Jalal Maghfour,Vivian Liu,Angela Parks-Miller,Iltefat H. Hamzavi
Evaluating the Impact of Exclusion Criteria on the Generalizability of Hidradenitis Suppurativa Treatment Research
Exclusion criteria can limit the generalizability and translation of research findings into clinical practice. The objective of this study is to characterize the trends of exclusion criteria and explore the impact of exclusion criteria on participant diversity, length of enrollment, and the number of enrolled participants. A detailed search was performed using PubMed and clinicaltrials.gov. Nineteen published randomized controlled trials were included, where 2,664 patients were screened, and 2,234 patients (mean age: 37.6 years, 56.6% female) were enrolled from 25 countries. On average, there were 10.1 (standard deviation: 6.14, range: 3−25) exclusion criteria per randomized controlled trial. There was a weak to moderate positive correlation between the number of exclusion criteria and the proportion of enrolled participants (R = 0.49, P value = 0.040). However, no association was seen between the number of exclusion criteria, number of enrolled Black participants (R = 0.86, p value = 0.08), and enrollment length (R = 0.083, P value = 0.74). In addition, there was no discernable trend in the number of exclusion criteria over time (R = −0.18, P value = 0.48). Although the number of exclusion criteria appeared to impact the number of enrolled participants, the lack of skin of color representation in hidradenitis suppurativa randomized controlled trials does not appear to be influenced by the number of exclusion criteria.
Evaluating the Impact of Exclusion Criteria on the Generalizability of Hidradenitis Suppurativa Treatment Research

Exclusion criteria can limit the generalizability and translation of research findings into clinical practice. The objective of this study is to characterize the trends of exclusion criteria and explore the impact of exclusion criteria on participant diversity, length of enrollment, and the number of enrolled participants. A detailed search was performed using PubMed and clinicaltrials.gov. Nineteen published randomized controlled trials were included, where 2,664 patients were screened, and 2,234 patients (mean age: 37.6 years, 56.6% female) were enrolled from 25 countries. On average, there were 10.1 (standard deviation: 6.14, range: 3−25) exclusion criteria per randomized controlled trial. There was a weak to moderate positive correlation between the number of exclusion criteria and the proportion of enrolled participants (R = 0.49, P value = 0.040). However, no association was seen between the number of exclusion criteria, number of enrolled Black participants (R = 0.86, p value = 0.08), and enrollment length (R = 0.083, P value = 0.74). In addition, there was no discernable trend in the number of exclusion criteria over time (R = −0.18, P value = 0.48). Although the number of exclusion criteria appeared to impact the number of enrolled participants, the lack of skin of color representation in hidradenitis suppurativa randomized controlled trials does not appear to be influenced by the number of exclusion criteria.

Hidradenitis suppurativa (HS) is a chronic and debilitating skin condition characterized by recurrent nodules, abscesses, and tunnels primarily in intertriginous sites. It has a global prevalence of around 0.00033−4.1% and a 0.7 and 1.2% prevalence in the United States and Europe, respectively. On the basis of the United States estimates, the prevalence of HS among African Americans and Whites is 0.30 and 0.10% respectively (Nguyen et al., 2021). Comparable results were reported in a study conducted by Garg et al. (2017) in which authors revealed that the incidence of HS was 2.5 times higher in African Americans than in whites (30.6 [95% confidence interval = 29.1−32.2] per 100,000 vs. 11.7 [95% confidence interval = 11.3−12.2] per 100,000; P < 0.0001). Even though minorities, particularly Blacks, are disproportionally affected by HS (Lee et al., 2017), this prevalence is not reflected in recent randomized controlled trials (RCTs). According to a recently published study, Black patients make up only 14% of HS RCTs, whereas White patients comprise 68% of the participants (Price et al., 2021). Barriers to clinical research are multifactorial, with a recent study showing that fear, a lack of trust in the healthcare system, and limited information about clinical research are the main factors impeding minority individuals from participating in clinical research (Hughes et al., 2017). Clinical research can influence clinical practice and disease management, particularly for a condition that continues to represent a therapeutic challenge. Whether such treatment measures can be applied to clinical practice is based on the similarities between research and the general population affected by the disease which is influenced by the exclusion criteria in treatment research. Previous studies have shown that extensive exclusion criteria can limit the generalizability and translation of research findings into clinical practice. Specifically, RCTs with extensive exclusion criteria can result in research samples that do not represent the diversity and complexity of the clinical population (Anand et al., 2003; Baquet et al., 2006). This is of clinical importance for a disease that disproportionally affects SOC patients. In this study, the aim of this review is to examine the exclusion criteria of all published HS RCTs, characterize the most commonly used exclusion criteria, and explore the impact of exclusion criteria on participants 'diversity, length of enrollment, and number of enrollement.

A total of 112 records were identified, of which 79 were non-duplicated reports. Of the 79, 19 (24.1%) met the inclusion criteria (Figure 1) (Adams et al., 2010; Alavi et al., 2022; Bechara et al., 2021; ClinicalTrials.gov, 2021; Fajgenbaum et al., 2020; Glatt et al., 2021; Grant et al., 2010; Grimstad et al., 2020; Kanni et al., 2018; Kimball et al., 2016, 2012; Kirby et al., 2021; Mahmoud et al., 2010; Prens et al., 2021; Scheinfeld et al., 2016; Tzanetakou et al., 2016; Vossen et al., 2019a, Vossen et al., 2019b). Forty articles were excluded during the title and abstract screening for the following reasons: (i) non-RCT study design, (ii) nonhuman study, (iii) articles written in languages other than English, and (iv) RCTs not registered on a clinical trial website. Of note, one study reported two distinct RCTs (Kimball et al., 2016). As such, a total of 19 RCTs were included in this review. Of these, 11 (57.9%) studies reported race data. A total of 2,664 participants were screened, with 2,234 (420 excluded) participants (mean age of 37.6 ± standard devidation [SD]3.34 years, 56.6% female) enrolled from 25 countries. There were 16 RCTs that assessed the efficacy of interventions on adult patients with HS, whereas two RCTs assessed the efficacy of interventions on both pediatric and adult patients with HS. Biologics (15 [78.9%]) were the most common intervention assessed in the included studies. Among biologics, adalimumab was assessed in five (26.3%) RCTs. The enrollment period ranged from 2005 to 2020, and the average length of enrollment was 20.2 ± [10.5] months.

Participants with HS were enrolled globally. As illustrated in Figure 2, the regional distribution of HS RCTs was as follows: Europe, n = 12 of 19 (63.2%); North America, n = 14 of 19 (73.7%); Australia, n = 2 of 19 (10.5%); and Asia, n = 3 of 19 (15.8%). Eight studies were multicenter multinational clinical trials (Table 1).

Race was reported in 11 (57.9%) of the 19 included RCTs (Figure 3a), of which 9.9% (328 of 1,319) of participants were skin of color (SOC) patients. The race of 1,319 participants was reported, of which 1,189 (90.1%) were Whites, 214 (16.2%) were Blacks, 4 were Native Americans (0.3%), 3 were Asians (0.2%), and 90 (6.8%) were other/unspecified (Figure 3b). There were two studies that reported race-specific findings for one European country (Vossen et al., 2019a, 2019b). In these two published reports, 23 patients (82.2%) were White, three (10.7%) were Black, one (3.5%) was Asian, and one (3.5%) was Native American. Of the six studies conducted solely in the United States, only two (Adams et al., 2010; Fajgenbaum et al., 2020) (33.3%) reported race data, of which 39 (45.4%) participants were White, 33 (38.4%) were Black, 11 (12.8%) were Hispanic, and three (3.5%) were unspecified/other (Figure 3b). With regards to the enrollment patterns of Black participants, the period between 2010 and 2013 exhibited the highest enrollment of Black participants (14 [29%]), whereas the period between 2018 and 2021 was characterized by the lowest enrollment of Black participants (69 [10%]). In comparison, we identified an increased trend in the enrollment of White participants (Figure 4). In addition, the number of exclusion criteria did not correlate with the proportion of enrolled Black participants (R = 0.86 P = 0.08) (Figure 5a).

Exclusion criteria were reported in all the 19 RCTs. On average, there were 10.1 [± 6.14], range (=3−24) exclusion criteria per RCT. Justification for the choice of exclusion criteria was not provided in any of the RCTs. The most frequently reported exclusion criterion was a history of using antibiotics or biologics/immunomodulators used in the 6 months before the study initiation (n = 12, 63.2%). The second most commonly reported exclusion criterion was a history of recurrent and/or active infection or a previous infection requiring intravenous antibiotics (n = 10, 52.6%). This was closely followed by a history of neuromuscular disorders and/or demyelinating disease (n = 9, 47.4%) and a history of tuberculosis, hepatitis B virus, hepatitis C virus, or human immunodeficiency virus (HIV, n = 9, 47.4%). Other commonly reported exclusion criteria that we identified include female participants who were pregnant and/or lactating during study enrollment (n = 8, 42.1%), those with a history or evidence of malignancy (n = 8, 42.1%), those with current skin conditions that could interfere with the assessment of HS (n = 6, 31.6%), and those with a history or evidence of cardiovascular disease (n = 6, 31.6%). Of note, it was not specified which specific skin conditions could interfere with the assessment of HS lesions. The number of exclusion criteria did not correlate (R = 0.63, P = 0.127) with enrollment length (Figure 5b) but appeared to moderately correlate with the number of participants in each study (R = 0.49, P = 0.040) (Figure 5c). In addition, there was no significant trend in the number of exclusion criteria over time (R = −0.18, P = 0.48) (Figure 5d).

In this review, we sought to examine the current trends in the exclusion criteria of HS RCTs. Fifteen (83.3%) studies involved the use of biologics, and past studies on their safety have led to the exclusion of participants with serious infections (e.g., tuberculosis, hepatitis B virus, hepatitis C virus, and HIV), significant cardiovascular diseases, and recent malignancies and pregnant participants. Clinical trials of certolizumab have also resulted in the exclusion of patients with multiple sclerosis from RCTs involving biologics. Biologic agents have become widely used in the treatment of moderate-to-severe HS. Although they remain one of the most effective treatment modalities, they are associated with higher rates of adverse events than other forms of therapy. However, recent studies have shown that biologic agents may be considered appropriate treatment options for a select group of patients (Hsu and Tsai, 2020), suggesting that fewer exclusion criteria are necessary. In our study, one of the most common exclusion criteria was any woman who was pregnant or lactating. Although certain biologics such as ADA are currently considered pregnancy category B, a recent study reviewing records of 524 pregnant patients on ADA showed no significant difference in the rate of miscarriages from a disease-matched control. Studies have also documented no adverse effects on nursing infants (Freyer, 2009; Fritzsche et al., 2012) as ADA has been shown to be excreted in breast milk in very low concentrations (Collier et al., 2021). The data on the safety profile of biologics highlight that they have a better safety profile; therefore, future exclusion criteria should reflect this trend. Although previous studies (Huls et al., 2018) showed that stricter exclusion criteria limit the number of enrolled participants, this pattern was not seen in our study. Interestingly, we found a weak to moderate positive correlation between the number of exclusion criteria and the proportion of enrolled participants. This finding may be due to the fact that trials with more exclusion criteria also had greater numbers of participating trial sites to recruit participants. Studies that put forth more exclusion criteria may also anticipate greater difficulty in recruiting participants and thereby attempt to increase efforts at recruiting participants. With regards to the impact of exclusion criteria on participants' diversity and length of enrollment, our results suggest that the number of exclusion criteria did not impact those two variables. Even though the number of exclusion criteria was not associated with the proportion of enrolled Black participants, a significant limitation of the included RCTs is the lack of data on the demographics of excluded participants. We also found that having a history of significant infection or previous use of intravenous antibiotics was the second most frequently reported reason for excluding participants. In a recently published review on pancreatic cancer trials, it was noted that the exclusion criterion that predominantly contributed to the exclusion of Black participants was a history of HIV, hepatitis B virus, hepatitis C virus, and serum albumin levels (Samson, 2021). Therefore, it can be speculated that this type of exclusion criterion may have played a role in the underrepresentation of Black participants in HS RCTs. Between 2010 and 2021, we did not identify any discernable correlation between exclusion criteria and the number of enrolled Black participants (Figure 4). It is noteworthy that the highest enrollment of Black participants was observed in 2019 and 2020. However, the total number of enrolled participants in these studies was only 8 and 48, respectively, representing some of the lowest enrollment across all of the included RCTs (Fajgenbaum et al., 2020; Vossen et al., 2019a, Vossen et al., 2019b). Other than these two studies, the overall enrollment of Black participants remained consistently low across all clinical trials that reported race data. Given that there was no discernible trend between the number of exclusion criteria and the enrollment of Black participants, exploring whether type of exclusion criteria impacts the enrollment of minority participants is of clinical importance and merits further investigation. One of the major limitations of the study is that the majority of RCTs were conducted in Europe. As such, the population of people with SOC may not be as prevalent as that of the United States. Furthermore, because so few RCTs reported race data, it was difficult to draw conclusions from these studies. In addition, the missing demographic data regarding excluded participants limits the interpretation of this study. In clinical trials, participants who are excluded owing to ineligibility are considered screening failures (Elm et al., 2014). Although previous attempts have been made to standardize the collection of screening data, the differences in site processes and the nature of multicenter trials make it challenging to collect and analyze unifying data across clinical studies (Elm et al., 2014). It is therefore not surprising that many clinical trials do not report screening failures. Finally, there is no clear definition of 'screened ', which creates challenges in collecting important patients information (e.g., gender, ethnicity). This in turn impedes the ability to assess the generalizability and selection bias of clinical studies. Given the importance of identifying specific reasons that may contribute to the low enrollment of patients with SOC, we believe that it is essential for clinical trials to consistently and accurately collect and report screening data, which can serve as an early indicator for evaluating a center’s performance in a trial. Addressing barriers to enrollment needs to be approached from different fronts, and studies have shown that study design, enrollment sites, individual barriers, and social health determinants are the major players. Although the exclusion of some participants is inevitable, it is important to improve the transparency process regarding participants’ eligibility and the reasons why participants are excluded. This can be accomplished through effective and open communication with participants and active patient involvement in trial design. Participants’ active engagement is essential because it can lead to trial designs specifically focused on addressing outcomes that are important to patients, which in turn may result in greater patient enrollment (Van Spall et al., 2007). As evident in this study, people with SOC remain vastly underrepresented in HS research. Despite the paucity of data examining the factors that may explain the low enrollment of minority patients in dermatology research, emerging evidence revealed that successful recruitment of SOC patients in clinical trials relies on the implementation of community-based interventions (Heller et al., 2014). In a study conducted by Duda et al. (2011), investigators examined the impact of strategic planning (e.g., conferences, involvement of key stakeholders, and community organizations) on minority enrollment. Compared with institutions that did not implement strategic planning, those who did experienced a significant increase in the enrollment of minority participants in clinical trials. This finding highlights the importance of increasing clinical trial awareness and bridging community trust as important elements in the enrollment of minority participants. Addressing attitudes that deter physicians from discussing clinical trials with minorities is also essential because previous research has shown that implicit bias impacts physician−patient interactions. In one study (Moskowitz et al., 2011), it was shown that primary care physicians tend to trust White patients more than they trust minority patients. In another study (Sabin et al., 2009), physicians with high implicit bias viewed their minority patients as less likely to adhere to a treatment regimen. Although there are no specific studies that examined the implicit bias of healthcare professionals as a barrier to the enrollment of minorities, findings extrapolated from other studies (Moskowitz et al., 2011; Sabin et al., 2009; Wilson et al., 2021) suggest that clinicians are more likely to offer a clinical trial to patients who they perceive as good candidates. Current evidence strongly supports the significant burden of HS on minorities, particularly African Americans. As such, it is of clinical importance to address barriers that impede the recruitment of minorities in HS clinical trials. On the basis of previous studies, we propose a multilevel interventional model that can be used to support the recruitment of underrepresented patients in clinical trials (Figure 6). This multilevel model illustrates how an institution can respond to system-level and individual-level barriers. System-level barriers may include inadequate infrastructure (e.g., limited available clinical trials; little to no support staff; cost, if any, for participating) and the lack of physician support. Individual-level barriers represent the interpersonal (e.g., attitudes/perceptions of physicians toward patients) level barriers, which can be overcome by implementing a patient-centered approach to communication (e.g., question-prompt list enabling the engagement of participants). This form of intervention has been shown to improve physicians’ attitudes and communication skills related to discussing trials with minority patients as well as reduce some of the patient mistrust of physicians and researchers and physician implicit bias toward minorities. It is important to note that the proposed multilevel interventions will be of limited benefit if they are not implemented within an appropriate infrastructure that supports trials that match the clinical characteristics of a racially and ethnically diverse patient population. In summary, there is a paucity of studies examining specific barriers that impede the enrollment of patients in dermatology research. Future studies should examine the role of these factors in the enrollment of patients with SOC in HS RCTs, consistently report race data, and adjust exclusion criteria to better match current evidence on medication safety, while also addressing other barriers to enrollment in HS RCTs.

A comprehensive search of the literature was conducted using the PubMed and Embase databases for the period from January 1964 to the present. Searches used combinations of the following terms: hidradenitis suppurativa, acne inversa, clinical trials, randomized clinical trials, and RCTs. The inclusion criteria consisted of (i) published articles designed as RCTs and evaluating a therapeutic intervention, (ii) RCTs with exclusion criteria, and (iii) RCTs with a national clinical trial number. ClinicalTrials.gov was also surveyed for additional RCTs that reported race/ethnicity data. Statistical Package for the Social Sciences software was used to investigate whether an association between exclusion criteria, length of enrollment, and participants’ diversity exists.

No datasets were generated or analyzed during the study.

IHH is an investigator for PCORI, Incyte, L’Oréal/Laroche Posay, Beiersdorf, Estee Lauder, Unigen, Ferndale Healthcare, Pfizer, Allergan, Lenicura, Avita, and Johnson & Johnson and has served as a consultant for Pfizer, Johnson and Johnson, Abbvie, Incyte, UCB, Boehringer Ingelheim, Sonoma, Union Therapeutics, Novartis, Jansen, Avita, Galderma, and Beiersdorf. JM is a subinvestigator for Biofrontera, Avita Medical, Incyte, and Clinuvel. IHH is a board member and past president of the Hidradenitis Suppurativa Foundation and Global Vitiligo foundation. APM is the founding director and board member of Hope for HS (nonpaid). The remaining author have no conflict to disclose.