who drug information vol 17, no. 4, 2003 world health

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WHO Drug Information Vol 17, No. 4, 2003

WHO Drug Information

Contents

World Health Organization

Regulatory ChallengesMedical device regulation: a model

framework 231

Safety and Efficacy IssuesMaternal use of SSRIs and neonatal effects 234ACE inhibitor, diuretic and NSAID: a

dangerous combination 235Serious gastrointestinal effects with

colecoxib and rofecoxib 235Biphosphonates and ocular disorders 236Fluticasone and adrenal suppression 237Adhesion prevention solutions in

gynaecological procedures 238Treatment study for West Nile virus 238Blue discoloration and death from

FD&C No. 1 239Atazanavir and tenofovir combination

cautioned 240Rofecoxib, celecoxib and cardiovascular

risk 241Convulsions and blood dyscrasias

with mirtazapine 241Anti-epileptic drugs, pregnancy and fetal

malformations 242

Aspects of Quality AssuranceSupplying quality medicines for filariasis

elimination 244

Regulatory and Safety ActionRecommended influenza vaccine for 2004

(Southern hemisphere) 248Daclizumab: safety alert 248Nefazodone discontinued 248

Levomethadyl discontinued 249Daptomycin: new class of antibiotic

approved 249Tetrahydrogestrinone: grave risks to health 250Coronary stents and thrombosis 250Bicalutamide: do not use in localized

prostate cancer 250Recombinant antihaemophilic factor: dose

monitoring required 251Nimesulide-containing products

re-evaluated 251Memantine approved for Alzheimer disease 251Virologic non-response in more HIV

combinations 251

Personal PerspectivesPlacebo or active control? Either, as long

as it is in the patient’s interest 253

Current TopicsWHO review of NICE in the United Kingdom 257New advice on hormone replacement

therapy 260Direct-to-consumer advertising and patients 262Action against counterfeit medicines in Asia

and Africa 263

Essential MedicinesNeglected Diseases: Chagas disease 265

Recommended InternationalNonproprietary Names: List 50 267

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WHO Drug Informationis now available at:

http://www.who.int/druginformation

World Health Organization

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Medical device regulation:a model frameworkThe term “medical devices” covers a vast array ofproducts from simple tongue depressors tomagnetic resonance equipment. The intendedprimary mode of action of a medical device on thehuman body, in contrast with that of medicalproducts, is not metabolic, immunological orpharmacological although it may be assisted in itsfunction by such means. With around one and ahalf million different devices available, it is one ofthe fastest growing markets today. As a conse-quence, the regulatory approval and licensing ofmedical devices is becoming more and morechallenging.

Ensuring the availability of quality medicines andhealth care products begins with effective man-agement at national level. National medicinesregulatory authorities operate with varyingsuccess in many countries and aim to achieveeffective regulation of medicines. The responsibili-ties of regulatory authorities are broad andactivities may include licensing and control ofmanufacture, import, export, sale, distribution,promotion and advertising; supervision andcontrol of clinical trials; assessing safety, efficacyand quality; conducting post-marketing surveil-lance and monitoring adverse events; inspectingmanufacturers, importers, wholesalers anddispensers at regular intervals, and providingunbiased information to professionals and thepublic.

Curiously, medical devices have not received thesame attention as medicines despite the signifi-cant investment that their purchase may repre-sent for health care systems and the need toensure safety, quality standard conformity andperformance. This is partly because medicaldevices are frequently perceived as a procure-ment issue as opposed to an integral part ofpublic health policy. Few developing countrieshave an authority with discrete responsibility forthe management of medical devices. Unfortu-nately, lack of effective regulation may lead to theimport of substandard devices or illegal re-processing and re-packaging of products.

In 2003, WHO addressed this issue through twoprojects geared to strengthen the ability ofnational authorities to manage medical devices.

Strengthening national regulatoryauthorities for medical devicesThe first initiative was to expand the existingWHO tool developed to assess medicinesregulatory authorities to include medical devices(1). The expanded tool was used in the People’sRepublic of China in September 2003 to carry outa comprehensive review of the national systemsused to regulate vaccines and medicines andmedical devices. This was the first time that WHOhad organized such a joint assessment and theharmonized approach was appreciated by thenational health authorities and local WHO staff.

In carrying out the medical device assessment,six broad areas were identified, namely:

• Medical device regulatory systems• Marketing authorization• Postmarketing surveillance• Test laboratories• Quality systems auditing• Clinical trials.

These assessments form the basis of an institu-tional development plan, including training needs,and follow-up support. They are particularly usefulin identifying areas for improvement. For exam-ple, it is estimated that some costly and time-consuming procedures could be avoided by theadoption of existing international standards formedical devices. The joint assessment tool andfollow-up plans are now being refined and will beapplied in other countries.

Harmonization of medicaldevice regulationsThe Global Harmonization Task Force (http://www.ghtf.org) was set up in 1993 by the fivemajor global device producing and regulatorybodies — Australia, Canada, the European Union,Japan and the United States of America — with aview to harmonizing standards and regulatorypractices across countries. The objective is toreduce regulatory barriers, facilitate trade and

Regulatory Challenges

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improve access to safe, effective technologies.Much progress has been made towards thisobjective over the last decade yet developingcountries, who import around 90% of the medicaldevices they need, remain marginalized in thisprocess, largely because of lack of access toknowledge and best practice guidelines.

The recent WHO publication Medical DeviceRegulations: Global Overview and GuidingPrinciples (1) aims to bridge this gap. It provides amatrix of the entire life cycle of a medical device –from conception to disposal – and the policies thatshould be in place to manage each stage in thislife cycle. Priorities are recommended for coun-tries with limited infrastructure or resources, withsuggestions on how to build towards a moreeffective system. The major issues covered in thepublication are summarized as follows.

Safety: The safety of the patient – and indeed ofthe user and the community – is a priority forgovernments in authorizing the sale of a medicaldevice. A medical device must provide benefit forthe patient. Potential hazards need to be weighedagainst the gain. Devices are therefore classifiedaccording to the potential risks, and the higher therisk the more stringent the controls. All activedevices intended to administer or remove medi-cines, body liquids or other substances to or fromthe body are classified as low to moderate risk(e.g. hypodermic syringes or anaesthesia equip-ment). Devices incorporating a medicinal productthat is liable to act on the human body with actionancillary to the device is in the highest riskcategory (e.g. heparin-coated catheters or wounddressings incorporating antimicrobial agents).

Stages of regulatory control: the three mainstages of regulatory control are:

• pre-market: To ensure that the product to besold meets standards of safety and perform-ance;

• on-market: To ensure that the product isaccurately labelled and advertised; and

• post-marketing: To ensure the continued safetyand effectiveness of the product in use.

For pre-market regulations, governments withlimited resources are advised to take advantageof existing approval systems and internationalstandards rather than setting up demanding andcostly pre-market regulations. During the introduc-tion of the product on-market, priority should go to

ensuring a system for registering the vendor andthe device, which is essential for alerts or productrecalls during the post-marketing surveillancephase.

International standards: all medical devicesshould meet a recognized international standardfor quality and safety. An understanding of thedifferent standard-setting systems, the processesused to develop standards, and their use inconformity assessment is essential for theestablishment of medical device regulations. Thisis no mean task, since there are many types ofstandards that govern products, processes andservices. The WHO Medical Device Regulationsexplain the purpose of prescriptive, design,performance and management specifications andstandards of the International Standards Organi-zation (ISO) specifically relating to medicaldevices. A grasp of the difference betweenvoluntary or mandatory standards and currenttrends in their use is all the more important sincethe introduction of a new quality system formedical devices in 2003 (2).

Priority activities: regulatory programmes canbe developed in stages according to a country’sneeds and resources. However, a core pro-gramme, based on a clear policy and involvingthe government, manufacturers, vendors, usersand the patient, should encompass:

• Essential basic legislation to empower govern-ments to stop sale or withdraw unsafe products,and to penalize fraudulent advertising.

• Training of customs officials using the deviceacceptance criteria outlined in the nationalpolicy to prevent substandard devices fromentering the country.

• An information network to encourage thevoluntary sharing of information, e.g. to preventthe recurrence of an adverse event or toinvestigate a potential hazard. The next step willinvolve adherence to a larger, internationalnetwork for complaints and sharing of alerts.

• An inventory of devices and approved suppliers.It is the responsibility of the vendor to keepdistribution records so that all similar productsmay be identified in case of need.

• Adoption of an internationally recognizedmedical device nomenclature system to enableaccurate tracking and comparison.


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WHO supports the efforts of the Global Harmoni-zation Task Force towards global convergence ofregulatory requirements. WHO is also keen todevelop a uniform certification process formedical devices based on the principles of theWHO Model Certification Scheme on the Qualityof Pharmaceutical Products (3), as well as aninternational vigilance agency to increase thesafety of devices in use.

Guiding principles to ensureinjection device securityInjections are the most common health careprocedure worldwide. Best infection controlpractices for intradermal, subcutaneous andintramuscular injections recommend the use of anew, single use injection device for each injectionand for the reconstitution of each unit of medica-tion. Unsafe injection practices are avoidable butcontinue to place patients at risk. For example,41% of all new hepatitis C virus infections in 2000were transmitted through the reuse of injectiondevices without sterilization. WHO thereforerequests all donors and lenders who financeinjectable products to finance appropriate quanti-ties of single use injection devices, single dosediluents, safety boxes and the cost of sharpswaste management. All organizations involved inmedicine donations are also urged to follow thisrecommendation (4).

ConclusionThere is no medical device regulatory systemtemplate that fits all. Some countries are large

manufacturers of equipment and will need tofocus on good manufacturing practice andcomprehensive quality controls. Others mayreceive regular donations of equipment that willneed to fall within a clear needs assessmentpolicy, while many countries are currently inongoing crisis situations and need specialemergency assistance.

The two approaches outlined above – creatingawareness of international best practices andproviding WHO technical support to nationalregulatory authorities – are intended to addressthe need for medical device regulations at thenational and global level (5).

References

1. World Health Organization. Medical Device Regula-tions: Global Overview and Guiding Principles. ISBN 924 154618 2 Available from [email protected].

2. ISO 13485:2003. Information available from http://www.iso.org.

3. World Health Organization. WHO CertificationScheme on the Quality of Pharmaceutical Productsmoving in International Commerce. http://www.who.int/medicines.

4. Injection safety. Guiding principles to ensure injectiondevice security. Available from [email protected].

5. Department of Essential Health Technologies, WorldHealth Organization. e-mail: [email protected] or http://www.who.int/eht.


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Safety and Efficacy Issues

Maternal use of SSRIsand neonatal effectsMaternal use of selective serotonin reuptakeinhibitors (SSRIs) during or after pregnancy mayresult in adverse effects in newborn babies, dueto a withdrawal effect following intra-uterineexposure, or a toxic effect from ingestion of anSSRI in breast-milk. The Australian Adverse DrugReactions Advisory Committee (ADRAC) hasreceived 26 reports of neonates with symptomsattributed to withdrawal effects due to maternalthird trimester ingestion of SSRIs (paroxetine 10,sertraline 7, fluoxetine 7, citalopram 2). The tablebelow presents the most frequently reportedreactions. Other reactions included convulsions,tremor, fever and respiratory disorders (respira-tory depression, apnoea, tachypnoea). Twobabies had marked extensor posturing with back-arching. The usual day of onset, if reported, wasthe day of birth, but ranged from 0 to 4 days ofage. The symptoms resolved in 2–3 days in mostcases.

Frequent neonatal symptoms reportedin association with maternal SSRI ingestion

Symptoms Withdrawal Breast-milksyndrome transfer

Agitation/Jitteriness 15 4Poor feeding 7 4Hypotonia 7 1Sleepiness/Lethargy 0 3Gastrointestinal symptoms 3* 3

Total reports 26 13

* In one case the symptoms may have been from breast-milk transfer.

In addition, 13 reports have been received ofneonatal adverse effects probably resulting frombreast-milk transfer of an SSRI (sertraline 9,paroxetine 2, fluoxetine 2). There was someoverlap of symptoms resulting from drug transferinto breast-milk and from drug withdrawal (seetable above). However, sleepiness was reportedonly with breast-milk transfer, and in two casesthe baby slept for prolonged periods.

One study found that 12 (22%) of 55 neonatesexposed to maternal paroxetine in the thirdtrimester required prolonged hospitalization forneonatal complications (1). The most commonproblem was respiratory distress (9 cases), buttwo neonates had hypoglycaemia and one eachhad bradycardia, tachycardia, jaundice andfeeding problems. None had underlying pathologyand all recovered following a brief period ofintensive intervention. In the same study, expo-sure to paroxetine through breastfeeding causedsymptoms in 8 (22%) of 36 infants, with alertness,sleepiness and irritability.

In adult users, withdrawal effects followingparoxetine appear to be more likely than followinguse of other SSRIs, and hence neonatal with-drawal may be more likely with paroxetine, butthis is yet to be demonstrated in comparativestudies (2). However, paroxetine may have anadvantage in breastfeeding since breast-milktransfer is proportionately lower than withfluoxetine or citalopram (3). One study in 11infants detected sertraline in breast-milk but therewere no adverse effects associated with exposure(4). It is probable that neonatal withdrawal effectswould be minimized by using the lowest effectivematernal dose, while breast-milk transfer can betreated by stopping or reducing the dose of SSRI,or by using milk formula.

Extracted from the Australian Adverse Drug ReactionsBulletin,Volume 22, Number 4, August 2003.

References

1. Moldovan Costei, A., Kozer, E., Ho, T. et al. Perinataloutcome following third trimester exposure toparoxetine. Archives of Pediatric and AdolescentMedicine,156: 1129–1132 ( 2002).

2. Price, J.S., Waller, P.C., Wood, S.M. et al. A compari-son of the postmarketing safety of 4 SSRIs, includinginvestigation of symptoms occurring on withdrawal.British Journal of Clinical Pharmacology, 42: 757–763(1996).

3. Gardiner, S., Begg, E. Drug safety in lactation.Prescriber Update, No.21, June 2001: 10–23.

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4. Stone, Z.N., Owens, M.J., Landry, J.C. et al.Sertraline and desmethylsertraline in human breast milkand nursing infants. American Journal of Psychiatry,154: 1255–1260 ( 1997).

ACE inhibitor, diuretic and NSAID:a dangerous combinationThe control of hypertension by ACE inhibitors anddiuretics and their beneficial effects in heartfailure are antagonized by NSAIDs*. Concurrentuse of NSAIDs and diuretics is associated with atwofold increase in the risk of hospitalization forheart failure compared with diuretics alone (1).Moreover, ACE inhibitors, NSAIDs and diuretics,individually or in combination, are involved in over50% of cases of iatrogenic acute renal failurereported to the Australian Adverse Drug Reac-tions Advisory Committee (ADRAC).

More specifically, the combined use of ACEinhibitors, diuretics and NSAIDs, termed the “triplewhammy”, is implicated in a significant number ofreports to ADRAC of drug-induced renal failure(2). This effect is also seen with COX-2 inhibitorsand angiotensin receptor antagonists (“sartans”)(3). In 2002, 28 of the 129 reports to ADRAC ofacute renal failure implicated one of thesecombinations. Most reports to ADRAC of drug-induced renal failure relate to elderly patients, andthis applies as well to renal failure associated withthe triple therapy (median age 76 years). Thefatality rate for ADRAC cases of renal failure withthe “triple whammy” is 10%.

The use of ACE inhibitors and angiotensinreceptor antagonists is increasing, as is the use ofthese agents in combination products with adiuretic. Episodes of renal failure appear to beprecipitated by mild stress (e.g. diarrhoea,dehydration) in a patient taking the triple combina-tion or by the addition of a third drug (usually anNSAID) to the stable use of the other two. ADRACsuspects that the risk of acute renal failure isunderestimated and the syndrome underrecog-nized.

Extracted from the Australian Adverse Drug ReactionsBulletin,Volume 22, Number 4, August 2003. * Ed. note.Referenced articles not mention use of acetylsalicylicacid as an NSAID.

References

1. Heerdink, E.R., Leufkens, H.G., Herings, R.M.C. et al.NSAIDs associated with increased risk of congestiveheart failure in elderly patients taking diuretics. Archivesof Internal Medicine, 158: 1108–1112 (1998).

2. ADRAC, Thomas M. Diuretics, ACE inhibitors andNSAIDs — the triple whammy. Medical Journal ofAustralia,172: 184–185 (2000).

3. Boyd, I.W., Mathew, T.H., Thomas, M.C. COX-2inhibitors and renal failure: the triple whammy revisited.Medical Journal of Australia, 173: 274 (2000). (corr. MJA173: 504, 2000).

Serious gastrointestinal effectswith celecoxib and rofecoxibThe Australian Adverse Drug Reactions AdvisoryCommittee (ADRAC) has received a significantnumber of reports of peptic ulcer (with and withoutperforation or haemorrhage) and of gastro-intestinal (GI) haemorrhage with celecoxib(Celebrex®) and rofecoxib (Vioxx®).

Many of the patients with peptic ulcer had knownrisk factors: they were aged > 60 years (73% forcelecoxib vs 97% for rofecoxib), they had ahistory of peptic ulcer (18% vs 0%) or they weretaking other medication which increased their risk(45% vs 81%). However, 16 of those who de-veloped peptic ulcer with celecoxib (none withrofecoxib) were aged < 60 years and had nostated risk factors. In five of these cases the ulcerwas diagnosed within 4 weeks of initiation ofcelecoxib. In nine of the 16 cases, the diagnosiswas confirmed by endoscopy, radiology, or duringsurgery.

Reports of peptic ulcer or GI haemorrhagewith celecoxib and rofecoxib

celecoxib rofecoxib

PBS prescriptionsMay 2000 to Dec 2002 9.3 million 4.3 millionTotal reports 3315 637Total peptic ulcers 101 31-with risk factors 84 31-without risk factors 16 -Total GI haemorrhage 250 56-with risk factors 234 51-without risk factors 16 5

Of the reports of GI haemorrhagic events (in theabsence of a diagnosis of peptic ulcer), 16 caseswith celecoxib and five with rofecoxib involvedpatients aged < 60 years, with no stated history ofGI ulcer and no concurrent use of another NSAID.Those reports mentioning alcohol as a possiblefactor were excluded. For these 21 cases, time to

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onset ranged from 1 day to 8 months (median 13days). In four cases the reaction occurred after asingle dose, and in one of these cases thepatient’s haematemesis recurred following asingle dose a week later.

Initial results from clinical trials indicated a rate ofupper GI ulceration with celecoxib or rofecoxib ofaround 2 per 100 patient-years during 6-9 months’treatment, significantly lower than with thenonselective NSAIDs (1, 2). However, while apivotal study suggested that there may be a long-term advantage of rofecoxib over the nonselectiveNSAIDs for upper GI ulceration (1), results after12 months’ usage of celecoxib indicated similarrates of ulcer complications to diclofenac andibuprofen (3). The differences between celecoxiband rofecoxib apparent in the ADRAC data mayreflect the differences seen in the clinical trialsand/or they may relate to differences between thepopulations of users. Whatever the absolute ratesof peptic ulcer may be with celecoxib androfecoxib, the serious events reported to ADRACsuggest that selective COX-2 inhibitors should betreated with similar caution to other NSAIDs.

Extracted from the Australian Adverse Drug ReactionsBulletin,Volume 22, Number 4, August 2003.

References

1. Bombardier, C., Laine, L., Reicin, A. et al. Compari-son of upper gastrointestinal toxicity of rofecoxib andnaproxen in patients with rheumatoid arthritis. NewEngland Journal of Medicine, 343:1520–1528 (2000).

2. Silverstien, F.E., Faich, G., Goldstein, J.L. et al.Gastrointestinal toxicity with celecoxib vs nonsteroidalanti-inflammatory drugs for osteoarthritis and rheuma-toid arthritis. The CLASS Study. Journal of the AmericanMedical Association, 284:1247–1255 (2000).

3. Juni, P., Rutjes, A.W.S., Dieppe, P.A. Are selectiveCOX-2 inhibitors superior to traditional non steroidalanti-inflammatory drugs? British Medical Journal,324:1287–1288 (2002).

Bisphosphonatesand ocular disordersBisphosphonates inhibit bone resorption. Indica-tions for their use vary according to the individualproducts, but they are used primarily to prevent ortreat osteoporosis, Paget disease of bone,tumour-induced hypercalcaemia and conditionsassociated with increased osteoclast activity(predominantly lytic bone metastases and multiple

myeloma). International data from spontaneousreporting systems for visual reactions associatedwith bisphosphonates suggest that, in rareinstances, this class of medication can causeserious ocular adverse effects (1).

Pamidronate has been associated with ocularinflammation such as uveitis, nonspecific conjunc-tivitis, episcleritis and scleritis (1). Similar disor-ders have been linked to alendronate, clodronate,etidronate and risedronate (1–3). These oculareffects were initially thought to be related toamine-bisphosphonates, which includealendronate, pamidronate and risedronate.However, clodronate and etidronate, both non-amine-bisphosphonates, have also been impli-cated (1–3).

Health Canada received 27 domestic reports ofsuspected ocular and visual disorders associatedwith bisphosphonates since their introduction ontothe Canadian market. Of these reports, 13involved alendronate, 5 etidronate, 6 pamidronateand 3 risedronate. No cases of visual disordershave yet been reported in association withclodronate or zoledronic acid in Canada. Manyfactors, such as time marketed, exposure dataand varying indications for the different products,can influence reporting rates of adverse effects inspontaneous reporting systems.

Indications of ocular inflammation may includeeye pain, redness, abnormal vision (blurred ordouble vision, decreased vision, “floaters”) andphotophobia (1, 4). Although these ocular effectsmay be rare with bisphosphonates, health careprofessionals should be aware of their possibility.

The following guidelines have been suggested forthe care of patients receiving bisphosphonates(1):

•�Patients with visual loss or ocular pain should bereferred to an ophthalmologist.

•�Nonspecific conjunctivitis seldom requirestreatment and usually decreases in intensityduring subsequent exposure to a bisphos-phonate.

•�More than 1 ocular side effect can occur at thesame time (e.g., episcleritis in conjunction withuveitis). In some instances, the drug may needto be discontinued in order for the ocularinflammation to resolve.

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•�For scleritis to resolve, even during full medicaltherapy, bisphosphonate therapy must bediscontinued.

Extracted from the Canadian Adverse ReactionNewsletter, Volume 13(4), October 2003.

References

1. Fraunfelder, F.W., Fraunfelder, F.T. Bisphosphonatesand ocular inflammation. New England Journal ofMedicine, 348(12):1187–1188 (2003).

2. Ocular adverse effects of alendronic acid. PrescrireInternational,10(53): 82 (2001).

3. Fietta, P., Manganelli, P., Lodigiani, L. Clodronateinduced uveitis. Annals of Rheumatic Disease, 62(4):378 (2003).

4. Fraunfelder, F.W., Rosenbaum, J.T. Drug-induceduveitis. Incidence, prevention and treatment. DrugSafety, 17(3): 197–207 (1997).

Fluticasone and adrenalsuppressionInhaled corticosteroids are highly effective for thecontrol of asthma and the prevention ofexacerbations (1). However, there have recentlybeen several reports worldwide of adrenalinsufficiency in adults and children using inhaledcorticosteroids (2–5). Although adrenal insuffi-ciency can occur with any inhaled corticosteroid, itmay be more common with fluticasone becauseof the drug’s pharmacologic and pharmacokineticproperties, including its greater potency andhence lower equivalent dose (half the dose ofeither budesonide or beclomethasone) (2, 6, 7). Inaddition, this may result from higher-than-licenseddoses of fluticasone being more widely prescribedin children than other inhaled corticosteroids (5).

The Health Canada database was searched forsuspected adverse reactions involving endocrinedisorders reported from 1996 to 2002, associatedwith fluticasone, budesonide and beclometha-sone. There were no Canadian case reports ofsuspected adrenal insufficiency associated withthe use of budesonide or beclomethasone.

There were 9 reports involving fluticasone, 5 ofwhich involved children aged 4–13 years (wherespecified). Dosages (where specified) rangedfrom 250 to 1100 µg/d; in 4 cases the doseexceeded 1000 µg/d. Two patients experiencedadrenal crisis; one was a boy (age unspecified),and the other was a 72-year-old man.

Adrenal insufficiency associated with inhaledcorticosteroid use can occur because of systemicabsorption of the corticosteroid and consequentsuppression of endogenous glucocorticoids,which leaves insufficient adrenal reserve torespond to stressful stimuli (e.g., surgery, traumaand infection) (2, 3). Adrenal insufficiency mayalso result from abrupt discontinuation or non-compliance with treatment, which leads to acutesteroid deficiency (2, 3). Signs and symptoms ofadrenal suppression and crisis are nonspecificand include anorexia, abdominal pain, weightloss, fatigue, headache, nausea, vomiting,decreased level of consciousness, hypoglycaemiaand seizures (3, 5).

Clinicians are reminded that, beyond a certainlimit, increasing the dose of inhaled cortico-steroids offers minimal benefit but increases therisk of systemic adverse effects (1, 7, 8). Oncebest results are achieved, the dose should bereduced at appropriate intervals to determine theminimum dose required to maintain control. Inaddition, different inhalation techniques andpropellants can influence the portion of inhaleddrug, and thus systemic bioavailability (6, 9).


References

1. Boulet, L.P., Becker, A., Berube, D. et al. Inhaledglucocorticosteroids in adults and children. Use ofglucocorticosteroids in asthma. Canadian asthmaconsensus group. Canadian Medical AssociationJournal, 161(11 Suppl): S24–28 (1999).

2. Lipworth, B.J. Systemic adverse effects of inhaledcorticosteroid therapy. A systematic review and meta-analysis. Archives of Internal Medicine, 159: 941–955(1999).

3. Adverse Drug Reactions Advisory Committee.Fluticasone and adrenal crisis. Australian Adverse DrugReactions Bulletin, 22(2): 6 (2003).

4. Centre for Adverse Reactions Monitoring (CARM),Medsafe New Zealand. Adrenal insufficiency, hypogly-caemia, or seizure with fluticasone. Adverse Reactionsof Current Concern, 2003. http://www. medsafe.govt.nz/Profs/adverse/cc.htm.

5. Committee on Safety of Medicines. Inhaled corticos-teroids and adrenal suppression in children. CurrentProblems in Pharmacovigilance, 28: 7 (2002).

6. Todd, G.R.G., Acerini, C.L., Ross-Russell, R. et al.Survey of adrenal crisis associated with inhaledcorticosteroids in the United Kingdom. Archives ofDiseases of Children, 87: 457–461 (2002).

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Adhesion Prevention Solution was washed out.Inflammation was observed, and many internalorgans were adhered, with degradation of tissue.


References

1. IntergelTM Adhesion Prevention Solution [packageinsert]. Somerville (NJ): Ethicon Inc.; Johnson &Johnson Medical Products Canada [distributor] / Chaska(MN): Lifecore Biomedical [manufacturer]; 1998. p. 2.

2. Urgent voluntary recall of Gynecare IntergelTM

Adhesion Prevention Solution. Gynecare Worldwide; adivision of Ethicon, Inc., a Johnson & Johnson com-pany; 2003. http://www.fda.gov/medwatch/SAFETY/2003/Intergel.pdf

3. Urgent voluntary recall of Gynecare IntergelTM

Adhesion Prevention Solution. Gynecare Worldwide;issued in Canada by Johnson & Johnson MedicalProducts, 2 April 2003.

Treatment study forWest Nile virusA clinical trial evaluating an experimental treat-ment for patients infected with West Nile virus(WNV) has begun enrolling volunteers at 36 sitesIn the USA. This study is part of a larger effort bythe National Institutes of Allergy and InfectiousDiseases (NIAID) to develop new ways to preventand treat the disease which appears to bespreading more quickly and more widely thanduring 2002.

The new study will assess whether WNV-infectedindividuals given antibodies to the virus are betterable to fend off the severe symptoms of WNV,such as encephalitis, that contribute to the deathsof many individuals who become infected.Immunoglobulin treatment has been developedfrom the plasma of Israeli donors who have highlevels of antibodies to WNV which is endemic inIsrael. This study will provide information onsafety and efficacy of this treatment in preventingdeath or neurologic disability and will helpcharacterize the natural history of severe WNVinfection.

The study seeks to enroll 100 hospitalizedpatients 18 years of age or older who have WNV-related encephalitis or are determined to be atrisk of developing encephalitis based on clinicalsymptoms and the presence of antibodies to thevirus. Patients will be assigned at random to one

7. Holt, S., Suder, A., Weatherall, M. et al. Dose-response relation of inhaled fluticasone propionate inadolescents and adults with asthma: meta-analysis.British Medical Journal, 323: 253–256 (2001).

8. Drake, A.J., Howells, R.J., Shield, J.P.H. et al.Symptomatic adrenal insufficiency presenting withhypoglycaemia in children with asthma receiving highdose inhaled fluticasone propionate. British MedicalJournal, 324: 1081–1082 (2002).

9. Salvatoni, A., Piantanida, E., Nosetti, L. et al. Inhaledcorticosteroids in childhood asthma. Long-term effectson growth and adrenocortical function. Pediatric Drugs,5(6): 351–361 (2003).

Adhesion prevention solutionsin gynecological proceduresIntergelTM Adhesion Prevention Solution (0.5%ferric hyaluronate gel) has been indicated inCanada for use as an intraperitoneal instillate forthe reduction of adhesions following peritonealcavity surgery (1). It provides a transient, viscous,lubricant coating on peritoneal surfaces followingsurgical procedures. The product is contraindi-cated in patients with pelvic or abdominal infec-tion.

Health Canada issued a class III medical devicelicence in1999. Since then, there have been post-market reports of suspected late-onset postopera-tive pain and repeat surgeries following onset ofpain, noninfectious foreign-body reactions andtissue adherence associated with certaingynecological procedures. In some patientsresidual material was observed during surgery.

In March 2003, the product distributor issued anurgent worldwide voluntary withdrawal ofGynecare IntergelTM Adhesion Prevention Solutionand advised that all use of the product be immedi-ately discontinued (2, 3).

One report of a serious, unexpected reactionsuspected to be associated with the product wasreceived by Health Canada. A woman in her mid-30s (weight 64 kg) underwent laparoscopy andleft fimbrioplasty in November 2002. IntergelTM

Adhesion Prevention Solution was instilled at theend of the procedures. The following day thepatient was admitted to hospital with peritonitis-like symptoms. She was given antibiotics empiri-cally, and over 3 days her condition started toimprove but she was still in pain. In January 2003she presented with pelvic pain and was admittedto hospital for surgery. Residue of IntergelTM

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of three groups. Each participant will receive asingle-dose infusion of drug or placebo.

References

1. http://www.clinicaltrials.gov. 8 September 2003.

2. Information about NIAID’s research on WNV http://www.niaid.nih.gov/publications/wnile/default.htm.

Blue discoloration and deathfrom FD&C Blue No. 1The US Food and Drug Administration (FDA) hasadvised that several reports of toxicity, includingdeath, have been associated with the use ofFD&C Blue No. 1 (Blue 1) in enteral feedingsolutions. In these reports, Blue 1 was intended tohelp in the detection and/or monitoring of pulmo-nary aspiration in patients being fed by an enteralfeeding tube.

Reported episodes were manifested by bluediscolouration of the skin, urine, faeces, or serumand some were associated with serious complica-tions such as refractory hypotension, metabolicacidosis and death. Case reports indicate thatseriously ill patients, particularly those with a likelyincrease in gut permeability (e.g., patients withsepsis), may be at greater risk for these complica-tions. Because these events were reportedvoluntarily from a population of unknown size, it isnot possible to establish the incidence of theseepisodes.

A causal relationship between systemic absorp-tion of Blue 1 and the reported serious and life-threatening patient outcomes (including death)has not been definitively established. Indeed, itwould be very difficult to establish a clear, causalrelationship in the setting of complex medicalissues often seen in patients receiving feedingsvia enteral tubes. However, in vitro evidence thatBlue 1 can be a mitochondrial toxin lends plausi-bility to the idea that Blue 1 could cause thesekinds of serious adverse effects if significant orpersistent serum levels of the dye were to occur.

From the reports, it appears that neither theconcentration nor the total amount of Blue 1 usedin the enteral feeding solutions was unusuallyhigh compared to other patients in whom notoxicity was observed. Thus, if there is a causalrelationship between the dye and the seriousoutcomes, there could be underlying patient-related factor(s) that allow significant absorption

of Blue 1 in some enterally fed patients. A cause-and-effect relationship has not yet been clearlyestablished.

FD&C Blue No. 1 is a water-soluble dye allowedby the FDA for use in foods, drugs and cosmetics,based on numerous studies in animals. The dyeis batch certified by the FDA and is widely used infood products. There have been no reports oftoxicity associated with general use. However,there has been no evaluation by the FDA of thesensitivity and specificity of its use in tinting ofenteral feedings.

As of September, 2003, the FDA is aware of 20cases from the scientific literature or in FDA post-marketing adverse event reports associating theuse of blue dye in tube feedings with blue discol-oration of body fluids and skin, as well as moreserious complications. There have been 12reported deaths and one case with an unknownoutcome.

In more than 75% of all reported cases, patientshad a reported history of sepsis (and thereforelikely altered gut permeability) before or duringsystemic absorption of Blue 1.

Time of onset of toxicity from first use of Blue 1varied from several hours to 20 days of continu-ous use in enteral feedings.

At this time, the FDA believes practitioners shouldbe aware of the following points:

• Use of Blue 1-tinted enteral feedings for detect-ing aspiration has been associated with severalserious adverse events, including death,although a direct causal relationship has notbeen definitely established.

• The safety of Blue 1-tinted enteral feedings fordetecting aspiration has not been documented.Based on the reports received to date, patientsat risk for increased intestinal permeability,which includes those with sepsis, burns, trauma,shock, surgical interventions, renal failure,celiac sprue, or inflammatory bowel disease,appear to be at increased risk of absorbing Blue1 from tinted enteral feedings.

• In addition to the possibility of systemic toxicity,Blue 1-tinted enteral feedings may interfere withdiagnostic stool examinations, such as thehemoccult test.

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• Other blue dyes, such as methylene blue andFD&C Blue No. 2, may have similar if notgreater toxicity potential than Blue 1 and wouldnot be appropriate replacements.

References

1. FDA Public Health Advisory, 29 September 2003http://www.fda.gov

2. Systemic absorption of food dye in patients withsepsis. Maloney, J.P., Halbower, A.C., Fouty, B.F. et al.New England Journal of Medicine, 343(14):1047–1048(2000).

3. Maloney, J.P., Ryan, T.A., Brasel, K.J. et al. Food dyeuse in enteral feedings: A review and a call for amoratorium. Nutrition in Clinical Practice, 168–181(2002).

4. Metheny, N.A. Risk factors for aspiration. Journal ofParenteral and Enteral Nutrition, 26(Suppl): S26–33(2002).

5. McClave, S.A., DeMeo, M.T., DeLegge, M.H.et al.North American Summit on Aspiration in the Critically IllPatient: consensus statement. Journal of Parenteraland Enteral Nutrition, 26(Suppl): S80–85 (2002).

6. Pharmokinetic study of biliary secretion. II. Compari-son of excretion behavior in triphenylmethane dyes.Iga, T., Awazu, S., Nogami, H. Chemistry and PharmacyBulletin, 19: 273–281 (1971).

7. Metheny, N.A., Myra, A.A., Wunderlich, R.J. A surveyof bedside methods used to detect pulmonary aspirationof enteral formula in intubated tube-fed patients.American Journal of Critical Care Medicine, 8(3):160–167 (1999)

8. Potts, R.G., Zaroukian, M.H., Guerrero, P.A. et al.Comparison of blue dye visualization and glucoseoxidase test strip methods for detecting pulmonaryaspiration of enteral feedings in intubated adults.Chest, 103(1): 117–121 (1993).

9. Metheny, N.A., Dahms, T.E., Stewart, B.J. et al.Efficacy of dye-stained enteral formula in detectingpulmonary aspiration. Chest, 122(1): 276–81 (2002).

10. Reyes, F.G., Valim, M.F., Vercesi, A.E. Effect oforganic synthetic food colours on mitochondrialrespiration. Food Additives and Contaminants, 13(1):5–11 (1996).

Atazanavir and tenofovircombination cautionedThe manufacturer of atazanavir has informedclinicians of new pharmacokinetic (PK) dataconcerning coadministration of atazanavir sulfate

(Reyataz®) with tenofovir disoproxil fumarate(DF) (Viread®). Two studies have been con-ducted to evaluate potential PK interaction and anadditional ongoing clinical study has providedpreliminary data on the safety profile of thiscombination. Data from these trials are currentlyunder review by the US Food and Drug Adminis-tration.

The following observations were made from threetrials:

1. Study AI454–181: In healthy volunteersatazanavir AUC and Cmin were decreased byapproximately 25% and 40%, respectively, whenunboosted atazanavir sulfate 400 mg wascoadministered with tenofovir DF 300 mg oncedaily (QD) as compared to atazanavir sulfatealone. In addition, an increase of approximately24% in tenofovir AUC was observed.

2. Study PUZZLE 2 (ANRS 107): Atazanavir AUCand Cmin were decreased by approximately 25%and 23%, respectively, when atazanavir sulfate300 mg and ritonavir 100 mg (boosted atazanavirsulfate) were coadministered with tenofovir DF300 mg QD, as compared to atazanavir sulfate300 mg and ritonavir 100 mg administered withouttenofovir DF to HIV-infected patients.

For the combination of boosted atazanavir sulfatewith tenofovir DF, the atazanavir AUC and Cminobserved in the Puzzle 2 study were approxi-mately 1.2 and 4-fold higher than the respectivevalues observed for unboosted atazanavir sulfate,400 mg given alone, to healthy volunteers inStudy AI424-181.

3. Study AI424-045: Interim safety data from anongoing clinical trial suggest that the treatmentemergent adverse events of moderate or severeintensity are comparable for boosted atazanavirsulfate in treatment-experienced patients and forunboosted atazanavir sulfate treated patients inother clinical trials.

Based on these results

• Clinicians should use caution when administer-ing unboosted atazanavir sulfate with tenofovirDF. Unboosted atazanavir sulfate may be lesseffective due to decreased atazanavir concen-trations in patients taking atazanavir sulfate andtenofovir DF. As a result, the coadministration ofunboosted atazanavir sulfate with tenofovir DFmay lead to loss or lack of virologic responseand possible resistance to atazanavir sulfate

Safety and Efficacy issues

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• �If atazanavir sulfate is coadministered withtenofovir DF, consideration should be given toadministering atazanavir sulfate 300 mg withritonavir 100 mg and tenofovir DF 300 mg (all asa single daily dose with food), until additionaldata are obtained. Coadministration ofatazanavir sulfate 300 mg and ritonavir 100 mgQD is currently under clinical investigation.

The increase in tenofovir AUC does not appear tobe associated with increased toxicity over 24weeks.

Reference: Communication from Bristol Myers Squibbon http://www.fda.gov/medwatch 8 August 2003.

Rofecoxib, celecoxib andcardiovascular riskIn a randomized controlled trial of the efficacy ofrofecoxib in rheumatoid arthritis (the VIGORstudy) the incidence of myocardial infarction wassignificantly greater with rofecoxib than with thecomparator drug, naproxen (0.4% vs 0.1%) (1).While it was postulated that naproxen might havea cardioprotective effect, similar to that withaspirin, the result also raised the possibility thatrofecoxib might be prothrombotic, leading to anelevated rate of myocardial infarction (2). Twofactors in the VIGOR study which may haveincreased the risk of cardiovascular events werethe high dose of rofecoxib used (50 mg daily;approved dose 12.5–25 mg daily) and theexclusion of the use of aspirin by participants inthe study (2). Retrospective analysis indicatedthat aspirin for cardiovascular prophylaxis wasindicated in 4% of the patients in the VIGORstudy (1). Thirty-seven percent of the myocardialinfarctions occurred in this 4% (3).

A recent large-scale cohort study has providedsupport for the view that the risk of cardiovascularevents with rofecoxib may be dose-related (4). Inthe study, new users of high dose rofecoxib had arelative risk of serious coronary heart disease(CHD) of 1.93 compared with non-users of annon-steroidal anti-inflammatories (NSAIDs). Thestudy found no increased risk of CHD amongusers of other NSAIDs, including celecoxib, oramong users of lower doses of rofecoxib, and noprotective effect with naproxen.

At present the evidence for an associationbetween rofecoxib and a risk of cardiovascularevents is inconclusive and indirect. The evidencefor an effect with celecoxib is even weaker (2, 3).

Reflecting the current data, the Australian Ad-verse Reactions Advisory Committee (ADRAC)wishes to advise prescribers of the following:

• There may be an increased risk of cardiovascu-lar and cerebrovascular disease with rofecoxiband celecoxib.

• The increase in risk seems to be higher in thosewith pre-existing cardiovascular disease.

• The risk appears to be greater with rofecoxibthan with celecoxib, and appears to be dose-related.

• Rofecoxib should not be used at doses exceed-ing the maximum approved dose (25 mg/day).

• Cardiovascular risk should be evaluated beforeprescribing a coxib.

Some authors have advised taking low-doseaspirin with celecoxib or rofecoxib in patients withcardiovascular risk factors (3). However, aspirin,even in low dose, has the potential to reduce thegastroprotective benefit of the coxibs.

Extracted from Australian Adverse Drug ReactionsBulletin, Volume 22, Number 5, October 2003.

References

1. Bombardier, C., Laine, L, Reicin, A. et al. Comparisonof upper gastrointestinal toxicity of rofecoxib andnaproxen in patients with rheumatoid arthritis. NewEngland Journal of Medicine, 343: 1520–1528 (2000).

2. Mukherjee, D., Nissen, S.E., Topol, E.J. Risk ofcardiovascular events associated with selective COX-2inhibitors. Journal of the American Medical Association,286: 954–959 (2001).

3. Howes, L.G., Krum, H. Selective cyclo-oxygenase-2inhibitors and myocardial infarction. How strong is thelink? Drug Safety, 25: 829–835 (2002).

4. Ray, W.A., Stein, C.M., Daugherty, J.R. et al. COX-2selective non-steroidal anti-inflammatory drugs and riskof serious coronary heart disease. Lancet, 360: 1071–1073 (2002).

Convulsions and blood dyscrasiaswith mirtazapineMirtazapine (Remeron®, Avanza®, Mirtazon®),an antidepressant, antagonizes central alpha2adrenoceptors to cause an increase in noradrena-line and serotonin release. It is also a histamine


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H1 receptor antagonist, causing sedation, but haslittle anticholinergic activity. From May 2001 toMay 2003, almost 500 000 funded prescriptionswere dispensed.

The Australian Adverse Reactions AdvisoryCommittee (ADRAC) has received 253 reports formirtazapine. Common reactions reported are pre-sented in the table below. A prescription eventmonitoring (PEM) study conducted in England ofover 13 000 patients taking mirtazapine found thatthe most frequent adverse reactions were drowsi-ness/sedation and malaise/lassitude (5.8% and2.8% of patients in the first month) (1).

Potentially serious reactions reported to ADRACare convulsions (16 reports) and blood dyscrasias(15). None of the 16 patients who experiencedconvulsions with mirtazapine were known to haveepilepsy. Mirtazapine was the only drug taken ineight of the cases. No cases of convulsions wereidentified in the PEM study.

Common reactions reported toADRAC with mirtazapine 2001–2003

Reactions Number of reports

oedema 33anxiety/agitation 24myalgia/arthralgia 24sedation 23skin reactions 20blood dyscrasias 15convulsions 16hyperkinesis 15dizziness 15nightmares 14increased weight 14diarrhoea 11nausea/vomiting 11hepatic reactions 10hallucination 9serotonin syndrome 4

The blood dyscrasias reported were neutropenia(8), thrombocytopenia (6), lymphopenia (1) andpancytopenia (1). Two patients had fever withneutropenia. The time to onset was ≤ 2 months in8 out of the 11 reports where this information wasprovided. Mirtazapine was the only suspecteddrug in nine of the blood dyscrasia reports.

Health professionals should be alert for signs ofblood dyscrasias (fever, sore throat, petechiaeetc.) in users of mirtazapine.


ReferenceSafety and Efficacy issues1. Biswas PN. Wilton LV, Shakir SAW. Thepharmacovigilance of mirtazapine: results of a prescrip-tion event monitoring study on 13 555 patients inEngland. Journal of Psychopharmacology, 17: 12112–6(2003).

Anti-epileptic drugs, pregnancyand fetal malformationsFor some decades, an association has beenrecognized between maternal epilepsy and anincreased risk of fetal malformation. Althoughinadequately controlled epilepsy is associatedwith dangers to mother and fetus, anti-epilepticdrugs (AEDs) might cause adverse conse-quences in the fetus (1).

The Australian Adverse Reactions AdvisoryCommittee (ADRAC) receives occasional reportsof fetal malformations (FMs) associated with theuse of AEDs in pregnancy. However, for many ofthese reported malformations, there are fewpublished prospective data in human pregnancyindicating whether the AEDs involved increaserisk. To address this lack, prospective pregnancyregisters have been established in Australia,Europe, North America, and the United Kingdom.

Analysis of the 40-month data from the ongoingAustralian Pregnancy Register for Women onAntiepileptic Medication has yielded importantand clinically relevant information (2). Out of 403pregnancy outcomes for women taking AEDs,87.8% resulted in a healthy live birth, and 6.5%had an FM. (The remainder had spontaneousabortions or premature death in utero.) The FMrate was significantly greater in pregnanciesexposed to valproate in the first trimester (16.0%)compared with those exposed to all other AEDs(2.4%). Furthermore, the mean daily dose ofvalproate was significantly higher in those withFMs than in those without FMs.

A recently published, prospective Finnish study of970 pregnancy outcomes in women with epilepsyalso found an association between the use ofvalproate in pregnancy and FM; control group:pregnancies in women with epilepsy not usingAEDs in the first trimester) (3). Increased riskswere also seen with carbamazepine andoxcarbazepine, and with low serum folate concen-tration in early pregnancy.


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Prescribers should review the medication ofwomen on AEDs in pre-pregnancy planning.Treatment should aim to maximize seizure controlwhile minimizing the risk of FM. Folic acid supple-mentation prior to conception and during the firsttrimester is desirable in all pregnancies, espe-cially in those women taking AEDs.


References

1. ADEC. Anticonvulsants/antiepileptics. In: PrescribingMedicines in Pregnancy. 4th Ed. 1999, 17–19.

2. Vajda, F., O’Brien, T., Hitchcock, G. J. et al. CriticalRelationship between sodium valproate dose andhuman teratogenicity. Abstract presented at the meetingof the Australian Association of Neurologists, May 2003.

3. Kaaja, E., Kaaja, R., Hiilesmaa, V. Major malforma-tions in offspring of women with epilepsy. Neurology, 50:575–579 (2003).


Spontaneous monitoring systems are useful in detecting signals of relatively rare, serious and unex-pected adverse drug reactions. A signal is defined as "reported information on a possible causalrelationship between an adverse event and a drug, the relationship being unknown or incompletelydocumented previously. Usually, more than a single report is required to generate a signal, depend-ing upon the seriousness of the event and the quality of the information". All signals must be vali-dated before any regulatory decision can be made.

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Aspects of Quality Assurance

Supplying quality medicinesfor filariasis eliminationLymphatic filariasis is a disfiguring, disablingdisease transmitted by infected mosquitoes. It iscaused by threadlike parasitic filarial worms whichlodge in the lymphatic system and live for four tosix years, producing millions of immature micro-filaria that circulate in the blood. It is a seriouspublic health and socioeconomic problem in manytropical and sub-tropical countries.

Lymphatic filariasis is ranked as the second larg-est cause of long-term disability (1). More than 40million people are seriously incapacitated anddisfigured by the infection and, in India alone, theeconomic impact due to lost work and decreasedproductivity is estimated at US$ 842 millionannually (2).

Mass administration of DECIn 1997, the World health Assembly resolved toeliminate lymphatic filariasis as a public healthproblem by the year 2020 through interruption oftransmission and control of morbidity. The GlobalProgramme to Eliminate Lymphatic Filariasis(http://www.who.int/ctd/filariasis) set out toachieve this through measures including com-munity-wide mass drug administration (3).

To fulfil this mandate, it was estimated that 15years’ supply of diethylcarbamazine citrate (DEC)was needed — representing approximately 15billion quality assessed tablets, manufacturedaccording to good manufacturing practices (GMP)by reliable companies able to deliver on time (4,5). Good manufacturing practices (GMP) ensuresthat products are consistently produced to thestandards appropriate for their intended use andproduct specifications (6).

In order to identify sources of DEC, informationwas sought from:

• Regulatory authorities willing to supply informa-tion on manufacturers that had registered DECfor sale in countries where lymphatic filariasis isa public health problem.

• Lymphatic filariasis programmes which hadpurchased DEC.

• Lymphatic filariasis experts from around theworld having information on manufacturers ofDEC.

• Organizations such as the International GenericPharmaceutical Alliance, British GenericAssociation, and the on-line network, E-Drug(7).

A search was also launched through the Internet,advertisements in international journals, andpharmaceutical guides/compendia.

In November 1999, an inventory of DEC manufac-turers was prepared. The inventory included onlymanufacturers that supplied information on qualityassurance in their manufacturing sites. Becauseof the geographical distribution of the disease,many commercial manufacturers of DEC tabletswere identified in the developing world, withapproximately half of these in India.

Developing a modern assay for DECIn March 2000, the Programme organized aninformal consultation to secure consensus onappropriate standards and guidelines proposedfor DEC active pharmaceutical ingredient (API)and tablets and to discuss currently availableassay methods. Participants recommended thatWHO develop a modern stability-indicating assayfor DEC that meets current standards, includingdissolution. An HPLC analytical method wasdeveloped in Switzerland and validated byindependent laboratories in Germany, India andSri Lanka. The United States Pharmacopeia andthe Indian Pharmacopoeia have adopted the newmodern stability-indicating method for DEC (8, 9).

DEC prequalification processOnly manufacturers are eligible for prequalifica-tion within the DEC Project. Before an on-siteinspection can take place, the Project teamrequires that an independent laboratory evaluateDEC and the manufacturer is requested tocomplete the WHO Information Questionnaire forProspective Suppliers of Pharmaceutical Prod-

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ucts. This provides information on manufacturingfacilities (the plant master file), all technicaloperations, the DEC master file, the qualityassurance system used by the company, valida-tion of analytical methods, and quality controllaboratory, GMP and Good Laboratory Practices(GLP) used by the company and at the DECmanufacturing site. Manufacturers on the Inven-tory are asked if the company will permit aninspection team to conduct an in-depth inspectionof the manufacturing site for DEC.

DEC manufacturers were inspected by a skilledteam established to verify on-site compliance withGMP. Inspectors were chosen for their experiencein production of pharmaceuticals, APIs and bulkchemicals, quality assurance, inspection, andworking experience in a signatory country of thePharmaceutical Inspection Collaboration Scheme(PIC/S).

The inspection team included WHO staff andformer senior members of:

• a European regulatory agency, signatory of thePIC/S;

• a multinational pharmaceutical company;

• a pharmaceutical manufacturing facility inAustralia.

The manufacturer is requested to provide infor-mation on stability studies, a copy of the most re-cent batch record for manufacturing and packag-ing, information on sources of reference sub-stances, active pharmaceutical ingredients, andall other materials used in manufacture. Addition-ally, the company must test the stability of DECaccording to the WHO Stability guidelines forZone IV (hot and humid conditions) (10) and ICHguidelines for evaluation of stability of pharma-ceuticals in Zone IV (Quality Topic Q1F) (11)1.

The team requests national/state regulatoryauthorities to nominate inspectors to accompanythe inspection team. It discusses the DEC Projectwith the regulatory authorities, inspectors, and theMinister of Health for the state or country. Theinspection team uses WHO guidelines during theinspection as a general guide to GMP (6).

Prequalification2 of DEC manufacturersA manufacturer having an acceptable complianceprofile is confirmed as a prequalified DEC pro-vider (see Table 1). Prequalification is valid for 2years after which time manufacturers should bere-inspected and re-qualified, preferably by orwith assistance of the national drug regulatoryauthority, through an evaluation of recent docu-mentation and on-site inspection.


1 WHO and ICH have recently harmonized the approach to stability testing for Zone IV, see WHO Expert Committeeon Specifications for Pharmaceutical Preparations. Technical Report Series, No. 908. p. 13 (2003).

2 See boxed text on page 247.

Table 1. Prequalification process for DEC Manufacturers

No. of Phases of prequalification manu- Responses

facturers

1. Initial call for proposals – Regulatory and government authorities,known manufacturers, filariasisprogrammes

2. Suppliers/manufacturers providing 43 Australia, Bangladesh, Belgium, Brazil,basic information regarding GMP and Denmark, Egypt, France, India, Indonesia,G(QC)LP at manufacturing site Ireland, Malaysia, Malta, Netherlands,

Sri Lanka, Switzerland, Thailand, UnitedStates of America

3. Manufacturers audited on-site 13 Belgium, India, Malaysia, Singapore, SriLanka

4. Manufacturers prequalified 5 Belgium, India, Sri Lanka

5. Manufacturers currently listed 3 India

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Although a number of manufacturers have beenidentified by the DEC project, not all were compli-ant on various criteria and tests so that, as ofNovember 2002, the prequalified DEC tabletmanufacturers are:

• Panacea Biotech, New Delhi, India; and

• Unichem Laboratories, Goa, India.

There is one prequalified DEC API manufacturer:

• Syntholab Chemicals and Research, Mumbai,India.

WHO purchases DEC tablets from prequalifiedmanufacturers only. Country programmes arealso strongly encouraged to use prequalified DECmanufacturers for their purchases.

Developing a quality surveillance systemThe Programme is currently developing anongoing system to monitor the quality of pur-chased DEC. Randomized collection of samplesfrom each of the manufacturers is handled by anindependent company before laboratory testing iscarried out to determine whether DEC meetsinternationally recognized standards. WHOencourages adoption of this ongoing qualitysurveillance system in national programmes.

Savings linked to bulk purchaseProcurement officials know that increasing thenumber of tablets purchased normally reducesthe price per unit. Experience in WHO has alsoshown that consolidating orders for many coun-tries based on the projections of an annual globalforecast reduces the price even further. Within theproject, orders were consolidated for severalcountries and — utilizing funds provided to WHOby donors (12) — the price obtained per 1000DEC tablets was 30 % to 45 % lower whencompared to that paid in 1999. This processdemonstrates that a centralized process forpurchasing a large number of tablets for severalcountries lowers the cost. The initiative saves

money which enables purchase of additionalamounts of DEC tablets while at the same timeassuring the highest standards of quality. (SeeTable 2 below).

Capacity buildingThe Programme has built capacity in countriesaffected by lymphatic filariasis through provisionof training and expertise while improving compli-ance with GMP and GLP.

Through on-site inspections, both the manufac-turer and national regulatory personnel have theopportunity to gain experience, learn, andimprove production procedures and qualityassurance systems. During an inspection, theteam explains why a procedure is not acceptableor acknowledges compliance. During theinspection, the team encourages participants touse the exercise as a learning experience,thereby contributing to expanding understandingand improving application of internationallyrecognized standards.

The DEC Project collaborates with manufactur-ers to ensure that they implement correctiveaction and maintain GMP and GLP during theentire period of validity of the prequalificationstatus for DEC. The initiative to eliminatelymphatic filariasis benefits from all improve-ments that manufacturers make. The manufac-turer is provided with a report listing the observa-tions made during the inspection and a summaryof any deficiencies in GMP or GLP.

Since initiation of the project in August 1997,WHO has invested both technical and humanresources to:

• develop and validate new analytical methodsfor DEC (13, 14);

• perform dissolution tests of DEC tablets;

• test DEC API and DEC tablets in an independ-ent laboratory;


Table 2. Purchase of DEC tablets by WHO*

Strength 2000 2001 2002 2003 Total tablets

50 mg 22.2 111.02 17.13 5.43 155.78 million

100 mg –– 37.96 40.82 107.6 186.38 million

* Annual Report on Lymphatic Filariasis, 2001 WHO/CDS/CPE/CEE/2002.28, and Annual Report on LymphaticFilariasis 2002. WHO/CDS/CPE/CEE/2003.38

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• conduct various on-site inspections; and

• provide necessary technical assistance andfollow-up.

The benefits gained from the programme aretherefore substantial. The initial investment isdesigned to give long term benefit by ensuringthat national programmes to eliminate lymphaticfilariasis administer quality DEC tablets in 60 ofthe 80 endemic countries during the 15 years ofmass drug administration.

ConclusionThe prequalification process has ensured thatDEC tablets and active pharmaceutical ingredi-ents have been manufactured in compliance withinternational standards. In this way, supplies ofDEC have been made available for the require-ments of the Programme on Elimination ofLymphatic Filariasis at a low cost.

The prequalification process has functioned verysuccessfully. The project must now ensure thatmanufacturing is sustained and sufficient quanti-ties of quality DEC are provided to meet the long-term requirements of the Programme. In order tomeet the global forecast, bulk purchasing throughan international competitive bid mechanism mustcontinue to be strengthened to enable costreduction leading to tangible savings. (15).

References

1. World Health Organization. The World Health Report2000. Geneva, 2000. p. 170

2. Ramaiah, K.D., Das, P.K., Michael, E. et al. TheEconomic Burden of Lymphatic Filariasis in India.Parasitology Today, 16 (6): 251–253 (2000).

3. Das, P.K., Ramaiah, K.D., Augustin, D.J. et al.Towards Elimination of Lymphatic Filariasis in India.Trends in Parasitology, 17 (10): 457–460 (2001).

4. Lymphatic filariasis. Weekly Epidemiological Record,76 (20):149–156 ( 2001).

5. Elimination of Lymphatic Filariasis. Weekly Epidemio-logical Record, 77 (22):177–184 (2002).

6. World Health Organization. Quality assurance ofpharmaceuticals. A compendium of guidelines andrelated materials. Volume 2. Good manufacturingpractices and inspection. Geneva, 1999.

7. E-Drug. Satellife discussion group. [email protected]

8. United States Pharmacopeia, 25th edition. UnitedStates Pharmacopeial Convention, Inc. 2002.

9. The Indian Pharmacopoeia, 1996, Addendum 2002The Indian Pharmaceutical Association

10. World Health Organization. WHO Expert Committeeon Specifications for Pharmaceutical Preparations.Annex 5. Guidelines for stability testing of Pharmaceuti-cal Products containing well established drug sub-stances in conventional dosage forms. Technical ReportSeries, No. 863. 65–77 (1996).

11. ICH guidelines for evaluation of stability of pharma-ceuticals in Zone IV (Quality Topic Q1F). http://www.ifpma.org

12. Global Alliance for the Elimination of LymphaticFilariasis. http://www.filariasis.org

13. WHO Expert Committee on Specifications forPharmaceutical Preparations. Annex 5. Validation ofanalytical procedures used in the examination ofpharmaceutical materials. Technical Report Series, No.823.117–121 (1992).

14. International Conference on harmonisation ofTechnical Requirements for Registration of Pharmaceu-ticals for Human use (ICH), Step 4 Guidelines (QualityTopic Q2A & Q2B). http://www.ifpma.org

15. Kitler, M., Zagaria, N. Ensuring supplies of qualitydiethylcarbamazine citrate (DEC). Journal of ClinicalPharmacology, 43; 477–490 (2003).


Unified standards for prequalificationThe “prequalification” of diethylcarbamazine (DEC) described in this article commenced before theunified general prequalification procedures were adopted by the World Health Organization. Theprocedure for assessing the acceptability, in principle, of pharmaceutical products for purchase byUnited Nations agencies is published as Annex 8 in: World Health Organization, Report of the Ex-pert Committee on Specifications for Pharmaceutical Preparations, Technical Report Series No.908, pp. 113–124 (2003). More information about the joint prequalification project of the UN agen-cies, WHO, UNICEF, UNAIDS and UNFPA, with the support of the World Bank, is available from thewebsite: http://www.who.int/medicines. The “prequalification” of diethylcarbamazine (DEC) doesnot necessarily follow all the principles and standards of the unified prequalfiication project de-scribed above.

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Regulatory and Safety Action

Recommended influenza vaccinefor 2004 (Southern hemisphere)World Health Organization — National Authori-ties are responsible for recommendations regard-ing the use of influenza vaccine and shouldapprove the specific vaccine viruses used in eachcountry.

It is recommended that influenza virus vaccines tobe used in the 2004 season (Southern hemi-sphere winter) contain the following:

• an A/New Caledonia/20/99 (H1N1)-like virus;

• an A/Fujian/411/2002 (H3N2)-like virus {A/Kumamoto/102/2002 and A/Wyoming/3/2003 anegg-grown A/Fujian/411/2002 (H3N2)-like virus}

• a B/Hong Kong/330/2001-like virus {Currentlyused vaccine viruses include B/Shandong/7/97,B/Hong Kong/330/200, B/Hong Kong/1434/2002. B/Brisbane/32/2002 is also available as avaccine virus.}

Information concerning reagents for use inlaboratory standardization of inactivated vaccineand reference strains for antigenic analysis isavailable on http://www.who.int/influenza.

Reference: Weekly Epidemiological Record, No. 43. 24October 2003.

Daclizumab: safety alertNorth America — Two new warning statementshave been added to the prescribing informationfor daclizumab (Zenapax®) indicated for for theprevention of graft rejection. These includeincreased mortality in a cardiac transplant studyand updated information regarding hypersensitiv-ity reactions.

The use of daclizumab as part of an immuno-suppressive regimen including cyclosporine,mycophenolate mofetil, and corticosteroids maybe associated with an increase in mortality. In arandomized, double-blind, placebo-controlled trial

of daclizumab for the prevention of allograftrejection in 434 cardiac transplant recipientsreceiving concomitant cyclosporine, myco-phenolate mofetil and corticosteroids, mortality at6 and 12 months was increased in those patientsreceiving daclizumab compared to those receivingplacebo, sometimes through a higher incidence ofsevere infections. Concomitant use of anti-lymphocyte antibody therapy may also be afactor.

Severe, acute (onset within 24 hours) hypersensi-tivity reactions including anaphylaxis have beenobserved both on initial exposure to daclizumaband following re-exposure. These include hypo-tension, bronchospasms, wheezing, laryngealoedema, pulmonary oedema, cyanosis, hypoxia,respiratory arrest, cardiac arrhythmia, cardiacarrest, peripheral oedema, loss of consciousness,fever, rash, urticaria, diaphoresis, pruritus, and/orinjection site reactions. If a severe hypersensitivityreaction occurs, therapy with daclizumab shouldbe permanently discontinued. Medications for thetreatment of severe hypersensitivity reactionsincluding anaphylaxis should be available forimmediate use. Patients previously administereddaclizumab should only be re-exposed to asubsequent course of therapy with caution. Thepotential risks of such re-administration, specifi-cally those associated with immunosuppression,are not known.

Additionally, the following adverse reactionsoccurred more frequently in paediatric transplantpatients than adult transplant patients: diarrhoea,postoperative pain, fever, vomiting, aggravatedhypertension, pruritus and infections of the upperrespiratory and urinary tracts.

Reference: Communication from Roche Pharmaceuti-cals available on http:// www.fda.gov/medwatch andwww.hc-sc.gc.ca dated 6 November 2003.

Nefazodone discontinuedCanada — In consultation with Health Canada,the manufacturer of nefazodone (Serzone-5HT2®)has decided to discontinue sales of the productfrom the market in Canada effective 27 November

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2003. Nefazodone has been associated withadverse hepatic events including liver failurerequiring transplantation.

Nefazodone is indicated for the symptomaticrelief of depressive illness. Since introduction in1994, nefazodone has been temporally associ-ated with hepatic adverse events such as jaun-dice, hepatitis and hepatocellular necrosis inpatients receiving therapeutic doses. As ofDecember 2002, there were 51 Canadian reportsof hepatotoxicity, ranging from no symptoms totransplantation, suspected to be associated withnefazodone use. One of two transplant recipientssubsequently died. Cases of liver injury haveoccurred as early as a few weeks after initiation oftherapy or after continuous use for up to 3 years.To date, no risk factor to predict patients who willdevelop irreversible liver failure with nefazodonehas been identified. Also, no clinical strategy,such as routine liver function tests, could beidentified to reduce the risk of liver failure.

Reference: Communication from Bristol Myers Squibb,2 October 2003 on www.hc-sc.gc.ca

Levomethadyl discontinuedUnited States of America — The sale anddistribution of levomethadyl hydrochloride acetate(Orlaam®) oral solution, 10 mg/mL will be discon-tinued after the current inventory is depleted inthe first quarter of 2004. Since the introduction oflevomethadyl in 1995, the manufacturer hasreceived increasing reports of severe cardiac-related adverse events, including QT intervalprolongation (15), Torsades de Pointes (8) andcardiac arrest (6). Other cardiac-related adverseevents have also been reported, includingarrhythmias, syncope, and angina. These eventsled to the removal of levomethadyl from theEuropean market in March 2001. A very smallnumber of patients may benefit from levometha-dyl, but the risk of continued distribution and useno longer outweighs the overall benefits.

Levomethadyl is a synthetic opioid agonistsolution indicated for the management of opiatedependence, reserved for the treatment of opiate-addicted patients who fail to show acceptableresponse to other adequate treatments for opiateaddiction.

Due to the forecasted unavailability shortly afterthe beginning of 2004, no new patients should beinitiated on levomethadyl therapy. For existing

patients, it is extremely important for healthcareproviders to transfer patients to alternativetreatments as soon as possible prior to theproduct’s unavailability. Patients maintained onlevomethadyl may be transferred directly tomethadone. Because of the difference betweenthe two compounds’ metabolites and their phar-macological half-lives, it is recommended thatmethadone be started on a daily dose at 80% ofthe levomethadyl dose being replaced; the initialmethadone dose must be given no sooner than48 hours after the last levomethadyl dose.Subsequent increases or decreases of 5 to 10 mgin the daily methadone dose may be given tocontrol symptoms of withdrawal or, less likely,symptoms of excessive sedation, in accordancewith clinical observations.

Reference: Communication from Roxane Laboratorieson http:// www.fda.gov/medwatch

Daptomycin: new class ofantibiotic approvedUnited States of America —The Food and DrugAdministration (FDA) has announced the approvalof daptomycin (Cubicin®) injection for the treat-ment of complicated skin and skin structureinfections, including major abscesses, post-surgical skin wound infections, and infectedulcers. Daptomycin is the first of a new class ofantibiotics called cyclic lipopeptide antibacterialagents.

Daptomycin is specifically indicated for thetreatment of complicated skin and skin structureinfections caused by susceptible strains of thefollowing Gram-positive microorganisms: Staphy-lococcus aureus (including methicillin-resistantstrains), Streptococcus pyogenes, S. agalactiae,S. dysgalactiae subspecies equisimilis andEnterococcus faecalis (vancomycin-susceptiblestrains only). Daptomycin is not indicated for thetreatment of pneumonia.

Approval was based on a review of clinicalstudies involving over 1400 adults. Adverseevents reported in the clinical studies were mild tomoderate in intensity and included: gastro-intestinal disorders, injection site reactions, fever,headache, insomnia, dizziness, and rash.

Blood tests showing muscle injury were foundrarely in patients in clinical trials. Most of thesepatients had no symptoms, and the blood testsreturned to normal after therapy. Patients receiv-

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ing daptomycin should be monitored for thedevelopment of muscle pain or weakness. Creat-ine phosphokinase (CPK) levels should bemonitored weekly. Those who develop unex-plained elevations in CPK should be monitoredmore frequently.

Reference: FDA Talk paper, T03-66. 12 September2003 on http:// www.fda.gov

Tetrahydrogestrinone:grave risks to healthUnited States of America —Tetrahydrogestrin-one (THG) is reportedly used by athletes toimprove their performance. The Food and DrugAdministration (FDA) has determined that THG isan unapproved new drug and is working withother Federal law enforcement agencies toaggressively engage, enforce, and prosecutethose firms or individuals who manufacture,distribute, or market THG. FDA believes that itsuse may pose considerable risks to health.

THG may be represented as a dietary supplementbut it is a purely synthetic “designer” steroidderived by simple chemical modification fromanother anabolic steroid that is explicitly bannedby the US Anti-Doping Agency.

This substance is closely and structurally relatedto two other synthetic anabolic steroids, gestrin-one and trenbolone.

Reference: FDA statement. 28 October 2003.

Coronary Stents and thrombosisUnited States of America —The Food and DrugAdministration (FDA) has informed physiciansthat more than 290 reports of thrombosis (clotting)have occurred one to 30 days after the procedureto implant a Cordis Corporation’s Cypher Coro-nary Stent®.

In more than 60 of these reports, use of thedevice was associated with the death of thepatient; in the remainder, the device was associ-ated with injury requiring medical or surgicalintervention. FDA has also received more than 50reports, including some deaths, that are consid-ered to be possible hypersensitivity reactions. Thesymptoms include: pain, rash, respiratory altera-tions, hives, itching, fever, and blood pressurechanges.

However, hundreds of thousands of patients havebeen successfully treated with the Cypher® stent.FDA does not have enough information to deter-mine whether the incidents of thrombosis andhypersensitivity reactions differ from thoseexperienced with bare metal stents.

The Cypher® stent was approved in April 2003for patients undergoing angioplasty procedures toopen clogged coronary arteries. The stent, acylindrical metal mesh, is designed to keep thearteries from re-clogging after the procedure. It iscoated with a thin polymer containing the drugsirolimus that is slowly released and is intendedto reduce the rate of re-blockage that occurs withother stents.

The FDA is requiring the manufacture to conducta 2000-patient post-approval study and continueevaluating patients from ongoing clinical trials toassess the long-term safety and effectiveness ofthe stent and to look for rare adverse events thatmay result from use of the product.

Reference: FDA Talk Paper, T03-71. 29 October 2003.

Bicalutamide: do not use inlocalized prostate cancerCanada — In November 2002, bicalutamide(Casodex®) 150 mg, was conditionally approvedin Canada for patients with localized prostatecancer inappropriate for surgery or radiationtherapy. Approval was based on the promisingnature of clinical evidence and time to objectiveprogression.

The manufacturer has now alerted healthcareprofessionals to important emerging safetyinformation arising from a planned secondanalysis of the Early Prostate Cancer (EPC) trialprogramme which compared bicalutamide withplacebo.

For the progression-free survival endpoint, therecontinues to be a significant reduction in the riskof experiencing disease progression after 5.4years of follow-up. However, conclusions can onlybe made regarding early benefits or risks. Pa-tients treated in the adjuvant setting show nodifferences in survival, though survival data in thissetting are still relatively immature at this time.

In view of these data, and in the absence offactors to suggest high risk of disease progres-sion, it is recommended that clinicians discon-


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tinue bicalutamide in patients with localizedprostate cancer otherwise undergoing watchfulwaiting. It should be noted that metastatic pros-tate cancer patients taking bicalutamide 50 mgper day are not affected by the new information(1).

United kingdom — The Committee on Safety ofmedicines has advised that for patients withlocalized prostate cancer, the balanced riskbenefit of biculatimide is unfavourable and theproduct is no longer licensed for the treatment ofthis condition. Other approved uses are notaffected.

Patients receiving biculatimide for localizedprostate cancer should be reviewed at the earliestopportunity and treatment discontinued (2).

References

1. Communication from AstraZeneca Canada Inc. 18August 2003 on http://www.hc-sc.gc.ca

2. Communication from the Committee on Safety ofmedicines. 28 October 2003. [email protected]

Recombinant antihaemophilicfactor: dose monitoring requiredCanada — Recombinant antihaemophilic factor[BDDrFVIII] (ReFacto®) has been licensed inCanada since 2002, and is indicated for thecontrol and prevention of haemorrhagic episodesand for routine and surgical prophylaxis inpatients with haemophilia A (congenital factor VIIIdeficiency or classic haemophilia). ReFacto®does not contain von Willebrand factor and henceis not indicated in von Willebrand disease.

Reports of lack of effect, mainly in prophylaxispatients, have been received during clinical trialsand post-marketing. Lack of effect and/or lowfactor VIII recovery has now been reported inother patients such as bleeding into target joints,bleeding into new joints, other bleeding or asubjective feeling by the patient of new onsetbleeding.

In order to ensure an adequate therapeuticresponse, it is important to individually titrate andmonitor each patient’s dose, particularly wheninitiating treatment.

Reference: Communication from Wyeth, 15 September2003 on http://www.hc-sc.gc.ca

Nimesulide-containing productsreevaluatedEuropean Union — Nimesulide, is a COX-2inhibitor first launched in Italy in 1985. Since then,it has been marketed in about 50 countriesthroughout the world. Reports of adverse drugreactions, including hepatic reactions and a reportof necrotizing fascitis leading to death, have led toa re-evaluation.

In July 2003, the Committee on ProprietaryMedicinal Products (CPMP) of the EuropeanAgency for the Evaluation of Medicinal products(EMEA) determined that the benefit-risk profile ofnimesulide-containing products for systemic andtopical use is favourable. It recommended thatuse should be restricted to treatment of acutepain, symptomatic treatment of painfulosteoarthritis and primary dysmenorrhoea forsystemic formulations and symptomatic relief ofpain associated with sprains and acute traumatictendinitis for the topical formulation.

Reference: EMEA/CPMP/3754/03. 1 August 2003.http://emea.eu.org

Memantine approved forAlzheimer diseaseUnited States of America — The Food and DrugAdministration (FDA) has approved memantine(Namenda®), for the treatment of moderate tosevere Alzheimer disease.

Alzheimer disease is a degenerative conditionaffecting memory, judgment and the ability toreason. The new drug — an N-methyl-D-asparate(NMDA) antagonist — is thought to work byblocking the action of the chemical glutamate.Although memantine helps treat the symptoms ofAlzheimer disease in some patients, there is noevidence that it modifies the underlying pathologyof the disease.

The first two double-blind studies, each of aboutsix months duration, were conducted in the UnitedStates. The larger study of 400 patients wascarried out in subjects already taking donepezil, adrug already approved for the treatment ofAlzheimer disease. Both studies showed thatpatients on memantine experienced less deterio-ration in their symptoms compared to patientstreated with placebo during the study. The third


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study, conducted in nursing homes in Latvia, wasa 12-week double-blind study in 166 patients withsevere Alzheimer disease and also showed astatistically significant advantage of memantineover placebo.

Reference: FDA News, P03-82. 17 October 2003.

Virologic non-responsein more HIV combinationsSpain — Lamivudine (Epivir®) and didanosine(Videx®) in combination with tenofovir (VireadTM),should not be used as a triple antiretroviraltherapy when considering a new treatmentregimen for naïve or pre-treated HIV-1 infectedpatients.

A recent 24 week/24 patient study carried out todetermine efficacy and safety has observed ahigh (91%) lack of virologic response in HIVpatients treated with this combination. Theprecise nature of non-response in this study is notknown.


The Committee on Proprietary Medicinal products(CPMP) of the European Medicines EvaluationAgency (EMEA) has requested more detailedinformation on the study. In the meantime thefollowing action is recommended:

• No new patients should be initiated on a tenofo-vir + didanosine + lamivudine combinationregimen.

• The viral load of patients currently administeredthis combination should be closely monitored. Inthe event of an increase, therapy should beadjusted accordingly.

References

1. Spanish Agency for Medicines and Health Products.http://www.msc.es/agemed/csmh

2. Virologic non-response in HIV drugs. WHO DrugInformation, 17(3): 149 (2003).

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Personal Perspectives

Placebo or active control?Either, as long as it is in thepatient’s interest*The appropriate use of placebo in controlledclinical trials is still debated. This article brieflyreviews different conditions of applicability of theplacebo dilemma in the light of patients’ interestsand needs. We also test our assumptions that (a)what should justify the authorization of new drugsis their proven superiority over the best availablecomparators; (b) superiority to placebo is onlyclinically meaningful in patients who cannotbenefit from the standard active comparator; (c)non-inferiority of new drugs compared to availabletreatments can only be assessed when additionalbenefits over active controls are foreseeable andadequately tested. Ethical committees shouldadvocate these principles in defence of patients’interests. Public funds should support independ-ent clinical research, which would help addressquestions of high priority for public health, but beof no commercial appeal for industry

The discussion raised by the latest version of theDeclaration of Helsinki (1) about the legitimacy ofusing placebo in controlled clinical trials is stillalive. Temple and Ellenberg (2) state that theacceptability of placebo depends on whether thepatient will be harmed by deferral of effectivetreatment. Emanuel and Miller (3) advocate amiddle-ground alternative, which allows the use ofplacebo when no therapy is available for a givenindication or when the lack of benefit (not neces-sarily harm) or the discomfort to patients receivingplacebo is negligible. Lewis et al (4) argue thatplacebo-controlled trials remain the only means ofassessing the efficacy of new medicines, whosepotential advantages over recognised alternativeslie in areas other than efficacy.

The debate focuses on patients’ well-being as theonly aim of clinical investigation. Life, however, is

different and the placebo or active-control di-lemma can hardly be resolved in an environmentessentially driven by the strong economic inter-ests of the pharmaceutical industry wherepatients’ needs and interests are not the onlysources of clinical research hypotheses. In ouropinion what matters is not so much the method-ology as the aim and independent conduct oftrials. Once identified, any clinical question that istruly relevant for patients and independentlypursued would in itself imply the best way to beaddressed. When the questions identified haveonly relative importance for patients, any meth-odological discussion on how best to answerthem is an exercise of limited value.

Use of placebo not targetedto patients’ needsIn order to maintain its level of profitability, thedrug industry has to contain its risks and costs,and increase its revenues and market. One wayto limit risks and costs is to use placebo trials,whenever possible, in order to obtain a slice of anexisting market rather than to risk an expensivefailure trying to prove an advantage over activecomparators. Most placebo-control trials are donenot because there are no alternatives, butbecause it is easier to show an effect and there-fore to claim efficacy to the regulatory authorities.

The strategy is to position a new product so thatits superiority can be suggested with advertisingand incentives to doctors and pharmacists withouthaving to prove it scientifically. A drug that isscientifically proven to be superior to its compara-tor is unlikely to need such efforts to sustain itssales and convince doctors to prescribe it. Butefforts are certainly needed with most copies,which are by definition very similar: for most ACE-inhibitors, sartans, antidepressive agents ornonsteroidal anti-inflammatory drugs it is verydifficult to make a choice on the basis of patients’needs (5), as these products were not developedto provide a better treatment in the first place.

Clearly, me-too drugs aim at finding a place in themarket rather than in therapy. Therefore, thewhole issue of clinical trials requires discussion of

*Authors: Silvio Garattini, Vittorio Bertele, Luca LiBassi,“Mario Negri” Institute for Pharmacological Research,Regulatory Policies Laboratory, Milan, Italy

(Views expressed in signed contributions remain the responsibility of the authors.)

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a fundamental question that is preliminary to anyothers about study design and controls: “Is itethical to submit patients to clinical trials whosesole purpose is clearly to gain access to themarket?”

Placebo is sometimes not usedwhen it should bePlacebo-controlled studies in depressive orhypertensive patients resistant or intolerant toavailable therapies would be appropriate, as theywould respond to a real need; patients resistant tocurrent therapy would lose out from the lack ofthese studies. But in the eyes of drug companiesthis approach would mean gaining approval for arestricted indication and, consequently, a limitedmarket and profits. This is why such trials are notusually done. That the use of placebo in thesecircumstances is not a satisfactory solution forpharmaceutical companies is demonstrated bythe fact that often they do not avoid comparisonwith active controls, but only test the equivalenceor — more often nowadays — the non-inferiorityof new drugs with respect to the available compa-rators. Non-inferiority studies raise two majorquestions: one methodological, one substantial.

Placebo does not addto non-inferiority testsThe arguments raised (2–4) on the methodologi-cal deficiencies and inconsistent messages ofnon-inferiority trials are fully endorsed (6–8). Whatwe object to here is that inclusion of a placeboarm would overcome the potential lack of sensitiv-ity of this kind of study (2, 4). As was the casewith trials for depression (9), the inclusion ofplacebo may show whether the test and controltreatments are truly effective. However, even so,the claimed similarity of the test drug and theactive comparator would remain an artefact:because of the weak power of the study in view ofthe small number of patients, this similarity may infact hide important clinical differences (7–10).

According to pre-specified definitions, non-inferiority limits include an excess of outcomeevents associated with the test treatment. Two,five, or ten more deaths, strokes, fractures,interventions every hundred treated patients maynot be considered enough to mark a differencebetween the new and the control drug, thuspermitting the conclusion of non-inferiority of theformer. A poorer outcome with the new drug thanwith current available treatment is not acceptable,

even if better than in a concurrent placebo arm.Poor sensitivity is intrinsic to non-inferiority trials,which deliberately aim at overlooking differencesrather than highlighting them.

As with superiority over placebo, non-inferiority toactive comparators might also allow onto themarket drugs that in fact are less active (or safe,tolerable, convenient, etc.) than those alreadyavailable, usually with consolidated propertiesand a lower cost. Moreover, these approaches donot meet patients’ or physicians’ needs to definethe place in therapy and respective roles of newand available treatments.

Active controls are not used as theyshould beThe solution of a methodological problem (sensi-tivity of non-inferiority trials) does not in any eventdignify a hypothesis (non-inferiority of the testdrug) that has no or little importance for patients.Besides sensitivity, the main problem with thesetrials is that they lack ethics (8). Here the point isnot even about placebo or active control. Simply,these studies deliberately disregard patients’interests in favour of commercial ones. Non-inferiority studies do not provide any possibleadvantage to patients. Like placebo-controlledstudies, they aim at claiming efficacy, and possi-bly additional advantages, without providing proof.

These trials only have an economic interest andwe believe few patients would agree to participateif the industrial sponsor’s message were clearlyconveyed in the “informed consent” as follows: “Iwant to recruit a number of patients and letchance decide whether they should go on takingthe effective treatment they are currently given, ortry my new drug, which is not expected to be anybetter. To me it is enough to establish that mydrug is equivalent to or not worse than the otherone”. It is surprising that these trials obtainclearance by Ethical Committees in the absenceof other advantages.

The excuse for carrying out these trials is usuallythat physicians need several alternatives becausenot all patients respond the same way. But again,if this is the case, why not use placebo-controlledtrials in patients not adequately responding toother treatments? In contrast, just as it does notsolve methodological problems, the inclusion of aplacebo arm in non-inferiority trials is even lesslikely to solve these ethical problems.


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Placebo does not help distinguish trueand false innovationThere may still be a place for non-inferiority trialswhen there are potential advantages for patientsand/or the community, besides similar efficacy. Anon-inferiority study can be regarded as ethicalwhen a drug similar to its comparator in terms ofefficacy may nevertheless have better safety,convenience, or cost-effectiveness: for example,a Cox-2 selective inhibitor with fewer gastro-intestinal adverse effects, a sartan inducing lesscough than ACE-inhibitors, an orally available ironchelator for children with thalassaemia, anestrogen patch replacing daily pills, a vaccinecombination. What is important is that the claimedadvantages and their impact on patients and/orthe community be appropriately tested anddocumented, as is required for efficacy. Thisapproach in fact implies documentation ofsuperiority.

It is hard to envisage here any role for placebo(4): potential advantages should be assessed incomparison with any recognised active control, ofcourse. The advantage should be pre-specifiedand serve as a guide for establishing an accept-able limit of non-inferiority, meaning the differencein outcome allowed for two products still to beconsidered similar. The excess of events allowedto document similar clinical efficacy while lookingfor other potential advantages should be explicitlyjustified: how many more deaths, infarctions,interventions, etc would we consider acceptablein testing (and possibly proving) that the new drugis actually, safer, better tolerated, easier to use, orcheaper than its comparator?

More independent clinical research as a solutionMost divergences on the use of placebo or activecontrol would be minimised if public healthinterest were constantly kept as the primaryobjective. If the study plan and conduct reflectthis, investigators’ intellectual independence withrespect to the tested hypothesis would be as-sured too. Financial interests can equally becovered when proven advantages are provided toindividual patients or their community. In thisrespect, medicinal products cannot be regardedlike any other product, because their value shouldonly lie in the public health gains they provide,which need to be documented objectively.

Ethical Committees are urged to look morecarefully at trial protocols to establish not only that

no harm will result to patients involved in the trialbut also whether the trials are appropriatelydesigned to demonstrate any foreseeable benefitfor patients for whom the drug is intended afterits approval.

Public funds supporting independent clinicalresearch play a critical role in helping thescientific community keep its intellectual freedomwith respect to priority objectives, identification ofclinical hypotheses and appropriate trial design.It also enables public health institutions toaddress questions that are not in the directinterests of industry (11), which cannot beexpected to pursue, and fund, scientific andpublic health objectives that are not in line with— and may even be against — its commercialaims. In the United States health policy makershave correctly understood these principles andensured an adequate level of funding for inde-pendent research.

Good examples are the results achieved withpublic funds for HIV/AIDS treatments at the timethe public health interest for this area wasparticularly important (12). The same cannot besaid at present for the European Community,which still has to develop its own policy in thisarea and decide on the level of funding it consid-ers useful to cover the public health interest. It isimportant to note that independent researchwould also indicate to industry what kind ofproducts public health needs, and could there-fore be a powerful stimulus to re-orientateindustrial clinical research too.

References

1. The World Medical Association, Inc. The Declarationof Helsinki (2000). Available on http://www. wma. net.

2. Temple, R., Ellenberg, S.S. Placebo-controlled trialsand active-control trials in the evaluation of newtreatments. Part 1: ethical and scientific issues. Annalsof Internal Medicine, 133: 455–463 (2000).

3. Emanuel, E.J., Miller, F.G. The ethics of placebo-controlled trials - A middle ground. New EnglandJournal of Medicine, 345: 915–919 (2001).

4. Lewis, J.A., Jonsson, B., Kreutz, G. et al. Placebo-controlled trials and the Declaration of Helsinki. Lancet,359: 1337–1340 (2002).

5. Anonymous. Drugs in 2001: a number of rusesunveiled. Prescrire International, 11: 58–60 (2002).



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6. Bertele, V., Torri, V., Garattini, S. Inconclusivemessages from equivalence trials in thrombolysis.Heart, 81: 675–676 (1999).

7. Barbui, C., Violante, A., Garattini, S. Does placebohelp establish equivalence in trials of new antidepres-sants? European Psychiatry, 15: 1–6 (2000).

8. Garattini, S., Bertele, V. Adjusting Europe’s drugregulation to public health needs. Lancet, 358: 64–67(2001).

9. Kupfer, D.J., Franck, E. Placebo in clinical trials fordepression. Complexity and necessity. Journal of theAmerican Medical Association, 287: 1853–1854 (2002).

10. Greene, P.J., La Vaque, T.J. Postmarketing surveil-lance and black box warnings. Journal of the AmericanMedical Association, 288: 957 (2002).

11. Writing group for the women’s health initiativeinvestigators. Risks and benefits of estrogen plusprogestin in healthy postmenopausal women. Journal ofthe American Medical Association, 288: 321–333(2002).

12. Consumer Project on Technology backgrounder onthe development of fourteen FDA-approved HIV/AIDSdrugs. Available on http://www.cptech.org/ip/health/aids/druginfo.html



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Current Topics

The National Institute of Clinical Excellence (NICE) is responsible for providing guidance to theNational Health Service in England and Wales on the clinical- and cost-effectiveness of medicinesand medical technologies. In 2002, NICE commissioned a series of internal reviews of their work,while an external review was carried out by the WHO Regional Office for Europe.

The WHO team of experts reviewed a series of technology appraisals and carried out extensivediscussions with NICE staff, members of the Appraisal Committee and Technical AssessmentGroups and other stakeholders during the course of two visits to NICE in 2003.

NICE was established as a Special Health Authority to address the introduction and use of newtechnologies and medicines within the United Kingdom National Health Service (http://www.nhs.uk.).The Review Team recognized that — in only four years — NICE had developed a well-deservedreputation for innovation and methodological development that represents an important model fortechnology appraisals internationally.

Achievements that are particularly valuable include:

• transparency surrounding the process of technology assessment.

• participation of different stakeholders and the inclusiveness of the approaches taken.

• commitment to using the best available evidence for decision-making.

• commitment of the technical and management staff.

• dedication of the appraisal team and Committee members.

The Review Team made the following recommendations which were drawn up with the aim toenhance operations within NICE and assist organizations with similar responsibilities in other coun-tries. The full rassessment eport is avalable on: http://www.nhs.ukand http://www.nice.org.uk

Recommendations

The principles• NICE should continue to develop operational

procedures that are consistent with its coreprinciples of transparency, consultation andinclusiveness with respect to stakeholders’involvement in evidence- gathering and deci-sion-making. The NICE model of partnership inthe scientific endeavour of health technologyappraisal offers valuable international leader-ship.

• NICE should seek to reconcile the inherentcontradiction between its principles of transpar-ency and its acceptance of evidence for thedecision-making process that a stakeholderdeems to be confidential. NICE should continuethe work already started on this issue to ensurethat all material submitted for consideration canbe made available to the public.

• The principle of transparency requires that NICEcodifies and justifies the specific criteria used indecision-making. Difficult but important ele-ments of this task are articulation of the ethical

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and social value judgements, and definition ofthe interaction of these judgements with theappraisal of the scientific evidence used by theAppraisal Committee in reaching its decisions.

The process – general issues•�For drug and device technologies where a

sponsor exists, the current hybrid process ofHTA used by NICE may give rise to unneces-sary duplication of effort. NICE may wish toconsider using different approaches dependingon the subject of the appraisal. The ReviewTeam suggests that an effort be made to ensurethat the Appraisal Committee is presented witha single set of analyses produced by theTechnical Assessment Group that incorporatesconsultation with and input from themanufacturer(s).

Start of the process and topic selection• The consultees’ meeting should become a

formal ‘Preliminary Exchange of Evidence’, atwhich time all stakeholders should be asked toprovide details of what they propose to submit.Only in extraordinary circumstances should theTechnical Assessment Group accept to include,as part of the review, information over andabove that declared for submission by thestakeholders at this meeting.

• More attention needs to be paid to the importanttask of setting the Scope of the appraisal. Thegeneral goal is to give timely and comprehen-sive guidance to the Technical AssessmentGroups on the question(s) to be addressed bythe Appraisal Committee, thereby reducing therisk of mismatch between the technical assess-ment report and the needs of the AppraisalCommittee.

• Stakeholder submissions should be required tobe lodged as soon as possible after the start ofthe assessment process.

Assessment and appraisal process• The timeframes for the assessment and ap-

praisal process should be reviewed, so that thecurrent time pressures at the end of the assess-ment report period and early appraisal periodare reduced and more time allowed for criticalevaluation of the consultees’ comments. Thisdoes not necessarily mean that the overalltimeline should be increased.

•The procedures for document management needto be carefully considered. This may include

keeping some hard copy files of key documentsfor each Guidance, as well as the electronicfiles.

• NICE should improve interaction betweenTechnical Assessment Groups, the NICEtechnical staff and the Appraisal Committeethroughout the assessment and appraisalprocess. This could include, for example, havingthe continued involvement of the TechnicalAssessment Group as technical experts afterthe initial review of the appraisal consultationdocument.

Functions of the Appraisal Committee• Given that a third Appraisal Committee is being

introduced, NICE should take the opportunity toconsider how to sustain the high quality per-formance of the Appraisal Committee. An issuethat needs particular consideration is thequestion of consistency in decision-makingacross the three committees. NICE is alreadygiving this question careful attention. Twopossibilities to consider are: 1) having threeindividual Chairs and one common Vice-Chair;and 2) having the three Committees assessdifferent types of technologies (e.g. diagnosticprocedures for one and specific classes ofpharmaceuticals for the other two).

• It should be made clear that membership of theAppraisal Committee is based on skills in andknowledge about evidence appraisal andjudgement rather than on the representation ofparticular interests. Although that there is aneed to ensure that manufacturers’ views aretaken into consideration, this should not bethrough membership of the Appraisal Commit-tee but through the consultation process.

• The role of the Chair may need to be furtherrefined. While it may be necessary for the Chairto continue to take an active role in leading thediscussion on many items, the possible risksassociated with this need to be carefullyconsidered. Asking members to play a greaterrole in the ongoing review of a technology wouldallow the Chair to facilitate rather than lead thediscussion, although the increased workloadthat would result for the Committee memberswould need to be assessed.

• NICE should assess whether the overallsustainability of the process and the functioningof the Appraisal Committee could be improvedby the introduction of some type of reimburse-ment for members’ time.

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• The induction and training process for AppraisalCommittee members needs to be furtherdeveloped to include, where appropriate,enhancing skills in the critical appraisal ofclinical evidence and economic evaluation.

• The Appraisal Committee procedures should bemodified to ensure that a clear statement ofwhat the Committee approves is recorded onthe same day.

Decision-making• NICE and the Appraisal Committee should

continue their process to develop a system ofdecision-making that encourages articulation ofthe grounds for a particular recommendation,including specification of the weight that isplaced on clinical evidence, economic evidenceand other factors, such as equity and socialvalues.

• As part of the process of articulating the criteriafor decision-making, NICE must resolve theconfusion related to the use of a value-for-money threshold. If a threshold is to be used asa basis for recommendations, it should bespecified and justified for reasons of transpar-ency.

• The Appraisal Committee may wish to considerhaving a legal advisor present during meetings,particularly those involving matters referred tothe Committee by the Appeal Board.

Appeals• In view of the considerable number of appeals

lodged and their time and resource implications,thought needs to be given to how to reduce thenumber of appeals and the length of the appealprocess. The further development of the appealprocess will help enhance the quality and thetransparency of the appraisal programme.

Budget impact and research• Although budget impact is not a consideration in

making recommendations on the use of atechnology within the NHS, it is important todevelop methods for budget impact modellingthat would enable NICE to provide moredetailed information on the implementationcosts to the local authorities. This could be atask for the technical analysts in NICE. Theadvantages of doing so include not only theprovision of useful advice to the Trusts, but alsothe avoidance of a duplication of effort by the

Trusts in making their budget analyses forimplementing the new technology.

• NICE should further develop the ResearchRequired section of the Guidance and link itspecifically with the review of Guidance reviewprocess. This would help to obtain the additionalclinical evidence needed to ensure full under-standing of the benefit of a technology. TheGuidance review process would be an ideal wayto stimulate the generation of such evidence.

• NICE should adopt more flexible timeframes forreviewing existing Guidance not only to ensurethat the review answers a specific question butalso to assist in managing workload. Oneapproach might be for the set review dates to bedependent on the emergence of new evidenceor significant changes in existing evidence.

Technical assessment report• The contractual arrangement between the

Technical Assessment Groups and the NCCHTAshould be revised to recognize NICE as theprimary client for the assessment reports.

• A handbook of standard methods for the assess-ment reports should be developed, afterconsultation between NICE staff, the AppraisalCommittee and the Technical AssessmentGroups. The handbook, which should beregularly updated, should also be used as thebasis for training new reviewers and new NICEstaff.

• A detailed template for the reports should bedeveloped, including standardized data presen-tation and summary material. This wouldfacilitate review of the information by theAppraisal Committee.

Input from the consultees• On the basis of experience to date, NICE should

consider what aspects of patient and profes-sional submissions are most useful and developstandards for the content of these types ofsubmissions.

• NICE should review the process for assessingcomments from consultees and others (includ-ing the general public) that are submitted afterthe appraisal consultation document is drafted.NICE should determine the most appropriateway of responding to these inputs and assesstheir value in the decision-making process.

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New advice on hormonereplacement therapy

The Million Women Study has been carried outwithin the United Kingdom and involves aroundone million women aged 50 years of age andover. The main focus of the study relates to theeffects of hormone replacement therapy use, butthe large size of the study means that a verybroad range of health issues were also investi-gated, including how various reproductive andlifestyle factors affect women’s health, as well asdiet, childbirth, breastfeeding, vitamin and mineralsupplement use, oral contraceptive use and

family history of illness. Results of the study werepublished in August 2003, and have provided newinsights into the risks associated with hormonereplacement therapy (HRT), in particular inrelation to breast cancer(1).

The United Kingdom Committee on Safety ofMedicine carefully reviews all new data on thesafety of HRT. Other important information on thelong-term risks of HRT — including coronary heartdisease, stroke and ovarian cancer —�wascommunicated in July 2002 following terminationof one arm of the Women’s Health Initiative (WHI)trial (2).

Summary table of risks and benefits associated with using HRT

Age of Number of Extra Number of cases in 1000 HRTCondition woman cases/1000 users over the same period

(yr) non-HRTusers

Cumulative cancer risk with time 5 years use 10 years use

Breast cancer 50–65 32 1.5 5estrogen only estrogen only

6 19combined HRT combined HRT

Endometrial cancer 50–64 5 4 10estrogen only estrogen only

{no data} <2combined HRT combined HRT

Ovarian cancer 50–69 9 1 3estrogen only estrogen only

{no data} {no data}

Cardiovascular risks over 5 years

Stroke 50–59 3 1 {no data}60–69 11 4

VTE 50–59 3 4 {no data}60–69 8 9

Benefits over 5 years Reduced number of cases in 1000 HRT users over the same period

Colorectal cancer 50–59 3 1 260–69 8 3 5–6

Fracture of neck 50–59 1–2 0–1 1of femur 60–69 7–8 2–3 5

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Findings of the Million Women Study showed thathalf the women had used HRT of which there hadbeen 9364 incidents of breast cancer and 637breast cancer deaths. Users of HRT were consid-ered more likely to develop breast cancer but pastusers were not considered at increased risk.Incidence was significantly increased for currentusers of preparations containing estrogen only,estrogen-progestogen and tibolone, but associ-ated risk for estrogen-progestogen was substan-tially greater than for other types of HRT. Tenyears use of HRT is estimated to result in 19additional cancers per 1000 users of estrogen-progestogen combinations. In conclusion, HRTcauses a duration-dependent increase in the riskof breast cancer that begins to decline when HRTis stopped and by 5 years reaches the same levelas in women who have never taken HRT.

The magnitude of the risk associated with estro-gen-only products has been confirmed. Forcombined HRT use, the risk is significantly higherthan with estrogen-only therapy. More specifi-cally, the study demonstrates that:

• The increase in risk of breast cancer associatedwith combined HRT (relative risk RR = 2.00compared with no use) is significantly higherthan for estrogen-only therapy (RR = 1.30) andfor tibolone (RR = 1.45).

• There is no evidence for a difference in risk ofbreast cancer between specific preparations ortheir route of administration within the classes ofoestrogen-only therapy and any type of com-bined HRT.

• The estimated number of extra cases of breastcancer occurring after 5 and 10 years of usingcombined HRT were almost identical in theMillion Women Study and the WHI trial.

The United Kingdom Committee on Safety ofMedicine has issued the following advice tophysicians and prescribers.

• For short-term use of HRT for the relief ofmenopausal symptoms, the benefits outweighthe risks for many women.

• For longer-term use of HRT, women must bemade aware of the increased incidence ofbreast cancer and other adverse effects.

• Each decision to start HRT should be made onan individual basis and treatment should beregularly reappraised (at least once a year).

• For combined HRT the benefits of the lower riskof endometrial disorders, including cancer,should be weighed against the new informationabout the increased risk of breast cancer (seetable). The risk of endometrial cancer withtibolone is not known.

• The results of the Million Women Study do notnecessitate any urgent changes to women’streatment.

SummaryHormone replacement therapy is an effectiveshort-term treatment option for controlling symp-toms of menopause. For each woman consideringuse of HRT, it is necessary that the benefits beweighed against the several risks that have beenobserved, including that of coronary heart diseasewithin one year and breast cancer after one yearof therapy.

Hormone replacement therapy should not beused for the long-term prevention of disease. Forwomen currently taking long-term hormonereplacement therapy for the treatment of oste-oporosis, the risks now documented must beconsidered when reviewing individual circum-stances as well as the consideration of thebenefits and risks of alternative therapies.

For younger women with premature menopauseor hypogonadism, the benefits of hormonereplacement therapy would be expected to begreater and the risks probably smaller than thosereported recently in the WHO study and MillionWomen Study (4).

References

1. Million Women Study Collaborators. Breast cancerand hormone replacement therapy in the Million WomenStudy. Lancet, 362: 419–427 (2003).

2. Women’s Health Initiative Writing Group. Risks andbenefits of estrogen plus progestin in healthy postmeno-pausal women. Journal of the American MedicalAssociation, 288: 321–333 (2002).

3. Information sheet for women available from Medi-cines and Healthcare Products Regulatory Agency(MHRA) website http://www.mhra.gov.uk

4. Therapeutic Goods Administration. ADEC statementon use of hormone replacement therapy. http://www.health.gov. au/tga

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Direct-to-consumeradvertising and patientsDirect-to-consumer advertising (DTCA) of pre-scription drugs has increased rapidly in the UnitedStates during the last decade, yet little is knownabout its effects on prescribing decisions inprimary care.

From 1996 to 2000, spending on direct-to-consumer advertising (DTCA) of prescriptiondrugs in the United States more than tripled (1),reaching US$2.7 billion in 2001 (2). The UnitedStates and New Zealand are the only industrial-ized countries that allow such advertising, al-though restrictive legislation in the EuropeanUnion (3) and Canada (4) has recently beenunder review.

Canada allows advertising of over-the-counter(OTC) drugs but prohibits DTCA of prescriptionmedicines, although a 1978 exemption, which wasintended to allow price comparisons, permitsadvertising of product name, price and quantity(4). Nevertheless, Canadians see advertisementsin US magazines and on US cable television, aswell as an increasing volume of domesticallygenerated DTCA of questionable legality (5).Proponents of DTCA argue that advertisementsempower patients, whereas critics counter thatthey encourage wasteful prescribing (6).

A recent study has compared prescribing deci-sions in a US setting where DTCA is approved(Sacramento) and a Canadian setting whereDTCA of prescription drugs is illegal (Vancouver)but some cross-border exposure occurs (7) .

The study showed that Sacramento patients weretwice as likely to request medicines as patients inVancouver and over twice as likely to requestadvertised drugs: request rates remained sub-stantially different: 14.2% in Sacramento versus8.8% in Vancouver. Advertising exposure wasmeasured through the number of listed products aperson had seen advertised, identification with anadvertised condition, and use of advertising as aninformation source. In Sacramento, all 3 meas-ures were associated with a higher probability ofDTCA drug requests. In Vancouver, only the useof advertising as an information source (3.5% ofpatients) was significantly associated with DTCAdrug requests.

Physicians fulfilled most requests for prescriptionsin both settings: in Sacramento 80% of patientswho requested prescriptions received them, ascompared with 63% in Vancouver. The maindifference was in the prescribing rate for re-quested nonadvertised drugs (81.4% v. 57.1%),although this difference was no longer statisticallysignificant after adjusting for patient and physiciancharacteristics. Prescribing rates for advertiseddrugs differed less: 77.6% v. 72.0%.

Sacramento patients reported more advertisingexposure and requested more advertised drugsthan patients in Vancouver and, in both settings,patients with higher exposure to advertisingrequested more advertised drugs. The prescribingrate for requested advertised drugs was similar,being about 75%.

Physicians judged 50% of prescriptions forrequested DTCA drugs to be a “possible” or“unlikely” choice. A key argument made in favourof DTCA is that patients are protected because,ultimately, the physician decides whether or not toprescribe (8). However, if physicians prescribeproducts that they would not have chosen other-wise, the protection offered by prescription-onlystatus is questionable. Also, patients do not obtainsufficient information from advertising to deter-mine side effects and appropriateness (9).Indeed, many of the products requested were“lifestyle drugs” (10) or symptomatic treatments.

This survey opens an intriguing window on theeffects of DTCA on patient–physician interactionsin primary care. Results are consistent both with adose-response to advertising at 2 differentpopulation exposure levels and, most importantly,with increasing industry investment in this market-ing technique (2, 11). If DTCA opens a conversa-tion between patients and physicians, thatconversation is likely to end with a prescriptiondespite frequent physician ambivalence abouttreatment choice.

References

1. Rosenthal, M.B., Berndt, E.R., Donohue, J.M. et al.Promotion of prescription drugs to consumers. NewEngland Journal of Medicine, 346(7): 498–505 ( 2002).

2. United States General Accounting Office. FDAoversight of direct-to-consumer advertising haslimitations. Report to congressional requesters. ReportNo. GAO-03-177. October 2000. http://rxpolicy.com/studies/gao-dtc-adv.pdf

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3. Watson, R. EC moves towards “direct to consumer”advertising. British Medical Journal, 323: 184 (2001).

4. Therapeutic Products Programme. Direct-to-consumer advertising of prescription drugs. Discussiondocument. Health Canada, Ottawa, 1999.

5. Silversides, A. Direct-to-consumer prescription drugads getting bolder. Canadian Medical AssociationJournal, 165(4): 462 (2001).

6. Kravitz, R.L. Direct-to-consumer advertising ofprescription drugs. Western Journal of Medicine, 173(4):221–222 (2000).

7. Mintzes, B., Barer, M.L., Kravitz, R.L. et al. How doesdirect-to-consumer (DTCA) affect prescribing? A surveyin primary care environments with and without legalDTCA. Canadian Medical Association Journal, 169(5):405 (2003).

8. Holmer, A.F. Direct-to-consumer prescription drugadvertising builds bridges between patients andphysicians. Journal of the American Medical Associa-tion, 281(4): 380–382 (1999).

9. Bell, R.A. Wilkes, M.S., Kravitz, R.L. The educationalvalue of consumer-targeted prescription drug printadvertising. Journal of Family Practitioners, 49(12):1092–1098 (2000).

10. Lexchin, J. Lifestyle drugs: issues for debate.Canadian Medical Association Journal, 164(10): 1449–1451 (2001).

11. Morgan, S., Mintzes, B., Barer, M. Direct-to-consumer advertising of prescription only drugs:prescribed to improve consumer welfare? Journal ofHealth Services and Resource Policy. In press.

Action against counterfeitmedicines in Asia and AfricaThe World Health Organization (WHO) haslaunched an action plan against substandard andcounterfeit medicines in six countries from theGreater Mekong sub-region. The plan followssimilar initiatives begun in Africa and will continueto expand in response to countries’ increasing callfor assistance to improve the quality of theirmedicines.

Counterfeit and substandard medicines arefrequently detected in Cambodia, China, the LaoPeople’s Democratic Republic, Myanmar, Thai-land and Viet Nam and the problem seems to beincreasing. Products most commonly counter-feited in this region include antibiotics and thoseused in the treatment of tuberculosis, malaria andHIV/AIDS. The use of poor quality or counterfeit

medicines has little or no therapeutic effect and inpoor settings may often lead to death.

At a meeting from 11–13 November 2003 inHanoi, Viet Nam, WHO and the six countries willkick-start joint activities to combat counterfeitingof medicines in the region, to promote advocacyactivities directed at key decision-makers, healthprofessionals and the general public and tostrengthen inspection and post-marketing surveil-lance.

Substandard medicines are thought to account for8.5% of medicines on the market in Thailand.Eight per cent of randomly collected samples inViet Nam and 16% in Myanmar failed laboratorytesting for quality assessment. From thesesamples, rifampicin showed the highest failurerate at 26% followed by trimethorprim–sulfadoxineat 24%. In 2001, there were estimated to be over2800 illegal medicine sellers in Cambodia and1000 unregistered medicines on the market. Inthe Lao People’s Democratic Republic, 2100illegal drug sellers are said to exist.

With more complex combination medicines nowbeing recommended for drug-resistant malaria,there is a strong possibility that more substandardand counterfeit medicines will enter the market inmalaria-endemic countries. Even in terms ofolder, more traditional antimalarials, the quality ofthe medicines is often poor.

A recent WHO survey of the quality of antimalar-ials in seven African countries revealed thatbetween 20% and 90% of the products failedquality testing. The antimalarials in question werechloroquine-based syrup and tablets, whosefailure rate ranged from 23% to 38%; andsulfadoxine/pyrimethamine tablets, which showed90% to be below standard. The medicines were amixture of locally produced and imported prod-ucts. Samples were submitted by Gabon, Ghana,Kenya, Mali, Mozambique, Sudan, and Zimba-bwe.

Poorly equipped laboratories, under-fundedregulatory authorities, poor handling and manu-facturing practices were the main contributors tothe presence of substandard and counterfeitmedicines. Many tools exist to improve qualitycontrol of medicines and supply systems, butresources are lacking to support implementation.Most of the countries with the lowest qualitypharmaceuticals are also the ones with thehighest disease burden and the poorest econo-mies.

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The findings of the report have provided a basisfrom which to address potential problems in thetransition to artemisinin-based medicines for drug-resistant malaria and has given impetus to thefight against poor quality and counterfeit medi-cines in Africa. WHO is now running a series oftraining workshops in several African countries toshow manufacturers how to upgrade their stand-ards, and show regulatory authorities how toimprove practices in the screening and testing oflocal and imported products.

Reference: WHO Press Release, 11 November 2003.http://www.who.int

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Chagas diseaseAmerican trypanosomiasis, or Chagas disease, isa protozoan zoonotic disease caused by thehaemoflagellate Trypanosoma cruzi, and istransmitted to humans either by blood-suckingtriatomine vectors, blood transfusion or congenitaltransmission. This parasite infects over 150species from 24 families of domestic and wildmammals, as well as humans. In the vertebratehost, T. cruzi infects many different cells, but inthe human host, the disease is conspicuouslylimited to the myocardium and to gut nerve fibres.

Chagas disease is present in 18 countries on theAmerican continent in two different ecologicalzones: the Southern Cone region, where the mainvector lives inside human homes and inperidomiciliary areas; and Central America andMexico where the main vector species lives bothinside dwellings and in uninhabited areas.Country-wide crossectional surveys in the 1980sfound an overall prevalence of 17 million cases,with 4.8–5.4 million people exhibiting clinicalsymptoms, an annual incidence of 700 000-800 000 new cases and 45 000 deaths due to thecardiac form of the disease.

Global distributionLarge-scale regional initiatives to halt vector-borne transmission and improved screening ofblood-donors have been successful. At present,estimates indicate an infection prevalence of 13million, with 3.0–3.3 million symptomatic casesand an annual incidence of 200 000 cases in 15countries. The disease remains a priority healthproblem due to: the need for surveillance andcontrol in areas where sylvatic vectors can invadedwellings; the medical and social costs of care forinfected people in the absence of efficient andwell-tolerated therapy, especially against thechronic form of the disease; the difficulty inobtaining priority for control activities and vectorelimination in areas where vectorial transmissionhas been interrupted; and the need to continuestrengthening mandatory blood-donor screeningin endemic areas, as well as in non-endemicareas where increased travel and/or immigrationof potentially infected donors might compromisedonated blood supplies.

DevelopmentsThe complexity of the pathology of Chagasdisease and the diversity of its clinical manifesta-tions have made the understanding of its

Neglected DiseasesThe newly created Drugs for Neglected Diseases Initiative (DNDi) plans to spend around $250million over the next 12 years to develop treatments to combat three killer diseases threatening acombined 350 million people every year: Chagas disease, sleeping sickness, and leishmaniasis. TheDNDi is a not-for-profit association established in partnership with Médecins Sans Frontières, OswaldoCruz Foundation/Far Manguinhos, the Indian Council of Medical Research, Institut Pasteur, the Minis-try of Health of Malaysia, and the Kenya Medical Research Institute, with WHO as a permanent ob-server.

The DNDi will identify opportunities and initiate and coordinate drug research and developmenrt (R&D)projects in collaboration with the international research community, the public sector, the pharmaceu-tical industry, and other relevant partners. In addition, the DNDi will support the implementation ofresearch projects, including those in collaboration with South-South and North-South R&D networks.

The DNDi aims to build its R&D portfolio with drug discovery projects targeted at the identification ofnovel drug development candidates and drug development projects by taking candidate compoundsthrough the different stages of development to the point where they can be registered and recom-mended for use. The DNDi website is available on: HTTP://www.dndi.org

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pathogenesis difficult. The autoimmune hypoth-esis, once widely accepted, has increasingly beenchallenged by the parasite persistence hypoth-esis. Arguments for the latter hypothesis comefrom demonstrations of the presence of parasitesin tissues of chronic patients, and the fact thattreatments that decrease parasite burden areassociated with a decrease in clinical symptoms.The two hypotheses might not be mutuallyexclusive since anti-immunopathogenic re-sponses in chagasic patients might be driven bythe parasite burden. Although further studies areneeded, including elucidating the role of therecently described parasitokines, these resultsindicate an urgent need for the development ofnew antiparasite medicines, and their evaluationin large-scale randomized clinical trials, as well asfor progress in the development of vaccines andimmune interventions against pathogenesis.

New approaches for the characterization of T.cruzi and its vectors have been applied in labora-tory, diagnostic, clinical and epidemiologicalstudies, as well as in support of disease control.They have shed new light on the biology andgenetics of these organisms, as well as on thegenetics of the infected population, and stronglyindicate that human infections are due to T. cruzisubgroup II. A possible breakthrough in clinicalmanagement of the chronic chagasic cardiomy-opathy might involve the autologous transplanta-tion of bone marrow cells into the circulation;patients with severe chagasic cardiomyopathysubjected to this therapy experienced improve-ment of the cardiac functions of up to 30%, in onecase occurring one month after transplantation(17).

A Southern Cone initiative to eliminate the mainvector, and interrupt transfusional transmission of

T. cruzi was launched by the health ministries inArgentina, Bolivia, Brazil, Chile, Paraguay, andUruguay in 1991. More than 2 500 000 houseswere sprayed with insecticide between 1992–2001. Uruguay and Chile were declared free ofvectorial transmission in 1997 and 1999, respec-tively, as were 9 of the endemic states of Brazil in1990, and 4 endemic provinces of Argentina in1991. Blood donor screening is mandatory ineach of these countries. The extension of thismodel to Mexico, Central America, the Amazonand Andean Regions, however, will requireadaptation and testing of vector control strategiesto suit local epidemiological conditions.

Future prospectsThe greatest risk to this improved trend in Chagasdisease control comes from the success that hasalready been achieved, as the need for continuedsurveillance and selective interventions becomesless appreciated at the political level.

As the T. cruzi genome project nears completion,new approaches will become available for theidentification and validation of new drug targets,early diagnostic indicators of infection andvaccine candidates, and for the elucidation of themechanisms underlying host cell invasion,immune response and pathogenesis. The chal-lenge will be to transform new knowledge intocost-effective, equitably affordable interventionsand to guarantee their access to the patients andpopulations of endemic countries.

Regular updated information is available from theUNDP-World Bank-WHO Special Programme forResearch and Training in Tropical Diseases(TDR) on http://www.who.int/tdr/dw/chagas2003.htm

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