Collaboration among Industry, Regulatory Agencies, and Professional Societies Drives Progress in Treating Kidney Diseases

In 2014, the Centers for Disease Control and Prevention estimated that there were more than 20 million Americans with chronic kidney disease (CKD) and 661,648 prevalent cases of ESRD (1, 2). In 2013, patients with CKD represented 10 percent of the Medicare population, with expenditures exceeding $50 billion accounting for 20 percent of total expenditures (2). The ESRD population is less than 1 percent of the total Medicare population, with expenditures of $30.9 billion accounting for 7.1 percent of the overall Medicare paid claims (2).

The cost of drugs is an important component of these expenditures, and both public and private payers are moving to bundled payments in an attempt at cost containment. The nephrology community has been in the vanguard of such changes, with a prospective payments system (PPS) for kidney dialysis services introduced in early 2011 (3). Intravenous drugs were included in the bundle for the first time, having previously been reimbursed separately from the dialysis treatment. In the first year after implementation of the PPS, utilization of these drugs declined 34 percent (4). Hirth et al. interpreted this decline as resulting from changes in provider behavior in response to financial incentives within the PPS as well as changes in the label for erythropoieisis-stimulating agents (ESAs) during this time period (4).

Concern has been expressed that the PPS may put at risk the development of innovative therapies or devices. This may add one more potential barrier in exploring new treatments for ESRD patients. Already the number of randomized clinical trials published in nephrology between 1996 and 2010 is lower than other specialties in internal medicine (5). The introduction of several new expensive prescription drugs has rekindled debate over the costs attributed to drug development.

Well designed clinical trials are a key component of marketing approval of any new drug but do not represent the sole cost of developing a new drug. A systematic review of published estimates in 2010 found a ninefold range in the estimates of drug development from $161 million to $1.8 billion of capitalized US dollars (6). The authors concluded that no published estimate of the cost of developing a drug can be considered a gold standard. Tufts Center for the Study of Drug Development announced in November 2014 that the cost to develop and win marketing approval for a new drug was $2.6 billion (7), although this figure has been challenged (8). In the same announcement, the authors noted that the development process often lasted longer than 10 years, however, the lengthening of development and approval time were not responsible for driving up the development costs. The same authors reported that the clinical approval success rate had declined from 21.5 percent in 2003 to 11.8 percent currently, and these drug failures are key contributors to development costs (9).

In September 2012, the American Society of Nephrology, recognizing the lack of clinical trials and the huge unmet need, established, under a memorandum of understanding with the Food and Drug Administration (FDA), the Kidney Health Initiative (KHI) (10). Its mission is “to advance scientific understanding of the kidney health and patient safety implications of new and existing medical products, and to foster development of therapies for diseases that affect the kidney by creating a collaborative environment in which the FDA and the greater nephrology community can interact and optimize evaluation of drugs, devices, biologics and food products.”

One of the key obstacles KHI identified was the lack of well-defined clinical trial end points for studies of treatment of CKD progression that would be acceptable to regulatory agencies for registration. Progression of CKD as measured by loss of GFR is typically 2–5 mL/min per year, and clinical manifestations occur late in the disease. The FDA has previously accepted a doubling of serum creatinine as a surrogate endpoint for assessing a drug’s efficacy along with evidence of the drug’s effect on all-cause mortality and ESRD (11). A doubling of serum creatinine corresponds to an approximately 57 percent decline in estimated GFR using the CKD-EPI equation.

In December 2012, the National Kidney Foundation and the FDA sponsored a workshop on GFR decline as an end point for clinical trials in CKD. Levey et al. conducted a series of meta-analyses of cohorts and clinical trials and simulations of trial designs and analytic methods (12). They concluded that a confirmed decline in estimated GFR of 30 percent over 2 to 3 years may be an acceptable surrogate end point in some circumstances but that the pattern of treatment effects on GFR must be examined, specifically acute effects on estimated GFR. An estimated GFR decline of 40 percent may be more broadly acceptable than a 30 percent decline across a wider range of baseline GFRs and patterns of treatment effects on GFR. If this surrogate is accepted, there is a potential for studies to be shorter and to enroll fewer patients for outcome trials. The European Medicines Agency also has recognized this problem, having issued a draft guideline on the clinical investigation of medicinal products to prevent development/slow progression of chronic renal insufficiency in June 2014. It defined treatment goals; study designs; outcome measures, including estimated GFR as an end point; and data analyses (13); it suggests that for smaller studies actual measured GFR using an exogenous filtration marker may be preferable to creatinine-based eGFR. As drug development is global, further clarity on acceptable end points for major agencies must be sought. The draft guideline was open for consultation until January 2015 and a final guideline is pending.

KHI has identified two pilot projects affecting clinical trials (10). A workgroup in partnership with the Lupus Nephritis Trial Network is analyzing existing data to test for clear end points for lupus trials. Pharmaceutical companies have been contacted to discuss the inclusion of their data into the planned analysis. On completion, the workgroup will recommend a core set of outcome measures, biomarkers, surrogate markers, and clearly defined terms that they propose should be incorporated into future lupus nephritis trials. A separate workgroup comprising KHI members from patient groups, health professional organizations, and industry and FDA representatives will examine, define, and explain the major barriers to innovation in kidney health and identify potential solutions to those barriers.

It is important to recognize that any drug approval requires a thorough assessment of benefits as well as risks, and a 2- to 3-year study is usually required to assess long-term safety data.

Despite all of these issues, progress has occurred in the treatment of our patients. Unadjusted mortality rates in Medicare patients with CKD have decreased 35.9 percent since 2001, whereas for those without CKD, the decrease was 18.1 percent over the same time period (2). The incidence rate of ESRD plateaued beginning in 2001 and declined in all but one year between 2007 and 2012, and it was essentially unchanged in 2013 (2). Mortality rates for dialysis patients fell by 5 percent from 1996 to 2003 and 23 percent from 2004 to 2013 (2). The recent collaborative efforts of all stakeholders should, in the years to come, affect our common mission of improving the lives of patients with CKD and ESRD.

References

1

Centers for Disease Control and Prevention (CDC). National Kidney Disease Fact Sheet. General Information and National Estimates on Chronic Kidney Disease in the United States, 2014. Atlanta, GA, US Department of Health and Human Services Centers for Disease Control and Prevention, 2014.

2

US Renal Data System. USRDS 2015 Annual Report. Atlas of Chronic Kidney Disease and End-Stage Renal Disease in the United States, Bethesda, MD, National Institutes of Health and National Institute of Diabetes and Digestive and Kidney Diseases, 2013.

3

Medicare Improvements for Patients and Providers Act, Pub 1 No. 110–275, 122 Stat 2553, 2008.

4

Hirth RA, et al. The initial impact of Medicare’s new prospective payment system for kidney dialysis patents. Am J Kidney Dis 2013; 62:662–669.

5

Palmer SC, Sciancecalepore M, Strippoli GFM. Trial quality in nephrology: How are we measuring up? Am J Kidney Dis 2011; 58:335–337.

6

Morgan S, et al. The cost of drug development: A systematic review. Health Policy 2011; 100:4–17.

7

How the Tufts Center for the Study of Drug Development Pegged the Cost of a New Drug at $2.6 Billion, Boston. The Tufts Center for the Study of Drug Development, 2014.

8

Avorn J. The $2.6 billion pill—methodological and policy considerations. N Engl Med 2015; 372:1877–1879.

9

DiMasi JA, Grabowski HG, Hansen RW. The cost of drug development. New Engl J Med 2015; 372:1972.

10

Kidney Health Initiative Inaugural Review 2012–2014. https://www.asn-online.org/khi/KHI_YER_2014.pdf.

11

Thompson A, Lawrence J, Stockbridge N. GFR decline as an end point in trials in CKD: A viewpoint from the FDA. Am J Kidney Dis 2014; 64:836–837.

12

Levey AS, et al. GFR decline as an end point for clinical trials in CKD: A scientific workshop sponsored by the National Kidney Foundation and the US Food and Drug Administration. Am J Kidney Dis 2014; 64:821–835.

13

European Medicines Agency. Draft Guidelines on the Clinical Investigation of Medicinal Products to Prevent Development/Slow Progression of Chronic Renal Insufficiency (EMA/CHMP/355988/2014).