1114

1 ’9 million-a worrying policy doubt remains. The first priority of any drug regulatory authority must be the protection of public health. Such protection can only be ensured when the evidence on which licence decisions are made is open to public scrutiny. Summary bases of approval of a product licence would be a start but have been resisted by the MCA on the grounds of commercial confidentiality. This argument is spurious. What is legitimately confidential about, for example, clinical experience with a drug? The best trials will be published anyway, which makes it all the more important that a full picture be disclosed. A new fee structure, introduced in May, 1991, means that the MCA is now financially dependent on pharmaceutical companies. The relationship between drug regulation (viewed by government as a business in its own right) and drug marketing has become a commercial one. The MCA is competing for its share of European drug regulatory business, and the potential for conflict has not been discussed. The organisation of European drug regulation, by contrast, is in crisis. The communautaire spirit has deserted many EC member states during their scramble to preserve their own decision-making autonomy in anticipation of the 1993 single market. The system of European community multi-state approval has been "a total failure" according to Marie Donnelly of the European Commission. Approval of a product licence by one country is supposed to lead to "mutual recognition" by other member states. Although only 10% of applications pass through the multi-state system, none has been accepted without question by other countries. Between 1986 and 1990, Italy rejected 93% of multi-state applications, the Netherlands 92%, and Belgium 88%. Despite Professor Poggiolini’s assurances that objections could be ironed out at preliminary meetings, the European Commission clearly takes the view that this system has generated more work than is necessary and

change. Proposals for future systems have focused on two competing approaches. A centralised agencyfavoured by both the European Commission and pharmaceutical companies-would provide products for a European single market and prevent duplication of assessment procedures in individual member states. The alternative, a decentralised system, would still rely on mutual recognition. Neither system could be in place much before the late 1990s. The MCA has emphasised the need to phase in any new decentralised plans, to avoid a debacle similar to that of mutual recognition in the multi-state procedure. Trust between member states might be fostered by forming regional groupings-eg, the Benelux countries and the UK and Ireland. Rights of appeal must be incorporated into the evaluation process, and must

inter-state assessment standards need to be harmonised. If the Committee for Proprietary Medicinal Products becomes an arbitrator for

to decisions made by member states, it be seen to be at least as competent as the national agencies. However, the EC financial constraints that have led to a reduction in both the frequency of the Committee’s meetings (9 to 7 per year) and their length (3 to 2 days) are hardly a good omen. A European medicines evaluation agency has also beeen proposed. This would evaluate new medicines and coordinate adverse drug reporting; it would be accountable to the European Parliament, the Council of Ministers, and probably the European Commission. Debate continues as to whether this agency should be separate from the Committee for Proprietary Medicinal Products or encompass the Committee and thereby strengthen it. The UK broadly supports the idea but thinks that the proposal lacks sufficient detail to permit a proper judgment. Consensus over the nature of European drug regulation during the 1990s and into the next century remains elusive: words are rarely matched by actions. Individual member states will not relinquish power

objections

must

their own pharmaceutical markets until they feel they can trust their European colleagues. Furthermore, some EC countries are content to have on their pharmacy shelves products that others find weird. However, too much discussion may simply delay moves towards harmonisation. A choice must be made between a centralised and a decentralised regulatory system. A compromise whereby the two systems were run in parallel would lead to over

that

unacceptable duplication. Objections to applications made through a centralised procedure could be channelled through representatives of individual member states who would sit on the adjudicating committee. The role of national agencies, such as the MCA, would require clarification if such a centralised body came into being. A decentralised network of regulatory authorities would have to adhere to mutual recognition and a country would need to prove that it had the skill and facilities to judge applications before being allowed to make decisions on behalf of the EC as a whole. This mechanism might mean that just a few countries would come to dominate the licensing process. Lastly, what about drug withdrawals? This important aspect of drug regulation has been neglected. Many examples (triazolam most recently) spring to mind. Suspension of a product licence or its alteration on safety grounds must not be allowed to flounder in a sea of bureaucracy. Persistent

anogenital

warts

manifestation of human infection of the anogenital tract. Such HPV infections have an adjusted annual incidence of about 8% in an unselected Scandinavian female population,’ and anogenital warts are the commonest viral sexually transmissible disease in England.2 The patient’s immune response probably

Anogenital warts are papillomavirus (HPV)

one

1115

determines whether infection will become manifested

clinically and how well the resulting condylomas respond to treatment. HPV DNA replicates in the suprabasal cells of the epidermis, but the considerably more antigenic complete viral particles are produced only in differentiating keratinocytes, which are distant from cutaneous immunological defences. HPV infections may also be associated with local immunoparesis.3,4 Whatever treatment is used, efficacy probably depends on (a) removal of tissue containing viral particles and (b) disruption and release of previously sequestered viral antigens and their exposure to the immune system. Scientific evaluation of treatment is difficult. For example, it may be hard to assess objectively the severity and response of clinically apparent lesions. Warts of different types and duration may not respond in the same way to different regimens, and the role of HPV typing in terms of clinical behaviour and therapeutic responsiveness has not been fully explored.s Patient variables such as sexual practices, smoking, human immunodeficiency virus infection, oral contraceptive use, and nutritional status may likewise be important. Trials of therapy seldom control for all these factors, tending to concentrate instead on patients with newer lesions that are more responsive to most treatments than are persistent warts. Follow-up is often no more than 3 or 6 months, despite the known propensity of warts to relapse and to remit spontaneously.6 Reinfection during treatment may be difficult to exclude, and use of condoms during and after therapy may influence the results. Another complication is that fomites may help to maintain infection-in one triaF the relapse rate was increased in patients whose underwear contained HPV DNA. It is unclear whether concurrent treatment of sexual partners enhances the success of treatment.

associated with a more vigorous immune response4and are generally more responsive to all the established treatments, so patients should be encouraged to present early. Nevertheless, a large minority of patients with anogenital warts do not respond adequately to first-line treatment with podophyllin, podophyllotoxin, or cryotherapy. The considerable distress and pressure on sexual relationships caused by the diagnosis are compounded by patients’ increased awareness of the putative link between HPV infection and anogenital cancers. Repeated courses of podophyllin have progressively fewer benefits,8 and destructive methods such as cryotherapy, electrodesiccation, and laser fulguration, either separately or in various combinations, may be necessary. Choice of treatment largely depends on locally available skills and resources; cure rates vary from 27 to 91%.9,10 Different types 11,12 and doses of interferons given locally 13 or systemicallyl4 have been tried for various lengths of time. Most trials have been on patients with previously untreated warts, for which the chances of Fresher

warts are

better than with older, larger, or recalcitrant lesions.1s,16 For persistent warts, interferon combined with a destructive method may improve the clearance rate. 17 Although the frequency, dose, type, and indications for interferons in the treatment of anogenital warts remain to be fully established, use of a combination of methods should lead to at least temporary clearing of visible lesions in most cases; repeated treatments may be necessary occasionally. We do not know whether HPV DNA is eradicated completely as a consequence of any of the wart treatments. 18 Moreover, it will be some time before we know whether elimination of the clinical manifestations of genital HPV infection reduces infectivity for sexual partners or alters any risk of subsequent anogenital cancer. One view is that vigorous therapy should be used in the minority of individuals whose warts harbour so-called high-risk types (HPV 16, 18, 31, 33, 35, and 39); the more common "low-risk" types are HPV 6 and 11. However, several other factors influence the rate of progression of lesions.,19 and HPV typing is not routinely available. Until these issues have been addressed, enthusiastic calls for widespread destruction of skin with evidence of subclinical HPV infection should be resisted. Patients with anogenital warts are likely to have put themselves at risk of acquiring other sexually transmitted human infections, including immunodeficiency virus, so it is essential to offer counselling and screening for these disorders. Such screening not only allows treatment of previously undiagnosed conditions but also may aid management of the warts, since epidermal irritation caused by coincidental genital pathogens may encourage growth of the lesions.2° Because wart treatment sometimes extends over several months, screening ma-- have to be repeated as the patient’s lifestyle changes. It is important to determine the patient’s sexual history so that recent partners can be offered screening. In view of the concern about HPV and anogenital cancer, cervical cytology is recommended, in addition to biopsy of any atypical lesions. The treatment of anogenital warts has fostered a rich heritage of folklore2l and the continuing controversy surrounding existing regimens, none of which is uniformly effective, safe, and cheap, shows how little we understand the pathogenesis and management of this infection. Ample scope here for properly controlled and blinded trials of new cure are

treatments. 1.

Syrjänen KJ. Epidemiology of human papillomavirus (HPV) infections and their associations with genital squamous cell cancer. APMIS 1989; 97: 957-70.

Department of Health. New cases seen at NHS genito-urinary clinics in England years 1988/89 and 1989/90: summary information from form KC60. London: Department of Health, 1991. 3. McMillan A, Bishop PE, Fletcher S. An immunohistological study of condylomata acuminata. Histopathology 1990; 17: 45-52. 4. Vardy DA, Baadsgaard O, Hansen ER, Lisby S, Vejlsgaard GL. The cellular immune response to human papillomavirus infection. Int J Dermatol 1990; 29: 603-10. 2.

1116

5. Gal

D, Friedman M, Mitrani-Rosenbaum S. Transmissibility and

treatment

6.

failures of different types of human

papillomavirus. Obstet

Gynecol 1989; 73: 308-11. Tyring SK, Cauda R, Baron S, Whitely RJ. Condyloma acuminatum: epidemiological, clinical and therapeutic aspects. Eur J Epidemiol 1987; 3: 209-15.

7. Bergeron C, Ferenczy A, Richart R. Underwear: contamination by human papillomaviruses. Am J Obstet Gynecol 1990; 162: 25-29. 8. von Krogh G. Podophyllotoxin for condylomata acuminata eradication. Clinical and experimental comparative studies on podophyllum lignans, colchicine and 5-fluorouracil. Acta Derm Venereol 1981; 98 (suppl): 1-48. 9. Larsen J, Petersen CS. The patient with refractory genital warts in the STD-clinic. Dan Med Bull 1990; 37: 194-95. 10. Baggish MS. Improved laser techniques for the elimination of genital and extragenital warts. Am J Obstet Gynecol 1985; 153: 545-50. 11. Reichman RC, Oakes D, Bonnez W, et al. Treatment of condyloma acuminatum

with

three

different

interferons

administered

intralesionally. Ann Intern Med 1988; 108: 675-79. 12. Zouboulis CC, Stadler R, Ikenberg H, Orfanos CE. Short-term systemic recombinant

interferon-&ggr;

treatment is ineffective in

recalcitrant

condylomata acuminata. J Am Acad Dermatol 1991; 24: 302-03. 13. Eron LJ, Judson F, Tucker S, et al. Interferon therapy for condylomata acuminata. N Engl J Med 1986; 315: 1059-64. 14. Condylomata International Collaborative Study Group. Recurrent condylomata acuminata treated with recombinant interferon alfa-2a: a multicenter double-blind placebo-controlled clinical trial. JAMA 1991; 265: 2684-87. SA, Hughes CE, Trofatter K. Interferon for the therapy of condyloma acuminatum. Am J Obstet Gynecol 1985; 153: 157-63. 16. Schonfeld A, Nitke S, Schattner A, et al. Intramuscular human interferon-&bgr; injections in treatment of condylomata acuminata. Lancet 1984; i: 1038-42. 17. Petersen CS, Bjerring P, Larsen J, et al. Systemic interferon alpha-2b increases the cure rate in laser treated patients with multiple persistent genital warts: a placebo-controlled study. Genitourin Med 1991; 67: 15. Gall

99-102. 18.

Mitao M, Nagai N, Silverstein SJ, Crum CP. Latent papillomavirus and recurring genital warts. N Engl J Med 1985; 313:

Ferenczy A, 784-88.

19. Gissmann L. Linking HPV to cancer. Clin Obstet Gynecol 1989; 32: 141-47. 20. Kinghom GR. Genital warts: incidence of associated genital infections. Br J Dermatol 1978; 99: 405-09. 21. Steele K. Wart charming practices among patients attending wart clinics. Br J Gen Pract 1990; 40: 517-18.

Not

a

classless society

Life in inner cities is often tough for the underprivileged people who congregate there. In the USA the health indicators of these urban areas are very poor. Grisso and colleaguesl found that, during the course of a year, no less than 10% of the estimated

population of 31

032 inner city women aged 15 years and older in western Philadelphia, Pennsylvania, sustained injuries that ended in death or in a visit to an accident and emergency department. For those aged 25-34, the figures were even higher-16%. Falls, violence, and motor vehicle accidents were the main cause of injury; violence was the leading cause of death for the 25-34-year group. The overwhelming majority of residents and injured women in the low-income area under study (median family income $11 810 vs US median family income in 1989 of $34 213) were blacks. This study of injuries-the first to be carried out in an inner city area-confirms earlier observations that, for most types of injuries, black women and men have higher injury rates than their white counterparts. For example, homicide rates in blacks are 1 ’38 times higher than in whites.22 Black/white mortality differentials in the USA have lately featured in medical and lay publications, in

which concern has been expressed about the perceived deterioration of the health conditions of blacks and other minorities. On average blacks live 2190 days less than whites. In response, the US Government has called for a national effort to reduce these mortality differentials.3 Yet the primary focus on race as the subject of analysis and stimulation for change is insufficient to solve the problems of minorities, or those of the rest of the US population. Navarro4 has argued that class should also be considered in US Government mortality statistics. He believes that ignoring class differentials reinforces the widely held perception that race is the determining factor in explaining the poor predicament of minority groups. That the notion is false was confirmed by Grisso et al, who found that in the low-income community being studied, white women and black women had similar rates of injury. National data show that differentials in homicide rates by income group are much larger than black/white differentials. The homicide rates in the lowest per caput income area of residence are almost double those in the highest per caput income area,s and most residents in the low-income and highincome areas are white. Although within each residential area blacks are likely to have worse rates than whites, the reality that class differentials are much greater than race differentials cannot be denied. If race is not the main reason why the mortality rates are higher for blacks than for whites, racism probably is. Because of racial discrimination, blacks and other minorities have low-income jobs, live in poor housing (the death rate due to house fires is 4-6 times higher in low-income areas than in upper-income areas), and reside in poor areas. They share these conditions with millions of whites who are also part of the unskilled working sector of the population. The overwhelming majority of black women and men and other ethnic minorities are members of the burgeoning low-paid working class-the class that, for most causes of death, has higher mortality rates than do the middle and upper classes, who earn more. Publication of mortality statistics by class as well as race would help to show that the poor conditions of blacks and other minorities are not based on the genetic, psychological, or cultural factors that are frequently held to be responsible for their plight and would help to unite rather than divide those at the bottom of the social scale. Will the US Government pick up this gauntlet? 1. Grisso

JA, Wishner AR, Schwarz DF, Weene BA, Holmes JH, Sutton RL. A population based study of injuries in inner-city women. Am J Epidemiol 1991; 134: 59-68. 2. Baker SP, O’Neill B, Ginsburg M, Li G. Table 1, number of deaths and death rates by sex and race, 69 causes. Injury fact book. 2nd ed. Oxford: Oxford University Press (in press). 3. Goals for the nation for the year 2000. Washington, DC: Public Health Service, US Department of Health and Human Services, 1989. 4. Navarro V. Race or class versus race and class: mortality differentials in the United States. Lancet 1990; 337: 1238-40. 5. Baker SP, O’Neill B, Ginsburg M, Li G. Table 8, death rates per 100 000 population by per capita income of area of residence and place of residence, 69 causes, 1980-1986. Injury fact book. 2nd ed. Oxford: Oxford University Press (in press).

Persistent anogenital warts.

1114 1 ’9 million-a worrying policy doubt remains. The first priority of any drug regulatory authority must be the protection of public health. Such...
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