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Success in Academic Surgery Series Editors: Lillian Kao · Herbert Chen Timothy M. Pawlik Julie A. Sosa   Editors Clinical Trials Second Edition Success in Academic Surgery Series editors: Lillian Kao McGovern School The University of Texas Health Science Centre Houston, TX USA Herbert Chen Department of Surgery University of Alabama at Birmingham Birmingham, AL USA More information about this series at Timothy M Pawlik  •  Julie A Sosa Editors Clinical Trials Second Edition Editors Timothy M Pawlik Chair, Department of Surgery The Urban Meyer III and Shelley Meyer Chair for Cancer Research The Ohio State University Wexner Medical Columbus, OH USA Julie A Sosa Leon Goldman, MD Distinguished Professor of Surgery and Chair Department of Surgery University of California, San Francisco San Francisco, CA USA Professor, Department of Medicine University of California, San Francisco San Francisco, CA USA ISSN 2194-7481    ISSN 2194-749X (electronic) Success in Academic Surgery ISBN 978-3-030-35487-9    ISBN 978-3-030-35488-6 (eBook) © Springer Nature Switzerland AG 2014, 2020 This work is subject to copyright All rights are reserved by the Publisher, whether the whole or part of the material is concerned, specifically the rights of translation, reprinting, reuse of illustrations, recitation, broadcasting, reproduction on microfilms or in any other physical way, and transmission or information storage and retrieval, electronic adaptation, computer software, or by similar or dissimilar methodology now known or hereafter developed The use of general descriptive names, registered names, trademarks, service marks, etc in this publication does not imply, even in the absence of a specific statement, that such names are exempt from the relevant protective laws and regulations and therefore free for general use The publisher, the authors and the editors are safe to assume that the advice and information in this book are believed to be true and accurate at the date of publication Neither the publisher nor the authors or the editors give a warranty, expressed or implied, with respect to the material contained herein or for any errors or omissions that may have been made The publisher remains neutral with regard to jurisdictional claims in published maps and institutional affiliations This Springer imprint is published by the registered company Springer Nature Switzerland AG The registered company address is: Gewerbestrasse 11, 6330 Cham, Switzerland Contents 1The History of Clinical Trials�����������������������������������������������������������������    1 Janice Hu, Justin Barr, and Georgia M Beasley 2Ethics (Informed Consent and Conflicts of Interest)����������������������������   17 Kara K Rossfeld, Jordan M Cloyd, Elizabeth Palmer, and Timothy M Pawlik 3Generating a Testable Hypothesis and Underlying Principles of Clinical Trials ��������������������������������������������������������������������   33 Cecilia G Ethun and Shishir K Maithel 4Trial Design: Overview of Study Designs����������������������������������������������   37 Puneet Singh, Yu Shen, and Kelly K Hunt 5Defining the Study Cohort: Inclusion and Exclusion Criteria������������   47 Emily Z Keung, Lisa M McElroy, Daniela P Ladner, and Elizabeth G Grubbs 6Pragmatic Trials and Approaches to Transforming Care��������������������   59 Peter G Stock, Rita Mukhtar, Hila Ghersin, Allison Stover Fiscalini, and Laura Esserman 7Clinical Trials: Ensuring Quality and Standardization ����������������������   77 Mihir M Shah and Darren R Carpizo 8Steps in Device and Drug Pathway Development: Clinical Trials, Similarities, and Differences ����������������������������������������   87 Timur P Sarac 9Statistics: Setting the Stage ��������������������������������������������������������������������  101 M Abdullah Arain, Adil H Haider, and Zain G Hashmi 10Clinical Trials: Handling the Data���������������������������������������������������������  117 Douglas S Swords and Benjamin S Brooke v vi Contents 11Data Safety Monitoring Boards��������������������������������������������������������������  137 Rachael A Callcut 12Planning for Data Monitoring and Audits ��������������������������������������������  143 Benjamin K Poulose 13The Budget������������������������������������������������������������������������������������������������  151 Shuab Omer and Faisal G Bakaeen 14Regulatory Considerations in Human Subjects Research ������������������  167 H Richard Alexander Jr and Howard S Hochster 15Publishing Your Clinical Trial����������������������������������������������������������������  181 Warren Gasper and Michael Conte 16Pragmatic Clinical Trials������������������������������������������������������������������������  187 Peter C Minneci and Katherine J Deans 17Cooperative Clinical Trials����������������������������������������������������������������������  195 Casey J Allen, Giampaolo Perri, and Matthew H G Katz 18International Trials: Surgical Research Networks�������������������������������  213 Marc A Gladman 19Inclusion of Patient-Reported Outcomes in Clinical Trials ����������������  229 Lindsey M Zhang, Cord Sturgeon, Anthony D Yang, and Ryan P Merkow 20Participation in Clinical Trials as a Clinical Trialist for the Community Surgeon��������������������������������������������������������������������  237 Jonah D Klein and Ned Z Carp Index������������������������������������������������������������������������������������������������������������������  251 Chapter The History of Clinical Trials Janice Hu, Justin Barr, and Georgia M. Beasley 1.1  Introduction A clinical trial is a purposeful comparison of medical interventions, including placebos, against one another to determine the safest, most efficacious means of treating pathology The history of clinical research in surgery sheds light on both the successes and the challenges that academic surgeons faced when developing therapies for their patients 1.2  Early History Clinical trials had little role in the ancient world where accepted disease theories rendered them all but irrelevant In many older cultures, disease and healing were perceived to stem from supernatural and divine forces In Greece during the fifth century BCE, patients sought healing through “incubation,” or sleep, in temples of the healing god Asclepius It was around this time that a new form of medicine arose, marking a major innovation in the treatment of disease Unlike supernatural theories, Hippocrates’ method involved seeking the cause of illness in natural J Hu Duke University School of Medicine, Durham, NC, USA J Barr Duke Department of Surgery, Durham, NC, USA G M Beasley (*) Duke University School of Medicine, Durham, NC, USA Duke Department of Surgery, Durham, NC, USA e-mail: © Springer Nature Switzerland AG 2020 T M Pawlik, J A Sosa (eds.), Clinical Trials, Success in Academic Surgery, J Hu et al factors involving the composition of the body’s humors An oeuvre of texts known as the Hippocratic Corpus, written by numerous authors over many decades until the first half of the fourth century BCE, established that physicians could learn through observations and actions Yet the ancient Greeks did not perform clinical trials to test their hypotheses Moreover, the highly individualized understanding of disease made broadly applicable treatments rare, vitiating the value of clinical trials The Greek had “freed himself of religion to become the prisoner of philosophy” [1] This dogma largely continued through the Roman world [2] In 1025  CE, the Persian physician Avicenna wrote the widely used medical treatise The Canon of Medicine in which he laid down a precise guide for empirical investigation of the effectiveness of medical drugs and substances [3] He recommended studying two cases of contrary types, along with the timing and reproducibility of drug effects so that consequence and accident are not confused Moreover, he advocated for experimentation on the human body, since testing a drug on a lion or a horse might not prove anything about its effect on man The pharmacology discussed in Avicenna’s treatise was used extensively in medical schools across Europe as late as 1650 [4] Although Avicenna advocated for the empirical study of drugs, his Canon did not lead to the widespread engagement of experiments and empiricism Instead, the Medieval Era (800–1400 CE) was characterized by textual dependence and interpretation that prized the authority of the ancients over experimental evidence [5] Moreover, while extant sources such as the Hippocratic Corpus and the Canon defined elite, academic-based medicine, the vast majority of medical care was delivered by untrained, unlicensed, and irregular practitioners, most of whom were illiterate This practice went largely unrecorded and likely relied on a combination of superstition, tradition, and empiricism 1.2.1  Early Modern Era (1500–1800) With the dawn of the early modern era in the sixteenth century, there was a general intellectual shift away from dogmatic textual dependence and toward empirical investigation This was evident in multiple arenas including heliocentric theories of astronomy put forth by Nicolaus Copernicus, anatomical observations made by Andreas Vesalius, and navigational feats like those by Christopher Columbus They also appeared in medicine One of the first clinical trials was accidentally conducted in 1537 by the French surgeon Ambroise Paré when he ran out of the boiling oil that was conventionally used to treat bullet wounds and resorted to giving some soldiers a balm made from egg yolks, rose oil, and turpentine [6] He awoke the following morning to find that patients who received the new treatment were resting well with little discomfort and swelling, whereas those who were cauterized with oil were “feverish with much 1  The History of Clinical Trials Fig 1.1  Ambroise Paré et l’examen d’un malade [Ambroise Paré examining a patient] by James Bertrand (1823–1887), from the Charles de Bruyères Museum collection in Remiremont (Source: Ji-Elle, license CC:BY-SA) [8] pain and swelling about their wounds.” Reflecting on this experience, he noted “I resolved with myself never more to burn thus cruelly poor men wounded with gunshot” [7] This observation, widely published, changed clinical practice as military surgeons across Europe began to eschew boiling oil in favor of less painful remedies (Fig. 1.1) Systematic tests of disease management tackled the pre-fifteenth century Galenic tradition of wound management, characterized by gradual “wet healing” that involved forcing wounds open and applying emollients This conventional method often led to poor outcomes From 1580 to 1583, Spanish surgeon Bartolomé Hidalgo de Agüero challenged this notion by examining hospital records, finding that his own method of “dry healing”—cleaning the wound with white wine, removing damaged tissue, bringing the edges together, applying drying compounds, and covering the wound with a bandage—led to a far lower mortality rate compared to the Galenic technique [9] The trend of empiricism continued to grow as physicians set forth hypotheses and began testing them through observation Paré and Agüero belonged to a group of sixteenth century practitioners who were willing to trust their observations and personal experience over ancient traditions and dogma Yet two centuries would pass before the launch of the first rigorous prospective trial Scottish surgeon James Lind randomized six pairs of sailors to different treatments for scurvy in 1747, finding that citrus fruits were the most effective therapy [10] Despite the soundness of his methods and the irrefragability of his results, his conclusion had little impact on medical opinion in Britain, exposing an ongoing theme through this history: the challenge of even the best clinical trial actually changing medical practice It ultimately requires many more decades, with thousands of additional deaths, for professional opinion to adopt lemons as a scurvy prophylactic J Hu et al 1.3  The Emerging Importance of Statistics Comparative retrospective analyses played an important role in building toward controlled trials in medicine and surgery Statistics, or the practice of collecting and analyzing large amount of numerical data, emerged as an important tool in treatment evaluation By the eighteenth century, several case series propelled arguments about the utility, methods, and timing of limb amputations [11, 12] Lithotomists published numerical evidence on bladder stone removal, debating the merits of lithotripsy compared to lithotomy and examining mortality among age subgroups [13–15] In the 1820s, Pierre-Charles-Alexandre Louis used his “numerical method” on aggregated clinical data to cast doubt on the practice of bloodletting [16, 17] Furthermore, statistics featured prominently in debates surrounding perioperative innovations such as anesthesia and Lister’s “antiseptic method” of carbolic acid for surgical wounds beginning in 1867 [18, 19] This portended the clear role and need for stronger evidence to evaluate theories of disease management It also demonstrated the shift from highly individualized disease states as understood in ancient and medieval medicine to a more ontological notion of sickness where a single intervention had the potential to apply to all patients suffering from the same pathology This critical theoretical transition made clinical trials relevant Moreover, as anesthesia and antisepsis allowed surgeons to delve further into internal organs and conduct more elective procedures, there arose a clear need to provide proof of safety and benefit 1.4  Prospective Clinical Trials Begin In the nineteenth century, surgeons joined in performing prospective trials by first using nonrandom methods of treatment assignment such as alternate allocation In perhaps the earliest example of this, an 1816 medical dissertation describes how military surgeons performed a controlled trial on 366 soldiers in the Peninsular War to assess the effects of bloodletting for fever Although there are uncertainties surrounding the authenticity of this report [20], it nonetheless illustrates the emerging desire among surgeons to control for factors other than the treatment of interest: It had been so arranged, that this number was admitted, alternately, in such a manner that each of us had one third of the whole The sick were indiscriminately received, and were attended as nearly as possible with the same care and accommodated with the same comforts One third of the whole were soldiers of the 61st Regiment, the remainder of my own (the 42nd) Regiment Neither Mr Anderson nor I ever once employed the lancet He lost two, I four cases; whilst out of the other third [treated with bloodletting by the third surgeon] thirty five patients died [21] The last decades of the nineteenth century witnessed the publication of other prospective surgical studies using alternate allocation These included catheterization for urethrotomies, capsulotomy following removal of cataracts, and pediatric hernia management [22–24] The goals of these researchers were twofold: (1) to 20  Participation in Clinical Trials as a Clinical Trialist for the Community Surgeon 243 The attitude that a physician has toward the value of clinical trials and the logistical ease of enrolling patients had direct correlation with more actively enrolling physicians (based on a retrospective analysis of CCOP) [15] This factor is especially important at a community hospital, as the involvement in a given research study is often voluntary from the standpoint of the clinician Being a principal investigator on a study also was associated with better recruitment Surgeons were noted to be less likely to accrue patients in a clinical trial compared to medical oncologists; older physicians are less likely to accrue than younger colleagues Additionally, factors that were associated with organizational context improve patient recruitment and physician enrollment These contextual factors include staff support for consenting and enrolling patients, institutional incentives and acknowledgements for enrollment, and training opportunities for physicians to learn about trial participation and patient enrollment [16] Also, institutions involved in more cancer control trials and quality of life were more likely to accrue patients in clinical trials Interestingly, the value clinicians place on involvement in clinical trials is independent of the organizational context in which they work, but both factors influence recruitment Practice location and type has played a variable role in patient recruitment Only 3–5% of eligible patients are enrolled in clinical trials Factors associated with enrollment include availability of trial, knowledge of availability of trial, trial exclusions, age, race, and gender [17] Younger, Caucasian males are more likely to be clinical trial participants Major barrier for patient involvement, in addition to knowledge of availability, include patient commitment and champions Commitment and champions from the standpoint of patients, as well as other entities including advocacy groups and professional societies, will also raise awareness and increase enrollment in community centers Another factor is to mitigate patient’s preexisting perspectives on clinical trials This may be more relevant in the community setting where patients aren’t expecting active clinical trials Clinicians must mitigate issues of mistrust that continue to loom from such cases as the Tuskegee syphilis experiment and inform patients of governing bodies such as the Office for Human Research Protections and mandated review board approvals to ensure the safety and ethical nature of trials Patients may also be under the impression that clinicians accrue patients to get kickbacks from sponsoring companies Clinicians must assure patients that the purpose of clinical trials is to improve outcomes and enhance ­quality of life 20.5  Community Center Versus Academic Training Center Community centers come with a wide range of academics and physician postgraduate training Some, as in the authors’, have medical and surgical resident and fellowship programs, whereas other community centers have none Regardless, research in all of these institutions is feasible whether through NCORP directly, being an NCORP affiliate, through drug and device trials, or independent clinical trials The primary differences between a community center and a university-based academic center are the availability of funds, institutional backing, and resources And 244 J D Klein and N Z Carp this trend continues with the range of community centers depending on the training offered and the nature of the associated health system At smaller, or private, community centers, finding the resources to get involved in clinical trials can be very challenging At larger academic centers, and even larger community centers, there is designated research staff that facilitates a large portion of the logistics and conversations The surgeon can mention the trial and spark a patient’s interest, but as far as scheduling, consenting, billing, detailed eligibility requirements, and other follow-up tasks, this is often relegated to the research staff designated to clinical trials At smaller community centers, this responsibility often falls on the surgeon or the clinical nurse, and in a busy practice, it can be burdensome This chapter’s section is designed to address those surgeons who may be at a small community hospital or based out of a more rural private practice, but would like to be involved in clinical trials While, this setting makes involvement much more challenging, it is still possible Suggested ways to initiate involvement is to select a mentor at a larger community site who is already involved in clinical trials, and/or attend a national or international society meeting on the topic of interest for clinical trial involvement This is where interested physicians can meet clinicians and discuss common interests and inquire about involvement These conversations, while informal, are what lead to awareness of clinical trials, networking with device and drug companies, and creation of a network of interested surgeons Once involved with one trial, a clinician will often be sought by other companies or trialists for involvement in additional trials And as one trial ends, the trial topic gets morphed into another follow-up trial continuing involvement Barriers that will be more difficult to overcome will be in the areas of cost, patient recruitment, and lack of personnel Addition costs may be accrued when initiating clinical trials to have documents reviewed (contracts and IRBs) by privately hired legal personnel Also, patients often seek community hospitals as their health center, and private practices for expertise, but not because of active clinical trials, which makes the trial recruitment process more difficult The staff that is part of the surgeons practice must be willing to make some sacrifices, such as extra time and responsibilities to support the clinical trials that are being performed, in addition to the existing clinical practice The surgeon must also make sacrifices and have understanding family and friends given that research time is added to, and doesn’t take the place of, clinical time But despite these added barriers and responsibilities, there are many community and private practice surgeons that have broken through and contributed to patient care improvement by initiating and persisting in clinical trials involvement 20.6  D  oing Clinical Trials with Pharma and Device Companies For a detailed, comprehensive outline of how the Food and Drug Administration (FDA) regulates pharmaceutical and device trials, please refer to Chap 10 This current chapter’s section will not focus on drug and device classification and the steps to approval, but more so the advantages, disadvantages, and recruitment of 20  Participation in Clinical Trials as a Clinical Trialist for the Community Surgeon 245 drug and device trials from the community surgeon’s perspective, and how the community surgeon can get involved in these trials As an example of a device trial, ACOSOG published a phase II trial (Z1072) in 2016 on the success of cryoablation therapy in the treatment of invasive breast cancer [18] This was a mutli-institutional surgical device clinical trial with participants from university and community health centers All cryoablation procedures were performed by the Visica 2™ Treatment System and sponsored by the manufacturing company Sanarus® Cryoablation was performed followed by mandated surgical resection This trial demonstrated a complete pathologic response to cryoablation therapy and concordance with detection in MRI for tumors less than 1 cm, and the follow-up trial without surgical resection is accruing (FROST trial) Community centers had leading recruitment numbers for this trial An example of a surgical drug trial was a study performed evaluating Alvimopan and its role in postoperative ileus in major abdominal surgery [19] This was a randomized, placebo controlled, multi-institutional, both community and academic centers, in North America, evaluating the use of Alvimopan in a modified intent-to-­treat study sponsored by the two involved pharmaceutical companies This study demonstrated that Alvimopan use significantly decreased time to gastrointestinal recovery and hospital discharge in patients undergoing bowel resection or radical hysterectomy There are also trials in vascular surgery that extend to the community surgeon An example of this is the currently recruiting TRANSCEND trial [20] This is a randomized, single-blind, non-inferiority trial evaluating patients with symptomatic peripheral arterial disease of the femoropopliteal system to the SurVeil drug-coated balloon, versus the IN.PACT Admiral drug-coated balloon This is a device sponsored trial and involves both large community and academic centers The primary advantage of a community surgeon’s involvement in trials involving investigational new drugs or investigational devices is the respective company’s sponsorship Most of the time, trial participants, recruiting physicians, and insurance companies are not charged for new drugs, except allowing of sponsors to break even on the cost of the drug by insurance companies Regarding investigational devices, the U.S.  Centers for Medicare and Medicaid Services (CMS), in most cases, will reimburse the cost of the device up to the current day standard or similarly approved marketed product The physician participating in the study must submit a Request for Reimbursement Letter to verify CMS reimbursement prior to conducting the study For device trials, depending on the complexity and novelty of the device, there may be required physician and staff training [21] 20.7  N  on-pharmaceutical, Non-device Community Clinical Trials Let’s start with another example of an impactful, purely surgical, clinical trial that had contributions by the community surgeon The Multicenter Selective Lymphadenectomy Trials (MSLT-I and MLST-II) published in the New England Journal of Medicine in 2006 and 2017, respectively, evaluated the contribution of 246 J D Klein and N Z Carp the sentinel lymph node biopsy and completion lymph node dissection in patients with melanoma In MSLT-I, patients with intermediate thickness of primary cutaneous melanoma were randomized to excision with post-operative observation of lymph nodes and lymphadenectomy, if clinical relapse or sentinel lymph node biopsy and immediate lymphadenectomy were positive The 5-year survival rate of those patients in the sentinel lymph node group was 20% greater compared to the observation group [22] The MSLT-II trial evaluated similar melanoma patients with sentinel lymph node metastasis, and compared serial ultrasound observation to immediate lymphadenectomy, and immediate lymphadenectomy did not ­demonstrate improved melanoma-specific survival [23] Both of these trials included contributions from community centers Given the infrastructure that the NCI has in place for community involvement in clinical trials, most clinical trials performed to date have been in the field of oncology There are previously mentioned device trials with endovascular devices, breast cancer, post-operative medications, but it is important to discuss clinical trials that have been performed in surgery, outside device and drug trials and outside of the field of oncology, and to further discuss the challenges involved with such trials A groundbreaking trial published in the New England Journal of Medicine in 1990 was the Program on the Surgical Control of Hyperlipidemia (POSCH) trial This trial was a randomized clinical trial testing the partial ileal bypass operation on the mortality due to coronary heart disease Eligible patients hospitalized after their first myocardial infarction were randomized to hospital discharge versus continued hospitalization for partial ileal bypass In follow up, fewer patients in the surgery arm were on cholesterol lowering medications, there were lower total cholesterol and LDL cholesterol and higher HDL cholesterol in the surgery arm and a 22% risk reduction in overall mortality and 28% risk reduction in cardiovascular mortality in the surgery arm Most importantly for this chapter, of the 838 patients from four institutions in the trial, 184 of them were from a community hospital, which was the second highest accruing center While ileal bypass is now not routinely used due to the safety and efficacy of statins, this trial demonstrates an early surgical trial involving a highly accruing community center [24] In 2010, the Annals of Surgery published a 25-year follow-up evaluation demonstrating an increase in cardiovascular mortality and all-cause mortality in the control arm [25] One of the biggest challenges in a community surgeon getting involved in a clinical trial, such as the previously mentioned NSABP surgical trials, or the POSCH trial, is the standardization from one surgeon to another and from one institution to another As in these cases, when the surgical intervention itself is the clinical trial, there are many elements that could potentially lead to challenges, biases, and questioned results such as anesthesia use, preoperative and postoperative care, different surgeons at different institutions, follow-up regimens, among others [26] While this problem exists in the academic setting, a benefit of community hospital involvement in surgical trials is increased accrual, and to take advantage of this, often trials will involve multiple centers There are varying degrees of standardization that will ­dictate the strength of a given trial’s outcome The surgical intervention itself can be standardized with respect to its written description, preparation, dissection, 20  Participation in Clinical Trials as a Clinical Trialist for the Community Surgeon 247 r­ esection, approach, closure, or a selection of these factors The same goes for the other variable factors The interventions need to be monitored for compliance to these standards, and there may be a training and preceptorship period prior to community surgeon involvement in order to optimize standardization 20.8  L  ifestyle and What’s in It for the Busy Community Surgeon? Major barriers in the utilization of the Cooperative Group Programs by community hospitals have been recruitment and reimbursement Community physicians desire patient involvement, but with increasing patient load and decreasing time per patient, there often isn’t time left for appropriate discussion of trial protocols And if there is time made for protocol discussion, there are often additional tests and follow-up not often covered by insurers There hasn’t been enough grant support, and physicians fear increasing out-of-pockets expenses for patients The time it takes for a “paying customer” is taken for a patient involved in a clinical trial It is sometimes difficult to justify the busy community surgeon’s involvement in clinical trials on top of existing clinical duties These barriers exist, but they are not inhibitory and can be overcome with collegiality, persistence, hard work, and desire [10] With all these barriers, what’s in it for the surgeon? This is an important question to ask With financial strains, resource limitations, intense regulatory processes, immense time commitment, and a lack of financial incentive, why should a busy community surgeon take on clinical trials? The answer is simply in the community surgeon’s desire to provide the best care to patients, optimize care for the best outcome, and satisfy one’s academic curiosity Given that the majority of cancer patients are seen and treated in community centers, it is imperative to continue to enroll these patients in clinical trials via active physician recruitment and participation Community surgeon clinical trial involvement is crucial to ensure the best care, best outcomes and best quality of life for their patients, and contribute to global advances in health care to provide the best care, best outcomes, and best quality of life to all surgical patients Acknowledgements  Paul B.  Gilman, M.D., Albert DeNittis, M.D., M.S., Jarrod Kauffman, M.D., Alexander Uribe, M.D., John Wellenbach, John H. Marks, M.D References National Center for Health Statistics, Center for Disease Control 2017 nchs/hus/contents2017.htm?search=Hospital_use Accessed 26 Mar 2019 Bauer TL Sr, Boughey JC. Community-based physicians and hospitals need to participate in clinical trials Bull Am Coll Surg 2014;99(4):46–7 248 J D Klein and N Z Carp Begg CB, Carbone PP, Elson PJ, Zelen M. Participation of community hospitals in clinical trials—analysis of five years of experience in the eastern cooperative oncology group N Engl J Med 1982;306(18):1076–80 Zon RT. Reforming the community research program: from community clinical oncology program to the National Cancer Institute Community Oncology Research Program ASCO Educ Book 2014;2014:e116–9 Coltman CA Jr Organizations and structures that facilitate community research Semin Oncol 1994;21(4 Suppl 7):107–11 Fisher B, Bauer M, et al Five-year results of a randomized clinical trial comparing total mastectomy and segmental mastectomy with or without radiation in the treatment of breast cancer N Engl J Med 1985;312(11):665–73 Fisher B, Montague E, et al Comparison of radical mastectomy with alternative treatments for primary breast cancer Cancer 1977;39(6):2827–39 Krag DN, Anderson SJ, et  al Sentinel-lymph-node resection compared with conventional axillary-lymph-node dissection in clinically node-negative patients with breast cancer: overall survival findings from the NSABP B-32 randomised phase trial Lancet Oncol 2010;11(10):927–33 Siegel RD, et  al National collaborative to improve oncology practice: the National Cancer Institute Community Cancer Centers Program quality oncology practice initiative experience J Oncol Pract 2009;5(6):276–81 10 McCaskill-Stevens W. The NCI Community Oncology Research Program: what every clinician needs to know ASCO Educ Book 2013;2013:e84–9 11 Institute of Medicine Participation by community physicians In: Institute of Medicine, editor A national cancer clinical trials system for the 21st century: reinvigorating the NCI Cooperative Group Program Washington, DC: The National Academies Press; 2010 p. 197–9 12 Institute of Medicine Tapping community practices In: Institute of Medicine, editor Implementing a national cancer clinical trials system for the 21st century: second workshop summary Washington, DC: The National Academies Press; 2013 p. 55–9 13 NP Office NCI Community Oncology Research Program (NCORP) Gets, NCI news note, Bethesda, MD: NCI; 2014 14 Cancer Trials Support Unit: a service of the National Cancer Institute Public/Default.aspx Accessed 15 Mar 2019 15 Jacobs SR, et al Organizational and physician factors associated with patient enrollment in cancer clinical trials Clin Trials 2014;11(5):565–75 16 Jacobs SR. Achieving high cancer control trial enrollment in the community setting: an analysis of the Community Clinical Oncology Program Contemp Clin Trials 2013;34(2):320–5 17 SCM Cancer Network Oncology 2019 Accessed 13 Mar 2019 18 Simmonr RM. A phase II trial exploring the success of cryoablation therapy in the treatment of invasive breast carcinoma: results from ACOSOG (Alliance) Z1072 Ann Surg Oncol 2016;23(8):2438–45 19 Wolff BG. Alvimopan, a novel, peripherally acting μ opioid antagonist results of a multicenter, randomized, double-blind, placebo-controlled, phase III trial of major abdominal surgery and postoperative ileus Ann Surg 2004;240(4):728–35 20 Safety and Efficacy of the SurVeil™ Drug-Coated Balloon (TRANSCEND) 2018 https:// Accessed 20 Mar 2019 21 Blake-Michaels M. Applied clinical trials 2010 considerations-medical-device-trials Accessed 13 Mar 2019 22 Morton DL.  Sentinel-node biopsy or nodal observation in melanoma N Engl J Med 2006;355(13):1307–17 23 Faries MB. Completion dissection or observation for sentinel-node metastasis in melanoma N Engl J Med 2017;376(23):2211–22 20  Participation in Clinical Trials as a Clinical Trialist for the Community Surgeon 249 24 Buchwald H. Effect of partial ileal bypass surgery on mortality and morbidity from coronary heart disease in patients with hypercholesterolemia Report of the Program on the Surgical Control of the Hyperlipidemias (POSCH) N Engl J Med 1990;323(14):946–55 25 Buchwald H. Overall mortality, incremental life expectancy, and cause of death at 25 years in the program on the surgical control of the hyperlipidemias Ann Surg 2010;251(6):1034–40 26 Blencowe NS. Standardizing and monitoring the delivery of surgical interventions in randomized clinical trials Br J Surg 2016;103(10):1377–84 Index A Academic training center, 243, 244 Accelerated-titration design, 38 ACOSOG Z0011 phase III trial design, 42 ACOSOG Z0011 trial, 42 ACOSOG Z1041 trial, 40 Adaptive (Bayesian) trials, 74 Adaptive design, 71 Adjusted risk difference (ARR), 128 Adverse event (AE) identification, 78 Affordable Care Act, 64 Allocation concealment, 106, 122 Alpha errors, 118 Alterations and renovations (A&R), 158 Alvimopan, 245 Amberson’s trial, American College of Radiology Imaging Network (ACRIN), 197 American College of Surgeons Oncology Group (ACOSOG), 197 American Joint Committee on Cancer (AJCC), 209 Animal pharmacology and toxicology studies, 96 Annual distribution number (ADN), 94 Antiretroviral drugs, 64 Association of Clinical Research Professionals (ACRP), 83 Athena Breast Health Network, 65 Autonomic nerve dysfunction, Avicenna’s treatise, Axillary lymph node dissection (ALND), 41 B Baseline adaptive randomization, 106 Baysesian probability statistical analysis, 140 Belmont Report, 52, 172 Beta errors, 119 Bevacizumab, 198 Bias, 120, 121 Blinding, 123 Blocked randomization, 104 Blue Cross Blue Shield Association, 68 Blue Cross Blue Shield companies, 68 Bonferroni correction, 118, 124 BRCA I and II mutation, 38 Breast cancer screening, 65 British Neurosurgical Trainee Research Collaborative (BNTRC), 218 Budget appropriate number of subjects, 165 audit charges, 165 backup plan, 164 consortiums/subawards, 159, 160 cost sharing, 154, 155 detailed budget, 155–159 direct costs, 157–159, 161–163 federal cost principles, 152 future predicting and planning, 160 immediate costs, 164 indirect costs, 161–163 industry-sponsored clinical trials, 160 inflation adjustment, 165 modular budget, 155 NIH, 151, 152 principal sponsors, 151 reimbursement timetable, 165 sponsors and investigators, 161 © Springer Nature Switzerland AG 2020 T M Pawlik, J A Sosa (eds.), Clinical Trials, Success in Academic Surgery, 251 252 C Canadian Group is the Canadian Cancer Trials Group (CCTG), 199 Cancer and Leukemia Group B (CALGB), 197 Cancer Therapy Evaluation Program (CTEP), 205 Cancer Trials Support Unit (CTSU), 241 Case report form (CRF), 80 Center for Devices and Radiological Health (CDRH), 174 Center for Drug Evaluation and Research (CDER), 174 Center for Health Quality and Innovation (CHQI), 67 Children’s Oncology Group (COG), 197 Chi-square test, 125 Clinical Research Organization (CRO), 82, 83 Clinical Research Professionals (CRPs), 83 Clinical Trial Management System (CTMS), 82 Clinical trial offices (CTOs), 11 Clinical trials alternate allocation, antiseptic method, autonomic nerve dysfunction, Avicenna’s treatise, breast cancer surgery, 7–9 chemical composition and dose, 10 Common Rule, 18, 19 conflict of interest financial COI, 28, 29 guidelines for managing, 28 physician-researcher conflicts, 27, 28 risk of influence on physician-­ investigator, 27 constipation, definition, 33 design innovation, 22 developing research question, 34, 35 early modern era (1500-1800), 2, ethical clinical trial fair patient recruitment, 21 independent oversight, 21 informed consent, 21, 22 protections of research subjects, 22 satisfactory balance of risks and benefits, 21 scientific validity, 20–21 societal value, 19 ethics of randomized controlled trials, 10, 11 guidelines on ethics, 20 hank truss, Hippocrates’ method, Index incubation, informed consent assessing patient understanding, 24, 25 complex decision-making, 26 emergent surgical disease, 26 insufficient patient understanding, 23, 24 minimal risk, 26 necessity requirement, 26 optimal presentation, 25 “reasonable persons” desire, 25 requirements of, 24 research-related adverse event, 23 surgical innovation deserve mention, 27 verbal and written communication, 23 vulnerable populations, 26 intervention, 33, 34 laboratory-based studies, 34 large-scale delay, large-scale patient recruitment, 12 liaison services, 11 medical treatise, modern biomedical ethics, 17–19 nonrandom methods, numerical method, PICO(T) format, 35 ptosis, publication authorship, 184, 185 CONSORT statement, 181 journal selection, 184 manuscript preparation, 183–184 publication committee, 182, 183 statistical analysis plan, 181 trial protocol, 181 quality and standardization, 34 randomized trials, 5–7 revised Common Rule, 19 testable hypothesis, 35, 36 time zero, 33 Clinical Trials and Translational Research Advisory Committee (CTAC), 200 Clinical Trials Network Australia New Zealand (CTANZ), 218 Code of Federal Regulations (CFR), 171 Cohort study balancing patient protection and participation, 54 Belmont Report, 52 definition, 47 eligibility criteria, 47, 52 exclusion criteria, 48, 49 external validity, 50 feasibility, 51 Index inclusion criteria, 48 inclusion of children, 53, 54 internal validity, 50 modifying selection criteria, 56 prior therapy, 49 recruitment methods, 51, 52 reporting selection criteria, 54, 55 sample size, 50, 51 women and minorities, 53 Collaborative Institutional Training Initiative (CITI) program, 78, 176, 242 College of American Pathologists (CAP), 209 Common Rule, 171 Community centers, 243, 244 Community Clinical Oncology Program (CCOP), 238 Community surgeon academic training center, 243–244 community centers, 243, 244 Cooperative Group Program, 237 history of clinical trials, 237–239 involvement and recruitment, 242, 243 legal and budgeting expertise, 242 lifestyle, 247 NCORP program, 239–241 non-device community clinical trials, 246 non-pharmaceutical, 246 pharma and device companies, 244, 245 resources and infrastructure, 241 training, 242 Comparative effectiveness research (CER), 111 Complion, 81 Computer-assisted instructional program, 25 Conflict of interest (COI), 27–29 Consolidated Standards of Reporting Trials (CONSORT), 54, 82, 133, 182 Consort checklist, 55 CONSORT flowchart, 183 Consortia, 82, 83 The Consolidated Standards of Reporting Trials (CONSORT) statement, 102 Continuation in part (CIP), 88 Contract research organizations (CROs), 89 Controlled with combined antiretroviral therapy (cART), 60 Cooperative clinical trials community-based clinical practices, 196 components of, 205 conduct of multicenter trials, 207, 208 guide therapy, 196 heterogeneous patient population, 195 LAPS, 199 MCT design, 195 253 NCI-funded cooperative groups ACOSOG Z9001 trials, 197 IOM, 198 NCORP, 199, 200 NCTN, 199 personal advantages and disadvantages, 207 protocol development communication, 209 consensus, 208 cooperative trial, 206 feasibility and costs, 208 idea generation and concept development, 204 network group, 206 quality control, 209, 210 staffing and implementation, 205 statistical design, 204 study activation, 205, 206 study monitoring, 206 scientific and administrative oversight, 200 well-designed and executed cooperative trials, 196 Cooperative Group Outreach Program (CGOP), 238 Coordinating Center for Clinical Trials (CCCT), 200 Cost sharing, 154, 155 Coverage with Evidence Development (CED) policy, 66 Cryoablation, 245 D Data and Safety Monitoring Board (DSMB), 81 Data handling ARR, 128 chi-square test, 125 clinical trial design allocation concealment, 122 blinding, 123 outcome ascertainment, 124 permuted-block randomization, 122 random allocation, 121 stratified randomization, 122 CONSORT criteria, 133 correlated data structure, 125 covariate adjustment, 129, 130 hypothesis testing bias and error, 120, 121 confidence interval, 119 null hypothesis, 118 statistical inference, 117 Index 254 Data handling (cont.) type I errors, 118, 119 type II errors, 119 ITT, 128, 129 Kaplan-Meier method, 127 MCAR assumption, 131 missing data, 131 multiple imputation methods, 132 NNT, 132, 133 outcome variables, 125 patient-reported outcomes, 117 reporting results, 133 RRRs, 127, 128 single imputation methods, 131 statistical test, 124, 125 subgroup analyses, 130 time-to-event outcomes, 126–127 trial protocols, 126, 127 variables, 126 Data monitoring and audits, 144 alternative monitoring techniques, 145 anxiety-provoking element, 147 centralized monitoring, 145 clinical registries, 148 clinical trials, 147 competitive fiscal and academic environment, 146 goals of monitoring, 145 good clinical practice guidelines, 143–144 investigators and clinicians, 148, 149 onsite monitoring, 145 registry based clinical trials, 148 review of individual patients, 146 risk-based approaches, 145 unannounced reviews, 146 Data safety monitoring boards (DSMBs), 90, 144 charter, 139 history, 137, 138 membership and training, 139 objectives of, 138 plans, 141 procedures, 140, 141 Device and drug pathway development comparison of, 98 continuation application, 88 CROs, 89 design freeze, 89 DSMB, 90 510(k) application, 91, 92 futility, 90 HDE, 94 IDE, 92–94 idea and documentation, 87 IND application, 95, 96 non-provisional “utility patent” application, 88 Notice of Allowance, 88 obtaining patent, 87 Orphan Drug application, 97, 98 PMA submission, 91 prototype/proof of concept, 89 provisional application, 88 Dichotomous variables, 124 Division of Cost Allocation (DCA), 154 Division of Financial Advisory Services (DFAS), 154 Dose-escalation scheme, 39 Dose-limiting toxicities (DLTs), 38 Double-blind studies, 123 Drug and Cosmetic Act, 90 E Eastern Cooperative Oncology Group (ECOG), 49, 197, 238 ECOG-ACRIN Cancer Research Group, 199 Electronic CRFs (eCRFs), 80 Electronic data management systems (EDMS), 81 Electronic health record (EHR), 207 End-stage renal disease (ESRD), 69 Ensure quality and standardization adverse events investigator responsibility, 78 reporting form, 80 sponsor responsibility, 79 CITI program, 78 CONSORT statement, 82 CRF, 80 CRO, 82, 83 CRPs, 83 DSMB, 81 EDMS, 81 GCP guidance, 78 implement training programs, 77 SOP, 80 Esophagectomy, 20 European Community Rules, 23 European Society of Coloproctology safe-anastomosis programme (EAGLE), 224 Evidence-based medicine (EBM), 101 Exclusion criteria, 48, 49 Index F Facilities and administrative cost, 162 Feasibility study, 93 Federal Drug Administration (FDA), 137 Federal Food, 90 Federal Food, Drug, and Cosmetic Act, 95 Federal law, 53 Federal Wide Assurance (FWA), 171 FINER criteria, 34, 35 Finite element analysis (FEA), 89 “First-in-humans” trial, 38 Fisher’s trial, 510(k) application, 91, 92 Fixed allocation, 103 restricted randomization, 104, 105 simple randomization, 104 stratified randomization, 105 Food and Drug Administration (FDA), 5, 43, 174, 175 Fragility index (FI), 132 Funding opportunity announcement (FOA), 152–153 Futility, 90 G Global surgical trials networks, 222, 223 GlobalSurg, 223 Good clinical practice (GCP), 78, 174 Good Manufacturing Practices (GMP), 175, 176 Google patents, 87 Gynecologic Oncology Group (GOG), 197 H Halsted mastectomy, Halsted radical mastectomy, 238 Hazard ratio (HR), 128 Health Insurance Portability and Accountability Act (HIPAA), 173 Helsinki Declaration, 169 Hippocratic Corpus, HIV-infected individuals, 63 HIV-negative kidney transplant, 63 HIV-positive kidney transplant recipients, 63 HIV-TR trial, 64 Human epidermal growth factor receptor (HER2), 40 Human immunodeficiency virus (HIV), 54, 60 Human Research Protections Office (HRPO), 171 Human subjects research Belmont report, 169 federal statutes, 167 255 Helsinki Declaration, 169 historical perspectives, 168 Nuremberg Military Tribunals, 169 regulation of Common Rule, 172 FDA, 174, 175 FWA, 171, 172 GMP, 175, 176 HIPAA, 173 investigator responsibilities, 176, 177 IRB, 172 minimal risk, 172 practical considerations, 177–178 Humanitarian device exemptions (HDE), 94 Humanitarian Use Device (HUD) program, 94, 97 I Immunosuppressive drugs, 64 Inclusion criteria, 48 IN.PACT Admiral drug-coated balloon, 245 Institute of Medicine (IOM), 198, 239 Institutional leadership, 146 Institutional overhead, 162 Institutional review board (IRB), 92, 96, 162, 172, 205, 241 Intention-to-treat analysis (ITT), 128, 129 International collaborative surgical trials, 222 International Committee of Medical Journal Editors (ICMJE), 133, 182 International Council for Harmonisation (ICH), 78 International Knee Documentation Committee Subjective Knee Form, 231 International trials benefits, 214 BNTRC committee, 218 Clinical Trials Network Australia and New Zealand, 218–220 conducting surgical trials, 213 EuroSurg, 221, 222 global surgical trials networks, 222, 223 GlobalSurg, 223 LMICs, 213 NIHR Global Health Research Unit, 223, 224 STARSurg, 221 surgical research collaborative networks, 224–226 UK Surgical Trials Initiative, 215–217 U.K, Trainee-Led Research Collaborative Network, 216 U.K trainee research collaboratives, 219 256 Investigational device exemption (IDE), 79, 92–94 Investigational new drug (IND), 79, 95, 96 Investigation of Serial Studies to Predict Your Therapeutic Response (I-SPY) trials, 71–74 Israel Penn International Transplant Tumor Registry, 69 K Kaplan-Meier method, 126, 127 L Laboratory test costs, 162 Large clinical studies, 51 Lead Academic Participating Site (LAPS), 199 Liver and kidney transplantation, 61 Low- and middle-income countries (LMICs), 213 M Magseed®, 43 Management organization (SMO) model, 82 Maximal tolerated dose (MTD), 38 Medicaid, 67 Missing at random (MAR), 131 Missing completely at random (MCAR), 131 Modified total direct cost (MTDC), 154 Modular budget, 155 Molecularly targeted agents (MTAs), 38 Multivariable Cox proportional hazards model, 129 N National Cancer Institute (NCI), 12, 196, 237 National Cancer Institute Community Oncology Research Program (NCORP), 240, 241 National clinical trials network (NCTN), 198, 199 National Committee for Quality Assurance (NCQA), 68 National Institutes of Health (NIH), 47, 78, 137, 151 National provider identification (NPI), 67 National Surgical Adjuvant Breast and Bowel Project (NSABP), 41, 197 Nazi experimentation, 10 Index NCI Community Cancer Center Program (NCCCP), 239 NCI Community Oncology Research Program (NCORP), 199, 200, 240 NCI’s Cooperative Group Program, 239 Neoadjuvant chemotherapy, 72 Nominal variables, 124 Non-randomly assigned controlled studies, 107–109 Non-steroidal anti-inflammatory drugs (NSAIDs), 222 North Central Cancer Treatment Group (NCCTG), 197 Number needed to treat (NNT), 132 Nuremberg Military Tribunals, 169 O Odds ratios (ORs), 127 Office for Human Research Protections (OHRP), 171 Olaparib, 39 Oncology trials, 54 OnCore, 81 Orphan Drug Act (ODA), 94 Orphan Products Development’s (OOPD) mission, 97 P Patient-Centered Outcomes Research Institute (PCORI), 64, 193, 230 Patient Protection and Affordable Care Act, 230 Patient-Reported Outcome Measurement Information System (PROMIS), 233, 234 Patient-reported outcomes (PRO) definition, 229 intervention, 231, 232 limitations and challenges, 234, 235 measuring and interpreting, 232–234 PCORI, 230 primary/secondary outcome, 230, 231 SPIRIT-PRO extension statement, 234 Pediatric Device Consortia (PDC), 98 Peninsular War, Permuted-block randomization, 122 Pharmacokinetics/pharmacodynamics (PK/PD), 38 Phase III noninferiority trial, 42 Physician Payments Sunshine Act, 28 PICO(T) format, 35 Index Pivotal study, 93 Population-based studies, 52 Postmarked study, 94 Power (1–β), 113–114 Pragmatic clinical trials challenges in, 193 characteristics of, 190, 192–193 definition, 187 diagnostic trials, 187 explanatory trials, 188–190 phase III trials, 188 phase IV trials, 188 pre-specified hypothesis, 187 prevention trials, 187 q trials, 187 RCT, 188 “real-world” practice, 188 screening trials, 187 treatment strategy, 189 treatment trials, 187 Pragmatic clinical trials (PCT), 110, 190 Pragmatic explanatory continuum indicator summary (PRECIS-2) tool, 190–192 Pragmatic trials and approaches aunique trial, 60 HIV and transplant funding trial, 61 future directions, 63, 64 impact on practice, 63, 64 incidence of end-stage kidney and liver disease, 61 organ donation, 60 recruitment of investigators, 63 safety of transplantation, 60 study participants recruitment, 62 trial, 63, 64 I-SPY TRIALS, 71–74 neoadjuvant breast cancer setting, 60 transplantation influence transplant decisions, 70 kidney transplantation, 69 lack of standards and consensus, 70 organ transplantation and management, 69 recommendations, 71 transplant eligibility, 70 WISDOM Blue Cross Blue Shield companies, 68 breast cancer screening, 65 CEP-based clinical research, 67 data collection, 68 fundamental approach, 66 257 modern software platform, 69 personalized screening, 66 pragmatic approaches, 65 “preference-tolerant” design, 65 recruitment of study participants, 67 self-insured plans and medicaid, 67 Pragmatic–Explanatory Continuum Indicator Summary (PRECIS), 110 Pragmatism, 190 Premarket approval (PMA) application, 91 Premarket notification approval (PMA), 90 Principal investigator (PI), 241 Prior therapy, 49 Program on the Surgical Control of Hyperlipidemia (POSCH) trial, 246 P-value, 113 R RACS Trainee Association (RACSTA), 218 Radiation Therapy Oncology Group (RTOG), 197 Radical mastectomy, 8, 41 Random error, 121 Randomized controlled trials (RCTs), 40, 188, 190 Randomized trials, 5–7 Registry based clinical trials, 148 Relative risk ratios (RRRs), 127 Response adaptive randomization, 106 Restricted mean survival times (RMSTD), 128 Restricted randomization, 104, 105 Royal Australasian College of Surgeons (RACS), 218 S Saliva-based genetic testing kits, 67 Sanocrysin, Serious adverse event (SAE), 90 Simple randomization, 104 Single-blind study, 123 Small rural community hospital, 241 “SMART” trial model, 73 The Society of Clinical Research Associates (SOCRA), 83 Solid organ transplantation, 61 Southwest Oncology Group (SWOG), 197, 238 Standardized patient-centered method, 79 Standard operating procedures (SOP), 80 STARSurg, 221 Statistical analysis plans (SAP), 184 Index 258 Statistics allocation concealment, 106 blinding, 107 CONSORT statement, 102 effectiveness trials, 110, 111 errors and statistical power, 112, 113 non-randomly assigned controlled studies, 107–109 outcomes, 112 randomization adaptive randomization, 105, 106 conscious and unconscious prejudices, 103 fixed allocation randomization, 103–105 resource intensive, 102 sample size, 114 statistically.sound study design, 102 study design, 102, 103 superiority/inferiority trials, 111, 112 surgical trials, 109, 110 time-consuming, 102 Stratified randomization, 105, 122 Student Audit and Research in Surgery (STARSurg), 220 Surgical trials, 109, 110 SurVeil drug-coated balloon, 245 Symptom threshold event, 232 T Tax identification number (TIN), 67 Testable hypothesis, 35, 36 “Therapeutic confirmatory”/“comparative efficacy” trials, 40–43 “Therapeutic exploratory” studies, 39, 40 Time zero, 33 Total mastectomy, 238 TRANSCEND trial, 245 Trastuzumab, 40, 198 Trial design dose-escalation scheme, 39 NSABP B-04 Phase III trial design, 41 phase I trials, 38, 39 phase II trials, 39, 40 phase III trials, 40–43 phase IV/device trial, 43 Triple-blind studies, 123 Type I errors, 113, 118, 119 Type II error (β), 113 U UK Surgical Trials Initiative, 215–217 Unadjusted Cox regression, 128 United States Patent and Trade Office (, 87 Upper gastrointestinal bleeding, US Federal Regulations, 23 U.S. Food and Drug Administration (FDA), 167 V Visica 2™ treatment system, 245 Vitamin C deficiency, 168 Voluntary cost sharing, 154 W West Midlands Research Collaborative (WMRC), 216, 225 WHO International Clinical Trials Registry Platform (ICTRP), 133 Women Informed to Screen Depending On Measures of risk (WISDOM), 64 ... 7-1 890/ Accessed Dec 2018 19 Pernick M. A Calculus of suffering: pain,... CA USA ISSN 219 4-7 481    ISSN 219 4-7 49X (electronic) Success in Academic Surgery ISBN 97 8-3 -0 3 0-3 548 7-9     ISBN 97 8-3 -0 3 0-3 548 8-6  (eBook) 8-3 -0 3 0-3 548 8-6 © Springer Nature... Accessed Dec 2018 1  The History of Clinical Trials 13 10 Lind J. A treatise
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