Edited by: Agnieszka Swiatecka-Urban, University of Pittsburgh School of Medicine, USA
Reviewed by: Rachel Lennon, University of Manchester, UK; Dagmara Borzych-Duzalka, Medical University of Gdansk, Poland; Abubakr A. Imam, Hamad Medical Corporation, Qatar
Specialty section: This article was submitted to Pediatric Nephrology, a section of the journal Frontiers in Pediatrics
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Focal segmental glomerulosclerosis (FSGS) is a renal pathology finding that represents a constellation of rare kidney diseases, which manifest as proteinuria, edema nephrotic syndrome, hypertension, and increased risk for kidney failure. Therapeutic options for FSGS are reviewed displaying the expected efficacy from 25 to 69% depending on specific therapy, patient characteristics, cost, and common side effects. This variability in treatment response is likely caused, in part, by the heterogeneity in the etiology and active molecular mechanisms of FSGS. Clinical trials in FSGS have been scant in number and slow to recruit, which may stem, in part, from reliance on classic clinical trial design paradigms. Traditional clinical trial designs based on the “learn and confirm” paradigm may not be appropriate for rare diseases, such as FSGS. Future drug development and testing will require novel approaches to trial designs that have the capacity to enrich study populations and adapt the trial in a planned way to gain efficiencies in trial completion timelines. A clinical trial simulation is provided that compares a classical and more modern design to determine the maximum tolerated dose in FSGS.
Focal segmental glomerulosclerosis (FSGS) manifests with proteinuria, hypertension, and in the worse cases progresses to kidney failure. FSGS is a renal pathology finding that represents a constellation of rare kidney diseases and results in a significant public health burden accounting for 5% of adults and 12% of children with incident end stage kidney disease (ESKD) in the US annually (
Despite the significant patient and health burden, there is a paucity of therapeutic options for those with FSGS. Therapies available include immunosuppression, renin–angiotensin–aldosterone blockade, lipid lowering agents, and other blood pressure lowering agents as necessary. Unfortunately, the available immunosuppression therapies have a significant toxicity profile that may be dose limiting. Side effects, such as those altering physical appearance (e.g., alopecia, hirsutism, and weight gain) or physical function (e.g., weakness, tremor, and infertility), may contribute to poor adherence. These decisions are further complicated by those with monogenetic forms of FSGS, who may respond to immunosuppression therapy, but at very low rates (
A number of underlying biological mechanisms, multiple causes of FSGS, and side effect profiles contribute to the present day challenge of identifying effective and acceptable treatments. Globally, research teams are seeking a better understanding of the underlying biological mechanisms of subgroups of patients with FSGS that may provide targets for future therapy (
A majority of therapies for FSGS (Table
Proteinuria remission (%) | Cost (1) | Monitoring (2) | |
---|---|---|---|
Corticosteroids | 25–59 | $ | + |
Calcineurin inhibitors | |||
Cyclosporine | 46–69 | $$$ | ++ |
Tacrolimus | $$$ | ++ | |
Mycophenolate | 33 | $$ | ++ |
Cyclophosphamide | 27–55 |
$ | +++ |
ACTH | 29 |
$$$$$ | + |
Rituximab | 38 |
$$$$ | + |
The initial selection of an appropriate therapeutic regimen by the treating physician is related to the anticipated likelihood of disease control (proteinuria resolution, preservation of kidney function) and the safety profile of the therapeutic agent. In the absence of more precise biomarkers, the subsequent tailoring of therapeutic regimens for patients are driven by disease characteristics (treatment response), side effect profile, or cost/convenience factors. Table
Medication | Common side effects |
---|---|
Corticosteroids | Weight gain, hyperglycemia, hypertension, osteopenia, mood changes, weakness |
Calcineurin inhibitors |
|
Cyclosporine | Hypertension, gingival hyperplasia, hypertrichosis, infection |
Tacrolimus | Hypertension, infection, tremor |
Mycophenolate | Nausea/diarrhea, leukopenia, teratogenic, infection |
Cyclophosphamide | Nausea, leukopenia, infection, alopecia, teratogenic |
ACTH | Weight gain, hypertension, rash, acne, hypertrichosis, mood changes, weakness |
Rituximab | Infusion reaction, infection, leucopenia |
Since the Orphan Drug Act was passed in 1983, an increased number of drugs and biologics have been approved for rare diseases in the US (
Although there is an ethical imperative to hold clinical trials in rare diseases to rigorous ethical and scientific standards, analyses of rare vs. non-rare clinical trials indicate that there are differences in design characteristics. Trials in orphan drugs are more likely to be smaller, non-randomized, lack blinding, and use disease response instead of progression or survival endpoints (
The utilization of traditional clinical trial designs may not be appropriate for rare diseases. Fortunately, a myriad of design and analysis options (see Table
Term | Brief description |
---|---|
3 + 3 trial design | A conventional and popular phase 1 dose escalation design that estimates the MTDa by sequentially studying cohorts of size 3 |
Adaptive design | A clinical study design that uses accumulating data to decide how to modify aspects of the study as it continues, without undermining the validity and integrity of the trial ( |
Bayesian methods | Bayesian methods use prior information on the differences between treatments before the trial is completed, and update this information based on data obtained from the trial. The difference between treatments is not a single fixed parameter in the Bayesian approach; rather, a distribution of potential values characterizes treatment differences |
Continual reassessment method (CRM) | CRM is an adaptive dose-finding study design that uses Bayesian methods to estimate the MTD. It frequently results in fewer adverse events and more accurately estimates the MTD |
Crossover design | A clinical trial design in which participants receive a sequence of different treatments, resulting in within-subject comparisons that generally reduced the required sample size. This design is in contrast to the parallel-group design where participants receive only one protocol-specified treatment |
Dose limiting toxicity (DLT) | Severe but (ideally) reversible adverse events that occur within a generally short protocol-defined period |
Frequentist methods | A framework of statistical inference that is generally taught in most introductory statistical courses, that treats the difference between treatments as an unknown and fixed parameter. Clinical trial results are considered from the perspective of multiple independent repetitions of the experiment which sometimes cause difficulties in the interpretation of results |
“Learn and confirm” clinical trial paradigm | An alternative to the traditional “phased” approach to drug development (i.e., phase 1, 2, and 3). The goal of the learning phase is to assess the relationship between the dose and administration of a new drug and its expected efficacy and safety. The goal of the confirming phase is to capitalize on the more complete information obtained in the learning phase to efficiently study the risk-benefit of the new agent |
Maximum tolerated dose (MTD) | The highest dose of a drug or treatment that does not cause unacceptable side effects ( |
N-of-1 design | Single-subject clinical trial that has the goal of determining the best intervention for an individual patient based on objective criteria |
Seamless trial designs | Clinical trial designs that address, within a single trial, objectives that are normally achieved through separate trials |
Classical drug development employs a “learn and confirm” paradigm over a series of steps. The drug development pipeline begins with discovery with preclinical
This classical drug development process is often not feasible in rare diseases. In this setting multistage designs, particularly adaptive designs, and seamless phase 1/2 or phase 2/3 trials may be used to maximize information while minimizing the strain on the available patient population [based on Orloff et al. (
These novel designs have been successfully used in a variety of therapeutic areas, including rare and common diseases. A modification of the time-to-event CRM approach (TITE-CRM) was used in a phase 1 study of continuous MKC-1 in patients with advanced or metastatic solid malignancies (
A common approach to the testing of novel agents for FSGS or other conditions will select a patient sample that has demonstrated resistance to standard therapies, positioning the novel agent as a salvage therapy. Depending on the investigational drug target, this approach may doom the agent to failure as the patients on study may have already entered a late or irreversible phase of the disease. FSGS targeted therapies may be best suited to patients in early or mid-disease where the potential for the drug to demonstrate activity against a molecular target can be shown. Enrichment designs represent a unique opportunity in FSGS by selecting patients who are more likely to respond to therapy, based on specific biomarkers. Such designs reduce sample size by reducing patient heterogeneity, improving the chance of successful enrollment. The development of biomarkers and targeted agents targeted agents in earlier phases of drug development in FSGS should help in assessing whether this strategy would be advantageous in later confirmatory stages (
Finally, FSGS affects patients of all ages. As the implications of uncontrolled FSGS resulting in kidney failure are similar across the lifespan, drug development strategies should include children in every setting where drug safety has not shown specific additional risk in immature preclinical testing.
The goal of FSGS therapies is the normalization of urinary protein excretion [measured urine protein/creatinine ratio (UP/C)], preservation of kidney function (
During the learning phase of drug development in FSGS, we investigate the correct dose range by investigating preliminary efficacy and ensuring that the drug meets minimal requirements for dose-limiting toxicity and tolerance. In the confirmatory phase, the goal is to obtain sufficient efficacy and safety information in well-controlled trials to support its acceptance. The control group may be placebo (superiority trials) or an active control (superiority, non-inferiority, or equivalence trials). The highest levels of medical evidence are achieved through the use of randomization, blinding, and concurrent controls, and there should be strong rationale for
Crossover designs and N-of-1 trials have been suggested for rare diseases (
The impact of design and analysis decisions should be fully evaluated. Frequentists calculate sample size based on the hypothesis testing framework that specifies the type I error, power, and expected treatment difference. The Bayesian approach does not employ a strict need to calculate sample size because the goal is to update prior beliefs about the null hypothesis with the data. In past FSGS trials, the traditional, equal-allocation, fixed sample-size design was most commonly used. Clinical trials simulations can be used for future trials to assess the tradeoffs between frequentist and Bayesian options, assessing characteristics of the design for specific agents and phases, such as probability of stopping for futility incorrectly and sample size options to achieve a certain decision criterion.
An adaptive design is defined as “a clinical study design that uses accumulating data to decide how to modify aspects of the study as it continues, without undermining the validity and integrity of the trial” (
In early phases of FSGS development, the following adaptive approaches may be most useful:
Adaptive designs that may be more useful during later stage drug development in FSGS include
The difference between treatments is assumed to be an unknown and fixed parameter in the frequentist framework, whereas the treatment difference is not a single fixed parameter in the Bayesian approach. It is characterized by a distribution of potential values (
A key stumbling block in Bayesian methods is elicitation of the prior distribution of the treatment difference and the degree of certainty and subjectivity (
Both the use of adaptive design methods and the Bayesian approach in clinical trials is consistent with the FDA’s
One context where using adaptive and Bayesian methods in clinical trials can benefit advances in FSGS therapies is in dose-finding trials. The methods that are used for dose-finding trials in non-rare diseases could be costly and imprecise. We can reduce the sample size needed for estimating the maximum tolerated dose while maintaining precision by using the CRM first presented by O’Quigley et al. (
The two main goals of dose-finding clinical trials are to put as many subjects as possible in the dose closest to the maximum tolerated dose (MTD) and to estimate the MTD as accurately as possible. The MTD is defined by the National Cancer Institute as “the highest dose of a drug or treatment that does not cause unacceptable side effects” (
As described by Storer (
The CRM is an adaptive and Bayesian method for dose-finding trials in which we use prior information combined with collected data to help find the MTD (Bayesian) and give future subjects doses based on estimates from collected and prior information (adaptive). After each subject is enrolled and treated, the outcome information is combined with prior information and previous outcomes to update the dose–response curve from which the MTD is estimated and given to the next subject. The sample size in CRM can be fixed or variable. To provide a fairer comparison with the 3 + 3 design, we used an early stopping rule to select the estimated MTD as the dose which is assigned seven times in the trial (which limits the maximum sample size to 24). Stopping rules of this kind were first used by Korn et al. (
For both 3 + 3 and CRM designs, we ran 10,000 trial simulations for four different true DLT probability scenarios. For each scenario, we compared the proportions of dose selected, the proportion of doses assigned, and the average and SD of sample sizes for both designs. We chose to always include the MTD of interest as one of the doses in our simulations for ease of comparison of trial types. The simulations were run using R and the package dfcrm created by Cheung (
In Scenario 1, the CRM selects the correct dose about 62% of time where the 3 + 3 design identifies the MTD just under 35% of the time (Table
Dose scenario | Design | Dose |
|||
---|---|---|---|---|---|
1 | 2 | 3 | 4 | ||
Scenario 1: (0.00, 0.30, 0.40, 0.60) | 3 + 3 | 50.3 | 14.6 | 0.6 | |
CRM | 10.9 | 24.1 | 2.8 | ||
Scenario 2: (0.05, 0.05, 0.30, 0.30) | 3 + 3 | 5.0 | 48.6 | ||
CRM | 6.1 | 21.5 | |||
Scenario 3: (0.05, 0.10, 0.15, 0.30) | 3 + 3 | 11.7 | 16.5 | 41.3 | |
CRM | 7.1 | 12.9 | 37.6 | ||
Scenario 4: (0.00, 0.25, 0.30, 0.45) | 3 + 3 | 39.7 | 30.6 | 4.6 | |
CRM | 5.9 | 47.8 | 12.4 |
The CRM tends to have about 12 subjects needed for the trial with SDs around 2 for all scenarios investigated (Table
Dose scenario | Design |
|
---|---|---|
3 + 3 | CRM | |
Scenario 1: (0.00, 0.30, 0.40, 0.60) | 10.1 (3.2) | 12.0 (1.7) |
Scenario 2: (0.05, 0.05, 0.30, 0.30) | 13.3 (3.5) | 11.8 (2.0) |
Scenario 3: (0.05, 0.10, 0.15, 0.30) | 14.4 (3.7) | 11.9 (2.2) |
Scenario 4: (0.00, 0.25, 0.30, 0.45) | 11.3 (3.7) | 12.1 (1.7) |
Our small simulation study shows the advantages of a Bayesian adaptive approach (CRM) over a more traditional clinical trial dose-finding design (3 + 3) in terms of assigning as many patients to the MTD as possible and selecting the correct MTD. In the long term, using the CRM over the 3 + 3 design could lead to enormous financial and time savings by increasing the probability that we move to further phases of clinical trials with the correct dose. Although there is no clear winner between the trial types for sample size under all scenarios investigated (Table
Focal segmental glomerulosclerosis therapies are challenging based on incomplete efficacy and safety information, leading to the inability to define the right agent for the right patient. Novel agents that are based on molecular profiling are emerging which will benefit from an enriched trial eligibility approach. While enrichment may improve signal, trials will need to be designed for feasibility in FSGS endophenotypes defined by molecular profiling and target-relevant biomarkers. Rational application of more modern clinical trials designs, that have found increasing acceptance in the pharmaceutical, regulatory, and academic environments, increases the chance of successful studies that evidence of safe and effective therapies in rare diseases, such as FSGS.
All authors give final approval to publish this work and agree to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. CS, JJ, DS, SM, JT, and DG: conception and design of the work, drafting the work, and revising it critically for important intellectual content.
DG serves as a consultant under contract between University of Michigan and the following companies: GlaxoSmithKline, Bristol-Myers Squibb, Janssen, and Retrophin. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
CS, JT, DS, SM, and DG are supported in part by a grant from NephCure Kidney International non-profit to the University of Michigan.