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Towards harmonisation on drug registration

The second International Conference onHarmonization of European, US, and

Japanese drug registration requirementsrevealed large gaps still needing to be

bridged despite backing for three commonguidelines, covering reproductive toxicitytesting, stability, and inclusion of geriatricsubjects in clinicals. At the meeting held inOrlando, Florida, last week, regulatorswere generally optimistic about the ICHprocess, with FDA Commissioner DavidKessler declaring a common registrationpackage "a realistic possibility" and thehead of the EC Commission pharmaceu-ticals division Fernand Sauer announcingthat he was "satisfied" with the way the

process had moved since the first ICHconference in 1991 (ICH-1). However,industry, especially European drugmakers, claimed that progress was slow andthat in some areas little had been achievedsince ICH-1. The director general of theEuropean Federation of PharmaceuticalIndustry Associations, Nellie Baudrihaye,said that regulators were "moving in theright direction, but slowly" and that theparties were clearly not yet in a position toharmonise practices. ,

1 he guideline on stability testing in

particular spawned heated debate betweenEuropean regulators and industry and theFDA. At the first ICH talks 2 years ago in

Brussels, all partners had agreed in prin-ciple the shape that the guideline wouldtake, but after a further 18 months of

drafting work, the FDA threw out theplanned text and demanded a rewrite.

Baudrihaye attacked FDA’s stance duringthe conference opening plenary sessions,saying that 2 years’ work had been wastedand that European drug makers were disap-pointed the guideline was not closer to theoriginal draft. European industry feels that the guide-

line (which the EC’s Committee for Pro-prietary Medicinal Products adopted lastmonth) now more or less extends US

requirements, particularly on storage con-ditions, to the EC and Japan rather thanreally harmonising the different rules into acompromise text. Under the guideline,long-term test requirements would meandrugs being stored at 25°C ± 2°C, with 60%relative humidity (RH) ±5% for a mi-nimum of 12 months, and that foraccelerated testing they should be kept at

40°C +2’C with 75% RH ±% for at least 6 6months. However, when a drug substancefails to meet specifications during theaccelerated testing, there must beadditional testing at an intermediate condi-tion such as 30°C ±2°C, 60% RH ±5%.For these products the initial applicationwould have to include a minimum of 6months’ data from an ongoing 1-year studyat 30°C, 60% RH.

Controversy also arose over a plannedguideline on clinical studies, because theFDA refused to support the draft that theEC’s CPMP and European industry hadco-authored. FDA wants to retain its own

requirements and does not want to makethe changes that the draft guideline wouldrequire, the Europeans complain.

: A subject close to Japanese hearts-namely, ethnic differences in drugevaluation-is to be further studied overthe next 2 years in the run up to the ICH-3talks in Yokohama. Ethnic differences, orthe way different races react to various

substances, could have a significant impacton efficacy questions such as the scopeof the required safety data base and inter-pretation of dose-response data across

regions.

Sara Lewis

Deaths due to druginteraction

Distribution of a new antiviral drug intro-duced in September has been temporarilysuspended by its manufacturer because ofthe drug’s association with deaths, believedto be due to its interaction with anti-cancer

agents. Sorivudine, (+ )-l-&bgr;-D-arabino- :furanosyl-5-[(E)-2-bromovinyl uracil

(Usevir, Nippon Shoji), is an antiviral drugdeveloped for treatment of herpes zoster. Itcan be given orally and the product has ahighly selective inhibitory action that is :approximately 50 times that of acyclovir.Over 500 000 tablets have already been soldto 10 000 medical institutions in Japan.

Before being put on the market, sorivu-dine had been known to induce severe

leucopenia when used in combination withthe pyrimidine metabolism antagonistfluorouracil, and a warning had been

printed with the instructions for use.

Despite this precaution, adverse effectswere reported in the month after the

introduction. There have been at least 7

reports of serious effects due to this druginteraction; 3 of the patients have died.Although there have been claims that the

drug warning instructions were insuf-

ficiently strong, a possible contributoryfactor could be the lack of informed patientconsent in Japan. Sometimes patients onantitumour drugs do not know that theyhave cancer. According to a nationwidesurvey conducted last year by the Ministryof Health and Welfare, only 18% of cancer

patients who had died had been informed oftheir diagnosis and 3 in 4 of the patients hadnot even been told what therapy they hadreceived. With the growing number ofchemotherapy treatments, the possibilityof their accidental prescription togetherwith sorivudine had been anticipated;patients who have chemotherapy are oftenin an immune suppressed state and so arepotential candidates for sorivudine. :

Apart from the action taken by the

manufacturer, the Ministry of Health hasissued an order to physicians to refrainfrom giving the drug to patients withunknown medication profiles and to peoplewith histories of cancer.

Makato Yawata

Debate on doctors’ workinghours

British demands that junior doctors shouldbe denied protection under EC legislationon working hours, night work, and holidaypay have been condemned in the EuropeanParliament. British Labour MEP StephenHughes said: "We can only wonder at thebarbarity of the UK government negotiat-ing a clause to exclude junior doctors fromthe terms of the directive". He said it was

"reprehensible in the extreme" that theBritish authorities should be prepared toput doctors’ health and that of their

patients at risk. Whether the legislation will

be enacted remains uncertain. Whitehallcontinues to dispute the idea that the

European Community is entitled to treatsuch matters as health and safety issuesunder the Treaty of Rome. The matter mayyet end up in the European Court ofJustice.

Meanwhile, Social Affairs Commis-

sioner Padraig Flynn was given a rough rideat the Parliament’s October session when

he said he was reluctant to take up thecudgels with. the Council of Ministers in aneffort to wrest more concessions. Onlywhen the assembly threatened to reject theentire proposal did he agree to supportStrasbourg’s amendments-having war-

ned that the entire directive might be lost.: Spokesman for the Social Affairs Com-

mittee, Belgian MEP Mr RaphaelChanterie pinpointed the key amendmentsamong the many being sought by MEPs-that the directive should include a "non-

regression" clause to prevent memberstates using the EC legislation as a pretextto water down existing national standards;that it should incorporate a specific refer-ence to ILO standards and set out a

reference period over which night workcould be calculated; and that it shouldcreate "a basic level of protection for asmany workers as possible", not provideexemptions for numerous occupations.Another sticking point concerned

implementation: members states wouldhave three years to transpose the directiveinto national legislation and would thenhave seven years as an "opting out period".

Arthur Rogers