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Published in the Quinacrine Newsletter 2000 |
Risk/benefit Criterion vs. Single Standard for QS Trials
Elton Kessel, MD, MPH
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The main objection to clinical trials of quinacrine nonsurgical female sterilization (QS) is that they have not been approved by regulatory agencies, such as the United States Food and Drug Administration (FDA) or the World Health Organization Special Programme of Research, Development and Research Training in Human Reproduction (HRP). What is demanded are additional toxicology studies. Some newer mutagenicity studies were recently concluded confirming again that quinacrine is a mutagen. One member of the HRP toxicology panel, knowledgeable about European regulatory procedures, is confident that no European regulatory agency will approve clinical trials of quinacrine because of its proven mutagenicity. The FDA requires as a next step a rodent carcinogenicity study that would take three years to complete at a cost of one million dollars. Fund raising for this undertaking is in progress.
An important organizational difference between the FDA and HRP should be noted. The FDA bases decisions concerning a clinical trial on risks and benefits of the trial - for Americans. The HRP does not depend on a risk/benefit analysis, but rather requires approval by their toxicology panel, whose decision is based on completed classical toxicology studies. This administrative arrangement is specific for HRP. For instance, the World Health Organization Special Programme for Research and Training in Tropical Disease (TDR) uses a risk/benefit criterion and may conduct clinical trials and toxicology studies concurrently. We agree with TDR that a risk/benefit criterion is the only logical one (1).
In conducting a risk/benefit assessment of any contraceptive clinical trial with potential for raising contraceptive prevalence, it becomes apparent that the benefits for a developing country far outweigh those for an industrialized society. A developing nation with low contraceptive prevalence, high population growth and high maternal mortality benefits greatly from increased contraceptive prevalence. For example, in many of their rural areas, maternal mortality is 5 per 1000 live births and each additional sterilization is estimated on average to prevent two births. In such a situation, each 1000 additional sterilizations by QS would prevent 10 maternal deaths. QS is known to be highly acceptable and easily delivered and would surely raise contraceptive prevalence when available (2). On the other hand, for an industrialized country with high contraceptive prevalence, low or zero population growth and low maternal mortality, the benefits of QS are much lower in terms of maternal mortality.
For surgical sterilization, it has been estimated in the USA that between one and two lives are saved per 1000 procedures by reduction in birth and ectopic pregnancy related mortality (3). The introduction of QS in the USA would only slightly increase contraceptive prevalence, thus providing minimal improvement in maternal mortality. It is not unreasonable for the FDA to require a rodent carcinogenicity study in light of the relatively modest benefits of QS for American women and considerable American resources. It is equally reasonable for a developing country to initiate trials of QS on the basis of what is known today of cancer risk of QS.
Figure 1. Uncertainties in interpretation of mutagenic and carcinogenic test results.
A. Accuracy of predicting human response with rodent carcinogenicity tests is unknown; sensitivity may reach 90% but specificity is low, although not accurately determined, with many false positive responses.
B. About 65% of chemicals with positive mutagenic tests are carcinogenic in rodent tests at maximum tolerated dose. But, negative tests may also be positive in rodent models.
C. Accuracy of predicting human response cannot be defined. Although sensitivity can be over 90% for tests showing DNA damage, mutations and chromosomal effects (genotoxic activity), specificity is low with many false positives. A negative mutagenicity response cannot reliably predict a lack of human response.
After Brusick D. Evolution of testing strategies for genetic toxicity. Mutation Research 1988; 205:69-78.
It should be made clear that mutagens are not always carcinogens and a carcinogen for a rodent has an unknown risk of being a carcinogen for humans. The uncertainties are shown in Fig. 1. Approximately 65% of mutagenic drugs prove to be carcinogens in rodent studies (4), although between rats and mice, two species more closely related than either is to humans, concordant results show only 70% (5). Also, these studies generally use the maximum tolerated dose of the drug that is many times the human therapeutic one. At the maximum tolerated dose many food items, such as roasted coffee and broiled hamburgers, are carcinogenic for rodents (6). Human experience in ordinary diets is quite different. Even at maximum tolerated dose given orally, quinacrine is not carcinogenic for rats (7) and there is some evidence that quinacrine is anticarcinogenic for some malignancies in rats (8). The ability of rodent studies to predict cancer in humans is largely unknown and their use by regulatory agencies involves enormous built-in safety factors which do not reflect true risks (6). Such studies are more appropriate for a new drug than for a new use of an approved drug with a long history of safe utilization.
There is extensive experience in oral use of quinacrine in humans as an antimalarial, helvetica with no report of cancer from this. If any increased risk of cancer exists with oral use it must be small. Transcervical administration involves a much lower dose than for malaria prophylaxis or treatment. Intrauterine quinacrine will be at a high level for the 30 minutes' dissolution time of the pellets but is reduced to a low level within 7 days and essentially disappears within 30 days (9). An inflammation leading to a permanent scar in the intramural tube occurs within 6 weeks (10). Inflammation produces mutagenic oxidizing agents and stimulates cell division (11). We know that chronic inflammation is associated with increased risk of cancer, as in hepatitis B for cancer of the liver. However, there is no evidence of increased cancer risk from an acute, non-infective inflammatory process as seen in QS. Follow-up studies of the longest use of quinacrine for sterilization showed no increased risk of cancer (12). Actually, no drug given once or twice in a person's lifetime at a therapeutic dose has ever been reported to cause cancer. Cancer risk of QS is probably low if it exists at all (13).
It is clear that for most developing countries benefits of QS outweigh the risks. Countries with modest maternal mortality and wide availability of surgicalsterilization may still find it advisable to use QS for women at predictable increased risk of a serious surgical complication from a general anesthetic, diabetes mellitus, chronic respiratory disease, previous pelvic or abdominal surgery, history of pelvic inflammatory disease, obesity or HIV infections (14,15).
At this time additional clinical trials are required to confirm leads for the improved efficacy of QS and for large field trials to further document its safety and acceptability in various settings.
References
1. Godal T. Fighting the parasites of poverty: public research, private industry, and tropical diseases. Science 1994; 264:1864-6.
2. Hieu DT, Tan TT, Tan DN, Nguyet PT, Than P, Vinh, DQ. 31,781 cases of nonsurgical female sterilization with quinacrine pellets in Vietnam. Lancet 1993; 342:213-7.
3. Kawachi I, Colditz GA, Hankinson S. Long-term benefits and risks of alternative methods of fertility control in the United States. Contraception 1994; 50:1-16.
4. Gold LS, Sawyer CB, Magaw R, et al. A carcinogenic potency database of the standardized results of animal bioassays. Environ Health Perspect 1984; 58:9-319.
5. Ames BN, Magaw R, Gold LS. Ranking possible carcinogenic hazards. Science 1987; 236:271-80.
6. Ames BN, Gold LS, Willett WC. The causes and prevention of cancer. Proc Natl Acad Sci 1995; 92:5258-65.
7. Fitzhugh OG, Nelson AA, Calvery HO. The chronic toxicity of quinacrine (Atabrine). J Pharmacol Exp Ther 1945; 85:207-21.
8. Dabancens A, Zipper J, Guerrero A. Quinacrine and copper, compounds with anticonceptive and antineoplastic activity. Contraception 1994; 50:243-51.
9. Dubin NA, Blake DA, DiBlasi MC, Parmley TH, King TM. Pharmacokinetic studies on quinacrine following intrauterine administration to cynomolgus monkeys. Fertil Steril 1982; 38:735-47.
10. Merchant RN, Prabhu SR, Kessel E. Clinicopathologic study of fallopian tube closure after single transcervical insertion of quinacrine pellets. Int J Fertil. 1995; 40:47-54.
11. Shacter E, Beecham EJ, Covey JM, Kohn KW, Potter M. Activated neutrophils induce prolonged DNA damage in neighboring cells. Carcinogenesis 1988; 9:2297-364.
12. Sokal DC, Zipper J, Guzman-Serani R, Aldrich TE. Cancer risk among women sterilized with transcervical quinacrine hydrochloride pellets, 1977-1991. Fertil Steril 1995; 64:324-34.
13. Tice RR, Griffith J, Recio L. An evaluation of the mutagenicity and carcinogenicity of quinacrine. Family Health International 1990, Research Triangle Park, NC, 27 pp.
14. DeStefano F, Greenspan JR, Dicker RC, Peterson HB, Strauss LT, Rubin GL. Complications of interval laparoscopic tubal sterilization. Obstet Gynecol 1983; 61:153-8.
15. Verkuyl DAA. Practicing obstetrics and gynaecology in areas with a high prevalence of HIV infection. Lancet 1995; 346:293-6.
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