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Clinical trials in reproductive surgery: randomization and life-table analysis
Vol. 52, No. 1, J uly 1989
FERT ILITY AND S T ERILITY Copy right
0
Prin ted in U.S. A .
1989 T he American Fertil ity Society
Clinical trials in reproductive surgery: randomization and life-table analysis
Togas Tulandi, M.D .* Director of Fertility Center and Associate Professor of Obstetrics and Gynecology
Nicola Cherry, Ph.D. Associate Professor, School of Occupational Health M cGill University, M ontreal, Quebec, Canada
Received December 9, 1988. * Reprin t requests: T ogas Tula ndi, M.D., Department of Obst etrics and Gynecology, M cGill U niversity, W om en 's Pavilion , 687 Pine Avenue W est, M on t real, Quebec H 3A lAl , Canada.
12
Tulandi and Cherry
The growing importance of surgery in the treatment of infertility is evidenced by the formation in 1984 of the Society of Reproductive Surgeons, a subsociety of The American Fertility Society. Concern that such therapeutic procedures should be effective is demonstrated by the recent increase in the number of published reports oftherapeutic trials. In an earlier review, Olive 1 found only 44 such reports in this journal in the 30 years to 1983. In the 5 years since then, some 70 further reports (excluding studies on in vitro fertilization) have been published in Fertility and Sterility. Unhappily, the increase in number of clinical trials has not been matched by an increase in the strength of research design. Only 6 of the 70 recent papers with pregnancy as the end point were of a randomized controlled design, a proportion barely changed from that (3/44) reported by Olive 1 for the preceding 30 years. We may reasonably ask why randomized trials have not gained much general acceptance in fertility studies. One answer might be that the value of randomized allocation to treatment is not widely appreciated. The validity of all evaluative studies of any therapeutic procedure depends on the level of certainty that exists on what would have happened without it. Patients who seek advice on infertility, who are advised to have a particular form of treatment and subsequently accept it, are highly selected. Without a comparison group of untreated but closely similar patients, it is impossible to assess the findings with any confidence. Although some basis for expectation can be obtained in certain nonexperimented study designs, it has been clear for many years that no approach is as reliable as that which results from a system of random allocation. Even this, of course, cannot guarantee equality, any more than tossing coins will ensure equal numbers of heads and tails. Conversely, the probability that an observed difference is more than might occur by chance can be tested statistically. Even where the value of randomized trials is appreciated, some may hesitate to use them if the number of suitable cases presenting at a clinic is so SI:(l.all as to make a truly randomized design prohibitively lengthy. The use of historical controls (patients undergoing the standard procedure in previous years) as a comparison group for patients currently undergoing a new procedure may appear an attractive alternative, cutting in half the number of new patients required for the evaluation. This gain in time is bought at a considerable price; changes in type of patient, severity of presenting illness, methods of ancillary treatment, and in the assessment of outcome all will put in doubt the validity of such historic comparisons. The use of a multicen-
Editor 's corner
Fertility and Sterility
ter trial to supplement the number of patients is a preferable approach, used in two ofthe randomized trials recently reported in this journa1. 2 ,3 Rock et a1. 4 report an interesting alternative, the use of a sequential design with random allocation, in which the number of cases required to demonstrate no difference in outcome was appreciably less than the fixed sample size previously calculated. Randomization may not always be medically feasible nor ethically acceptable. It is obviously unethical to deny or to delay treatment to a couple when there is some clear and absolute explanation for their infertility, such as azoospermia or bilateral tubal occlusion. Few studies, however, involve withholding treatment but rather randomizing patients either to the treatment previously thought to be optimal or to an innovative procedure believed either to increase conception or to decrease complications. Here the ethical problem involves mainly the unforeseen hazards of the new procedure; however, it would be equally unethical to undertake new types oftreatment without taking steps to test their effectiveness. In designing such a trial, it must be recognized that randomized controlled trials remain the hallmark of a scientific evaluation in clinical medicine, and reproductive surgery should not be an exception. Until this approach is more widely accepted in our subspeciality, scientifically valid conclusions on the efficacy of specific surgical procedures will not be achieved. Difficulties in obtaining consent from infertile patients sometimes can arise. This may be less of an issue where the treatment to be evaluated is a relatively minor variation in surgical technique, but will be appreciable where the alternative treatment involves risks or discomfort not present in the standard approach. A possible solution, not yet reported in fertility trials, is that proposed by Zelen. 5 In this design, eligible patients are randomized into two groups, and patients in the first group are offered a standard treatment, which they are free to accept or not. Patients in the second group are asked to consent to the experimental treatment and those who are unwilling are treated in the standard manner. The outcome for all those in the second group, regardless of treatment, is compared with that of the first. Clea"rly, if a large proportion of patients refused the experimental treatment, this would seriously dilute its measurable effect, but the advantage of this approach is that both physician and patient are informed as to the proposed treatment before agreement is sought or given; the choice of treatment is not seen, for the Vol. 52, No.1, July 1989
experimental group, as depending on the "toss of a coin," but as an informed decision between the new and standard treatments. Under these circumstances, participation may well be increased. Another approach, useful in some situations, is to classify suitable patients into pairs, similar in age and other relevant characteristics. Consent to randomization then is sought from all subjects, but only pairs in which both members agree are used in the analysis. As in any other human study, approval from an individual institutional review board is indicated before conducting a study on reproductive surgery. The success of a given surgical procedure is reflected in the occurrence of a pregnancy; in most publications this is reported as a pregnancy rate. It is a simple but ineffective and possibly biased way to assess success of fertility trials, which by their very nature have a variable follow-up time. Lifetable analysis is more appropriate for such studies and provides in addition some, admittedly imperfect, compensation for patients who have been lost to follow-up. The acceptance of life-table analysis for clinical trials in reproductive surgery has increased in recent years (Table 1). This may be due partly to description of this method in several publications,l,6,7 in this and other obstetric and gynecologic journals. The obvious advantages of this method over the use of crude pregnancy rates are such that life-table analysis must be considered the method of choice. Clinical trials are less precise and less homogeneous than laboratory experiments but even more important. The results of well-designed studies for evaluation in reproductive surgery will have great repercussions on the work of practicing physicians. The wider use of randomized trials and the use of optimal methods for analysis are essential if progress is to be made. Not all clinical trials can be ran-
Table 1 Clinical Trials in Reproductive Surgery With Pregnancy as the End Point (Excluding Studies on In Vitro Fertilization). Fertility and Sterility, 1983 to 1987 Randomized controlled trials
Year
Clinical trials
1983 1984 1985 1986 1987
15 13 9 20 13
3 1 2
2 3 3 4 6
Total
70
6
18
Tulandi and Cherry
Life-table analysis
Editor's corner
13
domized, but every effort should be made to see that unnecessary arguments and minor difficulties are not allowed to stand in the way of the widest possible use ofthis simple but potent device. REFERENCES 1. Olive DL: Analysis of clinical fertility trials: a methodologic review. Fertil SteriI45:157, 1986 2. Tulandi T, Vilos GA: A comparison between laser surgery and electrosurgery for bilateral hydrosalpinx: a 2-year follow-up. Fertil Steril44:846, 1985 3. Rock JA, Siegler AM, Meisel MB, Haney AF, Rosenwaks
14
Tulandi and Cherry
Editor's corner
4.
5. 6.
7.
Z, Pardos-Vargas F, Kimball A W: The efficacy of postoperative hydrotubation: a randomized prospective multicenter clinical trial. Fertil Steril42:373, 1984 Rock JA, Bergquist CA, Kimball AW Jr, Zacur HA, King TM: Comparison of the operating microscope and loupe for microsurgical tubal anastomosis: a randomized clinical trial. Fertil SteriI41:229, 1984 Zelen M: A new design for randomized clinical trials. N Engl J Med 300:1,242, 1979 Guzick DS, Rock JA: Estimation of a model of cumulative pregnancy following infertility therapy. Am J Obstet Gynecol 140:573, 1981 Guzick DS, Bross DS, Rock JA: A parametric method for comparing cumulative pregnancy curves following infertility therapy. Fertil Steril 37:503, 1982
Fertility and Sterility
FERT ILITY AND S T ERILITY Copy right
0
Prin ted in U.S. A .
1989 T he American Fertil ity Society
Clinical trials in reproductive surgery: randomization and life-table analysis
Togas Tulandi, M.D .* Director of Fertility Center and Associate Professor of Obstetrics and Gynecology
Nicola Cherry, Ph.D. Associate Professor, School of Occupational Health M cGill University, M ontreal, Quebec, Canada
Received December 9, 1988. * Reprin t requests: T ogas Tula ndi, M.D., Department of Obst etrics and Gynecology, M cGill U niversity, W om en 's Pavilion , 687 Pine Avenue W est, M on t real, Quebec H 3A lAl , Canada.
12
Tulandi and Cherry
The growing importance of surgery in the treatment of infertility is evidenced by the formation in 1984 of the Society of Reproductive Surgeons, a subsociety of The American Fertility Society. Concern that such therapeutic procedures should be effective is demonstrated by the recent increase in the number of published reports oftherapeutic trials. In an earlier review, Olive 1 found only 44 such reports in this journal in the 30 years to 1983. In the 5 years since then, some 70 further reports (excluding studies on in vitro fertilization) have been published in Fertility and Sterility. Unhappily, the increase in number of clinical trials has not been matched by an increase in the strength of research design. Only 6 of the 70 recent papers with pregnancy as the end point were of a randomized controlled design, a proportion barely changed from that (3/44) reported by Olive 1 for the preceding 30 years. We may reasonably ask why randomized trials have not gained much general acceptance in fertility studies. One answer might be that the value of randomized allocation to treatment is not widely appreciated. The validity of all evaluative studies of any therapeutic procedure depends on the level of certainty that exists on what would have happened without it. Patients who seek advice on infertility, who are advised to have a particular form of treatment and subsequently accept it, are highly selected. Without a comparison group of untreated but closely similar patients, it is impossible to assess the findings with any confidence. Although some basis for expectation can be obtained in certain nonexperimented study designs, it has been clear for many years that no approach is as reliable as that which results from a system of random allocation. Even this, of course, cannot guarantee equality, any more than tossing coins will ensure equal numbers of heads and tails. Conversely, the probability that an observed difference is more than might occur by chance can be tested statistically. Even where the value of randomized trials is appreciated, some may hesitate to use them if the number of suitable cases presenting at a clinic is so SI:(l.all as to make a truly randomized design prohibitively lengthy. The use of historical controls (patients undergoing the standard procedure in previous years) as a comparison group for patients currently undergoing a new procedure may appear an attractive alternative, cutting in half the number of new patients required for the evaluation. This gain in time is bought at a considerable price; changes in type of patient, severity of presenting illness, methods of ancillary treatment, and in the assessment of outcome all will put in doubt the validity of such historic comparisons. The use of a multicen-
Editor 's corner
Fertility and Sterility
ter trial to supplement the number of patients is a preferable approach, used in two ofthe randomized trials recently reported in this journa1. 2 ,3 Rock et a1. 4 report an interesting alternative, the use of a sequential design with random allocation, in which the number of cases required to demonstrate no difference in outcome was appreciably less than the fixed sample size previously calculated. Randomization may not always be medically feasible nor ethically acceptable. It is obviously unethical to deny or to delay treatment to a couple when there is some clear and absolute explanation for their infertility, such as azoospermia or bilateral tubal occlusion. Few studies, however, involve withholding treatment but rather randomizing patients either to the treatment previously thought to be optimal or to an innovative procedure believed either to increase conception or to decrease complications. Here the ethical problem involves mainly the unforeseen hazards of the new procedure; however, it would be equally unethical to undertake new types oftreatment without taking steps to test their effectiveness. In designing such a trial, it must be recognized that randomized controlled trials remain the hallmark of a scientific evaluation in clinical medicine, and reproductive surgery should not be an exception. Until this approach is more widely accepted in our subspeciality, scientifically valid conclusions on the efficacy of specific surgical procedures will not be achieved. Difficulties in obtaining consent from infertile patients sometimes can arise. This may be less of an issue where the treatment to be evaluated is a relatively minor variation in surgical technique, but will be appreciable where the alternative treatment involves risks or discomfort not present in the standard approach. A possible solution, not yet reported in fertility trials, is that proposed by Zelen. 5 In this design, eligible patients are randomized into two groups, and patients in the first group are offered a standard treatment, which they are free to accept or not. Patients in the second group are asked to consent to the experimental treatment and those who are unwilling are treated in the standard manner. The outcome for all those in the second group, regardless of treatment, is compared with that of the first. Clea"rly, if a large proportion of patients refused the experimental treatment, this would seriously dilute its measurable effect, but the advantage of this approach is that both physician and patient are informed as to the proposed treatment before agreement is sought or given; the choice of treatment is not seen, for the Vol. 52, No.1, July 1989
experimental group, as depending on the "toss of a coin," but as an informed decision between the new and standard treatments. Under these circumstances, participation may well be increased. Another approach, useful in some situations, is to classify suitable patients into pairs, similar in age and other relevant characteristics. Consent to randomization then is sought from all subjects, but only pairs in which both members agree are used in the analysis. As in any other human study, approval from an individual institutional review board is indicated before conducting a study on reproductive surgery. The success of a given surgical procedure is reflected in the occurrence of a pregnancy; in most publications this is reported as a pregnancy rate. It is a simple but ineffective and possibly biased way to assess success of fertility trials, which by their very nature have a variable follow-up time. Lifetable analysis is more appropriate for such studies and provides in addition some, admittedly imperfect, compensation for patients who have been lost to follow-up. The acceptance of life-table analysis for clinical trials in reproductive surgery has increased in recent years (Table 1). This may be due partly to description of this method in several publications,l,6,7 in this and other obstetric and gynecologic journals. The obvious advantages of this method over the use of crude pregnancy rates are such that life-table analysis must be considered the method of choice. Clinical trials are less precise and less homogeneous than laboratory experiments but even more important. The results of well-designed studies for evaluation in reproductive surgery will have great repercussions on the work of practicing physicians. The wider use of randomized trials and the use of optimal methods for analysis are essential if progress is to be made. Not all clinical trials can be ran-
Table 1 Clinical Trials in Reproductive Surgery With Pregnancy as the End Point (Excluding Studies on In Vitro Fertilization). Fertility and Sterility, 1983 to 1987 Randomized controlled trials
Year
Clinical trials
1983 1984 1985 1986 1987
15 13 9 20 13
3 1 2
2 3 3 4 6
Total
70
6
18
Tulandi and Cherry
Life-table analysis
Editor's corner
13
domized, but every effort should be made to see that unnecessary arguments and minor difficulties are not allowed to stand in the way of the widest possible use ofthis simple but potent device. REFERENCES 1. Olive DL: Analysis of clinical fertility trials: a methodologic review. Fertil SteriI45:157, 1986 2. Tulandi T, Vilos GA: A comparison between laser surgery and electrosurgery for bilateral hydrosalpinx: a 2-year follow-up. Fertil Steril44:846, 1985 3. Rock JA, Siegler AM, Meisel MB, Haney AF, Rosenwaks
14
Tulandi and Cherry
Editor's corner
4.
5. 6.
7.
Z, Pardos-Vargas F, Kimball A W: The efficacy of postoperative hydrotubation: a randomized prospective multicenter clinical trial. Fertil Steril42:373, 1984 Rock JA, Bergquist CA, Kimball AW Jr, Zacur HA, King TM: Comparison of the operating microscope and loupe for microsurgical tubal anastomosis: a randomized clinical trial. Fertil SteriI41:229, 1984 Zelen M: A new design for randomized clinical trials. N Engl J Med 300:1,242, 1979 Guzick DS, Rock JA: Estimation of a model of cumulative pregnancy following infertility therapy. Am J Obstet Gynecol 140:573, 1981 Guzick DS, Bross DS, Rock JA: A parametric method for comparing cumulative pregnancy curves following infertility therapy. Fertil Steril 37:503, 1982
Fertility and Sterility