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  1. 1

    Death of a study: WHO, what, and why [editorial]

    Lancet. 1994 Apr 23; 343(8904):987-988.

    Earlier this year The Lancet received a package of material, much of it highly critical, relating to a report that we had published in July, 1993. A few weeks later virtually the same package arrived from a different source. The accompanying messages were broadly similar, essentially saying that the work in question had come in for heavy criticism and that the project itself had been abruptly halted. All this had taken place without any consultation with the researchers or proper debate. The study was by Hieu and colleagues in Vietnam and described the use of quinacrine pellet sterilisation in more than 30 000 women in that country. In this issue, Professor Hieu, Director of the Maternal and Child Health/Family Planning Department at the Ministry of Health in Hanoi, outlines his concerns, expressing dismay at the manner in which his work has come under attack. The Lancet is no stranger to controversy and its correspondence section is open to all (matters relating to efficacy and operator skill had in fact been aired in letters published in the Oct 2 issue, p 869), so why have Professor Hieu and his colleagues been treated in this underhand fashion? (excerpt)
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  2. 2

    A critique of WHO's position on QS. [Critique de la position de l'OMS sur la SQ]

    Kessel E


    In the statement issued by the WHO Special Programme of Research, Development and Research Training in Human Reproduction (WHO/HRP), intrauterine administration of quinacrine was defined as a new drug by nature of the route of administration, gender of recipient and use. In addition, a number of outstanding issues were voiced in the form of questions: 1) Is the preclinical pharmacology of the proposed new drug adequate? 2) Are its pharmacokinetic and pharmacodynamic data adequate to allow wide-scale human use? 3) Is the drug manufactured according to Good Manufacturing Practices? 4) Have the clinical studies been conducted according to Good Clinical Practices or their equivalent? 5) Are the available toxicology, genotoxicity, teratology and carcinogenicity data sufficient to assess the probable long-term safety of the new drug in humans? In general, the author's answer to each concern is in the affirmative; however, WHO/HRP gives the answers as either No or Unknown . In view of this, it is the opinion of the author that such differences stem primarily from the fact that the WHO/HRP guidelines for clinical trials do not require risk/benefit assessment.
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  3. 3

    Risk / benefit criterion vs. single standard for QS trials.

    Kessel E


    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 US Food and Drug Administration (USFDA) or the World Health Organization (WHO) Special Program of Research, Development and Research Training in Human Reproduction (HRP). Additional toxicology studies are called for, especially since some recently concluded mutagenicity studies reconfirm quinacrine as a mutagen. The USFDA requires as a next step a rodent carcinogenicity study. The author discusses the organizational differences between the USFDA and the HRP. The USFDA bases decisions concerning a clinical trial upon the risks and benefits of the trial, for Americans. However, the HRP does not depend upon a risk/benefit analysis, but instead requires approval by their toxicology panel, whose decision is based upon completed classical toxicology studies. The WHO Special Program for Research and Training in Tropical Disease (TDR) uses a risk/benefit criterion and may conduct clinical trials and toxicology studies concurrently. The author agrees with the TDR that a risk/benefit criterion is the only logical one. He discusses the risk/benefit assessment of any contraceptive clinical trial with the potential to increase contraceptive prevalence. It is clear that the benefits for a developing country far outweigh those for more developed countries, and that the benefits of QS outweigh the risks for most developing countries.
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  4. 4



    The QS Newsletter is published to provide information on progress in development of the quinacrine pellet method of female sterilization. Specialists in the population field describe this method as the most important contraceptive to emerge since the introduction of the Pill. Yet it is largely unknown. There are several reasons for this unfortunate state of affairs. First, it involves a drug that has been in the public domain for decades. Because information on its use for sterilization has been published, it cannot be patented. So it is not an attractive investment for a pharmaceutical house. Secondly, neither the World Health Organization (WHO) nor the regulatory agency of any industrialized country has given the method its blessing. The estimates are that it would take about 8 years and $8 million to obtain such approval. Family Health International with support of the United States Agency for International Development (AID) has twice sought approval and twice given up the effort. While little is known of this method, even among population experts, its use continues to spread in developing countries. By now, over 100,000 women in various settings in 19 countries have accepted QS. Some of this experience is with formal government sanction and much is "off-label use." Quinacrine is an authorized drug for other purposes, including treatment of malaria, in all these countries. Physicians prescribing any off-label use of a drug are exposed to a degree of liability if there is a complication resulting from procedures, especially if there has been no recommendation by a "consensus meeting" of experts. Fortunately, complications with QS are very infrequent and increasing numbers of doctors and nongovernmental agencies are offering QS as one of their services. We believe that feminist organizations will have a particular interest in QS because it affords an additional option for women. Comments from our readers are always welcome. (full text)
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  5. 5

    Quinacrine method of family planning [letter]

    Do Trong Hieu

    Lancet. 1994 Apr 23; 343(8904):1040.

    This letter is in reply to a news report by Malcom Potts that reviews a 46-month field trial of nearly 32,000 women who were given quinacrine pellets as a means of surgical sterilization. The program reached 33 provinces before it was halted in December when, as stated in a letter from Dr. F.T.G. Webb of the World Health Organization (WHO) to UN Population Fund director Linda Demers, experts from WHO and the US Food and Drug Administration (USFDA) expressed concern about the possible carcinogenicity of quinacrine. At that time there was no scientific evidence that quinacrine causes cancer in man, but the government discontinued trials in view of the authority of WHO. The FDA approved phase I clinical trials which used volunteers in San Antonio, Texas and followed the required toxicology work at Johns Hopkins University. The work was published and no objections were raised. A panel of toxicologists were asked by Family Health International in 1990 to evaluate quinacrine as a carcinogen; they found a lack of positive, in vivo data and of relevant human data. The authors in collaboration with FHI and Dr. Jaime Zipper of Chile conducted their own investigation in 1990 and found no evidence of excess risk associated with the use of quinacrine pellet transcervical sterilization. WHO and the Association for Voluntary Surgical Contraception (AVSC) have widely distributed their criticism of the authors' paper, which was published in Lancet and discussed at an AVSC meeting to which the authors were uninvited. This obstructs scientific debate. Unsubstantiated opinions should not be allowed to undermine this promising family planning method.
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  6. 6
    Peer Reviewed

    Quinacrine sterilisation revisited.

    Kessel E

    Lancet. 1994 Sep 10; 344(8924):698-700.

    Benagiano of the World Health Organization's (WHO) Special Program of Research, Development, and Research Training in Human Reproduction (HRP) stresses that the high standards of safety demanded in the testing and use of contraceptives should apply whether the subjects recruited to the studies are from developed or developing countries. The author of this commentary, however, with particular regard to transcervical quinacrine pellet research for nonsurgical female sterilization, criticizes the ethical and professional stand of Benagiano and HRP. He instead argues that the only sensible global standard for contraceptive research is a risk-benefit one which will vary according to the circumstances of the country involved in the research. Benagiano's September 3 letter is criticized as omitting an historical perspective and failing to discuss the differences of opinion concerning the appropriateness of proceeding with current and expanded clinical trials concurrently with additional toxicology testing. The author argues that in applying a developed country standard for contraceptive research to a developing country, HRP is making a value judgement based upon neither science nor logic. To support his argument, the author points to a difference between HRP guidelines and those of the WHO Special Program for Research and Training in Tropical Disease (TDR). TDR, unlike HRP, favors a risk-benefit guideline which takes account of the circumstances in which research is conducted. Although both programs follow accepted procedures for phase I, II, and III clinical studies, TDR is more likely to encourage these to proceed concurrently when the benefits seem to outweigh the risks of the trial. Feminist concerns discussed in Geneva, the self-imposed regulations of donor agencies such as the US Agency for International Development, the use of quinacrine as an anti-malarial drug, and North-South differences in contraception research are discussed.
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  7. 7

    Sterilisation by quinacrine [letter]

    Benagiano G

    Lancet. 1994 Sep 3; 344(8923):689.

    The journal's April 23 editorial accused the World Health Organization (WHO) of having failed to clearly present its criticism of the clinical use of quinacrine for tubal sterilization. The organization responded June 4 that it would undertake formal review of the use of quinacrine. That review was undertaken in July during a consultation of 22 experts from Australia, Chile, China, the Dominican Republic, Hungary, India, New Zealand, Turkey, Uganda, the UK, the US, and Vietnam. The group noted that there had been several technological advances since the last WHO review in 1983 and felt it time to identify promising approaches for use in developed countries, and to set priorities for research. Participants concluded that a safe, effective, non-surgical method of sterilization is indeed needed and should be developed. Chemicals are, however, limited, as are the methods by which they can be delivered reliably and consistently to the fallopian tubes. The standardized testing of all compounds with known or potential use as tubal occlusive agents should precede clinical studies which should be conducted in a stepwise fashion. With specific regard to locally applied quinacrine, toxicology testing completed more than a decade ago is inadequate. The further use of quinacrine requires the completion of necessary toxicology testing, including the full range of genotoxicity studies, and, if needed, long-term animal carcinogenicity testing. Other animal tests, including tests for teratogenicity, should be conducted if the initial results are satisfactory. Contingent upon the receipt of satisfactory results from initial toxicology tests, phase I and II clinical studies of intrauterine quinacrine should be initiated. Irrespective of the results of toxicology testing, retrospective studies of women already treated with quinacrine should be continued and completed. The high standards of safety demanded in the testing and use of contraceptives should apply whether the subjects recruited to the studies are from developed or developing countries.
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  8. 8

    AVSC technical statement: quinacrine pellets for nonsurgical female sterilization.

    Association for Voluntary Surgical Contraception [AVSC]

    New York, New York, AVSC, 1993 Sep. 8 p.

    Neither the US Food and Drug Administration nor WHO have yet endorsed intrauterine insertion of quinacrine for tubal occlusion in women. Quinacrine is very inexpensive and easy to produce and insert, which make it open to abuse. Free and informed choice and safety must be upheld as well as quality of care in family planning services. The few studies of quinacrine use for nonsurgical sterilization have small sample sizes and very short-term follow-up. They have largely occurred in Chile, Egypt, and Indonesia. One study suggests that quinacrine increases the risk of cancer. Recently a field trial of 31,781 women undergoing nonsurgical sterilization with quinacrine pellets was conducted in Viet Nam. The pregnancy rate at 1 year was 2.63. At 2 years it was 4.31 for cases with 2 insertions. At 5 years, for women with just 1 insertion, it was 5.15. There were 19 ectopic pregnancies. Major complications included 2 cases of severe bleeding, 2 hysterectomies (severe pain and amenorrhea, adhesions in the cervical canal), 1 case of premenstrual pain and dysmenorrhea, 1 case of pelvic inflammatory disease, and 1 allergic reaction. Only minor side effects occurred. The study methodology was flawed, however. For example, the researchers did not bide by the inclusion criteria they claim to have used. They also extrapolated failure rates and side effects based on subsets to the whole group. Thus, this study cannot be used to conclude that quinacrine pellets are safe and effective. Further, well-designed studies addressing short and long-term safety are warranted. If studies find quinacrine pellets to be safe and effective, their low cost and ease of insertion make it a promising method in areas of high maternal mortality, with low access and availability of family planning services, and great unmet need for permanent methods.
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  9. 9

    Quinacrine family-planning method [letter]

    Abdullah R

    Lancet. 1994 Jun 4; 343(8910):1425-6.

    Many Vietnamese women do not accept IUDs. Program planners, providers, and officials in Vietnam are therefore challenged with providing alternative methods of fertility control which are acceptable to the population. Nongovernmental organizations for women in Asia and the Pacific are concerned about Potts' assertion that the intrauterine insertion of quinacrine pellets is a safe and effective method of sterilization for Vietnamese women. Women's health advocates are most worried about safety, especially the long-term physiological effects and the risk of abuse or coercion. On the basis of a 1991 review, the World Health Organization Toxicology Panel recommended further study of the safety of quinacrine in sterilization, while Hieu et al from their report of a large field trial of Vietnamese women admitted their inability to study the risk of cancer of the uterus as a result of exposure with quinacrine. Work needs to be done before the use of quinacrine as a form of contraception may be declared safe and effective. Future field trials in Vietnam should interview users on their views and preferences. Moreover, since the administration of quinacrine involves no surgical procedure and the insertion procedure is identical for both IUD and quinacrine, some women may not fully understand that one method is permanent and the other is not. The right of women to make informed and individual choices about their fertility can easily be abused when countries try to achieve population growth and size targets. Efforts should be made to ensure that such abuses do not occur in Vietnam.
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  10. 10

    Quinacrine family-planning method [letter]

    Benagiano G

    Lancet. 1994 Jun 4; 343(8910):1425.

    The editorial in the April 23, 1994, issue of the Lancet accused the World Health Organization (WHO) of declining a request to comment publicly upon a paper by Hieu et al reporting a clinical trial of the quinacrine method of female sterilization of more than 30,000 women in Vietnam. The editorial also implicitly accuses the WHO of being discourteous and lacking courage for not openly airing criticisms; for resorting to anecdote, misinformation, and anonymity; and for trying to evade responding to the question at hand. Giuseppe Benagiano of the WHO Special Program of Research, Development, and Research Training in Human Reproduction counters the charges as unfounded and responds accordingly. He explains that individuals at the WHO read Dr. Hieu's paper published in the Lancet of July 24, 1993, after which they received several negative comments from scientists and national and international organizations. Involved parties opted to have a detailed discussion of quinacrine, including the Lancet report, by a group of experts and then issue an official statement. This discussion was to be included in a meeting on female sterilization already scheduled in Geneva for July 25-27, 1994, after which an official WHO position would be approved through the appropriate channels and presented for public perusal.
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