Assessment of clinical testing methodology

Anlbal Fatindes, M.D. Consejo Nacioual de Poblacidny Familia Secretariade Rstado de galud PClblica Dominicana Santo Domingo - Repiiblica

I. INTROLWCTION Clinical trials are the last link in a long chain of efforts aimed at the developmnt of new therapeuticor prophylacticmethods. They constitutea critical assessmentof efficacy and safety in man. Incoqetent or inadequateclinical trials may result in unwarranted exposure of the public to toxic effects and to inadequateprotection, especiallyin instanceswhere suitablealternativeregimsns are already available. Conversely,they can result in rejectionof superiorawzthodsthat could yield a much higher ratio of safety and effectiveness. Those who conduct clinical trials thus have a responsibility to society to conduct the most meaningful tests possible of eftime they have a fectivenessand risks of new therapies. At the sa respousibilityto the individualpatient not to expose him or her to haxards inconsistentwith potentialbenefits. The clinical testing of contraceptivemethods bears a specialburden because any given pregnancyusually representsonly a minirmm threat to the life and well-beingof the anther. At the same time, effectivecontraceptivemethods are of the highest mrtauce to the generalwellbeiugofmankiuI. Because of these considerations,efforts to improve the quality of the methodologyused in clinical trials of contraceptive methods becomes of prime importance. SooDeinvestigatorsand institutionshave attemptedto meet this challenge to improve end unify proceduresas, for example, in research design (5,51,53,54,55,69,121,161,162) and data analysis (6,113,114,165,166,169). At the same tinq continuedneed for -roved a&hods and for greater standardizationof methodologyis abuudantlyapparent. The present paper focuses on aspects of clinical testingmethodologythat need imediate attention. The recoamkmdations are intended to apply to clinical tests of performanceand safety as they axe conductedafter the completionof clinical pharmacology (Phase II) studies.

*

This paper Development Roy 0.

Accepted

was prepared Review

Greep,

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sponsored

of the

Reproductive

Biology

by The Ford Foundation,

under

ond Contmceptive the direction

of

Ph.D.

for publication

Jcmuary

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II. EVALUATIONOF DATA ANALYSIS PROCEDURES Techniquesused in data analysis are critical for the design of clinical tests and for interpretationof the findings. A discussionof problem areas follows. Estinmtionof Event Rates Present Status Earlier trials of new contraceptivesreported results simply in terms of the percentageof users who became pregnant during the period of study without consideringthe tier of months that each woman was exposed to the risk of pregnancy (14,15,83,146,157,182). The next step of sophisticatim was to calculate the Pearl Index rate, in which the total number of accidentalpregnanciesis divided by the total number of months of contraceptiveuse and multiplied by 1200 (or, in some instances,1300) to give the uumber of pregnancies per 100 wcmen years of exposure (2,3,4,7,9,11,12,16,17,22, 27,31,43,52,56,64,72,76,80,118,125,138). As early as 1960 the importanceof the length of the observation period as a factor affectingpregnancyrates was recognized (112). It is a cosxnm observationthat the Pearl Index pregnancyrate becomes lower the longer a group of contraceptorsis followed. This is because the women of higher fecundityand higher incidenceof exposure are especiallylikely to becom pregnant and thus be elfminatedfrom the study, in the earlier months, leaving behind a group of wcemm with lower fecundity. To overcOme this problem, the use of the lifetable approachwas proposed (113,114,165,166).In this method, the pregnancy rate is calculatedfor each ordinalmonth of use. Wlative rates can be calculatedfrom monthly rates for any desired intervalof experience. 'Ihelifetablemethod was first used in clinical trials of contraceptivesfor estimationof pregnancyrates, but it can obviouslybe used equally well to determinethe rate of occurrence of any other event being observed in the trial. Because lifetable methods were first used to analyze the results of clinical trials of intrauterinedevices and because Tietze'spaper (166) on their applicatim to IDD trials received such wide dissemination,many investigatorsmistakenlyconcluded that this approachwas appropiate only for IUD studies. mu an incompletereview of recent publications of clinical studies of new contraceptives,it was found that 33 out of 53 IlIDstudiesutilized the lifetablemethod, but only 7 of 100 clinical studies of other contraceptivemethods did so.

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Recommdations It is recommended that lifetable methods of analysis be used to analyze data from all clinical studies of all new fertility control methods and that they be applied to all estimates of rates of occurrence of discrete events in such trials.

Criteria for Classification of Events Considerable ambiguity in interpreting the results of clinical trials of contraceptives arises from the different definitions of events used by different investigators. This serious problem is frequently further compounded by the failure of investigators to specify the definitions that they have employed. Specific instances of this problem are discussed below. Non-Returnees Present Status Some studies do not include as part of the study population women who made an initial visit to the clinic with the intention of initiating a method but who failed to return. Some of these women, in fact, begin use of the method and then later discontinue its use, but never return to the clinic to report this fact. Others will have never initiated use because of some of the important characteristics of the contraceptive. For instance, a neighbor may have told the prospective user that the method produces cancer or thromboembolism; or she may have lost or misplaced the dosage form. All such reasons are related to the characteristics of a method, and hence they should be accounted for in the study's data collection and analysis procedures. These problems arise to a lesser extent in studies of methods initiated by the physician, such as IUDs, injectables, and implants. Recommendations When continuation or use of a method is being evaluated, all subjects who accepted and were provided with the method should be included in the study. This includes even those who never returned to the clinic or ultimately failed to initiate use for whatever reason.

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Categories of Terminations Present Status The literature indicates general agreement that terminations be classified into the following categories: pregnancies, terminations for medical reasons, terminations for personal reasons, terminations at the investigator's choice, release from study and lost-to-follow-up. Subcategories are sometimes introduced. In the case of IUD's, there is the additional category of expulsions. The problems lie with the varying and frequently unnoted definition of the categories (2,11,29,37,45,94,181). The definition of "personal" and "medical" reasons for terminations is an example. Many physicians classify the reason for termination as "personal" if the symptom or side effect, in his judgement, is not attributable to the contraceptive. Other physicians might, however, have judged that the symptom could have been caused by the method and so classified it as a medical reason for discontinuing use. Problems also arise when additional, non-exclusive categories are added to those noted above. The category "change of method" is sometimes added, but it fails to take into account the important question of why the method was changed (114). Answering this question will place the subject in one of the standard classes of terminators. The practice of excluding from rate calculations women who discontinue for non-relevant reasons--as recommended by Tietze (166,167)--is generally accepted with few exceptions (60). Problems are minimized if the exclusions are limited to the categories of terminations resulting from the investigator's choice and release from the study, as recommended and defined by Tietze (166,167). The mode of handling, in the analysis, subjects that have been lost-to-follow-up represents a difficult problem in that the logical procedure varies with the contraceptive method being tested. The lost-to-follow-up category is used for subjects who do not return within a specified time after a scheduled visit and whose reaction to the method, therefore, remains unknown. In the instance of methods such as long-acting injectables or implants which cannot be discontinued at the will of the subject, it is logical to treat lost-to-follow-up as non-relevant terminations until the end of the estimated period of effectiveness and relevant from that time on. At the other extreme, in the instance of contraceptives that require a new supply or prescription at each visit, it is logical to assume that the subject discontinued use on the day the prescription or supply ran out (178). Since the women chose not to return for a new supply at the time of

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loss of protection,the case nust be considereda relevant discontinuation. Judgementis harder to make when the contraceptiveis comercially availableand when the socio-economiclevel of the study populationmakes it possible for the wonmznto replenishtheir supplieswith their own money. Some methods such as the IUD, require the physician'sintervention either for discontinuationor for continueduse. In such instances,it is logical to wait three or even six months before making an assessment. one is then left with possibilitiesranging from all patients having continueduneventfuluse to all patients having discontinuedafter pregnancyor other relevant reasons. It is then logical to reach the compromiseof assuming the intelmediate possibilitiesas reconscended by Tietze, that is, to treat lost-tofollow-upas a non-relevantdiscontinuation. Recammndations The classificationof terminationsshould be restrictedto the categories:pregnancies,terminationfor medical reasons, termination for personal reasons, terminationat the investigator'schoice, release from the study and lost-to-follow-up.Subcategorieswithin these classificationsshould be exclusiveof the standard categories and should be fully defined. Medical reasons for terminationshould include all terminations resulting from health or physical complaintsby the wife or husband attributedto the methods, whether consideredrelevant by the investigatoror not. "Change to anothermethod" should not be listed as a reason for closure; rather the reason for the change to the other method should be stated and classifiedunder one of the acceptedcategories. Exclusionof women who discontinuedfor non-relevantreasons should be confined to "terminationsat the investigator'schoice" and "release from study", as recunnendedby Tiet?.e*(166,167).

(*I

"Terminationsat the investigator'schoice" include terminations incidentalto research proceduresuch as endasetrialbiopsies in the case of IUD, and all other terminationsat the investigator's initiativefor nonlnedicalreasons. "Release from study" includewomen who are dropped from further observationas they move out of the reach of the investigator,but are knoun to continueuse of the method at the time of moving away. Deaths fran causes unrelated to the method should also be includedhe

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If continuation of a contraceptive requires a new supply or prescription at each visit, ten&nations prior to return for a new supply should be treated as a relevant discontinuation. In the case of methods that require a physiciau’s intervention to discontinue, lost-to-follow-up should be treated as a twnrelevant discontiuuation until the end of the estimated pxd of effectiveness and relevant froru that date on. In the instance of methods that can be either continued or discontinued by the subject without the physician’s intervention, it is better to perform a double computation using the alternatives of treating lost-to-follow-up as relevant and non-relevant discontinuation (114). Patient

Failure

Present

Status

and Method Failure

Since improper use of a stethod such as the omission of a pill or the use of foam too long before witus obviously results in poorer performance than that which the method is capable under ideal conditions, there is a strong temptation to eliminate from calculations any events associated with such lapses. Ihe legitimacy of doing so depends upon whether one is trying to assess the potential biological effectimness of the method or the effectiveness under conditions of actual use. The effectiveness under conditions of actual use will properly include failures related to the socio-cultural enviromnznt and the psychological behavior of the users. Attempts to separate patient failures from method failures and to report only method failures will be subject to quite different criteria by different investigators (7,39,75,79). %me will attribute the failures to the subject at the slightest suspicion of deviation from instructions, while others will classify all pregnancies as method failures unless the user had grossly and demonstrably misused the method. &commendations Investigators should always report total pregnancy rates. Such rates may be further classified into patient and method failures, if a full description of the criteria used for such a classification is presented.

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Time Units of Observation Present Status A partial review of the literature showed that nearly 60% of the papers reviewed used calendar months as the time unit of analysis. Almost 40% used the "menstrual cycle" as the time unit. Lunar months (28 days) and 30-day months were infrequently used as well. The use of the menstrual cycle as the time unit has biological support, since there is one risk of pregnancy for each individual cycle. In the case of the pill, the use of the cycle is further reinforced by the fact that the treatment itself produces cycles and the number of cycles coincides exactly with the number of prescription units or packages provided to the woman. But when such hormonal contraceptives as long-acting injectables, mini-pills, or subdermal implants have been tested, cyclic menstrual re&arity was lost; bleeding became erratic and the definition of the cycle was left to the criteria of the physician or to the woman herself. Cycle length varied from 15 to up to 45 or more days. As a result, the 10th ordinal cycle may have been the 6th month for a woman experiencing oligomenorrhea. The use of the calendar month as the unit of time makes analysis feasible in such instances, and the comparison of cases along a time scale will be in error by only a few days. Recommendations The use of the menstrual cycles as a time unit should be strongly discouraged. Calendar months should be employed as the time unit for analyses of data in the evaluation of all types of contraceptive methods.

Confidence Limits Present Status In order to make the most meaningful comparisons between the performance of methods in different populations or the performance of different methods in the same population, it is necessary that the variability of measurement be known. This is best expressed by indicating upper and lower confidence limits. A partial survey of the literature indicated that in roughly one tenth of all studies reviewed, the data was analyzed in such a way that the confidence limits could be established and the statistical significance

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of differences between groups evaluated (19,26,36,40,43,50,55,77, 90,102,107,117,134,137,147,159,168,187). An additional one-fifth of the studies calculated averages and reported ranges. The great majority gave only absolute numbers and percentages of pregnancies and other events. It is noteworthy that some authors provide measurements of statistical significance for their basic research data but do not do the same for their clinical data. Recommendations It is recommended that clinical studies report confidence limits in all instances in which it is possible to do so.

Definition of Study Populations Present Status Comparable studies of contraceptive methods among varying populations generally give very different results in different investigations (185) because the populations are of different ages and parity, or have different exposure to coitus or some are in the post-partum period or differ in more subtle ways, such as nutritional status (8,18,34,46,66,73,78,88,104,108,109,128,130, 133,149,150,171,179,182,183,192). Recommendations In order that studies be capable of comparison and interpretation, it is essential that the demographic characteristics of the population be described. At a minimum, this should include the age and parity distribution.

III.

EVALUATION OF THE ROLE OF RESEARCH DESIGN

Protocols for Clinical Studies Present Status Many clinical trials have begun without adequate examination of objectives and without sufficient attention to the design necessary to meet the objectives. Inadequate consideration has been given to the number of subjects that will be required to answer the principal questions of the study with acceptable confidence and to the factors that may confuse interpretation of the results (3,10,23,29,137,153,158).

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Typically, research design has been limited to the decision of which data will be registered and evaluated, how frequently women will be followed-up, the day(s) of the menstrual period on which the method must be initiated, the dosage and schedule of treatment when applicable, sometimes the minimum number of women to enter the study, and the length of the observation period. However, euen this minimal design is not fully followed in many instances. In some published studies, drugs, devices, dosages and schedules are mixed and evaluated as a unit without a previous demonstration that those changes do not significantly affect performance (16,33,48,71,82,84,119,151). Criteria to enter the study such as age, previcus fertility, previous use of contraceptives, time post-partum and post-abortion and present lactation are very seldom stated (9,13,56,131,145,152,174,1~~, 189). Recommendations Before clinical studies are begun, the objectives should be carefully set forth and assigned priorities. The design should be reviewed with statisticians who can advise on design and on factors necessary to meet the minimum objectives as well as with medical peers who can aid in identifying the pertinent medical factors that should be studied to provide adequate data on safety and side effects and that would bear on correct interpretation of the findings.

Selection of Subjects Present Status It is frequently obvious that inadequate criteria for subject selection in clinical tests of contraceptives has been used in that women of unproven fertility, women with less or no sexual contact, and women over 45 are included and given the same weight as other subjects (17,63,85,106). Even if such extremes are avoided, supposedly equivalent groups may vary greatly in identifiable factors that dispose to pregnancy or side effects. One evident solution to this problem is to break the total group into more homogeneous subgroups in the final analysis of data. As one method of facilitating comparison between studies, Reinke and Baker (122) have proposed a "multisort technique". 'Ihistechnique adjusts for the distortion deriving from the fact that certain sub-groups defined by age, parity, marital status or socio-economic level have higher or lower rates of

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pregnancy or other events. The method gives appropriate weights for each group in accordance with the percentage of that group in the study population (60,122). Recommendations Research protocols should carefully define the criteria used for accepting subjects into the study in light of the objectives of the study. Subjects should be described in terms of age, parity, marital status, socio-economic level, and other factors bearing on performance and the final data analysis should define changes in event rates associated with these variables.

Comparisons between Methods Present Status An ultimate objective of most studies is that of determining whether a given method performs better or worse than alternative methods and in what respect. Seldom is there reason to ask whether a contraceptive method gives greater protection against pregnancy than would no method at all. There is, however, frequent questions as to how many of the side effects would be observed even if placebos were given. Much as one would wish to know the answer to this question, there is seldom ethical justification in administering placebos to patients desiring protection against pregnancy. Comparisons between methods of similar appearance can, however, frequently be conducted on a randomized, double-blind assignment basis (41,50,53,54). This obviously allows much more meaningful comparisons than does comparisons with studies on other methods conducted at other sites or at other times at the same site. Sometimes, of course, the differences between methods are so obvious that the conduct of a randomized double-blind study is impossible. This is the case for comparison of a mechanical device with a drug or sometimes even for comparisons between different mechanical devices or for comparisons between materials given on widely different dosage schedules (62,92,101,111,127,176, 177). The comparison of the performance of groups studied at different times is particularly questionable (25,44). Changes in general knowledge, in attitudes towards contraception and in the availability of alternative methods are occurring so rapidly that a comparison of two studies conducted a few years apart can be quite misleading.

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As discussed above, collaborative studies in which the experience at several different sites is summed together provide measures of effectiveness and side effects over a wider range of variability of patient characteristics and of investigator bias than does any single study. Such studies therefore, give a better picture as to what is to be expected in general use than does the study at a single site. Recommendations Wherever possible, randomized double-blind studies should be used as a basis for comparing contraceptive methods. Where this is not possible, every effort should be made to run comparisons under as parallel circumstances as possible. Comparisons between groups studied several years apart should be viewed with skepticism. Multi-investigator, multi-site collaborative studies are especially useful in predicting performance under conditions of actual use. Comparison between Physicians versus Paramedical Prescription of Methods or Insertion of IUDs Present Status There is a clear need for transferring a larger proportion of family planning responsibilities from physicians to paramedical personnel. Several publications described comparative studies of physicians versus paramedical personnel prescription of pills or insertion of IUDs (110,132). Nevertheless, at least in some cases, the comparison may be seriously biased because the more difficult or complicated cases and border-line indications are referred to the physicians. Recommendations The continuation of use and side effects observed in women using contracept&ves prescribed or inserted by auxiliary personnel should be compared with similar groups of users under physicians' care. Attention should be given, in such studies, to avoid introduction of bias by reason of referral of difficult or complicated cases from paramedics to physicians.

Follow-up of Subjects Present Status The loss of large numbers of subjects who fail to return for follow-up visits renders the interpretation of any study uncertain (170).

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Most of the times, even the number and percent of such patients is not mentioned. Recommendations It is recommended that telephone, mail, mass media or even home visits be utilized to try to keep loss-to-follow-up under 10% of the patients entering the study of one year duration and percent of such patients should always be mentioned.

IV.

SOME SPECIFIC PROBLEMS IN CONTRACEPTIVE METHOD EVALUATION

Evaluation of Subjective Side Effects Present Status The evaluation of side effects which can be objectively measured gives rise to the relatively simple problems of assuring standard procedures and measurements (105,154,188). Subjective side effects are very much more diffiault to evaluate quantitatively, and accordingly, give rise to more complex problems. One alternative is to present the women with a detailed questionnaire in which she is asked if she had any of the listed complaints; another is to simply record the side effects reported spontaneously by the subject. There is no doubt that the checklist approach yields a higher incidence of side effects than results from spontaneous reporting (1,38,51, 59). The difficulty is that the significance of side effects listed by the check sheet becomes most difficult to evaluate. In one study of side effects associated with placebos (121), placebo pills "caused" a 30% decrease in libido and a 16% incidence of headaches. It is, of course, also true that without a check sheet, women are likely to forget the less impressive problems they had some days, weeks or months before. The second problem is the change of frequency of some side effects with time of use. It is often reported that a complaint is found in a high proportion of users in the first month but that it decreases in frequency as time passes (42,68). This may represent a real decrease in frequency or it may represent patient selection with a disproportionate share of those who experienced the symptoms discontinuing.

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A third problem is evaluation of side effects of low frequency but extreme seriousness such as carcinoma or thromboembolic disease. The difficulty is further compounded by the fact that some conditions, such as carcinoma, develop only at long intervals after the initial exposure (142). Recommendations The need for better means of evaluating and interpreting subjective side effects is evident, and research on such methodology should be encouraged. In the meantime, it seems best to record subjective side effects only if spontaneously reported by the subject, except in special studies where a suitable placebo group can be included. When side effects appear to change in frequency with time of use, the data should be further analyzed to determine whether it represents a real change in incidence among continuing users or an apparent change resulting from a more rapid dropout rate among those subjects who experience the side effects. Continuing research on indicators of serious complications that occur only with low frequency is to be encouraged. Planning, support, and conduct of long range, prospective epidemiological studies in connection with all methods that obtain wide-scale use should be strongly encouraged.

Recovery of Fertility after Discontinuation Present Status Women or couples choose the use of reversible methods with the idea of planning their families at will. This includes the possibility of having a baby if desired by simply discontinuing the use of contraceptive methods. Nevertheless, no sufficient studies have been done to demonstrate that reproductive capacity is fully recovered after short-term or long-term use of contraceptives, including some that are currently widely prescribed (52,65,67,87, 89,96,100,115,135,140,156~193). Recommendations There is a need for more comprehensive studies of recovery of fertility after various periods of use of the different contraceptives. They should give attention not only to conception but to the outcome of the pregnancy and the characteristics of the newborn.

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Measurement of Effects on Bleeding Patterns Present Status Newer fertility control agents such as depo injections or continuous, low-dose oral administration of progestins greatly modify bleeding patterns and yield complete distortion of menstrual cycle in a large proportion of cases (3,4,22,28,31,36, 43,47,64,81,95,125,126,138,139,141,143,155,172,173,180). In spite of this,most investigators continue to analyze bleeding patterns within the framework of a cyclic phenomenon trying to distinguish between "menstrual" and "intermenstrual" bleeding according to various unstandardized criteria. Based on arbitrary decisions on which bleeding is menstrual and which is not, length of cycles are estimated and more or less complicated statistical analysis are done without much consideration of the weak nature of the original data. In the case of oligo-amenorrhea the concept of cycle is further confused; one author may interpret a period of 90 days without bleeding as two 45-day "cycles" of amenorrhea, but for another it will correspond to three 30-day amenorrhea "cycles". Whatever the interpretation, they insist on treating a non-cyclic phenomenon as if it was actually cyclic (10,12,14,24,82,117). This problem has long been acknowledged (20,32,49,58,97,172,180), but only recently have there been attempts to find more objective procedures for analysis of bleeding data (21,98,129,136,148). Recosnnendations An objective procedure for the collection and analysis of data should be developed, in which no subjective, arbitrary definition is used, and no action is taken trying to force the bleeding experience into a cyclic framework. The method should collect the data through a standardized procedure and input them into a system of analysis without intending any subjective pre-interpretation or labeling in clinical terms. The analysis along time should not fall back on the 28-30-day cyclic concept but study each case through a more prolonged period of time.

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Evaluation of Acceptability Present Status Although the evaluation of acceptability is listed as an objective in many clinical trials (70,144,163), the methodology for its evaluation is still in a primitive state. This is in spite of the fact that, demographically, acceptance of a method is usually more important than its relative contraceptiveness in determining its effects on population growth. Reports of acceptability usually are confined to the investigator's impression that it is "well accepted", "very well accepted", and the like (23,37,57,74,91,93,95,99,103, 116,123,137,160). Besides being non-quantitative, such interpretations are frequently confined to impressions of "primary acceptability". Primary acceptability can be defined as the patient's initial choice of a contraceptive after having been informed about the different methods available, but without having personal experience with each method. This choice will be influenced by the information the patient has received and will, therefore, reflect in varying degrees the bias of the clinic personnel. "Secondary acceptability" represents choice or continuing use by the patient after personal experience with the method (36, 61,81,86,124,186,191). In this instance, the clinical characteristics of the contraceptives and quality of care in the clinic will be factors influencing secondary acceptance. Secondary acceptance in such an instance will, of course, also be a relative matter and will depend upon the alternative methods available. In very carefully controlled comparative studies, continuation rates can serve as indicators of secondary acceptability. Continuation of use is indeed the prime measure of interest from the point of view of the demographic effectiveness of a given contraceptive method (184 Nonetheless, continuation rates are frequently not estimated or reported in clinical trials of contraceptives. Recommendations There is urgent need for the development of suitable methodology for measurement of both primary and secondary acceptabilities. Continuation rates should be determined in all clinical trials of contraceptives.

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Communication of Results of Clinical Studies Present Status There is a general prejudice against publication of negative results. It is indeed true that negative findings often permit only the most tentative conclusions because studies that give such negative results will usually be aborted early and the number of subjects and the period of observation will accordingly be relatively small. Notwithstanding these attitudes and factors, early publication of results of clinical studies whether positive or negative does serve a very useful purpose. Positive results will stimulate other investigators to initiate trials of their own, thus speeding the evaluation of contraceptive candidates (27,30,35,95,120,190). More importantly, however, early publication of negative findings will alert investigators to proceed with care (164). In some instances, failure to publish negative findings results in the repetition of the same research by different investigators, with each believing he is attempting the approach the first time. In such cases, even if each of the individual papers must be regarded as preliminary and the conclusions as highly tentative, the combined evidence from several such investigations may assume sufficient weight to permit relatively firm conclusions. Ethical responsibility to patients requires early communication of high pregnancy rates or undesirable side effects so that the exposure of other subjects to such risks can be minimized. Recommendations It is recommended that preliminary clinical findings, especially findings concerning potential health hazards, be routinely published. Such publications should, of course, be appropriately qualified as to the preliminary and tentative nature of their findings.

V.

DISCUSSION

Throughout this paper, recommendations have been made calling both for greater standardization and for the development of new methodology in clinical testing, data analysis and research design. This review of the critical aspects of the methodology presently used, does not pretend to be complete and exhaustive, but intends to point out at least the most crucial problems leading to confusion, misinterpretation or delay in the progress of clinical contraception research.

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&velopment of new and better contraceptive procedures is a continuous and urgent plea from the field and a very painstaking, time-consuming and extremely complicated task. The lack of a careful, scientific and standardized procedure for clinical evaluatipn makes it even more difficult. A lot of time, funds and efforts are spent on unintended false leads, resulting from poorly designed and/or analyzed clinical trials. Another dimension of the problem of immediate practical consequences, is that published results are many times accepted as medical rules by clinicians who are not supposed to make a critical analysis of the papers they read so as to accept their results as universally valid, relatively or partially valid, or not valid at all. It is not then inmaterial or of mere academic interest to worry about the need for the development of new standardized methodology in clinical testing data analysis and research design. To reach this aim, we would like to suggest a few possible immediate steps: 1) Technical assistance, consultation or advice should be made available to clinicians involved in contraceptive research who are aware of their need for assistance in the different stages of clinical research. 2) Training Programs on Reproduction in Family Planning should include research methodology in their curriculae giving a higher priority to clinical investigations, which are usually not mentioned at all. 3) Supportive agencies should place greater emphasis on providing technical advice or assistance to their grantees, in order to improve the quality of clinical research up to as good a standards as are usually found in biological and social investigations in reproduction. 4) The critical aspects described here should be the subject of discussion in every forum (congresses, seminars, symposiums) attended by clinical investigators on contraception, 5) Journals' editors and reviewers also have the important role of giving advice to authors when reviewing the drafts of clinical studies submitted to them, and of encouraging the publication of papers on clinical research methodology.

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6) At international level, resident advisors and people responsible for international programs at universities and other institutions, should be more cautious when encouraging clinical research without the provision of as much assistance as necessary, in the form of direct consultation or training of the investigators involved. If those needs are not satisfactorily fulfilled, great efforts and resources will continue to be spent to produce results often of doubtful validity and impossible to compare with parallel experiences in the same field.

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Apelo,R. and Veloso,I. Clinical experience with micro-dose d-Norgestrel as an oral contraceptive. Fertil.Steril. 24:

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Aznar-Ramos,R., Giner-Vel&quez,J., Lara-Ricalde,R. and MarfinezManautou,J. Incidence of side-effects with contraceptive placebo. Amer.J.Obstet.Gynec. 105: 1144, 1969.

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Balakrishnan,T.R., Allingham,J.D. and Kantner,J.P. Analysis of oral contraceptive use through multiple decrement lifetable techniques. Demography 7: 459, 1970.

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Balin,H., Wan,L.S. and Rajan,R. Sequential approach to oral contraceptive therapy. Int.J.Fertil. 14: 300, 1969.

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