Cathleen Dohrn, PhD

Nonalcoholic steatohepatitis (NASH) is a form of nonalcoholic fatty liver disease (NAFLD) that remains largely unknown among the adult population in the U.S. In the coming years, however, the prevalence of this potentially deadly disease, which can lead to cirrhosis and even liver cancer, is expected to grow significantly. According to a 2018 study,

 instances of NASH in the U.S. are expected to increase 63% from 16.52 million to 27 million cases by 2030.

	The complications associated with NASH include cirrhosis and liver cancer, with an increased chance of dying from liver-related causes. According to the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK3), studies have shown that people with NAFLD have a greater chance of developing cardiovascular disease-the most common cause of death among people with NAFLD or NASH.

	To highlight the seriousness of NASH, there currently exists no FDA-approved therapy to treat the disease. In the next five years, more than 60 sponsors

 will attempt to randomize nearly 30,000 NASH patients into clinical trials. So pharmaceutical companies face an uphill battle to both increase awareness of this disease and enroll tens of thousands of patients in NASH clinical trials.

	Of all of the challenges that sponsors face in enrolling patients into NASH studies, the biggest is lack of awareness of the disease, even among patients most at-risk-those with type 2 diabetes, obesity, and hypertension.

	Continuum Clinical conducted a survey of 1,014 adults in the U.S. and found only 2% were aware of NASH. A follow-up study of 450 adults with comorbidities associated with NASH revealed only 6% were aware of the disease.

	Continuum also found that 48% of at-risk Hispanic/Latino respondents were most concerned about liver disease versus 32% of the total population surveyed. In addition, Hispanic/Latino respondents were significantly more interested in learning about a hypothetical NASH clinical research study (62% versus 49% of the total population).

	In addition to low awareness of NASH, targeting patients for clinical trials is challenging because the disease doesn’t manifest itself in consistent, overt ways. Many times, patients with NASH are asymptomatic.

	It’s estimated that as many as 30 million Americans currently have NASH, but only 180,000 have been diagnosed. Given the average participation rate in clinical trials is around 15% of a given diagnosed population-and coupled with an 80% screen/fail rate in this condition-that means the 180,000 patients will translate into only 3,000 randomizations.

	The FDA currently requires sponsor protocols to confirm patients’ NASH diagnosis via an invasive and potentially dangerous liver biopsy.

	In order for progress to be made against this disease, pharmaceutical companies must find solutions to some of the problems posed earlier. Where are these organizations begin? How does a drug company reach out to consumers who aren’t aware of a disease that they may or may not have to enroll in a clinical trial that requires a liver biopsy for a diagnosis?

 in December, which urges the pharmaceutical industry to develop/validate better biomarkers for NASH diagnosis and progression. In many regards, getting over the biopsy hurdle rivals the lack of general awareness of NASH, which is why we believe it is important for pharmaceutical organizations to invest in innovations (e.g., a variety of imaging techniques) to allay this patient burden, and subsequently persuade the FDA with strong data to accept those innovations as suitable endpoint markers for clinical trials. To that end, many researchers are investigating such biomarkers that will be as predictive, if not more so, than invasive liver biopsies.

	This long-term solution doesn’t help the number of trials that are enrolling today, however. Addressing the gap between the diagnosed patient population and the number of patients who will be needed to fill these trials requires implementing a robust patient recruitment program.

Sponsors with designs on this therapeutic area could consider increased investment in developing unbranded disease awareness campaigns alongside patient advocacy groups; the National Liver Foundation has begun to implement such an educational campaign on its own. In addition to these education efforts, incorporating fundamental disease education into clinical trial recruitment outreach materials is critical. This is unusual but not unheard of-Continuum has in the past successfully included institutional review board (IRB)-approved education information for an unaware patient audience for a different chronic disease campaign.

	In conjunction with a broad-based disease education plan, smart web development-for example, a site that funnels disease-aware or diagnosed patients to a different landing page than unaware or undiagnosed patients-will be necessary to motivate potential patients to complete study screening.

	Specific to this are materials that target patient demographics that are disproportionately affected by NASH or NAFLD, such as Hispanic and Latino patients. Directly engaging patients locally through educational and community events is critical to connect with those individuals both before and after diagnosis. Community-level engagement, especially important to populations typically underrepresented in clinical research, will ensure NASH patients receive education and information at the right time in their journey and can make recruitment campaigns more effective.

	Despite the potentially enormous patient population, the challenges industry will face in enrolling clinical trials are daunting and unique. NASH patients are diverse, both ethnically and in their diagnostic pathway. The only way to successfully achieve the required trial enrollment numbers is to be strategic, creative, and thorough in planning both for recruitment and retention.

		Li Q, Dhyani M, Grajo JR, Sirlin C, Samir AE. Current status of imaging in nonalcoholic fatty liver disease. 

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5767767/

https://www.niddk.nih.gov/health-information/liver-disease/nafld-nash/definition-facts

https://clinicaltrials.gov/ct2/results?cond=NASH&term=&type=Intr&rslt=&recrs=b&recrs=a&recrs=d&age_v=&age=1&gndr=&intr=&titles=&outc=&spons=&lead=&id=&cntry=&state=&city=&dist=&locn=&phase=1&phase=2&fund=2&strd_s=&strd_e=&prcd_s=&prcd_e=&sfpd_s=&sfpd_e=&lupd_s=&lupd_e=&sort=

https://www.raps.org/news-and-articles/news-articles/2018/12/fda-issues-draft-guidance-on-nash-drug-development

, PhD, is the Senior Scientific Director, Continuum Clinical

Articles

Addressing the current hurdles and potential solutions in nonalcoholic steatohepatitis awareness and clinical trial enrollment.

Challenges Emerge from Low NASH Awareness

	Nonalcoholic steatohepatitis (NASH) is a form of nonalcoholic fatty liver disease (NAFLD) that remains largely unknown among the adult population in the U.S. In the coming years, however, prevalence of this potentially deadly disease, which can lead to cirrhosis and even liver cancer, is expected to grow significantly. According to a 2018 study

, instances of NASH in the United States are expected to increase 63% from 16.52 million to 27.00 million cases by 2030.

	The complications associated with NASH include cirrhosis and liver cancer, with an increased chance of dying from liver-related causes. According to the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK

), studies have shown that people with NAFLD have a greater chance of developing cardiovascular disease-the most common cause of death among people with NAFLD or NASH.

 will attempt to randomize nearly 30,000 NASH patients into clinical trials. So pharmaceutical companies face an uphill battle to both increase awareness of this deadly disease and enroll tens of thousands of patients in NASH clinical trials.

	Of all of the challenges that sponsors face in enrolling patients into NASH studies, the biggest is lack of awareness of the disease even among patients most at-risk-those with type 2 diabetes, obesity, and hypertension.

	Continuum also found that 48% of at-risk Hispanic/Latino respondents were most concerned about liver disease versus 32% of the total population surveyed. In addition, Hispanic/Latino respondents were significantly more interested in learning about a hypothetical NASH clinical research study (62% versus 49% of the total population.)

	Right now, it’s estimated that as many as 30 million Americans have NASH, but only 180,000 have been diagnosed. Given the average participation rate in clinical trials is around 15% of a given diagnosed population-and coupled with an 80% screen/fail rate in this condition-that means the 180,000 patients will translate into only 3,000 randomizations.

	In order for progress to be made against this disease, pharmaceutical companies must find solutions to some of the problems posed above. Where are pharmaceutical companies to begin? How does a drug company reach out to consumers who aren’t aware of a disease that they may or may not have to enroll in a clinical trial that requires a liver biopsy for a diagnosis?

 in December, which urges the pharmaceutical industry to develop/validate better biomarkers for NASH diagnosis and progression. In many regards, getting over the biopsy hurdle rivals lack of general awareness of NASH, which is why we believe it is important for pharmaceutical companies to invest in innovations (e.g. a variety of imaging techniques) to allay this patient burden, and subsequently persuade the FDA with strong data to accept those innovations as suitable endpoint markers for clinical trials. To that end, many researchers are investigating such biomarkers that will be as predictive, if not more so, than invasive liver biopsies.

	This long-term solution doesn’t help the number of trials enrolling now, however. Addressing the gap between the diagnosed patient population and the number of patients who will be needed to fill these trials requires implementing a robust patient recruitment program.

	Sponsors with designs on this therapeutic area could consider increased investment in developing unbranded disease awareness campaigns alongside patient advocacy groups; the National Liver Foundation has begun to do such an educational campaign on their own. In addition to these education efforts, incorporating fundamental disease education into clinical trial recruitment outreach materials is critical. This is unusual but not unheard of-Continuum has in the past successfully included IRB-approved education information for an unaware patient audience for a different chronic disease campaign.

	Specific to this are materials that target patient demographics that are disproportionately affected by NASH or NAFLD, such as Hispanic and Latino patients. Directly engaging patients locally through educational and community events is critical to connect with patients both before and after diagnosis. Community-level engagement, especially important to populations typically underrepresented in clinical research, will ensure NASH patients receive education and information at the right time in their journey and can make recruitment campaigns more effective.

 is the Senior Scientific Director, Continuum Clinical. 

		Li Q, Dhyani M, Grajo JR, Sirlin C, Samir AE. Current status of imaging in nonalcoholic fatty liver disease. World J Hepatol. 2018 Aug 27; 10(8): 530-542.	

		https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5767767/	

		https://www.niddk.nih.gov/health-information/liver-disease/nafld-nash/definition-facts	

		https://clinicaltrials.gov/ct2/results?cond=NASH&term=&type=Intr&rslt=&recrs=b&recrs=a&recrs=d&age_v=&age=1&gndr=&intr=&titles=&outc=&spons=&lead=&id=&cntry=&state=&city=&dist=&locn=&phase=1&phase=2&fund=2&strd_s=&strd_e=&prcd_s=&prcd_e=&sfpd_s=&sfpd_e=&lupd_s=&lupd_e=&sort=	

		https://www.raps.org/news-and-articles/news-articles/2018/12/fda-issues-draft-guidance-on-nash-drug-development

Cathleen Dohrn, Senior Scientific Director for Continuum Clinical, describes the momentous challenges in clinical trials presented by low awareness of nonalcoholic steatohepatitis.

Low Awareness of NASH Presents Significant Clinical Trial Challenges

	Over the last several decades, advances in biomedical and clinical research have improved the health and well-being of all people. Some of the progress has been aided by the landmark policy set forth by the National Institutes of Health (NIH) two years ago requiring investigators to consider sex as a biological variable. In fact, there is a 

 as National Women’s Health Research Day, thanks to the strong efforts of organizations like the Women’s Health Research Institute at Northwestern University. Despite this progress, a sex-bias that significantly impacts the advancement of women’s health exists in both preclinical and clinical research. Particularly, on the second anniversary of the NIH policy that requires investigators to consider sex as biological variable (SABV) in preclinical research, reflection on the recent history of women in research is warranted. 

	In the past, females have been underrepresented in research studies due to the assumption that biological sex-differences did not exist outside of the reproductive system. In addition, protectionist views towards women and the roles as mothers, perhaps well-intentioned following the thalidomide tragedy of the 1960’s, led to an exclusion of women of childbearing years in clinical trials (FDA, 1977). In 1985, a report from the U.S. Public Health Service Task Force suggested that the exclusion of women from research was detrimental to women’s health (U.S. Public Health Service, 1985). While the Federal Drug Administration (FDA) issued a preclinical guidance to include female animals in 1988, it wasn’t until 1993 that they provided the guidance that pharmacokinetics and pharmacodynamics (PK/PD), safety, and efficacy, should be evaluated in both sexes. In that same year, the NIH Revitalization Act of 1993 mandated that women should be included in all NIH-funded clinical research (NIH, 1993).

	While these guidelines applied to clinical research conducted in humans, female cells and animals remained under-utilized or unreported in basic science research. Within the last several years, a number of reports have demonstrated a sex-bias in biomedical research and advocated for policies to mandate sex-inclusion at the cellular and animal level and sex-specific analyses and reporting of data (Beery & Zucker, 2011; NIH, 2012; Woodruff, 2014; Clayton & Collins, 2014). On January 25, 2016, the NIH established a policy which requires investigators to “consider sex as a biological variable,” (NIH, 2015). While this policy does not mandate the use of both sexes in basic science research, it does require that investigators provide strong rationale for single-sex studies.

Sex and gender in preclinical and clinical research  

	In the context of preclinical and clinical research, it is essential to define both sex and gender. Sex is a biological entity, defined by the sex chromosomes and is manifested through various biochemical and cellular processes. Gender, on the other hand, is a socio-cultural construct that shapes the roles, attitudes, and behaviors associated with being male or female. Animals, cells, and humans have a sex, whereas only humans have both a sex and gender. Given that the sex of an individual can influence various biological processes, it is no surprise that various diseases and disorders impact men and women differently. For example, there are a spectrum of diseases or conditions that disproportionately affect women-for example, in the United States, women:

	· make up almost two-thirds of the Alzheimer’s Disease population (Alzheimer’s Association, 2018);

	· are three times more likely to have an autoimmune disease compared to men (Jacobson et al., 1997);

	· are twice as likely to suffer from temporomandibular joint disorders (Warren, 2001);

	· and, have a greater lifetime risk of developing asthma (American Lung Association, 2010).

	Likewise, gender also plays a significant role in health and disease, shaping lifestyle choices from occupation, nutrition, and environment, to access to healthcare and doctor-patient interactions (Mastroianni, et al., 1994).

Impact of sex-based research in drug development  

	Given the fundamental sex differences in biology, treatments that are largely developed and evaluated in men may perform differently in women. We know that women are at nearly a two-fold greater risk of experiencing adverse drug reactions (ADR) than men (Tharpe, 2011). Forty percent of the drugs that were withdrawn from the U.S. market between 1997 and 2000 were found to pose greater health risks for women than men (Rabesandratanav, 2014). As recently as 2013, ADRs resulted in a label change for the popular sleep medication, zolpidem (AmbienÒ, Sanofi), when the FDA recognized a delayed clearance rate in women compared to men.

	However, even with these increased risks, there continues to be a paucity of data differentiating the safety and efficacy of medications commonly prescribed to women (Geller, et al., 2017; Clayton & Tannenbaum, 2016). The differentiation between the sex-related data should start early in the drug development process, with preclinical and translational medicine (Clayton, 2016), and carry through to current clinical trials. In preclinical trials, the percentage of preclinical manuscripts that included females has actually dropped from 8% in 1991 to 2% in 2011 (Yoon, 2014). Physicians believe that discussions about clinical trials should be part of standard of care (CenterWatch, 2017)-this holds true for both men and women. Nonetheless, in data gathered for NIH-funded Clinical Trials, the percentage of women enrolled remained static between 2004 and 2015 (~45%). However, the analysis of the data by sex was only seen in 28% of these trials in 2015 (Geller, 2017).

	Sex has not historically been considered as a biological variable, yet there has been guidance in place for clinical research since the 1990’s and for non-clinical research since January 25, 2016. The Institute of Medicine and National Research Council reported that the morbidity rates of women in the US are rising, while those of men are falling (2013). Is this because research is not considering sex as a biologic variable often enough? Basic science, translational, and clinical researchers in both academia and industry should thoughtfully consider how sex and gender influences their research questions and desired outcomes. In addition, collaborative partnerships and open-dialogue between academia and industry can help identify areas where sex- and gender-based research are needed to improve the health of both men and women.

https://www.fda.gov/scienceresearch/specialtopics/womenshealthresearch/ucm472932.htm

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1424718/

	Beery & Zucker, 2011. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3008499?

	NIH, 2012. https://www.ncbi.nlm.nih.gov/books/NBK84192/

https://www.ncbi.nlm.nih.gov/m/pubmed/24506076

https://www.ncbi.nlm.nih.gov/pubmed/24834516

	NIH, 2015. https://grants.nih.gov/grants/guide/notice-files/NOT-OD-15-102.html

https://www.ncbi.nlm.nih.gov/pubmed/9281381/

https://www.karger.com/Journal/Issue/226954/

	American Lung Association, 2010. www.lung.org/assets/documents/research/asthma-trend-report.pdf

https://www.ncbi.nlm.nih.gov/books/NBK236535/

https://www.ncbi.nlm.nih.gov/pubmed/21535369

http://www.sciencemag.org/careers/2014/03/adding-sex-and-gender-dimensions-your-research/

	Geller et al., 2017. https://www.ncbi.nlm.nih.gov/pubmed/29053489

https://jamanetwork.com/journals/jama/fullarticle/2577142/

	Clayton, 2016. https://www.ncbi.nlm.nih.gov/pubmed/26514164

https://doi.org/10.1016/j.surg.2014.07.001

http://www.centerwatch.com/news-online/2017/07/25/survey-discussions-clinical-trials-part-standard-care/

	Director of Science Outreach & Education

A sex-bias that significantly impacts the advancement of women’s health exists in both preclinical and clinical research.

Cathleen Dohrn, PhD

Articles

Challenges Emerge from Low NASH Awareness

Low Awareness of NASH Presents Significant Clinical Trial Challenges

Considering Sex as a Variable in Clinical Trials