Influence of Decisions Related to Business and Regulatory Considerations on Therapeutic Development for Kidney Diseases

Introduction Much has been written about the growing prevalence of CKD, especially CKD caused by diabetic nephropathy. Despite increased awareness of CKD as a worldwide medical problem, there remain few pharmacological therapies available to prevent or slow the progression of CKD to ESRD, much less therapies that result in a cure. The only drugs approved by the Food and Drug Administration (FDA) for CKD (specifically diabetic nephropathy) are drugs that inhibit angiotensin-converting enzyme (ACEi) and angiotensin receptor blockers (ARBs). Captopril (ACEi) is approved for use in type I diabetic patients with nephropathy and retinopathy (1), and losartan and irbesartan (ARBs) are approved for the treatment of type II diabetic patients with nephropathy, elevated serum creatinine, proteinuria, and hypertension (2,3). None of these drugs were initially developed for the treatment of CKD in general or diabetic nephropathy specifically. Although these classes of drugs have been major breakthroughs, clearly slow the progression of diabetic nephropathy (4–6), and are routinely used in the treatment of other forms of CKD, they do not stop the progression of CKD. To my knowledge, the FDA has approved no drugs with the initial indication being cure or slowing of the progression of CKD. Thus, in addition to extant therapies, new pharmacological therapies for CKD are needed. Why, then, are more novel drugs not available? Although I do not have the answers, some thoughts about this question will be provided based on a career spent mostly in academic medicine and the pharmaceutical industry. Review of specific potential targets or drug candidates in development for CKD is beyond the scope of this discussion. Although not mentioned, there is also a pressing need for new therapies for acute kidney injury (AKI). The development of a new drug is complex both scientifically and from a business perspective; it is lengthy and expensive, with a very small percentage of new molecules discovered in the laboratory succeeding in the development and regulatory processes and becoming available to patients (7,8). There are multiple points along the development continuum where decisions are made by pharmaceutical or biotechnology companies (also referred to as sponsors) to continue or halt development. Decisions may be based on results of scientific or clinical research or regulatory, market, or budgetary considerations among others up to that point. Given the long timeline, many of the factors going into these decisions change during the development process. Some of the major questions and considerations that factor into the answers that a sponsor may ask in the development of a novel drug are shown in Table 1. The list is not meant to be complete.Table 1: Some fundamental questions in development of novel drugsMedical Need/Market Opportunity in CKD It is estimated that, in the United States alone, over 20 million adults have CKD (9). CKD disproportionately affects African-Americans, Native-Americans, and Hispanics (10). The 2011 US Renal Data System report indicated that, in the United States at the end of 2009, there were 370,274 patients receiving chronic renal replacement therapy in the form of chronic hemodialysis, 27,522 patients receiving chronic peritoneal dialysis, and 172,553 patients had a functioning renal transplant (10). In 2009, 116,395 patients in the United States began treatment for ESRD (10). The 90-day mortality for ESRD patients is about 8%. Survival after 90 days with chronic dialysis is less than desirable, with average 5-year survival rates of approximately 35% with hemodialysis and approximately 47% with peritoneal dialysis (10). Although survival rates with renal transplantation are better (10), not all ESRD patients are candidates for transplantation, and for those patients who are candidates, the shortage of donor organs limits this treatment modality. Survival rates with chronic dialysis are less than rates for most of the common cancers, including colorectal, breast, and prostate, but not as poor as the rate of lung cancer (11). Although life-saving, the quality of life with chronic dialysis is less than optimal, and associated morbidity is much higher than in the general population (10). Finally, the economic impact of chronic renal replacement therapy is very large, with estimates of the annual cost per patient to Medicare (the primary payer in the United States) for 1 year of chronic hemodialysis in 2009 being more than $82,000. Excluding part D, ESRD accounted for $29 billion or 5.9% of the total Medicare budget in 2009 (10). When private insurance and personal funds are added to this number, the cost is even greater. Hence, the medical need and market opportunity for new safe, efficacious, and cost-effective therapies would seem to be quite evident. However, the decision to develop a novel therapy is a complicated one. Even if it seems that questions 1–5 (Table 1) can be successfully addressed, these answers do not ensure that a sponsor moves forward with development. Pharmaceutical and biotechnology companies have more potential opportunities for new drug development than their research and development budgets can afford. Considerations such as those listed in question 6 (Table 1) must also be addressed before decisions are made about which new opportunities to explore, particularly ones that may involve a therapeutic area with which the company (or anyone else) has had little or no previous experience. As the cost and time to develop novel drugs continue to rise (8), companies may choose to pursue new therapies in areas in which there are previously trodden development and registration pathways, which could well be the case with CKD. Stages of New Drug Development Discovery and Preclinical Phases The initial process of new drug development may be divided into discovery and preclinical testing, in which novel molecules are discovered or synthesized and tested in in vitro assays and ultimately, animal models of human disease. This process spans several years. If a sponsor must establish the infrastructure de novo for in vitro and animal testing or other activities specifically related to a given molecule or disease target, both the time and cost of these phases of development may be extended. Some key considerations in these early stages are the identification and validation of potential therapeutic targets and preclinical models. Exciting advances have been made recently in further understanding the genetics and biology of kidney disease. Multiple potential targets for pharmacological therapy have been identified that, if adequately inhibited or stimulated, might slow the progression of CKD. However, it seems, as with many other chronic diseases at least at this time, that there is no single target that, if adequately addressed, would result in a cure of CKD. More likely, there is the potential for new therapies to provide substantial improvement over existing ones in the rate of decline in renal function. Therefore, deciding on which potential targets to focus is a major decision for discovery and clinical scientists. This decision is highly dependent on research data generated in the academic community in addition to the individual company. Furthermore, although there are numerous animal models of CKD that have predicted the efficacy of currently approved drugs, few models, if any (to my knowledge), completely recapitulate human CKD. Consequently, promising compounds are generally tested in several animal models. Establishing the infrastructure to accomplish these early stages often involves critical collaboration with the sponsor and external groups, including academic and contract research organizations, that may already have much of the infrastructure in place. On average, only about 5 in 10,000 new molecules initially discovered in the laboratory successfully complete these early phases of development and enter the first stage of clinical testing (7). Phase I In this phase, promising new molecules shown to be safe and effective in animal models (and capable of meeting several other requirements, such as ones involving manufacturing, patents, etc.) are, after approval by regulatory authorities, first tested for initial safety in a small number of humans. Depending on several factors, particularly the preclinical profile, these studies may be conducted in healthy volunteers or patients with the target disease. In addition to preliminary safety data, information may also be obtained on pharmacokinetics and pharmacodynamics, including biomarkers relevant to the specific target and/or disease and rarely (because of the length of trials and numbers of subjects), the first hint of efficacy. Phase II Molecules successful in phase I next undergo testing in larger numbers of patients with the target disease to obtain more information on safety, pharmacokinetics, pharmacodynamics, and efficacy. In these phase II trials (and phase III trials), the novel therapy is generally added to an existing approved or generally accepted therapy. These trials may be particularly informative if reliable efficacy and safety biomarkers exist that may help determine a dose or dose range to be tested in subsequent trials and/or select patients who are at higher risk for more rapid progression of disease. In the case of CKD, it is not clear that many such biomarkers exist. Biomarkers and surrogate endpoints are discussed more below. Phase II trials are typically conducted in a few dozen to a few hundred patients. These patients are generally ones with few or no coexisting morbidities except for the target disease. The stringency of enrollment and inclusion/exclusion criteria may markedly affect the speed of enrollment in and thus, completion of phase II (and phase III) trials. These criteria are sometimes a significant source of tension between clinical investigators and sponsors. Phase III In this final phase in the development of a new drug before regulatory submission, the drug candidate is generally tested for safety and efficacy in a few to several thousand patients, which more typically reflect the target patient population. Pivotal losartan, irbesartan, and captopril clinical trials lasted over 4 years (4–6). Presumably, a novel therapy for CKD would be tested in patients concomitantly receiving one of these drugs. Using similar endpoints that supported approval of these drugs, depending on the efficacy of the novel treatment, one would predict the length of clinical trials for the new drug candidate to be at least of comparable or greater magnitude. In addition to showing efficacy, there is an increasing emphasis by regulatory authorities on providing more preapproval safety data. This emphasis along with increasingly complex clinical trial protocols (8) contribute to the time and escalating cost of late-phase clinical development. Other Clinical Trials In addition to the above trials, regulatory submissions for a novel drug generally contain a few to several dozen other clinical trials, such as ones specifically related to drug metabolism, drug formulations, pharmacokinetics, pharmacodynamics, drug–drug interactions, special patient populations, pharmacoeconomics, or other scientific questions, such as tissue imaging, etc. Approval by regulatory authorities elsewhere in the world may require additional clinical trials or other information not required by the FDA. The total time involved in the clinical testing of a new drug candidate is about 7 years (7,8). If the drug candidate is found to be safe and effective, a data package is submitted to regulatory authorities for review. In the United States, this is a New Drug Application. The entire New Drug Application or dossier submitted to other regulatory authorities is extraordinarily large and contains not only clinical trial data but also information on preclinical development, manufacturing processes, etc. The review process typically takes 1.5 years. If the submission is approved by regulatory authorities, the drug may be marketed. Thus, the total time involved in the development and review process is about 15 years. Only about one in five drug candidates or less that initially enter clinical testing are eventually approved by the FDA (7,8). The success rate is higher and the development cost is lower for biologics than small molecules (8,12). Although there may be some controversy about how costs are calculated, it is clear that the entire research and development costs to bring a novel drug to market are in the range of several hundreds of millions to well over $1 billion (7,8,13,14). Being shown to be safe and effective is necessary for regulatory approval, but alone, it does not ensure the therapy will be successful in the marketplace. The new therapy must also be shown to be cost-effective compared with extant therapies for payers to provide reimbursement for the new drug, a process that requires pharmacoeconomic analysis and market-oriented clinical trials (8,15). After the drug is on the market, companies have only a few years to recover their research and development costs and make a profit for their shareholders before patents or market exclusivity time periods expire and generic compounds may become available (16). Only a minority of new drugs making it to the market generate revenues equal to average industry research and development costs (8). Given the above considerations, some have questioned whether current methods of developing new drugs are sustainable and have offered suggestions on how to improve the process, particularly in those areas that represent the greatest innovation and thus, the greatest risks from a scientific and business standpoint (7,8,17,18). Some Opportunities There are some things that could be done to increase the pipeline of potential new drugs for patients suffering from CKD. The nephrology and CKD patient community is well aware of the need for new therapies. However, that need and potential market opportunity may not be as well understood in the corporate world. Payers should also have an interest in finding new drugs that could reduce the economic burden of CKD. Although I am cognizant of the potential for conflicts of interest, it seems to me that there is a need for more dialogue among members of the medical, academic, regulatory, patient, nephrology society, and business communities to educate each other about the need for new therapies for CKD and how they can all collaborate, using their specific areas of competence to discover and develop these new therapies. Importantly, successful development of new therapies requires contributions from these different groups. Although it may sound obvious, naïve, and almost trite, it is my experience that this sort of collaboration could be enhanced in the CKD arena. Decreasing timelines and costs of research are key to making the development of novel drugs for CKD more competitive with other therapeutic areas within the corporate world. One area that could be key is the discovery of better biomarkers to predict safety and efficacy and surrogate or new clinical endpoints that could be used in preclinical research and clinical trials (19,20). The most commonly used biomarkers previously used in CKD clinical trials are changes in albuminuria and proteinuria and ratios of these therapies with creatinine. Reduction in proteinuria seems to be predictive of (and may contribute to) efficacy in the case of the ACEi and ARBs (21), but whether it would be the case with drug candidates affecting other targets is less clear (22). Nevertheless, reduction in albuminuria (or urine albumin/creatinine ratios) has been used as an endpoint for a number of phase II trials of agents not primarily affecting the renin angiotensin system. Other endpoints used in recent phase II trials include changes in estimated GFR and changes from baseline serum creatinine concentrations. A listing of these trials may be found on the National Institutes of Health (NIH) clinical trials website (23). One advantage of these endpoints is that, presumably, they could be obtained in a shorter period of time than the endpoints used to support approval of ACEi and ARBs for diabetic nephropathy. Therefore, the main issue here is whether these types of data would provide a company with enough confidence to begin lengthy and expensive phase III trials using previously accepted or other endpoints and whether regulatory authorities would approve phase III trials based on those data. There is growing interest and activity in the biomarker field, and the potential for data in this area to facilitate the development of new therapies for kidney disease seems substantial. There are detailed reviews on this topic (24,25). There are well known opportunities to reduce regulatory review times. New therapeutic agents that provide major advances in treatment or provide treatment where no adequate therapy currently exists may be eligible for fast-track designation and priority review by the FDA (26). Novel drugs for CKD would seem to be obvious candidates for these processes. In addition, if acceptable surrogate endpoints could be identified, new drugs might receive accelerated approval by the FDA, wherein the drug receives conditional approval for marketing. Final (traditional) approval is contingent on phase IV trials providing confirmatory evidence with hard endpoints that the new therapy results in clinical benefit. Otherwise, the therapy may be withdrawn from the market (26). The endpoints that constituted the basis for approval in phase III trials with the ARBs were the composite of a doubling of the baseline serum creatinine concentration, ESRD, or death (5,6). Obviously, the key issue here is identification of a surrogate endpoint in which regulatory authorities and the sponsor are confident. Whether other endpoints, such as changes in albuminuria or measured or estimated GFR (22,27), would be accepted as surrogate endpoints for slowing the progression of CKD by regulatory authorities, corporate sponsors, and clinical investigators requires validation, which to my knowledge, has not yet been accomplished. It is, of course, possible that these or other endpoints could be used for registration in the absence of their validation as surrogate endpoints. However, the drug label would only allow a company to market the drug for the endpoints shown to be altered in clinical trials, and whether this labeling would provide a sufficient commercial opportunity to justify the cost of development is the major question that would need to be assessed by the sponsor. A more in-depth discussion of the topic of surrogate endpoints for clinical trials of CKD progression is in ref. 22. Clearly, if other endpoints, surrogate or clinical, could be identified that would result in more efficient and shorter clinical trials, these endpoints would provide incentive for development of new drugs for CKD. More academic, industry, and governmental collaboration for the development and validation of new genetic and biomarkers for CKD and AKI is needed. The CKDGen consortium (28) and the Chronic Kidney Disease Biomarker Discovery and Validation Consortium funded by the NIH (29) provide two examples. Several of the areas mentioned, including clinical trial design and endpoints, biomarkers, opportunities for partnership between the corporate, academic, and regulatory communities, some drug candidates in clinical development, etc., were topics of discussion at a recent NIH-sponsored conference (30). Conclusion It has been almost 20 years since the captopril trial and over 10 years since the losartan and irbesartan trials in diabetic nephropathy were reported (4–6). Again, none of these drugs were initially developed for CKD. Patients with CKD are waiting for novel therapies to be developed. Success in this effort would be facilitated by a greater understanding of the medical and economic needs by all parties required for and benefitting from such development, the challenges involved for each party, and how more collaboration can be fostered to reduce the impediments to such development. The needs of patients are too great for this effort not to succeed. Disclosures T.D.M. is retired from Eli Lilly and Company as a Distinguished Medical Fellow and is a former Professor of Medicine and Nephrology Division Director at Indiana University Medical Center.