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Nonalcoholic Steatohepatitis: Current Thinking from the Division of Hepatology and Nutrition at the Food and Drug Administration
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Frank A. Anania, Lara Dimick-Santos, Ruby Mehta, Joseph Toerner, and Julie Beitz
From the Center for Drug Evaluation and Research Office of New Drugs, Office of Inflammation and
Immunity, Division of Hepatology and Nutrition, US Food and Drug Administration, Silver Spring, MD.
Abstract
As part of a larger reorganization of the US Food and Drug Administration (FDA) Center for Drug Evaluation and Research (CDER) Office of New Drugs, the former Division of Gastroenterology and Inborn Errors Products (DGIEP) has been divided into three review divisions with more focused disease areas, including the new Division of Hepatology and Nutrition (DHN). DHN's review activities are focused on three general areas: (1) drug development and review of early and late phase clinical trials of drugs for treatment of specific diseases of the liver, (2) consultations from any FDA review division on drug‐induced liver injury (DILI), and (3) development and review of early and late phase clinical trials for nutrition products.
As part of a larger reorganization of the US Food and Drug Administration (FDA) Center for Drug Evaluation and Research (CDER) Office of New Drugs, the former Division of Gastroenterology and Inborn Errors Products (DGIEP) has been divided into three review divisions with more focused disease areas, including the new Division of Hepatology and Nutrition (DHN). DHN's review activities are focused on three general areas: (1) drug development and review of early and late phase clinical trials of drugs for treatment of specific diseases of the liver, (2) consultations from any FDA review division on drug-induced liver injury (DILI), and (3) development and review of early and late phase clinical trials for nutrition products.
As part of a larger reorganization of the US Food and Drug Administration (FDA) Center for Drug
Evaluation and Research (CDER) Office of New Drugs, the former Division of Gastroenterology and
Inborn Errors Products (DGIEP) has been divided into three review divisions with more focused disease
areas, including the new Division of Hepatology and Nutrition (DHN). DHN's review activities are
focused on three general areas: (1) drug development and review of early and late phase clinical trials of
drugs for treatment of specific diseases of the liver, (2) consultations from any FDA review division on
drug-induced liver injury (DILI), and (3) development and review of early and late phase clinical trials for
nutrition products.
DHN views nonalcoholic steatohepatitis (NASH) with liver fibrosis as a serious and life-threatening
condition. NASH with liver fibrosis affects more than 5 million people in the United States and is an
important area of investigational drug development. DHN reviews drug development programs for NASH
and is committed to the collaborative work needed to fill this critical unmet medical need. Drug
development for treatment of NASH can be challenging due to the gradual, slow progression of fibrosis
in the liver over years to decades. The magnitude of the benefit a patient receives with lifelong treatment
of NASH must be balanced with the safety profile of the drug. NASH patients are also vulnerable to other
diseases (1), and the investigational drug should not worsen comorbidities, including cardiovascular
disease, hyperlipidemia, metabolic disease, and diabetes, or cause liver injury.
The accelerated approval pathway for drugs intended to treat NASH with liver fibrosis is appropriate
because of the seriousness of the condition. Accelerated approval relies on adequate and well-controlled
clinical trials establishing that the drug affects a surrogate endpoint that is reasonably likely to predict
clinical benefit. A post-marketing clinical outcomes trial to verify the drug's clinical benefit should be
under way before the phase 3 trial data is submitted for review. The outcomes trial must also be adequate
and well controlled and carried out with due diligence (2).
While many non-invasive biomarkers are under study for consideration as a surrogate marker, none to
date have demonstrated reliability and consistency to be reasonably likely to predict clinical benefit, that
is, can be used as a surrogate efficacy endpoint for accelerated approval while post-marketing trials
confirm clinical benefit based on how a patient feels, functions, or survives. Sponsors should use noninvasive
biomarkers in clinical development, from proof-of-concept early phase 2 studies to their use as
secondary or exploratory endpoints in late stages of drug development (i.e., dose-finding or phase 2b
trials and phase 3 trials). We encourage use and evaluation of non-invasive biomarkers in any clinical
development program with a goal to describe and characterize a non-invasive biomarker with reliable
and consistent findings to be considered for use as a surrogate efficacy endpoint reasonably likely to
predict clinical benefit.
DGIEP issued a 2018 draft guidance on developing drugs for treatment of NASH with liver fibrosis.(3)
For NASH with moderate or bridging fibrosis (fibrosis stages 2 and 3 [F2 and F3]), the accelerated
approval pathway was offered as a potential route for approval based on the following histologic
endpoints:
(1) resolution of steatohepatitis (on overall histopathological reading) and no worsening of liver
fibrosis based on the NASH Clinical Research Network (CRN) fibrosis score,
(2) improvement in liver fibrosis greater than or equal to one stage (NASH CRN fibrosis score) and no worsening of
steatohepatitis,
or
(3) both resolution of steatohepatitis and improvement in fibrosis (as defined above).
These surrogate endpoints were based on the published Kaplan-Meier curve demonstrating reduced
overall survival and increased liver-related mortality that occurred with more advanced fibrosis.(3,4)
Cirrhosis (fibrosis stage 4 [F4]) is highly predictive of a significantly increased mortality rate compared to
F3 or F2, but both F3 and F2 are associated with substantially higher mortality rates compared to no
fibrosis (stage 0 [F0]) or minimal fibrosis (stage 1 [F1]). Fibrosis also appears to predict liver-related
clinical outcomes (3), and a strong association between histologic resolution of steatohepatitis and
improvement in fibrosis has been observed and reported in the literature (4-6). Therefore, the surrogate
histologic endpoints in the draft guidance for NASH patients with F2 and F3 appear to be a reliable and
consistent surrogate endpoint reasonably likely to predict clinical benefit. Sponsors and academia are
encouraged to continue evaluation of potential noninvasive biomarkers with this capability.
The draft guidance on NASH represents DHN's current thinking on the development of drugs intended to
treat NASH. DHN encourages sponsor engagement during the planning and conduct of NASH trials.
Despite well-recognized limitations, liver histology read by an experienced hepatopathologist remains the
gold standard for the classification of patients with F2 or F3. These limitations include but are not limited to
the following: (1) substantial (~40%) sampling error (7), that can result in disease severity being
misclassified and (2) inadequate samples with respect to length of the biopsy (8) and the number of portal
areas captured. Additional important challenges include differences in the interpretation of liver histology
findings among several pathologists (e.g., potential for low inter-reader concordance rate) and even with
their own previous interpretation of findings (intra-reader variability).
The inter-reader concordance rate for key components of both the nonalcoholic fatty liver disease
score (NAS)(5) (inflammation, ballooning, and steatosis) as well as the NASH fibrosis score (or stage)
can vary widely.(9) Conceivably, a high degree of discordance in liver histology interpretation could be
improved by pathologists' training, for example, having an adjudication committee of central pathologists
read baseline and treatment slides together and decide how each of the components of the NAS
system will be interpreted. Such training efforts, along with inclusion of a placebo control in the trial
design, should help to address many of the limitations of the histopathology reading of liver biopsies
and have liver histology be considered as a reliable and consistent surrogate efficacy endpoint. We
recommend sponsors review in detail their plan for liver biopsy procurement, processing, and
interpretation before embarking on their phase 3 trial.
Furthermore, NASH is a common disease, and trials that provide a sufficiently large preapproval
safety database will facilitate the assessment of risk and benefit. In accordance with the International
Conference on Harmonization (ICH) E1A guidance (10) which recommends a minimum number of
patients who should be enrolled in a trial for drugs intended for chronic administration, the size of the
preapproval safety database should ensure that low-frequency adverse event(s) can be detected and
appropriately described for an assessment of risk and benefit. Sponsors should be aware that the size of
one placebo-controlled trial adequately powered for efficacy might not be sufficient to support the drug's
safety and allow for the overall benefit-risk assessment that is necessary for drug approval; this is a
particular concern in NASH, in which millions of patients would be treated with the new drug, once FDA
approved.
Generally, premarketing trials for NASH plan to evaluate the histology surrogate endpoint at 12 to 18
months of treatment, and FDA's draft guidance endorses this approach. However, given the slow
gradual progression or improvement in inflammatory changes and fibrosis observed on liver
histopathology, sponsors might want to consider efficacy evaluations of the surrogate histopathologic
endpoint at 2 or more years because of subtle changes in histologic features associated with the disease.
Moreover, trials should be designed to follow patients who continue their randomized treatment
assignments (e.g., investigational drug or placebo in a double-blinded fashion) for clinical outcome
assessments in the post-market setting to be able to confirm clinical benefit following accelerated
approval. There are obvious challenges associated with this approach, for example, reconsenting patients
enrolled in the trials to ensure awareness of the availability of an FDA-approved drug under accelerated
approval. However, drug labeling under accelerated approval is required to have cautionary statements
that clinical benefit has not been confirmed, thereby demonstrating to patients, investigators, and
institutional review board committees that it may be ethically appropriate, if not highly desirable, to
continue randomized treatment assignments after an accelerated approval and minimize loss to follow-up.
Furthermore, in phase 3 development programs with large enough trial(s), confirmation of clinical
benefit and traditional approval could occur during a relatively short period of time after accelerated
approval.
Clinical outcomes conferring benefit in post-marketing studies were listed in both the noncirrhotic NASH
with fibrosis guidance (2), and the guidance for NASH-related compensated cirrhosis. (11) If a product
merits accelerated approval for NASH based on the histologic efficacy endpoints, the accelerated
approval pathway requires a phase 4 clinical outcomes trial to verify clinical benefit. The phase 4 trial is
a randomized, double-blind, placebo-controlled study in which patients are followed on the drug to
determine clinical outcome assessments. These outcome assessments include decompensation events
associated with progression of NASH, such as a slowing of progression to cirrhosis, reduction in hepatic
decompensatory events (variceal bleeding, ascites, hepatic encephalopathy, etc.), improvement in
Model for End-Stage Liver Disease (MELD) score (from ≤12 to ≥15), reduction in death (all-cause
mortality), and need for liver transplantation. Success of the phase 4 trial verifying clinical benefit
conveys full-market approval of the sponsor's drug.
Sponsors should be aware of the impact of how the standard of care (SOC) permitted in caring for all
NASH patients enrolled in a clinical trial could impact a placebo response rate. This is likely within
developed countries and could be influenced by cultural differences that may influence how individuals in a
placebo cohort respond to or participate in SOC measures in NASH clinical trials. Published literature
indicates that a substantial number of patients in placebo cohorts achieve histological improvement (12), on
liver biopsies obtained during study treatment—that is, a substantial number of placebo-treated patients
often meet a successful finding on the surrogate endpoint. Trial participation may represent a favorable
environment for patients with NASH to receive and willingly follow dietary counseling advice and
embark on exercise programs that result in weight reduction. As a result, trial participation could result in
a higher than expected placebo response rate and a lower than expected observed treatment difference
from the investigational drug. Therefore, it is important to ensure that the SOC is uniform across all
treatment arms as described in published guidelines by authoritative scientific bodies13, and
differences in SOC should be considered when analyzing international trials (e.g., stratification by
geographical/cultural areas).Sponsors should account for such differences in SOC across geographic
areas to appropriately power their phase 3 studies and account for these issues.
Summary
FDA's draft guidance for noncirrhotic NASH, issued in December 2018, provides our current
thinking on clinical trials conducted in the support of successful approval of new drugs for NASH
with F2 and F3. Phase 3 studies demonstrating a successful treatment difference on liver histology
surrogate endpoint(s) and an adequate safety profile can receive an accelerated approval with a
requirement to verify and confirm clinical benefit after approval. For clinical trials in compensated
cirrhosis secondary to NASH, we continue to recommend a traditional approval pathway based on
improvement in clinical benefit outcomes. DHN is open to discussions with sponsors about other options
for approval for this population.
Limitations in clinical trials for marketing approval of NASH drugs include a current lack of surrogate endpoint biomarkers other than liver histology. Although liver histology remains the gold standard, the
shortcomings of liver histology interpretation can lead to significant discordance among blinded
hepatopathologists. Sponsors should provide additional reassurance that the histologic endpoint is reliable
and consistent, for example, by use of an adjudication committee of at least two pathologists trained in
evaluating liver biopsy. Study duration and follow-up of patients in liver histology trials can be challenging
and impose undue burdens. Nonetheless, well-designed and adequately controlled trials are essential, not
only for efficacy assessment but also for accruing a safety database that ensures that a thorough benefit-risk
assessment can be conducted given the likelihood that any drug approved for NASH will be a lifelong
therapy in patients. The published literature also suggests that patients in placebo treatment arms may
have a higher than expected success rate in achieving primary histologic endpoints. Whether this is a result
of clinical trial participation is not fully known. However, sponsors may want to be more explicit in
standardizing SOC maneuvers across all treatment arms. Finally, because many patients with NASH
have comorbid conditions that could be adversely affected by a potentially lifelong NASH treatment,
clinical outcomes trials are essential for verifying and establishing the clinical benefit of successful
findings on a surrogate endpoint resulting in accelerated approval. NASH with fibrosis is a serious
condition, (14) and therefore sponsors are encouraged to meet with DHN at key stages of drug
development and avail themselves of FDA's expedited drug development programs.
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