- Email: [email protected]
African Americans, Kidney Disease, and Drug Development: A Regulatory Perspective
Supplement Article
African Americans, Kidney Disease, and Drug Development: A Regulatory Perspective Carolina Panico and Aliza Thompson Given the burden of kidney disease in African Americans, the discovery of safe and effective medical products to slow the progression of kidney disease and reduce the risk for kidney failure would have a tremendous impact on this population. Differences in response to treatment have been observed in African Americans, highlighting the importance of studying medical products in African Americans. Although historically the African American community has not been well represented in clinical trials, efforts are underway to address this issue. Recent advances in understanding the genetic contributions to disease progression in African Americans, including the discovery of risk variants in the apolipoprotein L1 gene (APOL1), raise the possibility of using genetic information to better tailor treatments for African Americans. One could envision developing therapies that target these variants or possibly using them to help enrich trial populations with patients more likely to experience disease progression.
Introduction Chronic kidney disease is associated with significant morbidity and mortality. Although a number of medical products have been approved to treat the complications of kidney disease, few have been approved to slow kidney disease progression. The discovery of such therapies would have a tremendous impact on the health of African Americans, given the disproportionate burden of kidney disease in this population. In the United States, the risk for kidney failure is 3-fold higher in African Americans when compared to the general population, suggesting potential differences in the underlying pathophysiology of kidney injury in this population. In addition, whereas African Americans constitute w13% of the US population, they account for 35% of US dialysis patients.1 The high prevalence of kidney failure in African Americans and the recent advances in understanding the genetic contributions to disease progression in this population highlight 2 issues: the importance of studying medical products for kidney diseases in African Americans and the use of genetic information to better tailor treatments for African Americans with kidney diseases. This article addresses the inclusion of African Americans in drug development programs for kidney diseases and drug development considerations related to recent advances in understanding the genetic contributions of disease progression in African Americans. In this article, terms such as “African American,” “black,” “white,” and “Caucasian” reflect their use in the cited references. However, we acknowledge that black persons from other countries may not be representative of African American populations in the United States because of differences in diet, potential differences in genetics, and other factors. Inclusion of African Americans in Clinical Trials Supporting Drug Approval It is widely recognized that different subgroups of patients with a disease, defined by sex, age, racial and ethnic AJKD Vol 72 | Iss 5 | Suppl 1 | November 2018
Complete author and article information provided before references. Am J Kidney Dis. 72(5)(Suppl 1):S33-S36. doi: 10.1053/ j.ajkd.2018.06.023 Published by Elsevier Inc. on behalf of the National Kidney Foundation, Inc. This is a US Government Work. There are no restrictions on its use.
backgrounds, comorbid conditions, background medications, or other factors, may differ in their response to a treatment. Hence, including a more diverse population in trials can provide important information on whether the response of a subgroup differs from that observed in the overall trial population if the subgroup is reasonably well represented in the trials. Historically, African Americans have not been well represented in clinical trials. According to a 2011 report on engaging women and minorities in clinical trials, African Americans represented 5% of clinical trial participants, a significantly lower proportion than would be expected based on the proportion of African Americans in the United States.2 Some recent drug approvals for cardiovascular and kidney-related disease suggest that this issue persists. For example, in the development program supporting the 2015 US Food and Drug Administration (FDA) approval of patiromer (Veltassa) for the treatment of hyperkalemia, <1%, or w5 of 700 trial participants were black or African American.3 In the pivotal trial that led to the 2015 FDA approval of sacubitril/valsartan (Entresto) to reduce the risk for cardiovascular death and hospitalization for heart failure in patients with chronic heart failure (New York Heart Association class II-IV) and reduced ejection fraction, 5%, or 428 of 8,442 trial participants, were black or African American.4,5 Factors Contributing to the Lack of Diversity Several factors contribute to the lack of diversity in clinical trials. According to field research conducted by the Coalition to Eliminate Disparities and to Research Inclusion in Clinical Trials (CEDRICT), many African Americans who were surveyed indicated that they did not participate in clinical trials because they were simply not asked, were unaware of the trials, or would participate if they had more education about the trials.2,6 A telephone survey conducted during the recruitment phase of the African S33
Supplement Article American Study of Kidney Disease and Hypertension (AASK) suggests that health-related factors such as health risk associated with clinical trials played a significant role in nonparticipation.7 A significant proportion of investigators, cancer center leaders, and referring clinicians have also been surveyed, and in this case, distrust, transportation and insurance barriers, “language discordance,” “discomfort with the inherent uncertainty of trial participation,” and the “negative connotation of clinical trials” were named as obstacles to enrollment of African Americans in clinical trials.8 Another factor that has been cited is the global nature of drug development. For various reasons, including access to a larger pool of patients and cost savings, data supporting the efficacy and safety of drugs is often provided by international trials or, in some cases, by trials conducted exclusively outside the United States.9,10 For example, the patiromer development program, in which <1% of participants were black or African American, was largely conducted outside the United States3 (Fig 1). In the phase 3 trial that was conducted to support the approval of valsartan/sacubitril for the treatment of heart failure, 5% of trial participants were enrolled from sites in the United States4 (Fig 2). In contrast, in the Systolic Blood Pressure Intervention Trial (SPRINT), an intervention trial that was conducted in the United States and had a specified recruitment target for minorities, 31% of participants were African American.11 Differences in Response to Therapy: Examples How concerned should we be about generalizing the overall efficacy and safety findings of a study to specific subgroups based on race, age, and sex? In the cardiovascular and renal fields, there are certainly examples of efficacy and safety responses that have differed based on self-reported race, sometimes for reasons that are not well understood. At one extreme is BiDil, a combination of isosorbide dinitrate and hydralazine hydrochloride that is < 1% White (708 PaƟents)
Black or African American (5 PaƟents) Asian (1 PaƟent)
NaƟve Hawaiian or Pacific Islander (1 PaƟent) 99%
Figure 1. Demographics of efficacy trials by race for Veltassa (patiromer). Data source: US Food and Drug Administration.15 S34
2%
9% White (5579 Paents) Black or African American (428 Paents)
18%
Asian (1510 Paents)
5%
66%
American Indian or Alaska Nave (172 Paents) Other *(753 Paents)
Figure 2. Demographics of efficacy trials by race for Entresto (sacubitril/valsartan). Data source: US Food and Drug Administration.15 *All other races combined.
indicated specifically for “self-identified black patients” for the treatment of heart failure to improve survival.12 In other settings, data have supported efficacy in all races but suggest a smaller treatment effect in one population. For example, angiotensin-converting enzyme inhibitors such as lisinopril lower blood pressure less in black hypertensive patients than in nonblack hypertensive patients, suggesting a potential difference in the underlying pathophysiology of hypertension in black patients.13 Differences in safety profiles have also been observed between Caucasian and black patients, including higher rates of angioedema observed in black patients treated with angiotensinconverting enzyme inhibitors and sacubitril/valsartan.14 Regulatory Initiatives to Address Diversity Over the years, through policy and law, steps have been taken to improve the inclusion of African Americans and other subgroups in clinical trials. The National Institutes of Health (NIH) policy on inclusion of women and minorities in NIH-funded phase 3 trials mandates that minorities be included in numbers adequate for valid analysis of differences in intervention effect. FDA regulations require sponsors who submit applications for medical products to analyze clinical trial data by sex, age, and race. The FDA drug trials snapshot website provides public information about who participated in clinical trials and whether there are differences in response among subgroups defined by sex, race, and age.15 However, there is no mandatory requirement that these trials include a certain number or proportion of African Americans. Nevertheless, it is widely recognized that it is important for development programs to collect data for treatment responses in African Americans. The FDA’s Office of Minority Health (OMH) promotes the collection of clinical trial data for racial and ethnic minorities, works to improve data quality related to minorities’ responses to treatment, and increases transparency and access to available data. OMH is charged with improving the FDA’s ability to respond to minority concerns and enhancing the FDA’s health and safety communications to minority populations. In addition, AJKD Vol 72 | Iss 5 | Suppl 1 | November 2018
Supplement Article OMH collaborates with outside organizations and other federal agencies to advance research in minority health and health disparities and improve outreach and communication, with a focus on minorities that have low English proficiency and/or low health literacy.16 One example of an activity to promote representation is the ongoing “Minorities in Clinical Trials Campaign,” which encompasses public service announcements, educational material, webinars, and print/digital outreach.17 Beyond these larger efforts, the FDA encourages the inclusion of diverse participants in interactions with sponsors18,19 and when there is a priori concern that the response to treatment may differ in African Americans, enrichment of the trial population is encouraged. At times, the FDA has also issued postmarketing requirements to better understand treatment responses in African Americans. For example, the approval letter for sacubitril/ valsartan for the treatment of heart failure contains a postmarketing requirement to conduct an epidemiologic study to evaluate the incidence of angioedema in black patients treated with sacubitril/valsartan compared to a control.20 Precision Medicine and Pharmacogenomics In early 2015, President Obama announced the creation of the Precision Medicine Initiative, a research initiative intended to provide “new tools, knowledge, and therapies to select which treatments will work best for which patients.”21(p 1) Precision medicine has been defined as disease treatment and prevention that take into account variability in genes, environment, and lifestyle for each individual. The goal of precision medicine is to predict more accurately the treatment and prevention strategies for a particular disease and population.22 Pharmacogenomics, defined as the study of how a patient’s genetic makeup affects his or her response to therapy, is an important component of precision medicine. From a drug development standpoint, there has been tremendous interest in using genetic information to help identify patients who are more likely to respond to a therapy (ie, incur a benefit or a particular toxicity) and to optimize dosing recommendations.23 Although further work is needed to realize the full potential of pharmacogenomics, this field has already led to more tailored treatments, as evidenced by the expanding list of products that contain pharmacogenomic information in the drug label.24 As discussed in other articles in this journal supplement, the discovery of risk variants in the apolipoprotein L1 gene (APOL1) represents a significant step forward in our understanding of the contribution of genetics to nondiabetic kidney disease in African Americans.25 To date, studies suggest that APOL1 risk variants, reported on Africanderived chromosomes, may play a role in kidney disease attributed to hypertension, focal segmental glomerulosclerosis, human immunodeficiency virus (HIV)-associated AJKD Vol 72 | Iss 5 | Suppl 1 | November 2018
nephropathy, and lupus nephritis, among others.26,27 This discovery could be used to develop therapies that target the APOL1 risk variants. In addition, APOL1 risk variant status, along with other risk markers and possibly as part of a risk score, could be used to enrich a trial population with patients who are more likely to experience disease progression. Whether such a strategy is sensible and will lead to enhanced trial efficiency may depend in part on the prevalence of the risk variants in the population of interest and the extent to which these risk variants improve risk prediction. For therapies that target APOL1 risk variants, it will be important to understand and consider the potential unintended consequences of diminishing or knocking out the activity of these variants. Available data suggest that APOL1 risk variants are protective against trypanosomiasis, or African sleeping sickness, which is caused by Trypanosoma parasites transmitted by the tsetse fly.28 Loss of this protective benefit may not be a concern for patients living in the United States; whether there are unintended consequences remains to be seen. Conclusions There is significant unmet need for safe and effective therapies for kidney disease. Given the burden of kidney disease in African Americans, the discovery of safe and effective medical products to slow the progression of kidney disease and reduce the risk for kidney failure would have a tremendous impact on the health of this population. Although differences in response to treatment have been observed in African Americans, historically this population has not been well represented in clinical trials. Although efforts are well underway to address barriers to inclusion in clinical trials, the increasingly global nature of drug development remains a challenge. Recent advances in understanding the genetic contributions to disease progression in African Americans, including the discovery of risk variants in APOL1, offer reason for hope; however, there is much work ahead. We must work expeditiously to translate these scientific advances into therapies that improve the lives of African Americans with kidney diseases. Article Information Authors’ Full Names and Academic Degrees: Carolina Panico, MD, PhD, and Aliza Thompson, MD, MS. Authors’ Affiliations: US Food and Drug Administration, White Oak, MD. Address for Correspondence: Aliza Thompson, MD, MS, Office of New Drugs, Center for Drug Evaluation and Research, US Food and Drug Administration, 10903 New Hampshire Ave, White Oak, MD 20903. E-mail: [email protected] Support: This article is part of a supplement that arose from the Frank M. Norfleet Forum for Advancement of Health: African Americans and Kidney Disease in the 21st Century, held March 24, 2017, in Memphis, TN. The Forum and the publication of this supplement were funded by the Frank M. Norfleet Forum for
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Supplement Article Advancement of Health, the Community Foundation of Greater Memphis, and the University of Tennessee Health Science Center. Financial Disclosure: The authors declare that they have no relevant financial interests. Disclaimer: This publication reflects the views of the author and should not be construed to represent the FDA’s views or policies. Peer Review: Received January 31, 2018, as part of a supplement invited by the journal. Evaluated by 2 external peer reviewers, with direct editorial input from the Health Equity Editor and a Deputy Editor. Accepted in revised form June 25, 2018.
References 1. Saran R, Robinson B, Abbott KC, et al. US Renal Data System 2017 Annual Data Report: epidemiology of kidney disease in the United States. Am J Kidney Dis. 2018; 71(3)(suppl 1):S1-S672. 2. Society for Women’s Health Research (SWHR) and USFDA Office of Minority Health (OMH). Dialogues on diversifying clinical trials. successful strategies for engaging women and minorities in clinical trials. 2011. https://www.fda.gov/downloads/ ScienceResearch/SpecialTopics/WomensHealthResearch/ UCM334959.pdf. Accessed December 5, 2017. 3. US FDA. FDA website. Drug Trials Snapshot: VELTASSA. https:// www.fda.gov/Drugs/InformationOnDrugs/ucm474619.htm. Last updated November 30, 2015. Accessed December 5, 2017. 4. US FDA. Drugs@FDA webpage. Entresto Medical Review. 2015. https://www.accessdata.fda.gov/drugsatfda_docs/nda/2015/ 207620Orig1s000MedR.pdf. Accessed December 7, 2017. 5. US FDA. FDA website. Drug Trials Snapshot: ENTRESTO. https://www.fda.gov/Drugs/InformationOnDrugs/ucm457521. htm. Last updated March 15, 2017. Accessed December 5, 2017. 6. CEDRICT. Field Research Component. http://www.npfrproject. org/_newsite/cederictovr.php#fieldresearch. Accessed December 5, 2017. 7. Gadegbeku CA, Stillman PK, Huffman MD, Jackson JS, Kusek JW, Jamerson KA. Factors associated with enrollment of African Americans into a clinical trial: results from the African American Study of Kidney Disease and Hypertension. Contemp Clin Trials. 2008;29(6):837-842. 8. Durant RW, Wenzel JA, Scarinci IC, et al. Perspectives on barriers and facilitators to minority recruitment for clinical trials among cancer center leaders, investigators, research staff and referring clinicians. Cancer. 2014;120(07):1097-1105. 9. Glickman SW, McHutchison JG, Peterson ED, et al. Ethical and scientific implications of the globalization of clinical research. N Engl J Med. 2009;360(8):816-823. 10. US FDA. Global Participation in Clinical Trials Report 20152016. https://www.fda.gov/downloads/Drugs/InformationOn Drugs/UCM570195.pdf. www.fda.gov. Accessed December 7, 2017. 11. Still CH, Craven TE, Freedman BI, et al. Baseline characteristics of African Americans in the Systolic Blood Pressure Intervention Trial (SPRINT). J Am Soc Hypertens. 2015;9(9):670-679. 12. BiDil (isosorbide dinitrate and hydralazine hydrochloride). Drug label. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm? setid=e1e63cd5-d1e4-4af5-bad5-1ad41ea46b00. Accessed December 7, 2017.
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13. Lisinopril. Drug label. https://dailymed.nlm.nih.gov/dailymed/ drugInfo.cfm?setid=27ccb2f4-abf8-4825-9b05-0bb367b4ac07. Accessed December 7, 2017. 14. Entresto (sacubitril/valsartan). Drug label. https://dailymed.nlm. nih.gov/dailymed/drugInfo.cfm?setid=000dc81d-ab91-450c8eae-8eb74e72296f. Accessed December 7, 2017. 15. US FDA. FDA website. Drug trials Snapshots. https://www.fda. gov/Drugs/InformationOnDrugs/ucm412998.htm. Last updated December 11, 2017. Accessed December 21, 2017. 16. US FDA. Office of Minority Health. FDA website. https://www.fda. gov/AboutFDA/CentersOffices/OC/OfficeofMinorityHealth/ default.htm. Last updated September 27, 2017. Accessed December 5, 2017. 17. US FDA. Minorities in clinical trials. FDA website. https://www.fda. gov/forconsumers/byaudience/minorityhealth/ucm472295.htm. Last updated December 8, 2017. Accessed December 21, 2017. 18. US FDA. FDA website. FDA encourages more participation, diversity in clinical trials. https://www.fda.gov/ForConsumers/ ConsumerUpdates/ucm535306.htm. Last updated January 1, 2017. Accessed December 5, 2017. 19. US FDA. Guidance for Industry: collection of race and ethnicity data in clinical trials. 2016. https://www.fda.gov/downloads/ RegulatoryInformation/Guidances/ucm126396.pdf. Accessed December 21, 2017. 20. US FDA. Drugs@FDA webpage. Entresto Approval Letter. 2015. https://www.accessdata.fda.gov/drugsatfda_docs/appletter/ 2015/207620Orig1s000ltr.pdf. Accessed December 7, 2017. 21. The White House. Office of the Press Secretary. Fact sheet: President Obama’s Precision Medicine Initiative. https:// obamawhitehouse.archives.gov/the-press-office/2015/01/30/ fact-sheet-president-obama-s-precision-medicine-initiative. January 30, 2015. Accessed December 5, 2017. 22. US National Library of Medicine (NLM). NLM website. https://ghr. nlm.nih.gov/primer/precisionmedicine/precisionvspersonalized. Last updated December 6, 2017. Accessed December 7, 2017. 23. US FDA. Paving the way for personalized medicine: FDA’s role in a new era of medical product development. https://www.fda. gov/downloads/ScienceResearch/SpecialTopics/Personalized Medicine/UCM372421.pdf. 2013. Accessed December 5, 2017. 24. US FDA. FDA website.Table of pharmacogenomic biomarkers in drug labeling. https://www.fda.gov/Drugs/ScienceResearch/ ucm572698.htm. Last updated October 3, 2017. Accessed December 5, 2017. 25. Freedman BI, Limou S, Ma L, Kopp JB. APOL1-associated nephropathy: a key contributor to racial disparities in CKD. Am J Kidney Dis. 2018;72(5)(suppl 1):S8-S16. 26. Kopp JB, Nelson GW, Sampath K, et al. APOL1 genetic variants in focal segmental glomerulosclerosis and HIVassociated nephropathy. J Am Soc Nephrol. 2011;22(11): 2129-2137. 27. Freedman BI, Langefeld CD, Andringa KK, et al. End-stage renal disease in African Americans with lupus nephritis is associated with APOL1. Arthritis Rheum. 2014;66(2):390396. 28. Thomson R, Genovese G, Canon C, et al. Evolution of the primate trypanolytic factor APOL1. Proc Natl Acad Sci U S A. 2014;111(20):E2130-E2139.
AJKD Vol 72 | Iss 5 | Suppl 1 | November 2018
African Americans, Kidney Disease, and Drug Development: A Regulatory Perspective Carolina Panico and Aliza Thompson Given the burden of kidney disease in African Americans, the discovery of safe and effective medical products to slow the progression of kidney disease and reduce the risk for kidney failure would have a tremendous impact on this population. Differences in response to treatment have been observed in African Americans, highlighting the importance of studying medical products in African Americans. Although historically the African American community has not been well represented in clinical trials, efforts are underway to address this issue. Recent advances in understanding the genetic contributions to disease progression in African Americans, including the discovery of risk variants in the apolipoprotein L1 gene (APOL1), raise the possibility of using genetic information to better tailor treatments for African Americans. One could envision developing therapies that target these variants or possibly using them to help enrich trial populations with patients more likely to experience disease progression.
Introduction Chronic kidney disease is associated with significant morbidity and mortality. Although a number of medical products have been approved to treat the complications of kidney disease, few have been approved to slow kidney disease progression. The discovery of such therapies would have a tremendous impact on the health of African Americans, given the disproportionate burden of kidney disease in this population. In the United States, the risk for kidney failure is 3-fold higher in African Americans when compared to the general population, suggesting potential differences in the underlying pathophysiology of kidney injury in this population. In addition, whereas African Americans constitute w13% of the US population, they account for 35% of US dialysis patients.1 The high prevalence of kidney failure in African Americans and the recent advances in understanding the genetic contributions to disease progression in this population highlight 2 issues: the importance of studying medical products for kidney diseases in African Americans and the use of genetic information to better tailor treatments for African Americans with kidney diseases. This article addresses the inclusion of African Americans in drug development programs for kidney diseases and drug development considerations related to recent advances in understanding the genetic contributions of disease progression in African Americans. In this article, terms such as “African American,” “black,” “white,” and “Caucasian” reflect their use in the cited references. However, we acknowledge that black persons from other countries may not be representative of African American populations in the United States because of differences in diet, potential differences in genetics, and other factors. Inclusion of African Americans in Clinical Trials Supporting Drug Approval It is widely recognized that different subgroups of patients with a disease, defined by sex, age, racial and ethnic AJKD Vol 72 | Iss 5 | Suppl 1 | November 2018
Complete author and article information provided before references. Am J Kidney Dis. 72(5)(Suppl 1):S33-S36. doi: 10.1053/ j.ajkd.2018.06.023 Published by Elsevier Inc. on behalf of the National Kidney Foundation, Inc. This is a US Government Work. There are no restrictions on its use.
backgrounds, comorbid conditions, background medications, or other factors, may differ in their response to a treatment. Hence, including a more diverse population in trials can provide important information on whether the response of a subgroup differs from that observed in the overall trial population if the subgroup is reasonably well represented in the trials. Historically, African Americans have not been well represented in clinical trials. According to a 2011 report on engaging women and minorities in clinical trials, African Americans represented 5% of clinical trial participants, a significantly lower proportion than would be expected based on the proportion of African Americans in the United States.2 Some recent drug approvals for cardiovascular and kidney-related disease suggest that this issue persists. For example, in the development program supporting the 2015 US Food and Drug Administration (FDA) approval of patiromer (Veltassa) for the treatment of hyperkalemia, <1%, or w5 of 700 trial participants were black or African American.3 In the pivotal trial that led to the 2015 FDA approval of sacubitril/valsartan (Entresto) to reduce the risk for cardiovascular death and hospitalization for heart failure in patients with chronic heart failure (New York Heart Association class II-IV) and reduced ejection fraction, 5%, or 428 of 8,442 trial participants, were black or African American.4,5 Factors Contributing to the Lack of Diversity Several factors contribute to the lack of diversity in clinical trials. According to field research conducted by the Coalition to Eliminate Disparities and to Research Inclusion in Clinical Trials (CEDRICT), many African Americans who were surveyed indicated that they did not participate in clinical trials because they were simply not asked, were unaware of the trials, or would participate if they had more education about the trials.2,6 A telephone survey conducted during the recruitment phase of the African S33
Supplement Article American Study of Kidney Disease and Hypertension (AASK) suggests that health-related factors such as health risk associated with clinical trials played a significant role in nonparticipation.7 A significant proportion of investigators, cancer center leaders, and referring clinicians have also been surveyed, and in this case, distrust, transportation and insurance barriers, “language discordance,” “discomfort with the inherent uncertainty of trial participation,” and the “negative connotation of clinical trials” were named as obstacles to enrollment of African Americans in clinical trials.8 Another factor that has been cited is the global nature of drug development. For various reasons, including access to a larger pool of patients and cost savings, data supporting the efficacy and safety of drugs is often provided by international trials or, in some cases, by trials conducted exclusively outside the United States.9,10 For example, the patiromer development program, in which <1% of participants were black or African American, was largely conducted outside the United States3 (Fig 1). In the phase 3 trial that was conducted to support the approval of valsartan/sacubitril for the treatment of heart failure, 5% of trial participants were enrolled from sites in the United States4 (Fig 2). In contrast, in the Systolic Blood Pressure Intervention Trial (SPRINT), an intervention trial that was conducted in the United States and had a specified recruitment target for minorities, 31% of participants were African American.11 Differences in Response to Therapy: Examples How concerned should we be about generalizing the overall efficacy and safety findings of a study to specific subgroups based on race, age, and sex? In the cardiovascular and renal fields, there are certainly examples of efficacy and safety responses that have differed based on self-reported race, sometimes for reasons that are not well understood. At one extreme is BiDil, a combination of isosorbide dinitrate and hydralazine hydrochloride that is < 1% White (708 PaƟents)
Black or African American (5 PaƟents) Asian (1 PaƟent)
NaƟve Hawaiian or Pacific Islander (1 PaƟent) 99%
Figure 1. Demographics of efficacy trials by race for Veltassa (patiromer). Data source: US Food and Drug Administration.15 S34
2%
9% White (5579 Paents) Black or African American (428 Paents)
18%
Asian (1510 Paents)
5%
66%
American Indian or Alaska Nave (172 Paents) Other *(753 Paents)
Figure 2. Demographics of efficacy trials by race for Entresto (sacubitril/valsartan). Data source: US Food and Drug Administration.15 *All other races combined.
indicated specifically for “self-identified black patients” for the treatment of heart failure to improve survival.12 In other settings, data have supported efficacy in all races but suggest a smaller treatment effect in one population. For example, angiotensin-converting enzyme inhibitors such as lisinopril lower blood pressure less in black hypertensive patients than in nonblack hypertensive patients, suggesting a potential difference in the underlying pathophysiology of hypertension in black patients.13 Differences in safety profiles have also been observed between Caucasian and black patients, including higher rates of angioedema observed in black patients treated with angiotensinconverting enzyme inhibitors and sacubitril/valsartan.14 Regulatory Initiatives to Address Diversity Over the years, through policy and law, steps have been taken to improve the inclusion of African Americans and other subgroups in clinical trials. The National Institutes of Health (NIH) policy on inclusion of women and minorities in NIH-funded phase 3 trials mandates that minorities be included in numbers adequate for valid analysis of differences in intervention effect. FDA regulations require sponsors who submit applications for medical products to analyze clinical trial data by sex, age, and race. The FDA drug trials snapshot website provides public information about who participated in clinical trials and whether there are differences in response among subgroups defined by sex, race, and age.15 However, there is no mandatory requirement that these trials include a certain number or proportion of African Americans. Nevertheless, it is widely recognized that it is important for development programs to collect data for treatment responses in African Americans. The FDA’s Office of Minority Health (OMH) promotes the collection of clinical trial data for racial and ethnic minorities, works to improve data quality related to minorities’ responses to treatment, and increases transparency and access to available data. OMH is charged with improving the FDA’s ability to respond to minority concerns and enhancing the FDA’s health and safety communications to minority populations. In addition, AJKD Vol 72 | Iss 5 | Suppl 1 | November 2018
Supplement Article OMH collaborates with outside organizations and other federal agencies to advance research in minority health and health disparities and improve outreach and communication, with a focus on minorities that have low English proficiency and/or low health literacy.16 One example of an activity to promote representation is the ongoing “Minorities in Clinical Trials Campaign,” which encompasses public service announcements, educational material, webinars, and print/digital outreach.17 Beyond these larger efforts, the FDA encourages the inclusion of diverse participants in interactions with sponsors18,19 and when there is a priori concern that the response to treatment may differ in African Americans, enrichment of the trial population is encouraged. At times, the FDA has also issued postmarketing requirements to better understand treatment responses in African Americans. For example, the approval letter for sacubitril/ valsartan for the treatment of heart failure contains a postmarketing requirement to conduct an epidemiologic study to evaluate the incidence of angioedema in black patients treated with sacubitril/valsartan compared to a control.20 Precision Medicine and Pharmacogenomics In early 2015, President Obama announced the creation of the Precision Medicine Initiative, a research initiative intended to provide “new tools, knowledge, and therapies to select which treatments will work best for which patients.”21(p 1) Precision medicine has been defined as disease treatment and prevention that take into account variability in genes, environment, and lifestyle for each individual. The goal of precision medicine is to predict more accurately the treatment and prevention strategies for a particular disease and population.22 Pharmacogenomics, defined as the study of how a patient’s genetic makeup affects his or her response to therapy, is an important component of precision medicine. From a drug development standpoint, there has been tremendous interest in using genetic information to help identify patients who are more likely to respond to a therapy (ie, incur a benefit or a particular toxicity) and to optimize dosing recommendations.23 Although further work is needed to realize the full potential of pharmacogenomics, this field has already led to more tailored treatments, as evidenced by the expanding list of products that contain pharmacogenomic information in the drug label.24 As discussed in other articles in this journal supplement, the discovery of risk variants in the apolipoprotein L1 gene (APOL1) represents a significant step forward in our understanding of the contribution of genetics to nondiabetic kidney disease in African Americans.25 To date, studies suggest that APOL1 risk variants, reported on Africanderived chromosomes, may play a role in kidney disease attributed to hypertension, focal segmental glomerulosclerosis, human immunodeficiency virus (HIV)-associated AJKD Vol 72 | Iss 5 | Suppl 1 | November 2018
nephropathy, and lupus nephritis, among others.26,27 This discovery could be used to develop therapies that target the APOL1 risk variants. In addition, APOL1 risk variant status, along with other risk markers and possibly as part of a risk score, could be used to enrich a trial population with patients who are more likely to experience disease progression. Whether such a strategy is sensible and will lead to enhanced trial efficiency may depend in part on the prevalence of the risk variants in the population of interest and the extent to which these risk variants improve risk prediction. For therapies that target APOL1 risk variants, it will be important to understand and consider the potential unintended consequences of diminishing or knocking out the activity of these variants. Available data suggest that APOL1 risk variants are protective against trypanosomiasis, or African sleeping sickness, which is caused by Trypanosoma parasites transmitted by the tsetse fly.28 Loss of this protective benefit may not be a concern for patients living in the United States; whether there are unintended consequences remains to be seen. Conclusions There is significant unmet need for safe and effective therapies for kidney disease. Given the burden of kidney disease in African Americans, the discovery of safe and effective medical products to slow the progression of kidney disease and reduce the risk for kidney failure would have a tremendous impact on the health of this population. Although differences in response to treatment have been observed in African Americans, historically this population has not been well represented in clinical trials. Although efforts are well underway to address barriers to inclusion in clinical trials, the increasingly global nature of drug development remains a challenge. Recent advances in understanding the genetic contributions to disease progression in African Americans, including the discovery of risk variants in APOL1, offer reason for hope; however, there is much work ahead. We must work expeditiously to translate these scientific advances into therapies that improve the lives of African Americans with kidney diseases. Article Information Authors’ Full Names and Academic Degrees: Carolina Panico, MD, PhD, and Aliza Thompson, MD, MS. Authors’ Affiliations: US Food and Drug Administration, White Oak, MD. Address for Correspondence: Aliza Thompson, MD, MS, Office of New Drugs, Center for Drug Evaluation and Research, US Food and Drug Administration, 10903 New Hampshire Ave, White Oak, MD 20903. E-mail: [email protected] Support: This article is part of a supplement that arose from the Frank M. Norfleet Forum for Advancement of Health: African Americans and Kidney Disease in the 21st Century, held March 24, 2017, in Memphis, TN. The Forum and the publication of this supplement were funded by the Frank M. Norfleet Forum for
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Supplement Article Advancement of Health, the Community Foundation of Greater Memphis, and the University of Tennessee Health Science Center. Financial Disclosure: The authors declare that they have no relevant financial interests. Disclaimer: This publication reflects the views of the author and should not be construed to represent the FDA’s views or policies. Peer Review: Received January 31, 2018, as part of a supplement invited by the journal. Evaluated by 2 external peer reviewers, with direct editorial input from the Health Equity Editor and a Deputy Editor. Accepted in revised form June 25, 2018.
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AJKD Vol 72 | Iss 5 | Suppl 1 | November 2018