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Accelerating the Drug Delivery Pipeline for Acute and Chronic Pancreatitis—Knowledge Gaps and Research Opportunities

Overview Summary of a National Institute of Diabetes and Digestive and Kidney Diseases Workshop

Uc, Aliye, MD*; Andersen, Dana K., MD; Borowitz, Drucy, MD; Glesby, Marshall J., MD, PhD§; Mayerle, Julia, MD; Sutton, Robert, DPhil; Pandol, Stephen J., MD#

doi: 10.1097/MPA.0000000000001176
Conference Reports

A workshop was sponsored by the Division of Digestive Diseases and Nutrition, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, on July 25, 2018, in Pittsburgh, Penn. The workshop was designed to bring together a multidisciplinary group of experts to accelerate the development of therapeutics for clinical application in inflammatory diseases of the exocrine pancreas. Three separate working groups (acute pancreatitis, recurrent acute pancreatitis, and chronic pancreatitis) were formed to address the needs, gaps, and opportunities. The working groups included patients with pancreatic diseases, pharmaceutical company leaders, basic scientists, clinical researchers, and representatives from the US Food and Drug Administration to assist with regulatory considerations and to identify the unmet needs, research targets, and opportunities to provide direction for successful development of therapeutic agents in these diseases. This article represents the summary of the overview presentations at the National Institute of Diabetes and Digestive and Kidney Diseases workshop including an ongoing drug trial in acute pancreatitis; a successful drug development network developed by the Cystic Fibrosis Foundation; and considerations for subject selection in drug trials, incorporating Food and Drug Administration guidelines on clinical trial design and clinical outcome measures. The summaries of each working group follow separately in accompanying articles.

From the *Division of Gastroenterology, Hepatology, Pancreatology, and Nutrition, Stead Family Department of Pediatrics, University of Iowa Carver College of Medicine, Iowa City, IA;

Division of Digestive Diseases and Nutrition, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health; and

Cystic Fibrosis Foundation, Bethesda, MD;

§Division of Infectious Diseases, Department of Medicine, Weill Cornell School of Medicine, New York, NY;

Department of Medicine II, Ludwig Maxmilian University and Polyklinik, Munich, Germany;

Royal Liverpool University Hospital and Institute of Translational Medicine, University of Liverpool, Liverpool, United Kingdom; and

#Division of Digestive and Liver Diseases, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA.

Received for publication August 1, 2018; accepted August 28, 2018.

Address correspondence to: Aliye Uc, MD, Stead Family Department of Pediatrics, The University of Iowa Carver College of Medicine, BT1120-C, 200 Hawkins Dr, Iowa City, IA 52242 (e-mail:

Research reported in this publication was supported by National Institute of Diabetes and Digestive and Kidney Diseases under award numbers R21 DK096327, U01 DK108334, R01 DK097820, DK108314, PePPP Center of Excellence MV ESF/14-BM-A55-0045/16; ESF MV V-630-S-150-2012/132/133); and DFG RTG 1947/A3. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

A.U. is a member of American Board of Pediatrics, Subboard of Pediatric Gastroenterology. R.S. is a consultant for AbbVie, CalciMedica, Cypralis, EA Pharma, GlaxoSmithKline, Lilly, and Novartis; R.S. has received research funding from Cypralis, GSK, and Merck; all resources and/or funds for the above have been gifted/paid to the University of Liverpool and/or Royal Liverpool and Broadgreen University Hospitals NHS Trust. The other authors declare no conflict of interest.

Inflammatory diseases of the pancreas, including acute, recurrent acute, and chronic pancreatitis, are costly and associated with significant morbidity and mortality. Despite the early promise of potentially beneficial medical therapies, currently there are no approved drugs that can alter the disease course or prevent progression to chronic inflammation, exocrine and endocrine dysfunction, or neoplasia. Through workshops sponsored by the National Institute of Diabetes and Digestive and Kidney Diseases, numerous gaps in knowledge have been identified in our understanding of the disease mechanisms in pancreatic inflammatory processes.1–4 These workshops stressed the importance of identifying drug targets that could be developed and tested to alter the natural history of pancreatitis. Potential therapeutic targets include reversing the effects of inherited gene mutations, abrogating the acute and chronic pancreatic inflammation, and reversing fibrosis, to name just a few.

There are several challenges in drug development for pancreatitis. To demonstrate that a pancreatitis drug is clinically efficacious, a clinical trial should capture subjects at the same stage of disease, at a time point when the outcome of the disease can be altered, and avoid numerous confounders related to the etiology and severity of the disease or the symptoms that are present. Moreover, there are no pancreatitis-specific guidelines available from the Food and Drug Administration (FDA) to inform investigators or commercial entities who seek to improve the outcomes of acute, recurrent acute, or chronic pancreatitis. Therefore, the current workshop “Accelerating the Drug Delivery Pipeline for Acute and Chronic Pancreatitis—Knowledge Gaps and Research Opportunities” was organized to bring together clinical investigators, basic scientists, representatives of the FDA, patients and patient advocates, and representatives of the pharmaceutical industry to address the needs, challenges, and requirements for the development of clinical trials for the drug treatment of these diseases.

In many ways, acute pancreatitis, recurrent acute pancreatitis, and chronic pancreatitis represent 3 different disease entities. Therefore, the outcome measures that are the focus of any drug trial may differ substantially and range from prevention or recovery from the systemic inflammatory response and organ failure in acute pancreatitis, to the prevention of complications and reduction in the frequency of attacks in recurrent acute pancreatitis, to the relief of persistent symptoms, maintenance of function, and prevention of complications in chronic pancreatitis. Because histologic evidence of improvement is not feasible in the clinical setting, well-defined patient-reported outcomes (PROs), physician-reported outcomes, and surrogate outcomes are essential to make progress in the treatment of these diseases.

The workshop, which was held on July 25, 2018, in Pittsburgh, Penn, immediately before the annual PancreasFest meeting, consisted of a series of overview presentations that featured description of an ongoing drug trial in acute pancreatitis to illustrate the issues surrounding subject selection and outcome measures, a presentation that described the success of the Cystic Fibrosis Foundation (CFF) in the development of drug treatments and a network of research centers and collaborators for drug trials, a discussion of the variations in trial design that are relevant in these diseases, and a presentation from the FDA on considerations for clinical trial design and outcome measures. These introductory presentations, along with an overview of the requirements and examples of PRO measures, are summarized below in this article.

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Despite many randomized clinical trials (RCTs) and systematic reviews, there is no consensus method to predict the course of acute pancreatitis on admission,5 and there are no FDA-approved therapies that ameliorate, let alone abort, acute pancreatitis.6,7 These deficiencies are likely due to the choice of agent, the selection of a subset of patients with acute pancreatitis, and speed of treatment delivery in randomized trials.7,8 In addition, prior trials have lacked widely applicable outcome measures in all patients,7 not only those developing persistent organ failure lasting longer than 48 hours. The randomization of subjects in past clinical trials typically occurred from 72 to 120 hours after admission, which is very late in the treatment of a medical emergency, and was further complicated by inaccurate prognostic indices to stratify the severity of acute pancreatitis.8,9 The failure of prognostication that precludes an accurate stratification in clinical trials is in part due to the absence of studies using systems medicine approaches. A new clinical drug trial was therefore developed in an effort to overcome these problems and to include the prompt randomization and treatment in all patients presenting to the emergency room with acute pancreatitis.

Tumor necrosis factor α has a central inflammatory role in acute pancreatitis shown in animal models.10 Its role is also confirmed in patients with inflammatory bowel disease treated with anti–tumor necrosis factor biologics such as infliximab compared with those receiving nonbiologics.6,7,11 RAPID-I is the Randomized treatment of Acute Pancreatitis with Infliximab: Double-blind, multicenter trial that includes transcriptomic biomarker detection and mechanistic evaluation. The study is funded by the UK Medical Research Council (London, United Kingdom) and National Institute of Health Research (London, United Kingdom) with drug supplied by Merck Sharp and Dohme Corporation (Hoddesdon, United Kingdom). In this study, adult patients admitted with a new diagnosis of acute pancreatitis of all severities and pain for less than 24 hours prior to admission are randomized to receive a double-blind infusion of 5 mg/kg infliximab or 10 mg/kg infliximab or saline, begun within 12 hours of admission. Exclusion criteria are advanced comorbidities and/or conditions precluding infliximab administration. The primary (surrogate) outcome measure is the cumulative C-reactive protein values; the secondary outcome measures are pain, nutritional deficits, systemic inflammatory response syndrome/Sequential (Sepsis-related) Organ Failure Assessment scores, pancreatic injury on computed tomography scan, complications, and length of stay. The trial will have 2 interim analyses to determine whether to continue all treatment arms and, if so, will require recruitment of 290 patients (261 with an additional number to allow for dropouts and withdrawals). The study will have 90% power and 2.5% risk of type I error to detect a 25% drop in cumulative C-reactive protein values with infliximab treatment in either active treatment arm. Transcriptome, cytokine, and leukocyte subset analyses will be conducted to gain mechanistic insight and test for predictive and prognostic markers of severity and treatment response. RAPID-I is designed to address issues in the design of previous randomized trials of treatment for acute pancreatitis, the results of which are expected in 2021.

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Cystic fibrosis (CF) is a complex, multisystem disease involving a small population. The CFF supports clinical research activities involving CF that include a highly successful drug development pipeline,12,13 the Therapeutics Development Network (TDN),14 and investigator-initiated studies.

Several factors have enabled the CFF to succeed in development of new therapies (Fig. 1). A seminal first step was the consideration of key questions and defining primary and secondary outcomes.15 The priority for CFF was defining the pulmonary outcomes. The forced expiratory volume in 1 second was a surrogate for survival, the ultimate tangible outcome, and it was accepted by the FDA as a primary outcome. Thus, despite other options and issues about how to express the data, it became the accepted primary outcome.



The TDN has been critical in implementing clinical studies. It initially started as a small group of CF centers with clinical research expertise and expanded over time to now almost 90 sites. There is a coordinating center that serves as a clearinghouse for new studies, provides prestudy consultation and protocol review, creates standard operating procedures, manages metrics, assists with investigator-initiated multicenter studies, helps with protocol design and creation, provides statistical services, and manages budgetary and administrative issues. There are also national resource centers that provide standardization of secondary outcomes.

The TDN defined patient populations by developing inclusion criteria and exclusion criteria that considered known confounders and safety factors. Another factor in the CFF's success was that initially the lack of treatment options allowed for the study of totally drug-naive populations. The challenge now is that many CF patients are on multiple medicines, including cystic fibrosis transmembrane conductance generator modulators.

Through TDN, the CFF team was able to develop iterative protocols. Defining critical protocol elements and standard operating procedures enabled the TDN to avoid “reinventing the wheel each time.” Creating repeatable protocol designs helped build up a cadre of sites that were familiar with a variety of protocols.

The combination of the factors listed above enabled the CFF to have “early wins” and “success on success” that bred hope for change and enthusiasm among clinicians (who then aspired to become clinical researchers), coordinators, patients, and families.

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“If it were not for the great variability among individuals, medicine might as well be a science and not an art.” —Sir William Osler (1892) 16

Historically, clinical decision making was dictated by the clinician's experience, which was frequently biased and constrained by limitations in available scientific knowledge.

To overcome these limitations, clinical trials were introduced in the 18th century. A well-known example of an early case-control study performed by the Scotsman James Lind was the introduction of citrus fruits to prevent scurvy in the Royal Navy. However, it took another 200 years until the advent of RCTs in the 1940s to reduce bias through randomization and prospective data collection.17

The focus of traditional clinical trials is identified in the 1979 Belmont Report18—the bible of clinical research ethics—which emphasizes that clinical research is distinct from clinical practice. Similarly, the regulatory agencies are mandated to focus on safety and efficacy when evaluating medical products.19 The standards for determining safety and efficacy are the same for all diseases and conditions, regardless of the disease prevalence. A fundamental principle in traditional trial design is understanding and controlling for the trial's false-positive rate. Adhering to this principle requires large trials and sample sizes in the hundreds and often in the thousands. Unfortunately, traditional RCTs do not accommodate the multiple facets created by biological variations.20 This is even more evident in complex diseases such as pancreatic cancer or pancreatitis accompanied by many underlying genetic predispositions or environmental factors. It is more challenging to develop therapies in rare disorders such as pancreatic diseases or their subsets as they never fit well into the traditional ways of trial planning. It is impossible to plan trials with sample sizes in the thousands when there are fewer than 100 patients ever described. The trial should be feasible to enroll sufficient subjects over a reasonable recruitment period; otherwise, results would be irrelevant when they are finally announced.21

The “precision medicine trials” are particularly challenging. There is an increasing interest in conducting mechanism-based trials in which eligibility is based on molecular targets rather than traditional disease-based definitions. One approach to perform such trials would be to set up a master protocol combining umbrella trials (to study multiple targeted therapies in the context of a single disease), basket trials (to study a single targeted therapy in the context of multiple diseases or disease subtypes), and platform trials (to study multiple targeted therapies in the context of a single disease in a perpetual manner, with therapies allowed to enter or leave the platform on the basis of a decision algorithm).22 All constitute a collection of trials or substudies that share key design components and operational aspects. Such adaptive trial designs that follow a master protocol offer a path forward for heterogeneous and low incidence diseases with high medical needs, such as pancreatitis. It has to be noted that even a master protocol and an adaptive trial design will require a valid end point; in many chronic diseases, a clinically meaningful and relevant end point has yet to be defined.23

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In 1962, Congress amended the Federal Food, Drug, and Cosmetic Act to add a requirement that, to obtain marketing approval, manufacturers demonstrate the effectiveness of their products through the conduct of adequate and well-controlled trials. Adequate and well-controlled trials generally include a clear statement of objectives, appropriate control for comparison, selection of patients with the disease or who are at risk of developing the disease, methods to minimize bias, methods for assessment of response, and methods of analysis. A goal of a development program is to demonstrate the clinical benefit of the therapy on a meaningful aspect of how a patient feels, functions, or survives as a result of treatment. There are a variety of methods that can be proposed for use in clinical trial(s) to measure a clinical benefit. A PRO instrument (ie, a questionnaire plus the information and documentation that support its use) is a means to capture PRO data that measure treatment benefit or risk in clinical trials. A PRO is any report of the status of a patient's health condition that comes directly from the patient, without interpretation of the patient's response by a clinician or anyone else.

Well-defined and reliable PROs are necessary components of clinical trials if disease symptoms are to be captured. Instruments to measure PROs range from single-item symptom ratings, such as visual analog or numeric rating scales for pain, or multiple-item disease-specific measures, to complex, multidimensional, health-related quality-of-life measures.24 Although generic PRO instruments, such as the RAND 36- or 12-item Short-Form Survey, may be useful to compare a given patient population to the general population,25 disease-specific instruments gather information relevant to those with the specific condition and are preferable as study end points because they are more relevant and important to patients and may be more sensitive to changes. The FDA PRO Guidance indicates that a well-defined and reliable PRO instrument, whether existing or newly developed, in appropriately designed investigations can be used to support a claim in medical product labeling if the claim is consistent with the instrument's documented measurement capability.26

In clinical trials of interventions aimed at modifying the natural history of recurrent acute or chronic pancreatitis, PROs are likely to be secondary end points. Studies aimed at treating symptoms of pancreatitis may have PROs as primary end points. All therapeutic trials may also consider using PRO instruments to capture patient-reported treatment-related symptoms.27 Importantly, end points should be limited to PROs that are actual targets of the intervention under study (Table 1).



Prior to use as end points, PRO instruments must demonstrate content validity (it measures what is relevant and important to the patients) and undergo psychometric evaluation and exhibit both reliability and validity within the context of use.24 Investigators have developed and psychometrically evaluated a quality-of-life instrument for chronic pancreatitis (PANQOLI),28,29 but no such instruments are available for acute or recurrent acute pancreatitis. Existing PRO instruments may need to be adapted and reevaluated to capture the impact of pancreatitis on patients and family members. Patient-reported outcomes of interest for patients with all forms of pancreatitis include missed school/work days, medication use for symptom management, health care utilization, and caregiver burden.

Assessing PROs in children and adolescents with pancreatitis has unique issues. There are existing and widely used generic instruments for assessing pain and its consequences both in children and adolescents,30–33 as well as their parents/families,30,34 although none has evaluated their use specifically for pancreatitis.

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The workshop also included presentations from working groups that specifically focused on the issues pertinent to the development of drug trials in acute pancreatitis, recurrent acute pancreatitis, and chronic pancreatitis. The summaries of those working groups are included in separate articles in this issue of Pancreas and address the issues of (1) definition and natural history of the disease, (2) diagnostic criteria and identification of complication risk, (3) definition of end points and/or outcomes and how they are to be measured, (4) performance characteristics (accuracy, sensitivity, specificity) of diagnostic and treatment measures/markers and caveats, (5) subject selection and timing of treatment for drug trials, (6) regulatory issues, and (7) gaps in knowledge, which provide recommendations for possible future funding initiatives by the National Institute of Diabetes and Digestive and Kidney Diseases.

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The participants of the workshop demonstrated a shared vision to rapidly accelerate drug development for inflammatory and fibrosing diseases of the exocrine pancreas. The overview presentations provided in this article are followed by summary and action plans of the 3 unique working groups (acute pancreatitis, recurrent acute pancreatitis, and chronic pancreatitis) who delivered their reports at the workshop. The groups focused on identifying PROs and end points, subject selection for clinical trials, drug development and/or repurposing of existing drugs, and regulatory guidance for clinical trials. Furthermore, additional and separate considerations were discussed for the pediatric population.

To maintain the momentum created at this workshop, each working group developed action plans with timelines delineated in their corresponding manuscripts. The workshop ended with a discussion, audience participation, and development of action plans on how best to move forward (Table 2 ). It is our hope that this overview summary and 3 working group articles will inform investigators, commercial partners, and the FDA as we expand treatment options for patients with these diseases and that they will mark the beginning of a dialog intended to identify effective treatments of early, recurrent, and chronic pancreatic inflammation. The future plans involve periodic review and revision of these actions plans as the groups reconvene at the annual PancreasFest and American Pancreatic Association meetings.



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The authors thank the National Pancreas Foundation (NPF) and Jane M. Holt and Patter Birsic, NPF cofounders; Matt Alsante, NPF executive director; Sokphal Tun, NPF programs manager; Jane Cross and Patrick Salami, NPF chapter chairs; Joy Jenko Merusi of the University of Pittsburgh; and Rachel Pisarski of Scientific Consulting Group, Inc, for logistical and organizational assistance.

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clinic trial; drug development; pancreatitis; patient-reported outcomes; study design

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