note that thisbecomes a contractual obligation on the part of thesupplier.

Label requirements: Clear, informative labels onmedical products are part of regulatory require-ments. Pharmaceutical product labels should state:

• The International Nonproprietary Name (INN) orgeneric name of the active ingredients and formu-lation in addition to the brand-name.

• Pharmacopoeial standard of the formulation (e.g.BP/EP/USP).

• Dosage form (e.g. tablets, capsules, syrup, injec-tion).

• Quantity of active ingredient(s) in the dosageform.

• Appropriate cautionary advice (use, warnings andprecautions),

• Number of units per package.

• Batch number.

• Date of manufacture.

• Expiry date of the product.

• Storage or handling instructions.

• Manufacturer’s name and contact details.

If the product carries the wholesaler's logo, thelabel must also contain the manufacturers nameand all other details listed above.

Quality of packaging (both inner and outer):Packaging is also an important issue, particularly asit can have a substantial impact on damage intransit/storage and on potential degeneration ofproducts. Do not be afraid to ask your supplier whatkind of packaging you can expect to receive as partof the price. Inadequate packaging can cause verysignificant hidden costs to purchasers.

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E. Heat-sensitive productsCold storage items refer to those medical productsthat are heat sensitive; that is, their efficacy isdependent on the surrounding temperature. Effec-tiveness may be reduced by a decrease or increasein the surrounding temperature. It is important tonote that most terms apply to temperate climatesand in many cases may not apply to the tropics orother climatic zones.

Generally speaking, substances that appear in thepharmacopoeias are formulated to be stable at aspecific temperature, or within a range of tempera-tures. One of the tests performed to this end is theaccelerated stability test, where a batch undergoesa series of temperatures for a defined period oftime, to assess product viability and thereforeeffectiveness. Depending on the product, tempera-tures may range from freezing to simulated tem-peratures found in extreme conditions. The market-ing licence will be related to these and other fac-tors.

If a product is reformulated to be stable at non-standard temperatures, it ceases to be a standardproduct (i.e., it cannot be referred to BP or USP).Be aware that products developed to be stable attemperatures prevailing in tropical areas will need anew monograph and may require specific stability,safety and bioequivalence tests and further clinicaltrials. This is a very expensive process.

Store frozen: This refers to some products such asvaccines which need to be transported within a coldchain and stored at –20 °C.

Store at 2–8 °C: This is for very heat sensitiveproducts. Products must not be frozen. Traditionallythey are kept in the first and second part of therefrigerator (never the freezer compartment).

Keep cool: This will mean storage between8–15 °C. Traditionally, the bottom part of a refrig-erator.

Store at room temperature: This is generallyassumed to mean storage at 15–25 °C.

Store at ambient temperature: This meansstorage at the surrounding temperature. Not awidely used term, due to significant variation inambient temperatures. It must be assumed to mean‘room temperature’ as above.

Storage: This means keeping in one place, andcan be short-term (such as the period of waiting tobe sent to consumer), medium-term (as whenwaiting at freight forwarders) or long-term (longterm storage at the consumer’s premises).

Storage temperature: Advice from the manufac-turer applies to long-term storage at the supplier’spremises, at the freight forwarder’s premises and atthe consumer’s premises. The supplier will holdsuch items in stock at the specified temperature.The freight forwarder is expected to keep the itemat this specified temperature if the length of time itwill take to actually ship the item is longer than therecommended period.

Transit: refers to the period in which a product isbeing shipped from one place to another.

Transit time: This is the time a product is in thestate of moving from one point of storage (forexample, the wholesaler’s warehouse or the freightforwarder’s warehouse) to another point, the latterbeing a point of medium- to long-term storage.Manufacturers will recommend a time-scale inwhich a ‘keep cool’ item can remain outside itsstorage temperature.

Transit temperature: Where a product requiresshipment at a specific storage temperature, themanufacturer will recommended the appropriatetemperature.

F. Medical equipment and medical devicesThis is one of the rather complex areas of procure-ment and supply. There is no essential list of com-monly used medical equipment and devices. Whileit may be considered ‘generic’ to use the descrip-tion ‘X-ray machine’ or ‘ultrasound machine’, thisdoes not suggest that these machines are availablein generic form. They remain heavily patent boundand available to buyers in brand form. This situationapplies equally to surgical instruments which tendto be known by a combination of the descriptiveand name function e.g. Lange Hohmann elevator,for reducing fractures; Kocher intestinal clamp, forocclusion of a section of intestine, rather than somegeneric functional name. This also applies mostfamously to suturing materials, where the manufac-turer and brand name Ethicon is accepted as analternative name for ‘suture’. Users of equipmenttend to be the ones who decide on the machine tobuy for their facility or practice.

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As users change, new staff will also request thepurchase of different machines or products, reflect-ing their own experiences of those machines, andnot other makes. Consequently, there is no univer-sally agreed minimum requirement with respect tospecifications or quality. The cost of procuring newand discarding other makes of machines canaccount for a great proportion of public healthexpenditure. There is therefore a serious need tostandardize equipment at all levels of health careservices. This not only saves money, but it alsohelps in training. It is advisable to use a source withan appropriate level of technical knowledge of theproducts, who can advise and give support wherenecessary.

Owing to the absence of clear guidelines, variationsexist in the quality and specifications of productsavailable in the market place. When it comes tolarger capital items, either new or reconditioned,issues such as reliability, technological appropriate-ness, mains supply (voltage and frequency), war-ranties, spare parts/technical support and consist-ency with what is already available in a country areall factors which should be borne in mind.

Ready-made kits: In certain situations, particularlyin the initial response phase of a rapid onset emer-gency or when building up a specialty or primaryfacility from scratch, ready-made kits offered by anumber of suppliers can sometimes be a verypractical way forward. However, buyers should beaware that even where kit contents are supposedlystandardized, such as with the WHO New Emer-gency Health Kit 1998, variations in product qualityand specifications between suppliers could beenormous. Quality assurance considerations whichare applicable to pharmaceuticals, consumablesand equipment generally should also be applied tothe individual components within a ready-made kit.

G. SamplesHealth authorities may advise that samples ofmedicinal or consumable products, or certainmedical devices should be supplied to the appropri-ate regulatory authority. The regulatory body willimpose requirements for samples needed in qualitycontrol testing or for the retention of a referencesample.

The requirement for samples applies mainly topharmaceuticals and sterile consumable products.Rarely would the authorities require samples ofexpensive capital equipment, such as X–ray ma-chines, preferring to inspect the products at the

point of manufacture or wholesale. Ensure familiar-ity with any requirements and request the supplierto provide samples whenever possible.

Sample invoice: The supplier will raise an invoiceof all required samples for the attention of customs.The invoice must show that the goods are forsample purposes only, and that they are free-of-charge to the customer, and have no commercialvalue. There should be no requirement to pay dutyon samples. However, this should be verifiedthrough the customs office.

Terms and definitionsfor medical equipment

Capital Equipment: This term is used loosely todescribe whatever medical equipment has requiredconsiderable capital to finance its procurement. Forexample, a self-financing primary health carecentre may describe forceps as capital equipment,whereas a referral hospital may not. Therefore, itdepends on the buyer to define what is meant by‘capital equipment’.

Consumable Products: This term refers to non-medicinal products. These products are ‘con-sumed’ and require regular replacement. This termcan apply to disposable sterile items such assyringes, needles, cannulae, etc.

ISO Standards: These are standards of generalquality assurance issued by the InternationalOrganization for Standardization (ISO), a non-governmental organization. The standards are notofficial standards and may be seen as voluntary,unless a government adopts them as part of regu-latory legislation. ISO standards apply to manufac-turing systems, or the creation and provision of aservice, with a view to assuring customer satisfac-tion.

ISO 9000 to 9004: refer to Quality Managementand Quality Systems. In this group, other relatedISOs are 8402 and 1013. These standards recom-mend modern approaches to management andhow to assure general product quality. They there-fore cover issues such as quality policy, manufac-turing process, design and development, construc-tion, installation and services.

European Norms (EN): These are standardssimilar to ISOs set by the European Union. Forexample, EN 29000 is identical to ISO 9000; EN45001 is similar to ISO 9001.

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The European Committee for Standardization(CEN): The CE symbol (which is the CEN’s seal ofapproval) indicates that the products are manufac-tured in accordance with ISO 9001 and EN 46001.This specifically applies to medical devices andsurgical products for use within the EU.

In the same way that the manufacture of pharma-ceutical products is subcontracted, a number ofmanufacturers of medical devices and surgicalproducts (cannulae, catheters, etc) based in the EUsubcontract the manufacture of these productsoutside the EU (either through pure subcontracting,or through joint venture agreements). In this event,the subcontracted party must meet the same rigourof quality assurance as expected of an EU-basedmanufacturer.

While many buyers use the CE symbol as thehighest indicator of quality, they miss out on anumber of excellent and good quality productsproduced specifically for non-European markets bymanufacturers outside the EU.

Electrical Safety: With electrical equipment, it isworth asking what safety and performance stand-ards the item you are buying meets. This informa-tion will tend to appear on technical specificationsheets and in operation and service manuals, but ifin doubt, ask the supplier to clarify. The mainaccepted international standards for both electricalsafety and performance are those set by the IEC(International Electrotechnical Commission) inGeneva.

Uninterruptible Power Supply (UPS): Whenordering electrical equipment, you should not forgetthe importance of obtaining a stabilizer or UPS asappropriate, to protect electrical equipment frompossible damage due to uncontrolled fluctuations inelectrical supply.

When looking at complex or expensive capitalequipment, it is prudent to stick to well-known andreputable manufacturers. Check which ones canoffer technical support in the region where theequipment will be in operation. It is wise to buy fromsuppliers who have both the technical capacity andthe ability to support you with accessories, spareparts, advice, technical backup and support as wellas in troubleshooting, maintenance, servicing andrepair.

Responsibilities of the partiesThe following categories of responsibilities areimportant with respect to claims being made ifgoods are damaged during storage at any one pointor during transit. The point handling cold storageitems would be liable in the event the goods weredamaged due to being kept at the wrong tempera-ture, or under wrong storage conditions

The supplierThe supplier is expected to :

• Ensure that appropriate storage facilities for heat-sensitive products are available and in workingorder;

• Store the products at the recommended tempera-ture;

• Ship the goods at the recommended temperature(documentation and information on packs tofollow); and

• Inform the freight forwarder and the customerabout the storage and transit requirements andrecommendation for heat-sensitive products beingshipped as set out in the shipping documents.

Freight forwarder• Ensures that appropriate storage facilities for

heat-sensitive products are provided;

• Refers to shipping documents for information onheat-sensitive products;

• Stores the goods at the recommended storagetemperature, as advised on documents and onpacks.

• Ships the goods at the recommended tempera-ture; and

• Ensures that the delivery period will be within therecommended transit time and temperature re-quirements will be respected.

Freighter or carrier• Ensures that appropriate storage facilities for

heat-sensitive products are available at theirpremises;

• Ensures that they have appropriate storage facili-ties for heat-sensitive products on board thechosen vessel or aircraft;

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• Refers to shipping documents for information onheat-sensitive products; and

• Ensures that the delivery period will be accordingto the recommended transit time and temperature.

Customs• Will ensure that they have appropriate storage

facilities for heat-sensitive products;

• Will refer to shipping documents for information onheat-sensitive products;

• Will receive heat-sensitive goods upon arrival;

• Will store heat-sensitive goods at recommendedtemperature as advised by the supplier (shippingdocuments); and

• Will inform the end-user of the arrival and storageof heat-sensitive products at customs.

Customer (end-user)• Ensures that appropriate cold storage facilities are

available;

Depending on the freight contract:

• Refers to shipping documents for information onheat-sensitive products;

• Clears through customs all heat-sensitive prod-ucts upon arrival in timely manner;

• Stores heat-sensitive products at recommendedtemperature.

Freight: shipping goodsand the risks involvedShipping of goods is a cost to be considered as partof the overall price. A variety of freight contracts areavailable to both the buyer and seller when ship-ping goods. Knowing the types of contracts avail-able enables an informed choice in freighting ofgoods. Knowing and selecting the appropriatecontract may often reduce the cost of procurement.

The method or mode selected to ship goods to theend-user or buyer’s destination must be seen as acontract to supply. This is the second part of theprocurement exercise, the first being the actualplacing of the order for the goods. Various freightcontracts are available, based on the InternationalChamber of Commerce terms: the current editionbeing INCOTERM 2000. These terms have histori-

cally applied to shipping of goods by sea andcarriage by road. However, they now apply to air;where a shipper or carrier is used, terms will applyto both ‘ship for sea freight’ and ‘airfreight’ carrier.

It is important to note that INCOTERMS are volun-tary and provide importers and exporters withguidelines on the responsibilities to be borne by theparties. Being terms that are reviewed annually, it isimportant to keep and refer to current terms in use.

CostsIt is important to define the term ‘Free’ as set out insome of the contracts. This does not mean that thebuyer is exempt from paying for the service. As withall other freight contracts, the cost of shipping is tobe borne by the buyer. In this event, it may beprudent to request the separation of freight andinsurance charges from the cost of goods.

Risks of loss or damage to goodsA number of freight contracts require that insuranceis taken out against loss or damage of goods. Inthese contracts, the risk and the cost of coveringsuch a risk is borne either by the seller (in the eventthe buyer has not requested insurance) or by thebuyer. Risk is, however, passed on from seller tothe buyer once the goods become the responsibilityof the buyer.

Terms and definitionsThe following are the most common freight contractterms:

Ex Works (at sellers’ premises): The seller’s onlyobligation is to provide goods at his premises forcollection by the buyer. It is the buyer’s responsibil-ity and obligation to load the goods and transportthem to the buyer’s destination.

FCA (Free Carrier to a named port of carriage):The seller’s obligation is to deliver goods into thehands of the first or only carrier, present at a namedport of carriage (seaport or airport). The buyer’sresponsibility is to pay for the onward shipment ofgoods to the destination.

FAS (free alongside ship): The seller’s obligationis to ensure that the goods are placed alongside theship, on the loading platform (or quay). The sellerwill be charged up to this point and it is for thebuyer to pay for the loading and onward shipping.This generally applies to sea freight.

FOB (free on board the carrier at a named portof shipment): The seller is responsible for placing

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the goods on board the first ship or carrier at astated port of shipment. Once the goods pass therails of the ship and are on the ship’s platform, therisks and responsibility pass onto the buyer, and sodoes the cost of onward shipping.

CFR (cost and freight to a named port of desti-nation): The seller covers all cost for freight ofgoods to a named destination port. Once the goodsleave the ship, the risk and other costs become theresponsibility of the buyer.

CIF (cost, insurance and freight to a named portof destination): As above, but the seller also paysfor the insurance on behalf of the buyer against lossor damage to goods. This cost is passed onto thebuyer.

Where insurance is not included, the seller maytake out additional insurance cover for loss ordamage to goods.

CPT (carriage paid to a named place of destina-tion): The sellers’ responsibility is to pay for freightof goods to the destination, loading onto the firstcarrier at the destination port. Costs of using subse-quent carriers will be borne by the buyer.

CIP (carriage, insurance paid to a named placeof destination): As under CPT, but that the sellerhas insured against loss or damage to goods duringtransportation to the first carrier.

DAF (delivered at frontier of a named port ofentry): The seller’s obligation (cost and risk) termi-nate once the goods arrive at the port of entry of anamed country, and the export clearance has beengranted. The buyer is obliged to pay for customsclearance and onward transportation in the country.

DES (delivered ex-ship, at port of destination):This means that the seller will bear the cost ofshipping the goods up to the docking of the ship atthe port of destination, making the goods availableto the buyer. It is then the buyer’s responsibility forcustoms clearance and unloading the goods, andfor onward carriage.

DEQ (delivered ex-quay at port of destination):The seller is obliged to present the goods to thebuyer at the quay or wharf at the destination port.That is, the seller pays for unloading of goods offthe ship and onto the quayside, bearing all risks.The buyer is responsible for customs clearance.DEQ is further subdivided into:

• Ex-quay duty paid: where the seller payscustoms duty; or

• Ex-quay duty on buyer’s account: where theduty is paid by the seller, but is then reimbursedby the buyer.

DDU (delivered duty unpaid to named port ofdestination): The seller covers all costs and risksfor taking the goods to the port of destination, thegoods remaining uncleared, import arrangements tobe administered by the buyer. The seller is notresponsible for duty or taxation.

DDP (delivered duty paid to named place ofdestination): This is where the seller delivers thegoods to the buyers’ door, meeting all costs andrisks incurred, including duties. Of course, thiscontract may be negotiated to exempt the sellerfrom paying local value added tax (VAT) and taxes.

Where one has no experience in freighting goods, itis best to contract an established freight forwarderwho can act on your behalf and make these ar-rangements for you (at a fee). Using establishedfreight forwarders can result in great savings incosts, as they have access to price cuts that maynot be available to the small or inexperiencedbuyer.

Taxes and dutiesValue added tax (VAT): An added cost to theprocurement of medical products is VAT or value-added tax, collected by the government. It is apercent charge of the value of the goods beingsold. This VAT affects those buyers based in thecountry of the seller (manufacturer or wholesaler).Many organizations based in Europe, purchasingmedical products in Europe for use overseas, arecharged VAT. They can claim this fee back fromcustoms at the time of export of goods. A qualitysupplier will provide you with all documents relatingto reclaiming VAT. However, an organization canbe VAT-exempt (i.e., it has this notification), andmay not be charged this tax if the goods procuredare for charitable work in-country, or for use over-seas.

Many charitable and nongovernmental organiza-tions providing health care services in developingcountries qualify for VAT-exemption. A buyershould be aware of the VAT status. If this status isunknown, VAT may be charged by the seller, thusincreasing costs unnecessarily.

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Customs duty: A duty is charged on all types ofgoods exported and imported. The organizationexporting goods to its projects overseas will have topay duty at the time of export, and duty in thecountry of import. In some cases, an organizationoffering charitable or free-of-charge health careservices, may be exempt from paying these duties.However, this is an exception rather than the rule.

As a buyer, you need to be familiar with the dutiesto be paid. Do find out if you are exempt frompaying duties in the recipient country. In somecases, religious organizations offering health careare also exempt from duties and VAT.

ConclusionMany quality assurance processes are involvedbefore medical products are finally delivered to theend-user. Procurement is a complex system, whichdoes not end at the point of needs assessment andplacing an order. Awareness of various aspects ofprocurement, such as product quality, countryregulations, etc., is crucial to carrying out the tasksuccessfully.

The same need to be knowledgeable applies tomanufacturers and more so to wholesalers. Medicalsuppliers nowadays come in a variety of shapesand sizes, and with varying levels of expertise,understanding and quality assurance capability. Asupplier’s competence in terms of understandingand quality assurance of the products which areoffered should always be questioned rather thanassumed. A competent and professional supplierwill be able to give you details not only of their ownquality controls on the products that they sell, butalso provide you with basic documentary evidencefrom the manufacturer confirming that they areauthorized, competent and manufacturing to certainspecifications. A supplier unable to provide thisbasic evidence is not fulfilling a crucial element oftheir responsibility which is the consistent andreliable supply of quality products.

Knowledge of related policy issues is important, aseconomic and political matters become increasinglyintertwined in health care provision. Information isneeded in order to understand the issues. Whilearguments persist about the role of industry inpublic health care, it is important to understand thebackground to these discussions.

Further reading and sources of information:

1. World Health Organization. Guidelines for Drug Dona-tions. WHO/EDM/PAR/99.4 (1999).

2. World Health Organization. Good ManufacturingPractices for Pharmaceutical Products . Technical ReportSeries, No. 823, 1992, Annex 1.

3. World Health Organization. Operational Principles forGood Pharmaceutical Procurement. WHO/EDM/PAR/99.5(1999).

4. World Health Organization. Certification Scheme on theQuality of Pharmaceutical Products Moving in Interna-tional Commerce. WHO/PHARM 82.4 Rev.5.

5. Rosenberg, H. Incoterms Update. In: Overseas Trade(Trade Finance), 26–27 (2000). www.brittrade.com/dbt

6. Rowbotham, M. Considering Customs . In: OverseasTrade (Customs), 24–26.(2000).

7. Hodgetts, M. Good Cause and Effect on StrategicBuying by Charities. In: Supply Management, 24–27(2000). (www.supplymanagement.co.uk).

8. Kennedy, D. Sweet and Sour Source (Sourcing inChina). In: Supply Management, 30–31 (2000).

9. International Chamber of Commerce. InternationalRules for the Interpretation of Trade Terms , 1990. Avail-able from: ICC, 14 Belgrave Square, London SW1X 8PSwww.iccwbo.org

10. IFPMA Code of Pharmaceutical Marketing Practicesand International Conference of Harmonisation (ICH)..International Federation of Pharmaceutical ManufacturersAssociations (IFPMA), 1211 Geneva 18, Switzerland. Tel:+41 (22) 340 12 00 Fax +41 (22) 340 13 80at: [email protected] or: www.ifpma.org

11. CEN Management Centre, 36 rue de Stassart, B-1050Brussels, Tel: +32 2 550 08 19; Fax: +32 2 550 08 11; at:[email protected] or: www.cenorm.be.

12. The American Society for Quality, 611 East WisconsinAvenue, P.O. Box 3005, Milwaukee, WI 53201-3005www.asq.org

13. ECHO International Health Services Limited, UllswaterCrescent, Coulsdon, Surrey, CR5 2HR, UK. Tel: +44(0)20 8660 2220; Fax: +44 (0)20 8668 0751; at:[email protected] or: www.echohealth.org.uk.

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14. Quality Systems for Pharmaceutical Inspectorates.Pharmaceutical Inspection Convention (PIC) and (PIC/S)Presentation at a seminar held in Zeist (Holland) 9–12June 1998. Available from: European Free Trade Associa-tion (EFTA), 9–11 rue de Varembe, CH-1211 Geneva 20,Switzerland)

15. Sharp, J. British Standards on Quality and the ISO9000 Series. In: Quality in the Manufacture of Medicinesand Other Healthcare Products. Pharmaceutical Press96–104 (2000)

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16. Sharp, J. The Regulatory Factor. In: Quality in theManufacture of Medicines and Other Healthcare Products.Pharmaceutical Press, 29–41 (2000).

17. One CE marking. Council Directive, 93/42/EEC,European Commission, 14 June 1993. www.eudra..org

18. Management Sciences for Health. Managing DrugSupply : Selection, Procurement, Distribution and Use ofPharmaceuticals in Primary Health Care, (1997).

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Recent Publications andSources of InformationNIH guidelines forstem cell researchThe US National Institutes of Health (NIH) haspublished its Guidelines for Research InvolvingHuman Pluripotent Stem Cells. The Guidelinesdescribe the documentation and assurances thatmust accompany requests for NIH funding forresearch using human pluripotent stem cells fromhuman embryos or fetal tissue. They state specificcriteria for informed consent and establish a reviewgroup to decide on compliance with the guidelines,thereby ensuring that NIH-funded research isconducted in an ethical and legal manner. Onlycells derived from frozen embryos that were cre-ated for the purposes of fertility treatment and werein excess of clinical need may be utilized. TheGuidelines prohibit the use of inducements fordonation of an embryo. The Guidelines set outthose areas where NIH will not provide funding,including research which creates or contributes to ahuman embryo, utilizes human pluripotent stemcells derived using somatic cell nuclear transfer, orthose combined with an animal embryo.

Human pluripotent stem cells can give rise to manydifferent types of cells, such as muscle, nerve,heart and blood cells. Research in this area couldhelp scientists to generate cells and tissue for usein transplantation to treat many diseases or toimprove understanding of the complex events thatoccur during normal human development and whatcauses diseases and conditions such as birthdefects and cancer.

Guidelines for Research Involving Human PluripotentStem Cells. Federal Register, 25 August 2000.

Opioid control policy:self assessment guidelinesThe purpose of these self-assessment guidelines isto encourage governments to achieve better painmanagement of cancer patients by identifying andovercoming regulatory barriers to opioid availability.The guidelines are intended for those who decide

national drug control policy and those who imple-ment it. Balance is needed to prevent illegal traffick-ing and diversion of opioids, while ensuring avail-ability for medical and scientific purposes.

Information is provided on the global problem ofinadequate cancer pain relief and why opioids areneeded. There are three barriers to adequate painmanagement: economic, medical and regulatory.While the Guidelines focus solely on regulatoryissues, it is well understood that other barriers playmajor roles, such as the inappropriate prescribingof expensive medication which is ineffective in late-stage cancer.

Achieving balance in national opioid control policy: Guide-lines for assessment. WHO/EDM/QSM/2000.4. Availablefrom: Quality Assurance and Safety: Medicines, EssentialDrugs and Medicines Policy, World Health Organization,Geneva.

Australian therapeutic guidelineson antimicrobialsThe Eleventh edition of Therapeutic Guidelines:Antibiotics has now been published. The guidelinesare endorsed by the Royal Australian College ofGeneral Practitioners and the National PrescribingService. They cover principles of antimicrobial useand contain in-depth information on infections anddiseases and the way they should be treated.Adverse reactions, interactions and the dangers ofresistance are set out in the appendices.

Therapeutic Guidelines: Antibiotics. Available from:Therapeutic Guidelines Ltd., Melbourne, Australia by e-mail: [email protected] or on http://www.tg.com.au

Reliable quality informationand the InternetGuidelines for medical and health information siteson the Internet have been published by the Ameri-can Medical Association (AMA). Access to medicalinformation through the Internet has the potential to

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speed the transformation of the patient-physicianrelationship from that of a physician providingadvice and treatment to that of shared decisionmaking between patient and physician.

Barriers to the provision of independent informationthrough the Internet include wide variations inquality of information, commercial interests whichinfluence Web site content, and uncertain preserva-tion of personal privacy. For example, insurers oremployers could monitor what diseases Web usersresearch.

To address these issues, the AMA has developedprinciples to guide development and posting ofInternet content, govern acquisition of informationand posting of online advertising and sponsorship,ensure site visitor and patient rights to privacy andconfidentiality and provide effective and securemeans of e-commerce. Although developed for theAMA Web sites, these principles may also be usefulto other providers and users of medical informationon the Internet.

Available from: Journal of the American Medical Associa-tion, 515 N State St. Chicago, IL60610, USA or http://jama.ama-assn.org.

Standards for Internet pharmaciesThe Council of the Royal Pharmaceutical Society inthe United Kingdom has published standards ofgood professional practice for those who wish toprovide pharmaceutical services via the Internet.For some time the Council has been aware of thedevelopment of on-line pharmacy services and hasbeen working to identify the specific issues suchdevelopments raise. The standards will be updatedas required.

The standards deal with protection of the confidenti-ality and integrity of patient information and requirethat all information must be encrypted and complywith National Health Service security standards.Pharmacists providing on-line pharmacy servicesmust advise patients to seek consultation wheneverthis is judged necessary. A questionnaire appropri-ate to the product must be completed and adviceoffered on all purchases. All information providedmust comply with the marketing authorization,patient advertising leaflet and advertising regula-tions. A record should be kept of any recommenda-tions made, and the pharmacy must retain recordsfor two years of all purchasers and the medicinessold.

Standards for the provision of on-line pharmacy services.Available from: Royal Pharmaceutical Society, 1 LambethHigh Street, London SE1 7JN, United Kingdom

Recent Publications and Sources of Information

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WHO Drug Information, Vol. 14, No. 3, 2000 RECOMMENDED INN: List 44

International Nonproprietary Names forPharmaceutical Substances (INN)

RECOMMENDED International Nonproprietary Names(Rec. INN): List 44

Notice is hereby given that, in accordance with paragraph 7 of the Procedure for the Selection of RecommendedInternational Nonproprietary Names for Pharmaceutical Substances [Off. Rec. Wld Health Org., 1955, 60, 3 (ResolutionEB15.R7); 1969, 173, 10 (Resolution EB43.R9)], the following names are selected as Recommended InternationalNonproprietary Names. The inclusion of a name in the lists of Recommended International Nonproprietary Names doesnot imply any recommendation of the use of the substance in medicine or pharmacy.Lists of Proposed (1–73) and Recommended (1–35) International Nonproprietary Names can be found inCumulative List No. 9, 1996.

��

Dénominations communes internationales RECOMMANDÉES(DCI Rec): Liste 44

Il est notifié que, conformément aux dispositions du paragraphe 7 de la Procédure à suivre en vue du choix deDénominations communes internationales recommandées pour les Substances pharmaceutiques [Actes off. Org.mond. Santé, 1955, 60, 3 (résolution EB15.R7); 1969, 173, 10 (résolution EB43.R9)] les dénominations ci-dessoussont choisises par l’Organisation mondiale de la Santé en tant que dénominations communes internationalesrecommandées. L’inclusion d’une dénomination dans les listes de DCI recommandées n’implique aucune recommandationen vue de l’utilisation de la substance correspondante en médecine ou en pharmacie.On trouvera d’autres listes de Dénominations communes internationales proposées (1–73) et recommandées (1–35) dans la Liste récapitulative No. 9, 1996.

� ��

Denominaciones Comunes Internacionales RECOMENDADAS(DCI Rec.): Lista 44

De conformidad con lo que dispone el párrafo 7 del Procedimiento de Selección de Denominaciones ComunesInternacionales Recomendadas para las Sustancias Farmacéuticas [Act. Of. Mund. Salud, 1955, 60, 3 (ResoluciónEB15.R7); 1969, 173, 10 (Resolución EB43.R9)], se comunica por el presente anuncio que las denominaciones quea continuación se expresan han sido seleccionadas como Denominaciones Comunes Internacionales Recomendadas.La inclusión de una denominación en las listas de las Denominaciones Comunes Recomendadas no suponerecomendación alguna en favor del empleo de la sustancia respectiva en medicina o en farmacia.Las listas de Denominaciones Comunes Internacionales Propuestas (1–73) y Recomendadas (1–35) se encuentranreunidas en Cumulative List No. 9, 1996.

184

RECOMMENDED INN: List 44 WHO Drug Information, Vol. 14, No. 3, 2000

Proposed INN Chemical name or description: Action and use: Molecular formula(Latin, English, French, Spanish) Chemical Abstracts Service (CAS) registry number: Graphic formula

DCI Proposée Nom chimique ou description: Propriétés et indications: Formule bruteNuméro dans le registre du CAS: Formule développée

DCI Propuesta Nombre químico o descripción: Acción y uso: Fórmula empíricaNúmero de registro del CAS: Fórmula desarrollada

adalimumabumadalimumab immunoglobulin G 1 (human monoclonal D2E7 heavy chain anti-human

tumor necrosis factor), disulfide with human monoclonal D2E7k-chain,dimer

adalimumab immunoglobuline G1, anti-(facteur a de nécrose tumorale humain) (chaînelourde de l’anticorps monoclonal humain D2E7), dimère du disulfure avec lachaîne��de l’anticorps monoclonal humain D2E7

adalimumab inmunoglobulina G1 (anti-factor � de necrosis tumoral humano), dímero deldisulfuro de la cadena pesada D2E7 monoclonal humana con la cadena �D2E7 monoclonal humana

adrogolidumadrogolide (5aR,11bS)-4,5,5a,6,7,11b-hexahydro-2-propylbenzo[f]thieno[2,3-

c]quinoline-9,10-diol diacetate (ester)

adrogolide diacétate de (5aR,11bS)-2-propyl-4,5,5a,6,7,11b-hexahydrobenzo[f]thieno=[2,3-c]quinoléine-9,10-diyle

adrogolida diacetato (éster)de (5aR,11bS)-4,5,5a,6,7,11b-hexahidro-2-propilbenzo=[f]tieno[2,3-c]quinolina-9,10-dilo

C22H25NO4S

NH

S

H3C

H

H

O

H3C

OH3C

O

O

alemcinalumalemcinal 8,9-didehydro-N-demethyl-9-deoxo-4'’,6,12-trideoxy-6,9-epoxy-

N-ethylerythromycin

alemcinal (2R,3S,4R,5R,8R,9S,10S,11R,12R)-5-éthyl-11-[[3-(éthylméthylamino)-3,4,6-tridésoxy-�-D-xylo-hexopyranosyl]oxy]-3-hydroxy-2,4,8,10,12,14-hexaméthyl-9-[(3-C-méthyl-3-O-méthyl-2,4,6-tridésoxy-�-L-erythro-hexopyranosyl)oxy]-6,15-dioxabicyclo[10.2.1]pentadec-1(14)-én-7-one

185


alemcinal 8,9-dideshidro-N-desmetil-9-desoxo-4'’,6,12-tridesoxi-6,9-epoxi-N-etileritromicina

C38H67NO10

O

H

CH3

CH3

H

H

H CH3H

H

O

CH3

CH3

H

O

N

CH3

OH

O

O

OCH3

CH3

CH3

O

CH3H3C

HO

H3C

OH3C

H

altiniclinumaltinicline (-)-5-ethynylnicotine

altinicline (-)-3-éthynyl-5-[(2S)-1-méthylpyrrolidin-2-yl]pyridine

altiniclina (-)-5-etinilnicotina

C12H14N2

N

CH

N

CH3

H

amiglumidumamiglumide (R)-4-(2-naphthamido)-N,N-dipentylglutaramic acid

amiglumide acide (4R)-5-(dipentylamino)-4-[(naphtalén-2-ylcarbonyl)amino]-5-oxopentanoïque

amiglumida (R)-4-(2-naftamido)-N,N-dipentilglutarámico

C26H36N2O4

NH

NCH3

CH3HO

O

CO2H

186


anisperimusumanisperimus [(6-guanidinohexyl)carbamoyl]methyl [4-[[(R)-3-aminobutyl]amino]butyl]=

carbamate

anispérimus [4-[[(3R)-3-aminobutyl]amino]butyl]carbamate de2-[(6-guanidinohexyl)amino]-2-oxoéthyle

anisperimus [4-[[(R)-3-aminobutil]amino]butil]carbamato de[(6-guanidinohexil)carbamoil]metilo

C18H39N7O3

H2N NH

HN

O NH

HN NH2

NH

O

O

H CH3

ataquimastumataquimast 1-ethyl-3-(methylamino)-2(1H)-quinoxalinone

ataquimast 1-éthyl-3-(méthylamino)quinoxalin-2(1H)-one

ataquimast 1-etil-3-(metilamino)-2(1H)-quinoxalinona

C11H13N3O

N

N

O

H3C

HN

CH3

axitiromumaxitirome ethyl (±)-4'-[[�-(p-fluorophenyl)-�,4-dihydroxy-m-tolyl]oxy]-

3',5'-dimethyloxanilate

axitirome ��

axitiromo (±)-4'-[[�-(p-fluorofenil)-�,4-dihidroxi-m-tolil]oxi]-3',5'-dimetiloxanilato de etilo

C25H24FNO6

and enantiomeret énantiomèrey enantiómero

HN

O CH3

O

H OH

F HO

CH3

H3C

O

O

187


bilastinumbilastine p-[2-[4-[1-(2-ethoxyethyl)-2-benzimidazolyl]piperidino]ethyl]-

�-methylhydratropic acid

bilastine acide 2-[4-[2-[4-[1-(2-éthoxyéthyl)-1H-benzimidazol-2-yl]pipéridin-1-yl]éthyl]phényl]-2-méthylpropanoïque

bilastina ácido p-[2-[4-[1-(2-etoxietil)-2-bencimidazolil]piperidino]etil]-�-metilhidratrópico

C28H37N3O3

N

N

OH3C

N

CO2H

CH3H3C

binetrakinumbinetrakin interleukin 4 (human)

binétrakine interleukine 4 humaine

binetrakina interleuquina 4 (humana)

HKCDITLQEI IKTLNSLTEQ KTLCTELTVT DIFAASKNTT

EKETFCRAAT VLRQFYSHHE KDTRCLGATA QQFHRHKQLI

RFLKRLDRNL WGLAGLNSCP VKEANQSTLE NFLERLKTIM

REKYSKCSS

cangrelorumcangrelor N-[2-(methylthio)ethyl]-2-[(3,3,3-trifluoropropyl)thio]-5'-adenylic acid,

monoanhydride with (dichloromethylene)diphosphonic acid

cangrélor monoanhydride dichlorométhylènediphosphonique N-[2-(méthylsulfanyl)éthyl]-2-[(3,3,3-trifluoropropyl)sulfanyl]-5’-adénylique

cangrelor monoanhidrido del ácido N-[2-(metiltio)etil]-2-[(3,3,3-trifluoropropil)tio]-5'-adenílico con ácido (diclorometileno)difosfónico

188


C17H25Cl2F3N5O12P3S2

N

N N

N

O

OHOH

OP

OP

NH

S

SH3C

F3C

P

O OHHO O

ClCl

O

HO

HO

cetuximabumcetuximab immunoglobulin G 1 (human-mouse monoclonal C225 �1-chain anti-human

epidermal growth factor receptor), disulfide with human-mouse monoclonalC225 �-chain, dimer

cétuximab immunoglobuline G1, anti-(récepteur du facteur de croissance humain del’épiderme) (chaîne �1 de l’anticorps monoclonal chimérique homme-sourisC225), dimère du disulfure avec la chaîne � de l’anticorps monoclonalchimérique homme-souris C225

cetuximab inmunoglobulina G 1, anti-(receptor del factor humano de crecimiento de laepidermis)(cadena �1-del anticuerpo monoclonal quimérico hombre-ratónC225), dímero del disulfuro con la cadena � del anticuerpo monoclonalquimérico hombre-ratón C225

cilomilastumcilomilast cis-4-cyano-4-[3-(cyclopentyloxy)-4-

methoxyphenyl]cyclohexanecarboxylic acid

cilomilast acide cis-4-cyano-4-[3-(cyclopentyloxy)-4-méthoxyphényl]cyclohexanecarboxylique

cilomilast ácido cis-4-ciano-4-[3-(ciclopentiloxi)-4-metoxifenil]ciclohexanocarboxílico

C20H25NO4

CO2H

NC

HO

H3CO

conivaptanumconivaptan 4'’-[(4,5-dihydro-2-methylimidazo[4,5-d][1]benzazepin-6(1H)-yl)carbonyl]-

2-biphenylcarboxanilide

conivaptan N-[4-[(2-méthyl-4,5-dihydroimidazo[4,5-d][1]benzaépin-6(1H)-yl)carbonyl]phényl]biphényle-2-carboxamide

conivaptán 4'’-[(4,5-dihidro-2-metilimidazo[4,5-d][1]benzazepin-6(1H)-il)carbonil]-2-bifenilcarboxanilida

189


C32H26N4O2

N

N

NHNH

O

O

CH3

crobenetinumcrobenetine (2R,6S)-3-[(2S)-2-(benzyloxy)propyl]-1,2,3,4,5,6-hexahydro-6,11,11-

trimethyl-2,6-methano-3-benzazocin-10-ol

crobénétine (2R,6S)-3-[(2S)-2-(benzyloxy)propyl]-6,11,11-triméthyl-1,2,3,4,5,6-hexahydro-2,6-méthano-3-benzazocin-10-ol

crobenetina (2R,6S)-3-[(2S)-2-(benciloxi)propil]-1,2,3,4,5,6-hexahidro-6,11,11-trimetil-2,6-metano-3-benzazocin-10-ol

C25H33NO2

N

CH3

CH3

CH3

H O

H CH3

OH

cystinumcystine L-cystine

cystine L-cystine

cistina L-cistina

C6H12N2O4S2

SCO2H

NH2H

SHO2C

H NH2

darusentanumdarusentan (+)-(S)-2-[(4,6-dimethoxy-2-pyrimidinyl)oxy]-3-methoxy-3,3-

diphenylpropionic acid

darusentan �� !"�

darusentán ácido (+)-(S)-2-[(4,6-dimetoxi-2-pirimidinil)oxi]-3-metoxi-3,3-difenilpropiónico

190


C22H22N2O6

CO2H

O

H

N

N

OCH3

OCH3

H3CO

donitriptanumdonitriptan 1-[[[3-(2-aminoethyl)indol-5-yl]oxy]acetyl]-4-(p-cyanophenyl)piperazine

donitriptan #��#�� $��

donitriptán 1-[[[3-(2-aminoetil)indol-5-il]oxi]acetil]-4-(p-cianofenil)piperazina

C23H25N5O2

HN

NH2

ON

N

NC

O

doxercalciferolumdoxercalciferol (5Z,7E,22E)-9,10-secoergosta-5,7,10(19),22-tetraene-#�,��-diol

doxercalciférol ��%��&�#'�(��)�(��%�#'�#&��*��#��

doxercalciferol (��%��)-9,10-secoergosta-5,7,10(19),22-tetraeno-#��diol

C28H44O2

H3C

H3C

CH3

H

H

H

HO

H H

OH

CH2

CH3

CH3H

emfilerminumemfilermin leukemia-inhibiting factor (human)

emfilermine facteur d’inhibition leucémique humain

emfilermina factor inhibidor de leucemia (humano)

191


SPLPITPVNA

PFPNNLDKLC

QKILNPSALS

SGKDVFQKKK

TCAIRHPCHN

GPNVTDFPPF

LHSKLNATAD

LGCQLLGKYK

NLMNQIRSQL

HANGTEKAKL

ILRGLLSNVL

QIIAVLAQAF

AQLNGSANAL

VELYRIVVYL

CRLCSKYHVG

FILYYTAQGE

GTSLGNITRD

HVDVTYGPDT

emivirinumemivirine 6-benzyl-1-(ethoxymethyl)-5-isopropyluracil

émivirine 6-benzyl-1-(éthoxyméthyl)-5-(1-méthyléthyl)pyrimidine-2,4(1H,3H)-dione

emivirina 6-bencil-1-(etoximetil)-5-isopropiluracilo

C17H22N2O3

HN

NO

O

CH3

CH3

OH3C

entecavirumentecavir 9-[(1S,3R,4S)-4-hydroxy-3-(hydroxymethyl)-2-

methylenecyclopentyl]guanine

entécavir 2-amino-9-[(1S,3R,4S)-4-hydroxy-3-(hydroxyméthyl)-2-méthylènecyclopentyl]-1,9-dihydro-6H-purin-6-one

entecavir 9-[(1S,3R,4S)-4-hidroxi-3-(hidroximetil)-2-metilenociclopentil]guanina

C12H15N5O3

HN

N N

N

O

H2NH H

OH

H OH

CH2

epitumomabumepitumomab mouse IgG 1 monoclonal antibody which binds the human muc-1 gene

product

épitumomab ��)�+��,��)*��-.�'��/��0�� (��(��(�1#2#��*��(��3��/��0�� (��(��(�1#2#

192


epitumomab inmunoglobulina G2a, anti-(antígeno CD20 humano) (cadena �� delanticuerpo monoclonal de ratón B1R1), dímero del disulfuro con la cadena �del anticuerpo monoclonal de ratón B1R1

epratuzumabumepratuzumab immunoglobulin G (human-mouse monoclonal IMMU-hLL2��-chain

anti-human antigen CD22), disulfide with human-mouse monoclonalIMMU-hLL2 �-chain, dimer

épratuzumab ��)�+��,��)*��-.��/��0�� (��(��(�4556��77��(��*��(��3��/��0�� (��(��(�4556��77��(�

epratuzumab inmunoglobulina G, anti-(antígeno CD22 humano)(cadena � del anticuerpomonoclonal humanizado de ratón IMMU-hLL2) dímero del disulfuro con lacadena � del anticuerpo monoclonal humanizado de ratón IMMU-hLL2

eptapironumeptapirone 4-methyl-2-[4-[4-(2-pyrimidinyl)-1-piperazinyl]butyl]-as-triazine-3,5(2H,4H)-

dione

eptapirone 4-méthyl-2-[4-[4-(pyrimidin-2-yl)pipérazin-1-yl]butyl]-1,2,4-triazine-3,5(2H,4H)-dione

eptapirona 4-metil-2-[4-[4-(2-pirimidinil)-1-piperazinil]butil]-as-triazina-3,5(2H,4H)-diona

C16H23N7O2

N

N

N

N

N

N

N

O

H3C

O

escitalopramumescitalopram (+)-(S)-1-[3-(dimethylamino)propyl]-1-(p-fluorophenyl)-5-phthalancarbonitrile

escitalopram (+)-(1S)-1-[3-(diméthylamino)propyl]-1-(4-fluorophényl)-1,3-dihydroisobenzofurane-5-carbonitrile

escitalopram (+)-(S)-1-[3-(dimetilamino)propil]-1-(p-fluorofenil)-5-ftalancarbonitrilo

C20H21FN2O

ON

CH3

CH3

F

NC

193


evernimicinumevernimicin O-(1R)-2,3-O-methylene-4-O-(6-methyl-�-resorcyloyl)-D-xylopyranosylidene-(1

3-4)-�-L-lyxopyranosyl O-2,3,6-trideoxy-3-C-methyl-4-O-methyl-3-nitro-�-L-arabino-hexopyranosyl-(1�3)-O-2,6-dideoxy-4-O-(3,5-dichloro-6-methoxy-4,2-cresotoyl)-�-D-arabino-hexopyranosyl-(1�4)-O-(1R)-2,6-dideoxy-D-arabino-hexopyranosylidene-(1�3-4)-O-6-deoxy-3-C-methyl-�-D-mannopyranosyl-(1�3)-O-6-deoxy-4-O-methyl-�-D-galactopyranosyl-(1�4)-2,6-di-O-methyl-�-D-mannopyranoside

évernimicine �� (�� (��#�� +��$�� (�� (��#��#�� (�� (��*��#�� (�� (��#�� (��)�� (��#�� (�� #�� +��$��*�� (��*��#�� (��

evernimicina �-2,3,6-tridesoxi-3-C-metil-4-O-metil-3-nitro-�� -hexopiranosil-(1�3)-O-2,6-didesoxi-4-O-(3,5-dicloro-6-metoxi-4,2-cresotoil)-�� -hexopiranosil-(1�4)-O-(1R)-2,6-didesoxi-�-�� -hexopiranosilideno-(1�3-4)-O-6-desoxi-3-C-metil-��manopiranosil-(1�3)-O-6-desoxi-4-O-metil-��galactopiranosil-(1��)-2,6-di-O-metil-��manopiranósido de O-(1R)-2,3-O-metileno-4-O-(6-metil-��resorciloil)-�-xilopiranosilideno-(1�3-4)-��lixopiranosilo

C70H97Cl2NO38

OO

O

CH3

OOH

CH3

OO

CH3 OO

CH3

O

CH3

OOH

OH3C

O

O

OCH3

OH3C

OO

O

OHO

O

O

O

O

CH3

OH3C

NO2

CH3

HO

OH

O

OOH

HO CH3

O

OCH3H3C

Cl Cl

OH

194


everolimusumeverolimus (3S,6R,7E,9R,10R,12R,14S,15E,17E,19E,21S,23S,26R,27R,34aS)-

9,10,12,13,14,21,22,23,24,25,26,27,32,33,34,34a-hexadecahydro-9,27-dihydroxy-3-[(1R)-2-[(1S,3R,4R)-4-(2-hydroxyethoxy)-3-methoxycyclohexyl]-1-methylethyl]-10,21-dimethoxy-6,8,12,14,20,26-hexamethyl-23,27-epoxy-3H-pyrido[2,1-c][1,4]=oxaazacyclohentriacontine-1,5,11,28,29(4H,6H,31H)-pentone

évérolimus (1R,9S,12S,15R,16E,18R,19R,21R,23S,24E,26E,28E,30S,32S,35R)-1,18-dihydroxy-12-[(1R)-2-[(1S,3R,4R)-4-(2-hydroxyéthoxy)-3-méthoxycyclohexyl]-1-méthyléthyl]-19,30-diméthoxy-15,17,21,23,29,35-hexaméthyl-11,36-dioxa-4-azatricyclo[30.3.1.04,9]hexatriaconta-16,24,26,28-tétraène-2,3,10,14,20-pentone

everolimus (3S,6R,7E,9R,10R,12R,14S,15E,17E,19E,21S,23S,26R,27R,34aS)-9,10,12,13,14,21,22,23,24,25,26,27,32,33,34,34a-hexadecahidro-9,27-dihidroxi-3-[(1R)-2-[(1S,3R,4R)-4-(2-hidroxietoxi)-3-metoxiciclohexil]-1-metiletil]-10,21-dimetoxi-6,8,12,14,20,26-hexametil-23,27-epoxi-3H-pirido[2,1-c][1,4]oxaazaciclohentriacontina-1,5,11,28,29(4H,6H,31H)-pentona

C53H83NO14

N

O

H3C

O

O

O

O

H3C

O

OCH3

OH

H

H3CO

H

H

H OCH3H

CH3H

H

OHH

H3C H

CH3

HH H

H

CH3CH3

O

OH

OH

ezlopitantumezlopitant (2S,3S)-2-(diphenylmethyl)-3-[(5-isopropyl-2-methoxybenzyl)amino]=

quinuclidine

ezlopitant (2S,3S)-2-(diphénylméthyl)-N-[2-méthoxy-5-(1-méthyléthyl)benzyl]-1-azabibyclo[2.2.2]octan-3-amine

ezlopitant (2S,3S)-2-(difenilmetil)-3-[(5-isopropil-2-metoxibencil)amino]quinuclidina

195


C31H38N2O

N

HN

H3CO

CH3

CH3

H H

fiduxosinumfiduxosin 8-phenyl-3-[4-[(3aR,9bR)-1,3a,4,9b-tetrahydro-9-methoxy[1]benzopyrano=

[3,4-c]pyrrol-2(3H)-yl]butyl]pyrazino[2',3':4,5]thieno[3,2-d]pyrimidine-2,4(1H,3H)-dione

fiduxosine ��&+��&��#��&+��#�+��$� �� +��8� �� $��9�� #��

fiduxosina 8-fenil-3-[4-[(3aR,9bR)-1,3a,4,9b-tetrahidro-9-metoxi[1]benzopirano[3,4-c]=pirrol-2(3H)-il]butil]pirazino[2',3':4,5]tieno[3,2-d]pirimidina-2,4(1H,3H)-diona

C30H29N5O4S

NN

O

OCH3

H

H NH

S

N

N

O

O

figopitantumfigopitant ��+�(��

�� #� � ��$��

figopitant (2S)-N-[2-[3,5-bis(trifluorométhyl)phényl]éthyl]-2-[4-(cyclopropylméthyl)=pipérazin-1-yl]-N-méthyl-2-phénylacétamide

figopitant (S)-N-[bis(3,5-trifluorometil)fenetil]-4-(ciclopropilmetil)-N-metil-�-fenil-1-piperazinaacetamida

C27H31F6N3O

N

NN

H CH3

O

CF3

CF3

196


implitapidumimplitapide (�S)-�-[�-(2,4-dimethyl-9H-pyrido[2,3-b]indol-9-yl)-p-tolyl]-

N-[(�R)-�-(hydroxymethyl)benzyl]cyclopentaneacetamide

implitapide (2S)-2-cyclopentyl-2-[4-[(2,4-diméthyl-9H-pyrido[2,3-b]indol-9-yl)méthyl]phényl]-N-[(1R)-2-hydroxy-1-phényléthyl]acétamide

implitapida (�S)-�-[�-(2,4-dimetil-9H-pirido[2,3-b]indol-9-il)-p-tolil]-N-[(�R)-�-(hidroximetil)bencil]ciclopentanoacetamida

C35H37N3O2

NH

OH

H

H

N

N

CH3

H3C

O

irampanelumirampanel 5-[o-[2-(dimethylamino)ethoxy]phenyl]-3-phenyl-1,2,4-oxadiazole

irampanel N,N-diméthyl-2-[2-(3-phényl-1,2,4-oxadiazol-5-yl)phénoxy]éthanamine

irampanel 5-[o-[2-(dimetilamino)etoxi]fenil]-3-fenil-1,2,4-oxadiazol

C18H19N3O2

O

N

CH3

H3C

N

NO

irofulvenumirofulven (R)-6'-hydroxy-3'-(hydroxymethyl)-2',4',6'-trimethylspiro[cyclopropane-

1,5'-[5H]inden]-7'(6'H)-one

irofulvène � 0�� 0��0��0��0� 0��( �� #��0��%0� 0��

irofulveno (R)-6'-hidroxi-3'-(hidroximetil)-2',4',6'-trimetilspiro[ciclopropano-1,5'-[5H]inden]-7'(6'H)-ona

197


C15H18O3

OHO

H3CCH3

OHCH3

itriglumidumitriglumide (R)-2'-(8-azaspiro[4.5]dec-8-ylcarbonyl)-4',6'-dimethyl-

3-(1-naphthyl)glutaranilic acid

itriglumide acide (3R)-5-[[2-(8-azaspiro[4.5]dec-8-ylcarbonyl)-4,6-diméthylphényl]amino]-3-(naphtalén-1-yl)-5-oxopentanoïque

itriglumida ácido (R)-2'-(8-azaspiro[4.5]dec-8-ilcarbonil)-4',6'-dimetil-3-(1-naftil)glutaranílico

C33H38N2O4

N

NH O

O

H3C

CH3

H

CO2H

laniceminumlanicemine ��

lanicémine (+)-(1S)-1-phényl-2-(pyridin-2-yl)éthanamine

lanicemina (+)-2-[(S)-�-aminofenetil]piridina

C13H14N2

N

H NH2

lusaperidonumlusaperidone 3-[2-(3,4-dihydrobenzofuro[3,2-c]pyridin-2(1H)-yl)ethyl]-2-methyl-

4H-pyrido[1,2-a]pyrimidin-4-one

lusapéridone 3-[2-(3,4-dihydrobenzofuro[3,2-c]pyridin-2(1H)-yl)éthyl]-2-méthyl-4H-pyrido[1,2-a]pyrimidin-4-one

lusaperidona 3-[2-(3,4-dihidrobenzofuro[3,2-c]piridin-2(1H)-il)etil]-2-metil-4H-pirido[1,2-a]pirimidin-4-ona

198


C22H21N3O2

N

N

N

CH3

O O

metreleptinummetreleptin N-methionylleptin (human)

métréleptine N-méthionylleptine humaine

metreleptina N-metionileptina (humana)

C714H1167N191O221S6

KTLIKTIVTR

YQQILTSMPS

GGVLEASGYS

INDISHTQSV

RNVIQISNDL

TEVVALSRLQ

SSKQKVTGLD

ENLRDLLHVL

GSLQDMLWQL

FIPGLHPILT

AFSKSCHLPW

DLSPGC

VPIQKVQDDT

LSKMDQTLAV

ASGLETLDSL

M

mitumomabummitumomab immunoglobulin G2b (mouse monoclonal BEC2 �2b-chain anti-GD3

ganglioside), disulfide with mouse monoclonal BEC2 �-chain, dimer

mitumomab immunoglobuline G2b, anti-(ganglioside GD3) (chaîne �2b de l’anticorpsmonoclonal de souris BEC2), dimère du disulfure avec la chaîne � del’anticorps monoclonal de souris BEC2

mitumomab inmunoglobulina G2b,anti-(gangliósido GD3)(cadena �2b del anticuerpomonoclonal de ratón BEC2) dímero del disulfuro con la cadena � delanticuerpo monoclonal de ratón BEC2

motexafinummotexafin 9,10-diethyl-20,21-bis[2-[2-(2-methoxyethoxy)ethoxy]ethoxy]-4,15-

dimethyl-8,11-imino-3,6:16,13-dinitrilo-1,18-benzodiazacycloeicosine-5,14-dipropanol

mot�xafine ��&�#'��'��#�+�(��#��8�##�� 9# �#��#�#8�+��$��$��(*��#�� #��

motexafina 9,10-dietil-20,21-bis[2-[2-(2-metoxietoxi)etoxi]etoxi]-4,15-dimetil-8,11-imino-3,6:16,13-dinitrilo-1,18-benzodiazacicloeicosina-5,14-dipropanol

199


C48H67N5O10

N

NHN

N

NCH3

CH3

H3C

H3C OH

OH

OO

OO

H3C

OO

OO

H3C

nebostinelumnebostinel (S)-4-amino-N-(4,4-dimethylcyclohexyl)glutaramic acid

nébostinel acide (4S)-4-amino-5-[(4,4-diméthylcyclohexyl)amino]-5-oxopentanoïque

nebostinel ácido (S)-4-amino-N-(4,4-dimetilciclohexil)glutarámico

C13H24N2O3

HO2C

HN

NH2H

O

CH3

CH3

onerceptumonercept glycoprotein TNF-BP (tumor necrosis factor-binding protein) (human

disulfide variant 1)

onercept 20-180-récepteur 1 humain du facteur de nécrose tumorale, protéineglycosylée (partie du domaine extracellulaire)

onercept glicoproteína TNF-BP (proteína de unión al factor de necrosistumoral)(disulfuro de la variante 1 humana)

C753H1156N228O247S25

DSVCPQGKYI HPQNNSICCT KCHKGTYLYN DCPGPGQDTD

CRECESGSFT ASENHLRHCL SCSKCRKEMG QVEISSCTVD

RDTVCGCRKN QYRHYWSENL FQCFNCSLCL NGTVHLSCQE

KQNTVCTCHA GFFLRENECV SCSNCKKSLE CTKLCLPQIE

N

*

* *

* glycosylation sites* sites de glycosylation* posiciónes de glicosilación

200


pegvisomantumpegvisomant 18-L-aspartic acid-21-L-asparagine-120-L-lysine-167-L-asparagine-

168-L-alanine-171-L-serine-172-L-arginine-174-L-serine-179-L-threoninegrowth hormone (human), reaction product with polyethylene glycol

pegvisomant [18-acide L-aspartique-21-L-asparagine-120-L-lysine-167-L-asparagine-168-L-alanine-171-L-sérine-172-L-arginine-174-L-sérine-179-L-thréonine]hormone humaine de croissance combinée à du polyéthylène glycol

pegvisomant producto de reacción con polietilenglicol de la 18-ácido-L-aspártico21-L-asparagina-120-L-lisina-167-L-asparagina-168-L-alanina-171-L-serina-172-L-arginina-174-L-serina-179-L-treoninahormona del crecimiento(humana)

FPTIPLSRLF DNAMLRADRL NQLAFDTYQE FEEAYIPKEQ

KYSFLQNPQT SLCFSESIPT PSNREETQQK SNLELLRISL

LLIQSWLEPV QFLRSVFANS LVYGASDSNV YDLLKDLEEK

IQTLMGRLED GSPRTGQIFK QTYSKFDTNS HNDDALLKNY

GLLYCFNADM SRVSTFLRTV QCRSVEGSCG F

*

*

*

* * *

* pegylation sites* sites de pégylation* posiciónes de pegilación

perflexanumperflexane tetradecafluorohexane

perflexane tétradécafluorohexane

perflexano tetradecafluorohexano

C6F14

F3CCF3

F F

FF

F F

FF

perflutrenumperflutren octafluoropropane

perflutrène octafluoropropane

perflutreno octafluoropropano

C3F8

F3C CF3

F F

201


pinokalantumpinokalant (±)-3,4-dihydro-6,7-dimethoxy-�-phenyl-N,N-bis(2,3,4-

trimethoxyphenethyl)-1-isoquinolineacetamide

pinokalant �� %��(�"��#�� +�(��

pinokalant (±)-3,4-dihidro-6,7-dimetoxi-�-fenil-N,N-bis(2,3,4-trimetoxifenetil)-1-isoquinolinacetamida

C41H48N2O9

N

N

O

H3CO

OCH3

H and enantiomeret énantiomèrey enantiómeroOCH3

OCH3

OCH3

OCH3

OCH3

OCH3

posaconazolumposaconazole 4-[p-[4-[p-[[(3R,5R)-5-(2,4-difluorophenyl)tetrahydro-5-(1H-1,2,4-triazol-

1-ylmethyl)-3-furyl]methoxy]phenyl]-1-piperazinyl]phenyl]-1-[(1S,2S)-1-ethyl-2-hydroxypropyl]-�2-1,2,4-triazolin-5-one

posaconazole 4-[4-[4-[4-[[(3R,5R)-5-(2,4-difluorophényl)-5-(1H-1,2,4-triazol-1-ylméthyl)=tétrahydrofuran-3-yl]méthoxy]phényl]pipérazin-1-yl]phényl]-2-[(1S,2S)-1-éthyl-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one

posaconazol 4-[p-[4-[p-[[(3R,5R)-5-(2,4-difluorofenil)tetrahidro-5-(1H-1,2,4-triazol-1-ilmetil)-3-furil]metoxi]fenil]-1-piperazinil]fenil]-1-[(1S,2S)-1-etil-2-hidroxipropil]-D2-1,2,4-triazolin-5-ona

C37H42F2N8O4

N N O H

O

FF

N

N

N

NN

N

H3COH

H OH

H3C

202


prinomastatumprinomastat (S)-2,2-dimethyl-4-[[p-(4-pyridyloxy)phenyl]sulfonyl]-

3-thiomorpholinecarbohydroxamio acid

prinomastat (3S)-N-hydroxy-2,2-diméthyl-4-[[4-(pyridin-4-yloxy)phényl]sulfonyl]=thiomorpholine-3-carboxamide

prinomastat ácido (S)-2,2-dimetil-4-[[p-(4-piridiloxi)fenil]sulfonil]-3-tiomorfolinacarbohidroxámico

C18H21N3O5S2

S

NNH

HO

S

O

NO

OO

H3CCH3

H

pumafentrinumpumafentrine (-)-p-[(4aR*,10bS*)-9-ethoxy-1,2,3,4,4a,10b-hexahydro-8-methoxy-

2-methylbenzo[c][1,6]naphthyridin-6-yl]-N,N-diisopropylbenzamide

pumafentrine (-)-4-[(4aR*,10bS*)-9-éthoxy-8-méthoxy-2-méthyl-1,2,3,4,4a,10b-hexahydrobenzo[c][1,6]naphtyridin-6-yl]-N,N-bis(1-méthyléthyl)benzamide

pumafentrina (-)-p-[(4aR*,10bS*)-9-etoxi-1,2,3,4,4a,10b-hexahidro-8-metoxi-2-metilbenzo[c][1,6]naftiridina-6-il]-N,N-diisopropilbenzamida

C29H39N3O3

N

N

N

O

H3CO

CH3H

HH3C

CH3 O

H3C CH3

CH3

or enantiomerou énantiomèreo enantiómero

relcovaptanumrelcovaptan (2S)-1-[[(2R,3S)-5-chloro-3-(o-chlorophenyl)-1-[(3,4-dimethoxyphenyl)=

sulfonyl]-3-hydroxy-2-indolinyl]carbonyl]-2-pyrrolidinecarboxamide

relcovaptan ��#�� #�� :(��#��+�� +��

relcovaptán (2S)-1-[[(2R,3S)-5-cloro-3-(o-clorofenil)-1-[(3,4-dimetoxifenil)sulfonil]-3-hidroxi-2-indolinil]carbonil]-2-pirrolidinacarboxamida

203


C28H27Cl2N3O7S

NN

S

ClOHH

HO

NH2

O

O

OH3CO

H3CO

Cl

repiferminumrepifermin 33-172-keratinocyte growth factor 2 (human)

répifermine 33-172-facteur 2 humain de croissance du kératinocyte

repifermina 33-172-factor 2 de crecimiento de queratinocitos (humano)

C723H1131N209O204S5

SYNHLQGDVR

GVVAVKAINS

WQHNGRQMYV

WRKLFSFTKY

NYYLAMNKKG

ALNGKGAPRR

FLKIEKNGKV

KLYGSKEFNN

GQKTRRKNTS

SGTKKENCPY

DCKLKERIEE

AHFLPMVVHS

SILEITSVEI

NGYNTYASFN

resiquimodumresiquimod 4-amino-2-(ethoxymethyl)-�,�-dimethyl-1H-imidazo[4,5-c]quinoline-1-

ethanol

résiquimod 1-[4-amino-2-(éthoxyméthyl)-1H-imidazo[4,5-c]quinoléin-1-yl]-2-méthylpropan-2-ol

resiquimod 4-amino-2-(etoximetil)-�,�-dimetil-1H-imidazo[4,5-c]quinolina-1-etanol

C17H22N4O2

N N

N

NH2

O

CH3

CH3

H3C OH

risarestatumrisarestat (±)-5-[3-ethoxy-4-(pentyloxy)phenyl]-2,4-thiazolidinedione

risarestat (5RS)-5-[3-éthoxy-4-(pentyloxy)phényl]thiazolidine-2,4-dione

204


risarestat (±)-5-[3-etoxi-4-(pentiloxi)fenil]-2,4-tiazolidinadiona

C16H21NO4S

NHS

OH3C

O CH3

O

OH

and enantiomeret énantiomèrey enantiómero

rubitecanumrubitecan 9-nitrocamptothecin

rubitécan (4S)-4-éthyl-4-hydroxy-10-nitro-1,12-dihydro-14H-pyrano[3’,4’:6,7]=indolizino[1,2-b]quinoléine-3,14(4H)-dione

rubitecán 9-nitrocamptotecina

C20H15N3O6

N O

N

O

O

HO CH3

O2N

sulamserodumsulamserod N-[2-[4-[2-[(8-amino-7-chloro-1,4-benzodioxan-5-

yl)carbonyl]ethyl]piperidino]ethyl]methanesulfonamide

sulamsérod N-[2-[4-[3-(8-amino-7-chloro-2,3-dihydro-1,4-benzodioxin-5-yl)-3-oxopropyl]pipéridin-1-yl]éthyl]méthanesulfonamide

sulamserod N-[2-[4-[2-[(8-amino-7-cloro-1,4-benzodioxan-5-il)carbonil]etil]piperidino]=etil]metanosulfonamida

C19H28ClN3O5S

N

HN

SCH3O

O

O O

O

Cl

H2N

tanomastatumtanomastat (S)-3-[(4’-chloro-4-biphenylyl)carbonyl]-2-[(phenylthio)methyl]propionic acid

tanomastat acide (2S)-4-(4’-chlorobiphényl-4-yl)-4-oxo-2-[(phénylsulfanyl)méthyl]=butanoïque

205


tanomastat ácido (2S)-4-(4’-clorobifenil-4-il)-4-oxo-2-[(fenilsulfanilo)metil]butanoico

C23H19ClO3S

HO2C

H

Cl

OS

tebipenemumtebipenem (+)-hydroxymethyl (4R,5S,6S)-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-3-

[[1-(2-thiazolin-2-yl)-3-azetidinyl]thio]-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate, 2-pivalate

tébipénem (+)-(4R,5S,6S)-3-[[1-(4,5-dihydrothiazol-2-yl)azétidin-3-yl]sulfanyl]-6-[(1R)-1-hydroxyéthyl]-4-méthyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ène-2-carboxy-late de [(2,2-diméthylpropanoyl)oxy]méthyle

tebipenem 2-pivalato y (4R,5S,6S)-6-[(1R)-1-hidroxietil]-4-metil-7-oxo-3-[[1-(2-tiazolin-2-il)-3-azetidinil]tio]-1-azabiciclo[3.2.0]hept-2-eno-2-carboxilato de metileno

C22H31N3O6S2

NO

S

H CH3H H

H3C

HOH

OO O

O

CH3

CH3H3C

N

S

N

tenofovirumtenofovir [[(R)-2-(6-amino-9H-purin-9-yl)-1-methylethoxy]methyl]phosphonic acid

ténofovir acide [[(1R)-2-(6-amino-9H-purin-9-yl)-1-méthyléthoxy]méthyl]phosphonique

tenofovir ácido [[(R)-2-(6-amino-9H-purin-9-il)-1-metiletoxi]metil]fosfónico

C9H14N5O4P

N

N N

N

NH2

O

P

O

OH

OH

CH3H

206


tiplimotidumtiplimotide D-alanyl-L-lysyl-L-prolyl-L-valyl-L-valyl-L-histidyl-L-leucyl-L-phenylalanyl-L-

alanyl-L-asparaginyl-L-isoleucyl-L-valyl-L-threonyl-L-prolyl-L-arginyl-L-threonyl-L-prolinamide

tiplimotide ��(�� 3��3��(�� ( ��)��(��3�� )��

tiplimotida D-alanil-L-lisil-L-prolil-L-valil-L-valil-L-histidil-L-leucil-L-fenilalanil-L-alanil-L-asparaginil-L-isoleucil-L-valil-L-treonil-L-prolil-L-arginil-L-treonil-L-prolinamida

C87H143N25O20

D-Ala Lys Pro Val Val His Leu Phe Ala Asn

Ile Val Thr Pro Arg Thr Pro NH2

10

valrocemidumvalrocemide N-(carbamoylmethyl)-2-propylvaleramide

valrocémide ��

valrocemida N-(carbamoilmetil)-2-propilvaleramida

C10H20N2O2

H3CNH

O

NH2

OH3C

vardenafilumvardenafil 1-[[3-(3,4-dihydro-5-methyl-4-oxo-7-propylimidazo[5,1-f]-as-triazin-2-yl)-

4-ethoxyphenyl]sulfonyl]-4-ethylpiperazine

vardénafil 2-[2-éthoxy-5-[(4-éthylpipérazin-1-yl)sulfonyl]phényl]-5-méthyl-7-propylimidazolo[5,1-f][1,2,4]triazin-4(3H)-one

vardenafil 1-[[3-(3,4-dihidro-5-metil-4-oxo-7-propilimidazo[5,1-f]-as-triazin-2-il)-4-etoxifenil]sulfonil]-4-etilpiperazina

C23H32N6O4S

HN

NN

NS

N

NH3C

OO

O CH3

O CH3 CH3

207


vofopitantumvofopitant (2S,3S)-3-[[2-methoxy-5-[5-(trifluoromethyl)-1H-tetrazol-1-yl]benzyl]amino]-

2-phenylpiperidine

vofopitant (2S,3S)-N-[2-méthoxy-5-[5-(trifluorométhyl)-1H-tétrazol-1-yl]benzyl]-2-phénylpipéridin-3-amine

vofopitant (2S,3S)-3-[[2-metoxi-5-[5-(trifluorometil)-1H-tetrazol-1-il]bencil]amino]-2-fenilpiperidina

C21H23F3N6O

HN

HN

H3CO

N

N

NN

F3C

H

H

208


AMENDMENTS TO PREVIOUS LISTSMODIFICATIONS APPORTÉES AUX LISTES ANTÉRIEURES

MODIFICACIONES A LAS LISTAS ANTERIORES

Recommended International Nonproprietary Names (Rec. INN): List 43

Dénominations communes internationales recommandées (DCI Rec.): Liste 43

Denominaciones Comunes Internacionales Recomendadas (DCI Rec.): Lista 43

(WHO Drug Information, Vol. 14, No. 1, 2000)

p. 50 eledoisinumeledoïsine remplacer le nom par le suivant:

élédoïsine

p. 57 idremcinalumidremcinal remplacer le nom chimique par le suivant:

��8��&��#'��##��#��8�#'�#��#��&�� (�� (��##��#�� (�� (�� #��+��#';�;#� ��#�#��%��

p. 59 lasofoxifenumlasofoxifène remplacer le nom chimique par le suivant:

(-)-(5R*,6S*)-6-phényl-5-[4-[2-(pyrrolidin-1-yl)éthoxy]phényl]-5,6,7,8-tétrahydronaphtalén-2-ol

p. 64 pimecrolimusum pimécrolimus remplacer le nom chimique par le suivant:

(1R,9S,12S,13R,14S,17R,18E,21S,23S,24R,25S,27R)-12-[(E)-2-[(1R,3R,4S)-4-chloro-3-méthoxycyclohexyl]-1-méthyléthényl]-17-éthyl-1,14-dihydroxy-23,25-diméthoxy-13,19,21,27-tétraméthyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9]octacos-18-ène-2,3,10,16-tétrone

p. 66 sarakalimumsarakalim remplacer le nom chimique par le suivant:

�� #��

#+��$� ��

209


Procedure and Guiding Principles / Procédure et Directives / Procedimientos y principios generales

The text of the Procedures for the Selection of Recommended International Nonproprietary Names for Pharmaceuti-cal Substances and General Principles for Guidance in Devising International Nonproprietary Names for Pharmaceu-tical Substances will be reproduced in uneven numbers of proposed INN lists only.

Les textes de la Procédure à suivre en vue de choix de dénominations communes internationales recommandéespour les substances pharmaceutiques et des Directives générales pour la formation de dénominations communesinternatio-nales applicables aux substances pharmaceutiques ont été publiés avec la liste 81 des DCI proposées etseront, à nouveau, publiés avec la prochaine liste des DCI proposées.

El texto de los Procedimientos de selección de denominaciones comunes internacionales recomendadas para lassus-tancias farmacéuticas y de los Principios generales de orientación para formar denominaciones comunesinternacio-nales para sustancias farmacéuticas aparece solamente en los números impares de las listas de DCIpropuestas.

Documents

WHO drug information 2000