TOBIAS BOY POLAK UNLOCKING THE VALUE OF EXPANDED ACCESS Ethical, Statistical, and Policy Considerations
Unlocking the Value of Expanded Access Ethical, Statistical, and Policy Considerations Tobias Boy Polak
Unlocking the Value of Expanded Access Statistical, Ethical, and Policy Considerations ISBN: 978-94-6483-275-4 Lay-out: Publiss | www.publiss.nl Cover Publiss | www.publiss.nl Print: Ridderprint | www.ridderprint.nl © Copyright T.B. Polak, 2023 All rights reserved. No part of this publication may be reproduced, stored in a retrieval system, or transmitted in any form or by any means, electronic, mechanical, by photocopying, recording, or otherwise, without the prior written permission of the author. The printing of this thesis was (financially) supported by: the Department of Epidemiology and Biostatistics, ErasmusMC University Medical Center, Erasmus University Rotterdam; myTomorrows; Servier; The Stichting for Improvement of the Quality of Cardiology; ChipSoft; S.C. De Wijs Topbridge; Brink Bridge; Daiichi Sankyo Nederland B.V. and Drijver Pro Bridge.
Unlocking the Value of Expanded Access Ethical, Statistical, and Policy Considerations De waarde van ‘expanded access’ verhandelingen over ethiek, statistiek en beleid Proefschrift ter verkrijging van de graad van doctor aan de Erasmus Universiteit Rotterdam op gezag van de rector magnificus Prof.dr. A.L. Bredenoord en volgens besluit van het College voor Promoties. De openbare verdediging zal plaatsvinden op dinsdag 10 oktober 2023 om 13:00 uur door Tobias Boy Polak geboren te Dordrecht
PROMOTIECOMMISSIE: Promotor: Prof.dr. C.A. Uyl – de Groot Overige leden: Prof.dr.ir. H. Boersma Dr. E. Bunnik Prof.dr. A. Caplan Copromotor: Dr. J. van Rosmalen
TABLE OF CONTENTS Prelude 08 Introduction Background and outline of this thesis 10 Chapter 1 Data collection in expanded access: real-world examples Pritelivir for treatment-resistant herpes simplex infections Poster at SSAI/ICHS 2022 and Oral at STI & HIV 2023 (adapted) Tabelecleucel for Epstein-Barr Virus-driven diseases Poster at EHA 2022 and ASCO 2022 (adapted) 20 Chapter 2 Expanded access in the Netherlands: prescribing unregistered medicine Nederlands Tijdschrift voor Geneeskunde 2021 30 Part I ♣ The clinical merit of expanded access 44 Prologue 47 Chapter 3 The clinical value of drugs under development in hematological The predictive value of a positive phase II ASH abstract for peerreviewed publication and progression to phase III Blood 2022 (adapted) Two decades of targeted therapies in acute myeloid leukemia Leukemia 2021 (adapted) 48 Chapter 4 Incremental benefits of novel pharmaceuticals in the United Kingdom: A cross-sectional analysis of NICE technology appraisals from 2010 – 2020 BMJ Open 2022 56 Epilogue 74 Part II ♦ The usage of expanded access data 78 Prologue 80 Chapter 5 Expanded access as a source of real-world data: An overview of FDA and EMA approvals British Journal of Clinical Pharmacology 2020 82 Chapter 6 Real-world data from expanded access programs in health technology assessments: a review of NICE technology appraisals BMJ Open 2022 100 Chapter 7 Results from expanded access programs: a review of academic literature Drugs 2023 124
Chapter 8 Data collection for the sake of data collection Response to Open Peer Commentaries on “Making It Count: Extracting Real World Data from Compassionate Use and Expanded Access Programs” The American Journal of Bioethics 2020 168 Epilogue 172 Part III ♥ Statistical inclusion of expanded access data 178 Prologue 180 Chapter 9 Augmenting treatment arms with external data through propensity-score weighted power-priors with an application in expanded access Statistics in Medicine: Under Revision. Preprint: Arxiv 2023 184 Part IV ♠ Policy implications and ethical considerations 216 Prologue 218 Chapter 10 The DRUG Access Protocol: access inequality and European harmonization Lancet Oncology 2022 220 Chapter 11 Generating Evidence from Expanded Access Use of Rare Disease Medicines: Challenges and Recommendations Frontiers in Pharmacology 2022 224 Chapter 12 The ethics of expanded access research JAMA 2023 236 Postlude 246 Summary 248 Discussion 253 Appendices 264 Nederlandse samenvatting 266 Bibliography 272 Portfolio 275 About the author 279 Acknowledgements (dankwoord) 280
PRELUDE
Prelude 10 INTRODUCTION To ensure patients and physicians have access to safe and effective drugs, regulators require the conduct of clinical trials to identify the risks and benefits of new treatments.1 The process of drug development requires effort and time, and as many as 15 years may pass to complete all phases of drug development.2 This encompasses preliminary pre-clinical research in petri dishes, followed by phase I trials involving healthy volunteers to evaluate safety and establish tolerable dosage levels. Next, in phase II, the investigational drug is tested on a larger group of patients with the targeted condition to determine its effectiveness, optimal dosage, and any further side effects. Finally, phase III trials test the drug on a large group of patients to compare the effectiveness and safety of the new drug or therapy with existing treatments or placebos. Despite remarkable advances in medicine for some disease areas, a substantial patient population remains without treatment options. Patients with mild, slowly progressing, non-lethal diseases may have the luxury of time at their disposal to await the outcomes of clinical trials to develop safe and effective medicine. Patients with life-threatening or seriously debilitating conditions cannot afford to await the results of regulatory evaluation and have sought access to investigational medicine through ‘expanded access’ pathways.3,4 The expanded access pathway provides a means to access investigational medicine when access through the preferred route - trial participation - is not possible. While patients may individually benefit from participating, clinical trials primarily generate knowledge for the collective advancement of medical science. However, a variety of barriers exist that impede patients from participating in trials, including ineligibility due to medical factors such as frailty, the presence of comorbidities, or the use of concomitant medications.5 Practical barriers, such as limited awareness of trials among patients and physicians, challenges with scheduling and travel to trial sites, or a complete lack of trials further hinder patient enrollment.6 Regrettably, research strongly suggests that sexist and racist factors worryingly hinder patient participation.7 When approved options are inadequate and trial participation is not feasible, patients in dire need may seek to access investigational drugs through legislated expanded access pathways. The history of expanded access The foundations of the expanded access pathway were laid in the United States (US).8,9 Prior to the 1980s, access to investigational drugs in the US was an informal process.10,11 The US Food and Drug Administration (FDA) permitted physicians to prescribe experimental treatments to severely ill patients on a case-by-case basis. The start of the AIDS crisis generated unprecedented attention to the regulatory process and sparked advocacy for broader access to treatments in research and increased patient involvement. Pressure from patient activists led the FDA to
Introduction: Background and outline of this thesis 11 formalize expanded access pathways in 1987, offering regulated access to experimental drugs to thousands of patients facing a life-threatening illness with no other recourse.12 Similar pathways have since been established around the globe to offer treatment options to patients in need. Over the years, there has been an increasing interest in expanded access, with various factors potentially causing its rise.13 External factors, such as improved understanding of the underlying biological mechanism of diseases through research have resulted in an increase in trials investigating potential treatments, in turn leading increased expanded access requests. Likewise, the rise of internet and social media has heightened awareness among patients and physicians of medicine in development.14 Expanded access itself has also evolved. Over time, familiarity with expanded access has increased, in part due to efforts such as the US ‘Project Facilitate’ which aims to educate patients, physicians, and industry on expanded access, and intends to improve efficiency in requesting expanded access.15,16 Companies must publicly post their expanded access policies online,17,18 and international research databases (e.g., clinicaltrials.gov) offer the ability to register expanded access programs. Before further examining expanded access and research conducted in tandem with it, we first need a clear and universal definition of expanded access. Finding common ground: what is expanded access? There is no globally accepted definition of expanded access. Even more, there is no consensus on the term expanded access itself.19 In English alone, expanded access is known as ‘named-patient use’, ‘compassionate use’, or as ‘managed’, ‘early’ or ‘special’ access, all referring to the provision of unlicensed medicine outside of a trial setting. Non-English speaking countries have implemented local equivalents. For example, the ‘authorisation temporaire d’utilisation’ or ‘accès précoce’ in France,20 the ‘Levering op Artsenverklaring’ in the Netherlands,21 the ‘Heilversuch’ in Austria,22 and ‘el uso compasivo’ in Spain,23 are all analogous to expanded access. Despite these variations, there are common theoretical principles that define expanded access.24 Said access pathways are open to patients who are 1. diagnosed with a seriously debilitating or deadly disease; 2. unable to benefit from registered treatment options; 3. disqualified to participate in clinical trials. The practical process of obtaining access typically involves obtaining informed consent from the patient, a prescription from the treating physician, involvement of a local ethics committee, cooperation from the product manufacturer, and approval from the local regulator.25,26 These
Prelude 12 steps collectively aim to ensure that the potential advantages outweigh the potential side effects. Naturally, the risk/reward balance varies per disease, and changes over time as more evidence becomes available. Types and timing of expanded access Expanded access programs are usually split into individual access programs (named-patient use) for single patients, and group programs that simultaneously allow multiple patients to access unregistered medicine.3 There is no rigid, formal timeline dictating when expanded access can be initiated. In theory, it is possible to request access for any unapproved drug at any stage of development. However, as an investigational product advances through clinical development, evidence accumulates, interest from physicians and patients increases, and singlepatient programs can evolve into group access programs.27 Furthermore, regulators and drug manufacturers are more prone to grant expanded access requests as safety and efficacy become increasingly established. Additionally, expanded access serves as a means of bridging the time between the completion of regulatory phase III trials and marketing approval. Frequently, drugs are launched in the United States first, making FDA approval the initial endorsement. This approval would spark interest in, for example, Europe, prior to the approval of the European Medicines Agency (EMA).28 Adding to the confusion, expanded access is not limited to pre-approval access, as it can also be used to access unregistered medicine after they have been withdrawn from the market. In certain regions, alternate forms of expanded access may be employed if a product has received approval from a regulatory authority outside their jurisdiction, as the associated risks are potentially reduced when another regulator has endorsed the product. Moreover, although not strictly considered ‘expanded access’, various regulators allow these programs to continue to bridge the time needed to obtain local reimbursement, particularly in countries with a national health system. If a drug is withdrawn from the market for any reason, the product reverts to the ‘unapproved’ status and, therefore, may strictly qualify for expanded access once more. Figure 1 depicts the relative interest in expanded access over the course of drug development.
Introduction: Background and outline of this thesis 13 Figure 1: Relative number of expanded access requests over a product’s life cycle. The strict common definition of expanded access would be ‘access to a medicine that is unregistered for any indication within its jurisdiction’. What is typically not considered expanded access? It is important to differentiate between expanded access and other types of unconventional product usage. Off-label usage is not the same as expanded access, as the former occurs when a label is approved in a different indication, and the latter is only possible when the product lacks any regulatory approval. Furthermore, expanded access programs are strictly speaking not synonymous with programs that aim to bridge the time between regulatory approval and reimbursement. Expanded access usually precedes regulatory approval and is not directly linked to reimbursement status. Expanded access is not limited to pre-approval access, as it can also be used post-withdrawal. As these ‘peri-approval, peri-reimbursement’ situations are simultaneously different and similar, some stakeholders use these terms interchangeably. Understandably, industry frequently employs one ‘managed access’ desk to handle all request from patients seeking access to drugs that are not available, regardless of whether this is due to a lack of registration or funding.
Prelude 14 The multiple stakeholders in expanded access Patients predominantly hope to benefit from accessing experimental treatments.29 However, this access is only clinically valuable if the experimental treatments themselves offer advantages. Whether investigational treatments, and thereby expanded access, meet these clinical expectations is unclear. In this thesis, we explore the clinical value of medicine that may be obtained through expanded access. Apart from patients, expanded access involves a range of stakeholders with varying incentives. Physicians strive to offer optimal treatment options for their patients,30 companies seek to demonstrate ‘compassion’, enhance patient/physician engagement, and uphold their reputation,31 and regulators aim to provide greater access to novel therapies. Simultaneously, expanded access presents several drawbacks. Patients should not be exposed to unsafe or ineffective treatments, and physicians face an increased workload and may encounter both safety and ethical concerns when prescribing unapproved medicine.32–34 Companies must bear the cost providing experimental medicine and must dedicate ample resources to navigate differing regulatory pathways, while regulators must balance the needs of current patients without hindering clinical development and thereby endanger broader access to future patients.4 This thesis examines the practical and ethical dilemmas that can arise from such conflicting interests. Expanded access programs are primarily designed to provide treatment, and as a result, data of patients that participate in expanded access programs are often overlooked.35 In fact, some jurisdictions specifically prohibit the collection of data other than safety events in this setting.22 Nonetheless, there has been growing attention to the potential for expanded access programs to generate evidence. In this way, patients could altruistically contribute to the overall assessment of safety and effectiveness of new medicine, physicians could cooperatively participate in research that informs future clinical decision-making, companies could collect data to support regulatory approvals, reimbursement decisions, or publications, and regulators obtain a broader view of how novel treatments work outside of clinical trial patients. In this thesis, we delve deeper into the value of expanded access as a means to generate evidence. Generating evidence through expanded access Generating evidence through expanded access pathways has become a growing area of interest,36 with anecdotal evidence suggesting that data collected from such programs can be used to inform publications, reimbursement appraisals, and regulatory decision-making.37 Some countries have even integrated the evaluation of treatments under expanded access pathways in regulatory and
Introduction: Background and outline of this thesis 15 reimbursement decision-making.38 Despite this growing interest, a systematic overview of the use and integration of expanded access data is absent. As a result, the extent to which these data are used by different stakeholders, such as scholars, patients, or regulators, remains uncertain. The reliability of data generated through expanded access remains unknown, and evidentiary requirements can vary depending on the intended use.37,39 For regulatory approval decisions, the highest-grade evidence, such as randomized controlled trials, can be more challenging to be supplemented by expanded access data. For other types of decisions, such as reimbursement decisions, different types of evidence than randomized controlled trials are appropriate. From a quantitative perspective, there is a scarcity of statistical techniques to interpret expanded access data,40 and these techniques may need evaluation or development to numerically incorporate expanded access. To what degree the nature of expanded access has changed, who stands to benefit from expanded access research, how, how often, and why data are collected, remains uncertain. Despite the potential benefits, the novel use of expanded access as data generation mechanism raises several concerns, including issues of patient protection, data quality, transparency, financial burden,41 and research oversight, among others. Research questions In this thesis, we will primarily investigate: ♣ What are the medical benefits for patients receiving expanded access to experimental treatments? ♦ What are the ways in which data obtained from expanded access programs are utilized, and by whom? ♥ Can existing statistical techniques be adapted to incorporate data from expanded access programs in the context of analyzing clinical trials? ♠ What ethical concerns emerge when using expanded access as a means to generate evidence, and how can improvements be made to expanded access policies? Methodology First, we illustrate the practical context of expanded access by providing real-world examples of the strategy, design, monitoring, and analyses of expanded access programs that we were involved in ourselves and inspired the writing of this thesis. In the theoretical context of expanded access, several research topics including ethics, health policy, and statistics warrant further exploration. We address this diverse range of issues by deploying an equally varied research armamentarium.
Prelude 16 We developed algorithms to facilitate the analysis of vast amounts of health policy documents, thereby sometimes even having to rely on modern techniques that are able to translate images into text (optical character recognition). In addition, we also made use of standard systematic reviews to answer our research questions. Furthermore, we acquired and analyzed individual patient-level trial data with expanded access data by developing novel statistical techniques, combining Bayesian dynamic borrowing and propensity score matching. Lastly, we investigated the ethical aspects of expanded access research, such as patient selection, access equity, and research oversight, and suggest policy improvements to overcome said concerns. This broad spectrum of research methods was necessary to address the variety of important ethical, practical, statistical, and policy implications that are vital for the future of expanded access.
Introduction: Background and outline of this thesis 17 Outline of this thesis The structure of this thesis will chronologically follow the progression of our research in four parts. Each part contains several chapters. To guide the reader through our research, we will provide further accompanying prologues and epilogues in between Parts. Hence, the outline described below is deliberately kept succinct. We start this thesis by providing the reader first-hand insight into two practical examples of expanded access programs design, conduct, and publication through two case studies of programs of which we presented the results at several conferences. We will cover all challenges and successes that accompany a real-world expanded access data collection program. As a prelude to the official thesis, we will explain (in Dutch) the way expanded access is regulated in the Netherlands as a reference for Dutch physicians. ♣ In Part I will assess the benefits of investigational drugs, as the clinical merit of expanded access is contingent upon the drugs it provides access to. The more expanded access is dedicated to highly effective pharmaceuticals, the higher the value of expanded access itself would be. We attempt to quantify the value of experimental drugs by exploring the likelihood that drugs advance through stages of clinical development and relate these probabilities to the assessed clinical benefit of drugs in development and new drugs on the market. ♦ We dedicate Part II to quantify the usage of expanded access data disseminated through scholarly publications, used by reimbursement bodies, and appraised by regulators. To process this information, we made use of computer algorithms to scan through large bodies of literature. The results of Part II form the basis of our further research and provide a basic understanding of when and how data from expanded access are used. ♥ Part III is dedicated to a novel statistical technique to incorporate expanded access data into clinical trial analyses. We will explore whether previous scholarship on dynamic borrowing of historical control information, together with more recent statistical advances put forth to include patient characteristics to determine the amount of information to borrow, can be adjusted to help
Prelude 18 inform trial data through expanded access programs. We will illustrate our method by analyzing individual patient-level data from the expanded access program and clinical trial of vemurafenib, a treatment for metastatic melanoma. We will evaluate how our method fares compared with traditional methods. ♠ In Part IV, we provide means to improve expanded access policies to expedite patient access together with evidence generation, discussing several inconsistencies in expanded access policies across jurisdictions. While ethical considerations, including the balance between patient autonomy, informed consent, and the potential for false hope, have been thoroughly discussed by previous scholars,25,31,42–47we expand upon their work by addressing the ethical implications of generating evidence through expanded access programs. Accordingly, we pose an outline of the ethical considerations surrounding expanded access research by evaluating if and when the benefits of additional evidence generation outweigh the research strains imposed on patients and physicians, and what policy improvements could be made to harmonize expanded access research in terms of data quality, oversight, and transparency, among others. Finally, our postlude concludes with a summary and discussion. While the limitations and interpretations of each individual research are described within their respective papers and parts, we dedicate the discussion to address the remainder of overarching issues related to expanded access and this thesis.
Introduction: Background and outline of this thesis 19 PERSONAL MOTIVATION This thesis was inspired by the practical challenges encountered in my daily work of designing, implementing, and analyzing expanded access programs. I was working for the company myTomorrows, a service provider in the field of expanded access.1 myTomorrows helps patients and physicians find and access treatment options, and simultaneously designs and conducts expanded access programs for the biopharmaceutical industry. In my daily work, I was responsible for overseeing the data collection and analysis for our clients. In 2019, I was working on designing a data collection program for pritelivir,48 an antiviral therapy for treatment-resistant herpes simplex virus, when I started searching for information on how others had implemented expanded access programs. I stumbled upon a single report highlighting examples of the regulatory use of expanded access data for efficacy assessments.37 This report included lutetium 177Lu dotatate (Lutathera™), a radioactive treatment for pancreatic and gastrointestinal cancers.49 The Lutathera program provided access to and collected data from 1,214 patients at a single center,50 the Erasmus MC in Rotterdam, making my hometown an ideal starting point for future research. Although some informal information was available online, I realized that there was a lack of systematic groundwork to help identify and avoid common pitfalls in executing expanded access programs, as well as an absence of literature on best practices. This sparked my interest and prompted me to embark on the journey of this thesis, aiming to strengthen the theoretical foundation of utilizing expanded access with the hope of addressing my day-to-day issues. On a personal level, back in 2020, I received a call from an old teammate of my bridge team facing bile duct cancer. By accompanying him to his weekly doctor appointments in Rotterdam, I witnessed firsthand the challenges faced by patients and doctors when no further treatment options are available. Sadly, my friend passed away on March 9th, 2021. I will forever remember our lively discussions on making the most of his remaining days, only a negligible part of these talks was dedicated discussing expanded access and clinical trials, putting the relative importance of the topics discussed in this thesis in perspective. 1 https://mytomorrows.com
CHAPTER I Data collection in expanded access: real-world examples Adapted from: Pritelivir for the treatment of resistant HSV infections in immunocompromised patients: update on an ongoing Phase 3 trial and Early Access Program Birkmann A, Marini A, Müller A, Polak TB, Rangaraju M, Sumner M, Trübel H, Wald A, Zimmermann H. STI & HIV, 2023 Chicago (Oral) Immunocompromised patients with Resistant HSV Infections: Results of the International Early Access Program of Pritelivir Avery RK, Polak TB, Birkmann A, Truebel H, Gunson S, Sumner M, Dickter J, Neofytos D, and Lee Y. SSAI/ICHS, 2022 Basel (Poster) Demographics and Treatment Outcomes in Patients with EBV+ PTLD Treated with Off-the-Shelf EBVspecific CTL (Tabelecleucel) Under an Ongoing Expanded Access Program in Europe: First Analyses Choquet S, Uttenthal B, Chaganti S, Comoli P, Trappe RU, Friedetzky A, Xing B, Li X, Polak TB, Gamelin L, Terwey J-H, and Dierickx D. EHA and ASCO, 2022 Vienna, Chicago (Posters)
Chapter 1 22 We here shift our focus from theoretical concepts to practical examples by examining the challenges faced when designing an expanded access program and associated data collection. We will illustrate the design, analyses, and limitations of running an expanded access programs through the lens of two distinct products: pritelivir and tabelecleucel. 1. Pritelivir, an investigational product in infectiology to treat treatment-resistant herpes simplex viruses. 2. Tabelecleucel, a cell therapy for relapsed/refractory patients with a variety of (cancerous) diseases caused in part by Epstein-Bar Virus re-activation in immune compromised patients. The two programs differ in a variety of aspects, such as the nature of the disease areas, type of product, development stage, and type of company. Pritelivir is a small molecule drug, taken as pill orally by patients at home. Tabelecleucel is an advanced therapy medicinal product, derived from human cells and can only be administered intravenously in specialized hospitals. Second, the marketing authorization submission of tabelecleucel was long underway while the expanded access program started, whereas the phase III trials for pritelivir are still ongoing at the time of writing this thesis. On a company level, AiCuris is a privately owned smaller biotech company operating from Wuppertal, Germany. In contrast, Atara Biotherapeutics is a NASDAQ (ATRA) listed, publicly traded company, operating from their headquarters in California in the United States. As a result, the reader receives two separate and diverse expanded access examples from both programs.
Data collection in expanded access: real-world examples 23 PRITELIVIR FOR TREATMENT-RESISTANT HERPES SIMPLEX INFECTIONS Background Pritelivir is being investigated as a treatment of herpes simplex virus 1 (HSV1) and 2 (HSV2) infections.51 While nucleoside analogs like acyclovir, (or valacyclovir, famciclovir, and ganciclovir) or phosphonic acid derivatives like foscarnet are the primary treatments for HSV infections, patients may develop resistance to these drugs or experience intolerable side effects, making trials or expanded access programs to drugs in development (like pritelivir) necessary. Patients with HSV suffer from painful lesions (blisters, sores) that usually appear around the mouth or genital area.52 Typically, these lesions present in episodes when the immune system is weakened. Immunocompromised patients, such as those living with HIV/AIDS, undergoing stem cell or solid organ transplant, or patients that depend on the use of immunosuppressants, may suffer from HSV infections that last longer, occur more frequently, and are less responsive to conventional therapies. Additionally, patients with persistent HSV infections often present with multiple underlying conditions that weaken their immune system, leading to severe complications from the infections. For example, patients could develop bedsores being unable to sleep due to pain caused by blisters or become morphine-dependent due to the severe pain associated with their HSV infection. For these severely ill patients, physicians sought access to pritelivir when conventional therapies were inadequately effective or safe. Pritelivir is an anti-HSV helicase-primase inhibitor that is currently in phase III clinical development for the treatment of acyclovir-resistant HSV infections in immunocompromised patients.53,54 Pritelivir is administered orally through tablets. In the ongoing PRIOH-1 trial (NCT03073967), pritelivir is compared with foscarnet, the only available treatment option for acyclovir-resistant HSV infections. Patients are initially treated with a 28-day course and if clinically necessary, this course may be extended up to 42 days. Setup and methodology of the expanded access program In addition to the trial, a global expanded access program was initiated by AiCuris (the sponsor) and myTomorrows (the service provider) for ineligible trial patients in 2019. Apart from the aforementioned medical reasons for ineligibility, there were also several practical reasons patients could not partake in the trial, either sites being fully enrolled, or sites not activated within traveling distance. Additionally, and different from the clinical trial, patients in the expanded access program were allowed to be previously treated with multiple cycles of pritelivir (nonnaïve) if lesions re-occurred. Hence, the patient population differed by design from the patients in the trial.
Chapter 1 24 Data were collected through an electronic data collection system (EDC), Castor, that is compliant with all regulatory requirements for a marketing authorization submission. Safety was monitored through standard pharmacovigilance practices. Efficacy was primarily analyzed by in-hospital physician-assessed evaluation of healing of the lesions within 28 or 42 days. Additionally, the assessments could be confirmed by taking both measurements (width times heigh) and photographs of lesions before, during, and after treatment. The difference in design between the trial and expanded access program led to various choices regarding analysis sets. For example, all patients could be analyzed, including those that were previously treated with pritelivir, hence including patents that had six different courses within the expanded access program multiple times. Else, one could opt to only analyze patients naïve to pritelivir– even excluding patients that had prior successfully been treated in the randomized trial. Results With a data cut-off on December 28th, 2022, we analyzed all requests for treatment through expanded access that were received through the online data collection program managed by myTomorrows.The number of requests and subsequently initiated treatment and assessed results are visualized in the flowchart in Figure 2. Figure 2: Flowchart of the expanded access program of pritelivir requests and outcomes.
Data collection in expanded access: real-world examples 25 The vast majority of requests 65% (79/122, 95% CI: [56%, 73%]) initiated treatment with pritelivir. These requests concerned 53 unique patients. Requests were received from 11 different countries across Europe, North America, and Africa. Safety Zero (0) serious adverse events that were drug-related were reported through the program. Efficacy The efficacy of all treatment cycles (including re-treatments) can be seen below (N=69) in Table 1. The high percentage of patients that re-initiated treatments when novel lesions appeared (36%) could be seen as a surrogate indicator of response. Table 1: Binary efficacy outcomes for pritelivir for all evaluable treatment cycles. Variable N = 691 95% CI2 Healed after 28-day course (cumulative) 37 (54%) [41%, 66%] Healed after 42-day course (cumulative) 42 (61%) [48%, 72%] 1n (%), 2CI = Confidence Interval Furthermore, we were also interested in the outcomes of patients that were naïve to pritelivir (i.e., the ‘trial’ population. Hence, we removed all patients that were re-treated in the EAP (N=23), and we removed patients that were treated in the EAP once but were also treated in the trial (N=4). For all naïve patients (N=69 – 23 – 4 =42), the cumulative outcomes are provided in Table 2. Table 2: Binary efficacy outcomes for pritelivir for all unique patients that were naïve to pritelivir. Variable N N = 421 95% CI2 Healed after 28-day course (cumulative) 42 21 (50%) [36%, 64%] Healed after 42-day course (cumulative) 42 25 (60%) [43%, 74%] 1n (%),2CI = Confidence Interval Limitations 1. Due to COVID, patients could not go to the hospital and lesion assessments were made through telephone visit confirmation via the physician, patient self-assessed lesion healing, or sent-through photographs made by patients or family members 2. Although ‘perfect’ trial patients may have exact squared or circles lesions, we faced a number of patients where the size of lesions was nearly impossible to measure, or certainly not through width times height. We relied on the physician assessment whether or not lesions were healed when exact measurements were unavailable.
Chapter 1 26 3. Due to the sensitivity of the disease, photographic confirmation of the lesion was done on a voluntary basis. We relied on the physician assessment primarily when photographic outcome confirmation was lacking. Conclusion At the time of data cut-off, 79 treatment rounds were administered via the expanded access program to 53 patients. The outcomes from the expanded access programs (subgroups) are comparable to the outcomes in the primary randomized controlled trial, where 83% (19/23, 95% CI: [60%, 94%]) healed upon pritelivir initiation. Hence, the expanded access program provides some evidence of the effectiveness of pritelivir in a broad patient population set. Nonetheless, these results have to be interpreted with caution due to the uncontrolled nature of the program, the potential impact of COVID-19 on data quality, and loss of follow-up. The large number of patients requesting re-treatment when lesions re-occurred is an important proxy measure of efficacy that could only be captured in the expanded access program, and not in the ongoing phase III trial.
Data collection in expanded access: real-world examples 27 TABELECLEUCEL FOR EPSTEIN-BARR VIRUS-DRIVEN DISEASES Background The second real-life example concerns a living cell therapy called tabelecleucel, developed by Atara Biotherapeutics.55 Atara Biotherapeutics and myTomorrows initiated an expanded access program to provide tabelecleucel to patients in Europe.56 Tabelecleucel (also known as tab-cel®) is an allogeneic, EBV-specific T-cell immunotherapy which targets and eliminates cells infected with the Epstein-Barr Virus. At the initiation of the expanded access program, tabelecleucel was in late clinical development for patients with post-transplant lymphoproliferative disorders (PTLDs). PLTD is a serious and potentially fatal complication in patients that have undergone a transplant, either allogeneic stem cell or solid organ. These patients are severely immunocompromised and thus may not be able to adequately control the virus, which may lead to lymphoproliferation and PTLD. In the program, requests for tabelecleucel could only be accepted if patients were relapsed or refractory to standard treatment options, such as rituximab or chemotherapy regimens, or were ineligible for registered therapies. Compared with the production of pritelivir in the previous chapter, the production of tabelecleucel is complex. Tabelecleucel is produced from T-cells harvested from human donors. The final products are tested for their capacity of eliminating Epstein-Barr Virus-positive cells in a Human Leucocyte Antigen (HLA)-restricted manner. By producing tabelecleucel with T-cells from different donors, various different cell lines of therapy could be pre-produced and stored in an inventory, making tabelecleucel a cell therapy that is available off-the-shelf. The product is selected for each patient from the existing inventory based on appropriate HLA restriction and allele profile, hence the HLA genotype information from patient and transplant donor is mandatory. Based on response assessment patients could potentially switch to a different cell line with a different HLA restriction as defined in the treatment plan. Being a cell therapy, there are unique requirements for the storage, handling, transportation, and administration of tabelecleucel. For example, the product is required to be monitored and packaged to ensure stability under extremely low temperatures (≤ -150°C), a process known as cold-chain shipment. As a consequence, only hospital sites with dedicated licenses to meet regulatory standards were allowed to participate in the expanded access program and training for product administration was required to ensure the safe and effective delivery of tabelecleucel to patients.
Chapter 1 28 On the 12th of December 2022, tabelecleucel was registered by the European Medicines Agency under the tradename Ebvallo® for the treatment of relapsed/refractory post-transplant lymphoproliferative disease for patients who test positive for Epstein-Barr Virus.2 Setup and methodology of the Expanded Access Program In addition to the trials, an ‘Expanded Access Program’ was initiated by the biotech company Atara (the sponsor) and myTomorrows (the service provider) for ineligible trial patients in Europe. The primary goal was to provide treatment to tabelecleucel to patients. Patients were first triaged for participation in clinical trials for tabelecleucel. If participation was impossible, patients were assessed for eligibility for expanded access and determined if treatment could potentially be of benefit to the patient. If appropriately matched product was available and the patient was eligible, the patient could participate in the expanded access program to receive tabelecleucel. In addition to PTLD-patients, patients with different types of diseases driven by the Epstein-Barr Virus could also be considered in the expanded access program, such as primary immunodeficiency‑driven lymphoproliferative disease (LPD), acquired immunodeficiency (AID)‑driven LPD, smooth muscle tumors (sarcomas including leiomyosarcoma) in line with the clinical development program. A separate observational study (ATA129-EAP-902) was set-up to describe the patient population, tabelecleucel usage, treatment outcomes, and safety in patients with Epstein-Barr Virus driven diseases treated with tabelecleucel under the expanded access program in Europe (see Figure 3). This observational study required additional consent, as it yearly followed-up on the survival status of patients after the start of tabelecleucel – even when patients were no longer under treatment in the expanded access program. Presented at EAN Virtual Congress, 2020 Patients All patients scheduled to be treated with tabelecleucel in the EU EAP that have consented to research Data Collection Limited to what is required for treatment to provide access and a minimum of 2 annual survival follow up Regions Europe: UK, DE, ES, FI, FR, IT, AT, NL, BE, CH, SE, FI, PT, DK Day 28 Assessment Treatment as per Treatment Plan or Clinical Practice Minimum 2 Year Survival Follow Up Study Objectives • Primary: Demographics and Disease Characteristics • Secondary: Outcomes (ORR, OS), Dosing Pattern and Safety Patient Consent for Inventory Check End-of-Treatment and 30-day safety follow-up after last dose Additional Treatment Expanded Access Use Request by HCP Clinical Trial Eligibility Check Triage to clinical trial Patient Consent for Research Inventory Check Patient Consent for Treatment Data Collection Observational Study ATA129-EAP-902 An observational study to describe the patient population, tabelecleucel usage, treatment outcomes, and safety in patients with EBV driven diseases treated with tabelecleucel under the Expanded Access Program in Europe Expanded Access Program Expanded Access Eligibility Check Figure 3: Flowchart for the expanded access program and data collection study for tabelecleucel. Figure adapted from poster publication.56 2 https://www.ema.europa.eu/en/medicines/human/EPAR/ebvallo
Data collection in expanded access: real-world examples 29 Results A total of 48 expanded access requests from nine countries for patients with Epstein-Bar Virus driven diseases were received. Twenty-two patients from seven countries consented to this research: 16 Epstein-Bar Virus +PTLD and six Epstein-Bar Virus +non-PTLD. We primarily focused on the PTLD patients. Of the 16 PTLD patients, 15 received at least one dose of tabelecleucel. One patient had not started treatment at data cut-off date. Safety No adverse events were reported as related to tabelecleucel by the treating physician. There were no reports of tumor flare reaction, infusion-related reaction, cytokine release syndrome, marrow rejection, or transmission of infectious diseases, including cytomegalovirus. There were no events of graft versus host disease or organ rejection reported as related to tabelecleucel. Efficacy The overall response rate as assessed by the treating physicians was 60% (9/15, 95% CI: [32% , 83%]), which is comparable to the overall response rate of 51% (22/43, 95% CI: [35%, 66%]) observed in the pivotal regulatory studies.55,57 Limitations 1. Due to the heterogeneity of the disease population, only the results for patients with PTLD are presented. Even within the PTLD-population, variability across disease characteristics, such as viral load or prior therapies, makes it difficult to interpret the results from the expanded access program. 2. Not all patients consented to the research study and are hence lacking from the analysis. Nonetheless, as every cycle response was known, these data are available. How the exclusion of these patients effects the outcomes remains unclear. 3. Assessment of efficacy was done per clinical judgement by each individual treating physician. There was no central blinded review of the outcome results. Conclusion The successful implementation and the patient participation of this European program demonstrates the feasibility of administering an off-the-shelf, allogeneic, T-cell therapy and the unmet medical need in this disease area. Although the setting of evidence generation in this program was unblinded, and uncontrolled, the results across benefits and risks reflect the results obtained in the regulatory trials.57 All adverse events were consistent with the underlying diseases of the patient and were considered unrelated to tabelecleucel.The outcome data for patients with relapsed/refractory PTLD are comparable to data observed in clinical trials. The European expanded access program with Atara Biotherapeutics ended when tabelecleucel received marketing authorization for PTLD patients.55
CHAPTER 2 Expanded access in The Netherlands: prescribing unregistered medicine Expanded Access: het voorschrijven van niet-geregistreerde geneesmiddelen Polak TB, Cucchi DGJ, van Rosmalen J. Ned Tijdschr Geneeskd. 2021 Feb 25;165:D5168.
Chapter 2 32 ENGLISH SUMMARY Expanded access is a pathway to access unregistered medicines if there are no registered treatments available and patients cannot enroll in clinical trials. For patients who currently are in dire need of treatment options and cannot await drug development processes, or for patient who may benefit from treatments that are not (or not anymore) registered in their jurisdiction, expanded access may serve as a last resort. Unregistered medicine can be acquired via named-patient pathways (‘Leveren op Artsenverklaring’) or via group programs (‘Compassione Use Programma’s). We describe the origins of expanded access and its daily practice in the Netherlands. We observe an increasing trend in expanded access requests. Expanded access enables physicians to facilitate access for patients with unmet medical needs. The potential risks these treatments provide, the option to cease further treatment and the preferences of individual patients should all inform the decision whether or not to pursue expanded access. SAMENVATTING Expanded access is een toegangsroute tot niet-geregistreerde geneesmiddelen als er geen bewezen effectieve middelen zijn en het onmogelijk is patiënten in onderzoeksverband te behandelen.Voor patiënten die dringend behandeling behoeven en het langdurige ontwikkelproces niet kunnen afwachten, en voor patiënten die gebaat zijn bij een middel dat lokaal niet (meer) is geregistreerd, kan expanded access uitkomst bieden. Niet-geregistreerde geneesmiddelen kunnen worden aangevraagd voor de individuele patiënt (Leveren op Artsenverklaring) of voor patiëntengroepen (Compassionate Use Programma’s). Hier beschrijven we hoe expanded access is ontstaan en in de praktijk kan worden uitgevoerd. Wij constateren een toename van expanded access gebruik in Nederland. Met expanded access hebben artsen een belangrijk middel om tegemoet te komen aan onbeantwoorde zorgvragen. De keuze over te gaan tot expanded access dient zorgvuldig te worden afgewogen tegen de risico’s van behandeling met experimentele medicijnen, opties tot het staken van verdere behandeling en de wensen van de individuele patiënt.
Expanded access in the Netherlands: prescribing unregistered medicine 33 ACHTERGROND Artsen mogen geneesmiddelen voorschrijven waarvoor in Nederland een handelsvergunning is afgegeven. Een medicijn krijgt een handelsvergunning, of wordt geregistreerd, als de verwachte positieve effecten opwegen tegen de bijwerkingen. Deze afweging is bij voorkeur gebaseerd op de resultaten van gerandomiseerd, dubbelblind klinisch onderzoek, waarmee de veiligheid van patiënten en de effectiviteit van het middel moeten worden gewaarborgd. De ontwikkeling van een medicijn neemt gemiddeld 12 jaar in beslag, van de ontdekking van het molecuul tot de goedkeuring door toezichthouders.58 Deze toezichthouders zijn de Food and Drug Administration (FDA) in de Verenigde Staten, het Europees Geneesmiddelen Agentschap (EMA) in Europa en het College ter Beoordeling van Geneesmiddelen (CBG) in Nederland. Voor sommige patiënten zijn er geen reguliere geneesmiddelen beschikbaar, bijvoorbeeld omdat het middel nog niet in Nederland op de markt is, of omdat het middel is teruggetrokken. Recent onderzoek laat zien dat 2,5% van alle patiënten een onbeantwoorde zorgvraag (‘unmet medical need’) heeft.59 Als er een veelbelovend medicijn wordt ontwikkeld, kunnen sommige patiënten niet wachten op goedkeuring, omdat ze bijvoorbeeld een agressieve maligniteit hebben. Ook kunnen deze patiënten vanwege strenge in- en exclusiecriteria vaak niet deelnemen aan trials. Zo komt 7-33% van de patiënten met kanker niet in aanmerking voor deelname aan onderzoek.60 Toch hebben zij mogelijk baat bij behandeling met een niet-geregistreerd geneesmiddel. Daarom zijn er wettelijke mogelijkheden om aan deze patiënten niet-geregistreerde middelen voor te schrijven. Hoe is de ‘expanded acces’-regeling ontstaan? In de jaren 80 stonden hiv/aids-activisten en de FDA in een soortgelijk dilemma lijnrecht tegenover elkaar. Er waren geen geregistreerde medicijnen om patiënten met een hiv-infectie te behandelen; veel patiënten konden niet deelnemen aan klinische trials en voor veel patiënten werd aids fataal. Er waren geen richtlijnen voor het gebruik van niet-geregistreerde medicijnen anders dan in onderzoeksverband. Onder druk van patiëntenverenigingen, artsen en de publieke opinie ging de FDA in 1987 overstag en introduceerde de ‘expanded access’-regeling.3,9 Uitzondering op de Geneesmiddelenwet Expanded access, ook wel ‘early access’, ‘pre-approval access’ of ‘compassionate use’ genoemd,19 voorziet in een uitzondering op het verbod op het voorschrijven van niet-geregistreerde geneesmiddelen wanneer aan alle 3 de volgende criteria wordt voldaan: (a) patiënten lijden aan een zeer ernstige of levensbedreigende aandoening (schrijnend geval); (b) geregistreerde adequate alternatieve geneesmiddelen zijn niet aanwezig; en (c) patiënten kunnen niet deelnemen aan klinisch onderzoek.24
Chapter 2 34 Normaal gesproken verbiedt de Geneesmiddelenwet geneesmiddelen beschikbaar te stellen waarvoor in Nederland geen handelsvergunning is afgegeven. Er bestaan uitzonderingen voor bijvoorbeeld studiemedicatie of geneesmiddelen die door een apotheker zelf worden bereid. Expanded access is een aanvullende uitzondering, waarvoor veel aandacht was rondom het gebruik van niet-geregistreerde medicatie voor de behandeling van patiënten met covid-19. Expanded access is iets anders dan offlabelgebruik. Offlabelgebruik wil zeggen dat geregistreerde geneesmiddelen buiten de geregistreerde indicatie worden gebruikt. Een voorbeeld hiervan is dat hydroxychloroquine en chloroquine werd gebruikt voor de behandeling van patiënten met ernstige covid-19. In Nederland valt offlabelgebruik níet onder expanded-accesswetgeving.Alleen geneesmiddelen die op het moment van voorschrijven in Nederland geen enkele registratie hebben vallen onder deze wetgeving. Er zijn twee manieren om een niet-geregistreerd geneesmiddel voor te schrijven via expanded access: (a) via het zogenoemde leveren op artsenverklaring en (b) via ‘compassionate use’- programma’s (CUP’s). LEVEREN OP ARTSENVERKLARING Leveren op artsenverklaring wordt gebruikt voor individuele aanvragen om een niet-geregistreerd geneesmiddel voor te schrijven.61 Dit staat ook bekend als ‘named-patient use’. Daarbij moet de behandelend arts een verklaring opstellen, waarin die verklaart dat: (a) de patiënt niet adequaat behandeld kan worden met geregistreerde medicatie en daarom een niet-geregistreerd geneesmiddel nodig heeft; (b) de patiënt nadrukkelijk is geïnformeerd over het niet-geregistreerde middel en de daarbij behorende risico’s; (c) de arts de volle verantwoordelijkheid draagt en de risico’s voor behandeling aanvaardt; en (d) de arts alle aan het middel gerelateerde bijwerkingen meldt. Behalve de bovengenoemde voorwaarden zijn er géén beperkingen voor het gebruik van nietgeregistreerde geneesmiddelen. Het middel hoeft niet elders goedgekeurd te zijn en hoeft niet een bepaalde fase van ontwikkeling doorlopen te hebben; leveren op artsenverklaring is mogelijk bij geneesmiddelen in fase I, fase II of fase III van de ontwikkeling. Wel geldt: hoe verder in het ontwikkeltraject, hoe meer inzicht er is in de verhouding tussen de risico’s en de baten. Het is ook mogelijk om middelen die in Nederland niet meer geregistreerd zijn, zoals levosimendan,62 voor te schrijven via het leveren op artsenverklaring. Termen als ‘early access’ en ‘pre-approval access’ doen echter anders vermoeden, waardoor we wellicht beter kunnen spreken van ‘post-withdrawal’ of ‘late access’.
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