"You can’t always get what you want": from doctrine to practicability of study designs for clinical investigation in endometriosis

The scenario emerging from this survey investigation conducted on a study population
of Italian women with endometriosis, poses fundamental questions to clinical investigators
in this specific area of research. In fact, only a small minority of patients would
accept enrollment in a RCT on the treatment of pelvic pain. If this situation is not
limited to our referral centre, generalizability of results of trials might be prevented
even when planning multicentre studies in order to overcome difficulties in recruitment.
In fact, the external validity of trials conducted on extremely selected study groups
would be low, limiting the possibility of extrapolating findings to a broader, heterogeneous
population.

Moreover, a comparison between medical and surgical therapy would be practically unfeasible,
thus confirming that patients are not prone to be casually allocated to very different
options 25]–30]. This could potentially further distort the evidence, as only selected RCTs could
be conducted (i.e., between two different medical treatments, but not between a medical
and a surgical treatment), thus preventing complete assessment of all available interventions,
as previously suggested 31].

Women appear nowadays much better informed than in the past, and wish to discuss treatment
alternatives and to choose the option that best fits with their personal needs and
expectations. In a sense, randomization impedes this tailored choice. This is confirmed
by the fact that the most frequently selected option on both questionnaires was the
patient preference trial. In other words, only some patients seem to be still willing
to participate in clinical research and, in most cases, at their conditions, not at
investigators’ conditions. In particular, 95 % of participants in our survey would
decline blinding.

A potential drawback of our study lies in the characteristics of our participants,
who are self-referred from the entire country, and sometimes have already undergone
unsuccessful medical treatments or surgical procedures. Possibly, they might have
a higher than usual level of knowledge on their disease, and of information on centers
of expertise. It could be argued that this type of survey should be conducted only
on women who have never been previously treated medically or surgically. Yet, this
collides with the possibility of obtaining a definite diagnosis in most patients.
Moreover, a laparoscopy performed with diagnostic purposes, eventually means treating
that patient surgically in case endometriosis is found, as it would be unethical to
visually confirm endometriosis without excising the lesions. In addition, the pattern
of answers was not different in the 301 women who had already undergone a surgical
procedure and the 199 who were never operated, thus questioning the impact of previous
treatment on the study outcome. Finally, a misdiagnosis bias in the latter group appears
highly unlikely, as the diagnosis of endometriosis was based on robust clinical, ultrasonographic,
and histological evidence 32]. As study participants were all assisted by the National Health Service, a potentially
spurious association between socioeconomic status and propensity toward participation
in clinical research can be safely ruled out. More in general, clinical investigation
is usually conducted in tertiary care centers thus this appear to be the type of population
that would be considered for recruitment in a RCT anyway.

The groups of women that would accept or decline randomization in a trial on medical
treatment did not differ significantly. However, our study was not originally powered
to investigate the distribution of baseline characteristics between the two subgroups
of women. Indeed, the number of participants was large and women were recruited consecutively,
thus limiting the possibility of selection bias. Patients were carefully instructed
about the different types of experimentation, on the objective of the present survey,
and on the hypothetical nature of our inquiry, which would not have implied future
obligations. They were allowed to ask questions and obtain clarifications by dedicated
medical personnel. In addition, the compilation of the two questionnaires was very
simple and could be performed rapidly. This helped avoiding refusals to participate
in the survey.

Women could not select more than one option. This can be considered as another weakness
of our survey and may explain why the patient preference trial was the most popular
choice. Allowing women to choose more than one study design option, and structuring
questions in a less “leading” format, would have probably helped clarifying whether
randomization was absolutely unacceptable or would be a possibility.

Several investigators recently focused on the growing barriers to the conduct of RCTs,
describing in details the types of impediments and suggesting different modalities
to overcome unnecessary obstacles 5]–8]. On the other hand, estimates of effect size in large observational studies may be
precise, but remain substantially weakened by bias and confounding that only random
allocation can control 8]. Indeed, the problem here is different: in spite of all shareable methodological
considerations, RCTs in the endometriosis area appear increasingly difficult to conduct,
at least in Italy, specifically because the vast majority of patients would decline
random allocation.

The adoption of the partially randomized patient preference trial design, in which
participants who do not accept randomization are allowed to chose their preferred
intervention 33], 34] or of the response-adaptive randomization trial design, in which the ratio of participants
assigned to each arm are actively adjusted in favor of the better performing intervention
based on already available data of patients previously recruited 35], does not seem to overcome the basic issue of unwillingness to accept randomization.
In any case, the resulting group of women allocated by chance would be too small to
be representative of the population of women with endometriosis. Moreover, the administrative
burden and the costs would be substantially the same as for the standard two-arm clinical
trial design.

To complete their studies, several investigators conducted part of the trial based
on random allocation of treatments, and part based on patient preference 25], 26], 29], 36]. Interestingly, more patients generally chose the patient preference option than
the random allocation one. Moreover, both the estimates of effect size and its precision
were substantially similar in the two study populations 25], 26], 29], 36]. Additionally, it has been reported that the results of well-designed observational
studies are generally similar to those of formal RCTs 37], 38]. Therefore, when preferences based on informed expectations exist, observational
methods may be an alternative to RCTs 39], 40].

When the objective is the comparison of already approved treatments for endometriosis
(i.e., phase IV studies, thus excluding truly novel, experimental interventions),
observational studies are easier and less costly to conduct than RCTs, can be carried
out in “real world” patient populations, and can be prolonged for longer periods on
a large number of participants, thus providing robust evidence on safety of interventions
2]. As treatments are not allocated randomly, multivariable statistical models must
be adopted to control for potential bias and confounding factors. The physician’s
selection of patients who should receive the treatment constitutes one of the main
confounders in observational studies. Therefore, it is important to try to limit this
bias. Considering the two hypothetical comparisons of our survey, two different study
designs could be adopted when RCTs appear unfeasible.

When large differences exist in the type of treatments to be compared and in associated
morbidity (in our survey, medical versus surgical treatment), the patient preference
trial might constitute a practical alternative. Differently from an observational
study comparing two case series, where clinicians allocate treatments, in the patient
preference, parallel cohort trial, treatment allocation is by patient choice. Whereas
clinicians may be prone to recruit different types of women to the two study arms,
allocation by the patients themselves should improve external validity. It has been
suggested that preference-based treatment allocation may optimize cost-effectiveness
of intervention 41], also because this research environment may be more similar to practical life conditions
33]. In case of functional outcomes, a comparison between two groups of participants
who have chosen their treatment emphasizes patient satisfaction, thus representing
the maximum possible effect size of the intervention 42]. However, a major selection bias is introduced in a study based completely on patient
preference, thus limiting the interpretation of the findings. Moreover, the effect
observed under these conditions can be referred exclusively to patients who specifically
choose that treatment 43].

When two similar treatments are being compared (e.g., a new versus an old progestin,
or a progestin versus a combined oral contraceptive), the patient-preference trial
design does not seem suitable, as women may not be able to clearly express a definite
preference. In these cases, the before and after study (or pre-post study), a quasi-experimental
design, may be an option 44]. The before and after study is usually adopted at a system level (clinics, hospitals)
to compare outcomes before and after an intervention is implemented 45]. A before and after study design could be used also to evaluate treatments, provided
some conditions are satisfied. In this case all new cases of patients with symptomatic
endometriosis would receive the same, standard medical therapy for a pre-planned period
of time, at the end of which all new cases with the same clinical characteristics
would receive the new medical treatment for the same period of time. The study gauges
the difference in the effect of the new drug compared with that of the standard one.

In order to infer that a variation in outcomes is the consequence of the implementation
of the new treatment, the characteristics of the participants in the “before group”
must be similar to those in the “after group”, otherwise such inference would be seriously
flawed. In order to avoid a selection bias, all eligible patients observed before
the introduction of the new intervention must be included in the “before group”, the
new treatment must be implemented at a precise time point, and all eligible patients
observed after that cut-off time must use only the new treatment and be included in
the “after group”. Any admixture of different treatments during the study period would
invalidate the findings. There should also be no evidence of a prevailing temporal
trend. Still, without a control group of patients in whom no variation in the intervention
has been implemented, it may reveal difficult to ascribe differences in outcomes to
the change of medical treatment. Moreover, only random allocation of treatments allows
genuine comparability of the study groups. In a before and after study, even a modification
in referral pattern during the study period may result in the creation of populations
that may differ for several characteristics, such as severity of symptoms or type
of lesions. Since it is unlikely to be able tocontrol for all known and unknown characteristics
that may influence the outcome, it may not be possible to exclude that any observed
between-group difference in a before and after study is due to confounding 45].