2015 Sep-Oct Issue
Transcription
2015 Sep-Oct Issue
R ESEARCH PRACTITIONER VOLUME 16, NUMBER 5 September–October 2015 104Therapeutic Treatments in Oncology Rife with Unknown Variables Sue Coons, MA 111 Is There Really a Shortage of Study Volunteers? Karyn Korieth 117 Continuing Education 119 Regulatory Update EARN 3 CONTACT HOURS IN THIS ISSUE R ESEARCH PRACTITIONER AUTHORS Sue Coons, MA Medical Writer, Columbus, OH Karyn Korieth Medical Writer, Boston, MA EDITORIAL BOARD Anna J. DeMarinis, MA, CQA(ASQ), MTA(ASCP)SBB Principal, The DeMarinis Group, North Attleborough, MA Lee Ferrell, CCRA, CCRP Senior DIrector, Americas Head – Clinical Leads, Quintiles, Inc., Durham, NC Terry Hartnett Medical Writer, Pittsburgh, PA Carolynn Thomas Jones, DNP, MSPH, RN Assistant Professor of Clinical Nursing, Lead Instructor, Masters in Applied Clinical and Preclinical Research, The Ohio State University, Columbus Nancy A. Olson, JD Director, Institutional Review Boards/Human Research Office, University of Mississippi Medical Center, Jackson, MS Dónal P. O’Mathúna, BS (Pharm), MA, PhD Senior Lecturer in Ethics, Decision-Making, and Evidence, School of Nursing and Human Sciences, Affiliated Scholar, Institute of Ethics Dublin City University, Dublin, Ireland Sandra M. Sanford, RN, MSN, CIP Nurse Planner Director, Quality Assurance, Chesapeake IRB, Columbia, MD Barbara S. Turner, PhD, RN, FAAN Elizabeth P Hanes Distinguished Professor, Director, Doctor of Nursing Program, Duke University School of Nursing Durham, NC Lynn D. Van Dermark, RN, BSN, MBA, CCRA, RAC CEO, MedTrials, Inc., Dallas, TX Elizabeth Weeks-Rowe, LVN, CCRA Principal CRA, Clinical Research Writer and Trainer San Diego, CA Janet F. Zimmerman, MS, RN Assistant Clinical Professor, Coordinator, Clinical Trials Research MSN Track, Drexel University College of Nursing and Health Professions, Philadelphia, PA MANAGING EDITOR, CENTERWATCH J. Michael Whalen MANAGING EDITOR Leslie Coplin GRAPHIC DESIGN Paul Gualdoni COVER PHOTO ©iStockphoto.com CNE PROGRAM Release Date: September 1, 2015 Expiration Date: October 31, 2016 Estimated Time to Complete Activity: 3 hours Provided by Tufts University School of Medicine Office of Continuing Education and CenterWatch Target Audience This activity has been designed to meet the educational needs of nurses involved in clinical trials. Statement of Need/Program Overview Research Practitioner is a bimonthly journal designed for physicians, nurses, and other professionals engaged in the practice of clinical research. Research Practitioner provides readers with up-to-date information regarding clinical trials. Articles focus on the methods and practice of clinical research, from in vitro studies to statistical analysis. Research Practitioner publishes original research and review articles about protocol design and implementation, research methodology, research practice management, ethical considerations, and regulatory requirements. Educational Objectives After completing this activity, the participant should be better able to: ■■ Discuss current thinking regarding specific methodologies in the design and execution of clinical research. ■■ Incorporate emerging ethical and legal principles in the practice of clinical research for the protection of human subjects and the research enterprise. ■■ Manage the conduct of clinical trials to ensure that they conform with federal and state regulations. Accreditation Statement Tufts University School of Medicine Office of Continuing Education is accredited as a provider of continuing nursing education by the American Nurses Credentialing Center’s Commission on Accreditation. Credit Designation This activity provides 3 contact hours for nurses. Requirements for Successful Completion To receive contact hours, participants must register, read the full journal, then go to: http://thci.org/researchpractitioner/welcome.aspx. Follow the instructions on that page to register with your account number, select this issue, complete the evaluation, successfully complete the post-test with a minimum score of 70%, and view and print your certificate. Research Practitioner (ISSN 1528-0330) is published bimonthly (6 times annually) by CenterWatch, 10 Winthrop Square, Fifth Floor, Boston, MA 02110. Copyright 2015 by CenterWatch. All rights reserved. Research Practitioner is a journal indexed by CINAHL. Media Journal Disclosure of Unlabeled Use This educational activity may contain discussion of published and/or investigational uses of agents that are not indicated by the FDA. Tufts University School of Medicine (TUSM) Office of Continuing Education (OCE) and CenterWatch do not recommend the use of any agent outside of the labeled indications. The opinions expressed in the educational activity are those of the faculty and do not necessarily represent the views of TUSM OCE and CenterWatch. Please refer to official prescribing information for each product for discussion of approved indications, contraindications, and warnings. Non Endorsement Statement The content and views presented in this educational activity are those of the faculty/authors and do not necessarily reflect the opinions or recommendations of TUSM OCE or CenterWatch. Inclusion in this activity does not constitute approval or endorsement of any commercial products or services. These materials have been prepared based on the best available information, but are not exhaustive of the subject matter. 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The following faculty, Sue Coons and Karyn Korieth, hereby state that they or their spouse/life partner do not have any financial relationships or relationships to products or devices with any commercial interest related to the content of this activity of any amount during the past 12 months. The following editorial board members, Lee Ferrell, Terry Hartnett, Dónal P. O’Mathúna, Nancy A. Olson, Elizabeth Weeks-Rowe, Sandra Sanford, Barbara Turner, and Janet Zimmerman hereby state that they or their spouse/life partner do not have any financial relationships or relationships to products or devices with any commercial interest related to the content of this activity of any amount during the past 12 months. Anna J. DeMarinis reports that her spouse is a full-time employee at Johnson & Johnson. Lynn Van Dermark reports that she is an employee and stock shareholder at MedTrials, Inc, and is on the board of directors at ACRP. Carolynn Thomas Jones reports she is an employee at Ohio State University and a consultant for Mycoses Study Group Education and Research Consortium. The planners and managers reported the following financial relationships or relationships to products or devices they or their spouse/life partner have with commercial interests related to the content of this CNE activity. The following TUSM OCE planner and manager, Karin Pearson, hereby states that she or her spouse/life partner do not have any financial relationships or relationships to products or devices with any commercial interest related to the content of this activity of any amount during the past 12 months. The following CenterWatch planners and managers, Sue Coons, Leslie Coplin, and J. 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For inquiries regarding subscriptions and back issues: (866) 219-3440, option 0 [email protected] For inquiries regarding advertising: (617) 948-5123 [email protected] CENTERWATCH PUBLICATIONS/SERVICES Periodicals: The CenterWatch Monthly CWWeekly CenterWatch News Online Books: Becoming a Successful Clinical Research Investigator Protecting Study Volunteers in Research Global Issues in Patient Recruitment and Retention The CRA’s Guide to Monitoring Clinical Research The CRC’s Guide to Coordinating Clinical Research Global Regulatory Systems: A Strategic Primer for Biopharmaceutical Product Development and Registration Regulatory Compliance: SOPs for the Conduct of Clinical Trials SOPs for IRBs SOPs for GCPs by Sponsors of Clinical Trials SOPs for GCPs by Sponsors of Medical Device Clinical Trials Services: Drugs in Clinical Trials Database Clinical Trials Listing ServiceTM JobWatch Market Research Services Medical Writing Services Research Center Profile Pages Industry Provider Profile Pages CenterWatch Clinical Trials Data Library Patient Education: Understanding the Informed Consent Process Volunteering for a Clinical Trial Therapeutic Treatments in Oncology Rife with Unknown Variables Field still shows so much promise, says researcher By Sue Coons, MA Learning Objectives: 1. Describe the evolution of anticancer therapies. 2. List some of the problems that happened during early gene therapy trials. 3. Explain some of the dif ferent t ypes of gene therapy. 4. Discuss how a “drug” may be defined in gene therapy. A quick Google search gives a look into the excitement over the possibilities of innovative therapies in oncology research. “Gene therapy treatment for cystic fibrosis may be possible,” says one headline. “Gene therapy treatment for cystic fibrosis moves a few steps closer,” says another. Articles talk of hope for HIV and cancer cures. But how close are clinical researchers to reaching these goals and what minefields line their path? In a recent webinar, George D. Demetri, a sarcoma expert and long-time IRB member, weighed in on the issue. The webinar, New Therapeutic Innovations in Oncology Research: Is Your IRB Ready? took place June 30 and was sponsored by WIRB-Copernicus Group (WCG), a Princeton, NJ, provider of regulatory and ethical review services for human research through its divisions that include WCG Oncology and WCG Biosafety.1 Besides being the senior vice president for experimental therapeutics at the Dana-Farber Cancer Institute in Boston as well as the director of its Center for Sarcoma and Bone Oncology, Demetri is also co-director at the Ludwig Center and professor of medicine at Harvard Medical School and an IRB member of the Dana-Farber/Harvard Cancer Center. In addition, Demetri is a member of the WCG Oncology Advisory Board. Demetri is known for his success in the treatment of sarcomas and gastrointestinal stromal tumors (GISTs). The work of his team led to the development and FDA approval of imatinib mesylate (Gleevec), one of the first targeted anticancer therapies. 2 A Glance Back Before the 20th century, Demetri says surgery was the primary anticancer therapy. “The 20th century brought nice advances with anti-hormone therapy, either medical or surgical; the application of radiation therapy to treat cancers; poisonous or cytotoxic chemotherapies; and the non-specific cell therapies of bone marrow and stem cell transplantation, which in addition to serving a supportive function of repopulating blood production also had some immunological graft versus leukemia effect,” he says. The 20th century also had the tumor infiltrating lymphocytes (TIL) cellular therapies pioneered by Steven Rosenberg at the National Cancer Institute (NCI). In comparison, the 21st century has brought a variety of new tools and a lot of new challenges, Demetri says. “Targeted therapies really started at the end of the 20th century with antibodies like rituximab or trastuzumab for breast cancer, and the targeted pill therapies like imatinib and some of the anti-EGFR therapies, erlotinib and others.” The immunotherapies are coming into their own, he adds. “You can’t pick up an issue of the New York 104 Research Practitioner | September–October 2015 Times without seeing something trumpeting the checkpoint inhibitors such as nivolumab and pembrolizumab and the genetically modified T-cell therapies that are the darlings of Wall Street these days with the so-called CAR T-cells. Then there are some gene therapies and epigenetic gene therapies that are on their way.” Each stage of development of many of these new therapies has brought unique challenges for investigators as well as for IRBs to consider, Demetri says. “First of all, there is an imprecise understanding of the actual mechanisms and implications of what might happen in a human,” he explains. “There is a difficulty of predicting the risks purely using animal models, which didn’t happen quite so much in the past with small molecules where you could pretty much predict what would happen in a human when you compared it to two different animal species. Balancing the risks and benefits when the risks are so unclear is an interesting ethical discussion and an interesting and important ethical consideration. Then there is the difficulty of informed consent with the imperfect information noted above, especially when it’s compounded by a lot of the hype that the lay public reads about these potentially curative therapies.” stitutions and research sites around the world to develop novel oncology products. Some of the ones receiving attention include: ■■ Amgen’s talimogene laherparepvec (T-Vec) – a modified live herpes simplex virus that is a novel genetically based oncolytic vaccine. “The idea is to go into melanoma cells, burst them as an oncolytic virus, and then have that cell release antigens so the immune system wakes up.” Demetri says. “That’s a strategy that many companies are taking, but that’s a particularly interesting one because the FDA held an advisory committee meeting where the advisors actually liked [the risk/benefit profile of this research] a lot.” ■■ Bavarian Nordic’s modified Vaccinia (Fowlpox) virus with TRICOM (LFA-3, ICAM-1, and B7.1 co-stimulators) for prostate cancer. ■■ Inovio’s synthetic DNA plasmid-based vaccines (VGX3100) for cervical cancer. ■■ TOCAGEN’s retrovirus (Toca 511) for glioblastoma. This immuno-oncology product turns cancer cells into “factories” for producing more retrovirus, Demetri says. In late August, FDA granted Tocagen’s Toca 511 and also Toca FC orphan drug designation for the treatment of glioblastoma. Each stage of The therapies do have theoretical benefits. “There is no denying that everyone is scientifically excited about human gene transfer, and there is definite evidence and reason to be excited about the immunology therapies,” Demetri says. “There is the potential to address the root cause of specific genetic diseases and really fix the problem, rather than merely manage symptoms. One could say that there is a possible role in the prevention of disease if a genetic certainty for susceptibility could be identified and repaired and if that genetic repair could happen safely and reliably.” Immune therapy has the ability to attack cancers in a manner that might not lead to resistance and it could possibly cure cancer, he says. “We actually think there is a significant chance for cure for many of these.” The potential of curing, as opposed to other targeted therapies where the patient sometimes has to be treated indefinitely or merely stabilized to get clinical benefit, plays to a wide range of emotions for both the doctors and the potential study subjects, Demetri says. development of many gene therapies has Public Perception brought unique Early problematic clinical trials using gene therapy did little to instill confidence in the public for the treatments. Eighteenyear-old Jesse Gelsinger’s death in a gene therapy trial at the University of Pennsylvania rocked the clinical research world. Gelsinger suffered from ornithine transcarbamylase deficiency, which prevented his body from metabolizing ammonia. Since he did not inherit the disease, he was able to live a fairly normal life on special medication and diet. On September of 1999, Gelsinger was injected with an adenoviral vector carrying a corrected gene to test the safety of the procedure. He died several days later, having a massive immune response triggered by the use of the viral vector, which caused brain death and organ failure. It was later disclosed that the Gelsinger family was not aware of previous adverse events and safety issues. In addition, the lead researcher had a direct financial stake in the study. “The Jesse case challenges for investigators as well as for IRBs to consider. Many companies are now collaborating with academic in September–October 2015 | Research Practitioner 105 shut down clinical research at U of Penn and set back the field of gene therapy several years and the trust of the public,” Demetri says. “It resulted in heightened regulations, such as guidance for consent language and additional data safety monitoring.” Then the New England Journal of Medicine reported on adverse events in a gene therapy study.3 Nine patients, who lacked an HLA-identical donor, underwent ex vivo retrovirus-mediated transfer of γ chain to autologous CD34+ bone marrow cells between 1999 and 2002. Gene therapy was initially successful at correcting immune dysfunction in eight of the nine patients, according to the researchers. However, acute leukemia developed in four patients, and one died. “This is a concerning side of gene transfer,” Demetri says. Even some of the tools used to activate the immune system have had early problems, he says. The “TeGenero Incident” in 2006, for example, used monoclonal antibody targeting human CD28 to activate T cells. Between 12 and 16 hours post-doses, all six patients dosed in the first-in-human Phase I trial suffered immediate lifethreatening organ failure. Although the six survived, one patient had all of his toes and the tips of several fingers amputated.4 “Extensive preclinical studies failed to indicate the severity of human reaction to this approach,” Demetri says. “The human system is simply different from any other animal or organism. This story gives you pause and makes you think about the imperfect information, even the best that the most rigorous science can have, when you are toying with the immune system.” For example, Seattle’s Juno Therapeutics, which develops cell-based cancer immunotherapies, had an initial public offering of $265 million in 2014. In July, Wired magazine wrote about the fascination with a genome editing tool called the clustered regularly interspaced short palindromic repeat (CRISPR)-associated system (Cas).6 Although Chinese researchers were roundly criticized for using CRISPR technology to alter human embryos (see sidebar on page 108), the article talks about the potential of the technology and how many companies are launching based on that approach. It also talks about a CRISPR patent dispute between researchers. At stake is billions of dollars of royalties. It’s important for researchers to take note of this financial news, Demetri says, because patients see and process it, too. Routes of Delivery So what is different about immune, cellular, or human gene therapy? To answer this, Demetri says, it is important to recognize that at some level, there are many types and many routes of delivery of these therapies. ■■ As investigators initiate more human gene therapy trials — more than 140 as of 2014, public perception has shifted as well. HBO’s cable show “VICE Special Report: Killing Cancer,” which aired on Feb. 27, showcased the stories of patients getting gene therapy to fight cancer. All of the patients’ cancers went into remission. But some researchers wondered if the series was too promising. “Is there too much therapeutic intent in early trials?” Demetri asks. “Does the show overstate the benefits of the gene therapy?” The show featured three patients, one of whom was a leukemia patient who had responded well to CAR T-cell therapy. What it doesn’t show is that a majority of these types of patients relapse within 1 year of the treatment, says Mikkael Sekeres, director of the Leukemia Program and vice-chair for clinical research, Cleveland Clinic Taussig Cancer Institute, Cleveland, OH.5 “I just hope that such programs aren’t raising false expectations about the rapidity with which we will be able to finally cure cancer,” he says. In addition, potential gene therapy patients can’t ignore the big money involved in biotech deals, Demetri says. 106 Research Practitioner | September–October 2015 In vivo gene therapy. The goal here is to introduce the genes into the human, directly into tissues or organs without removing body cells from the patient, he says. The challenge is to deliver it only to the intended tissues, but this is difficult within itself. How do you deliver it to every single intended tissue? How do you get it into the tissue in the first place? “There are viruses into which you can pop a human gene and use that as a kind of a Trojan horse to get into the patient. There are bacteria and these things called plasmids that can also act as delivery trucks to get these genes inside. Some of these vectors can be given by vein, but often they are directed directly into tissue and then can be taken up by the cells.” In vivo administration can be given different ways, such as subcutaneously or intramuscularly, by vein, into the tumor, even orally or into specific organs, Demetri says. “All of these things are variables. I am struck by how many details have to happen in these different experiments in humans. And that was just in vivo. In a sense that was the simplest case.” ■■ Ex vivo gene therapy. In this gene therapy, cells from the patient with the disease are removed. The cells are modified in the laboratory, the gene or something else is put into the patient’s cells, and then the modified cells are given back to the patient. “In general, you have a little bit more sense that this might be more effective than giving just the gene itself because the gene is already in some human cell, and then that human cell is given back to the patient from whom it came,” Demetri says. Which cells to use can be one question. Will the researcher use the patient’s own cells, called autologous cells? “If so, are they the long stem cells that give rise to blood? These are the hematopoletic stem cells that can live a long time,” Demetri says. Are they T lymphocytes in the immune system, which are medium-duration life? Are they tumor cells (short-lived)? “These are all different variables,” he explains. “Or are they allogeneic, someone else’s cells, or are they some cancer vaccine that was made from some other virus? Are they something else that is related to the cancer in the patient? All of these things are new variables.” For example, patients can have their T-cells, a certain kind of immune cell, collected by having their blood harvested. Those cells can then be transfected; it then fuses with the patient’s cell. The DNA comes out and goes in the gene of interest, gets integrated into the DNA of the patient’s cell, and then it starts making proteins that then pop out and are those Car T-cell membranes insertion sites. “Those are the chimeric antigen receptors that are now magically expressed by these T cells. Those T cells can then ‘grow up’ and given back to the patient…that’s the T cell adoptive transfer. Then we see what those T cells do.” Because of this, researchers have to consider how much is enough to wipe out a cancer by turning the immune system on and how much is too much, in which the patient gets damaged by the immune response. Also, how long do these T cells persist? “There are memory T cells that have lived within our body sometimes for 20 years or longer. How long will people have these genetically engineered T cells f loating around?” Demetri says. “It might be a good thing to have persistent ones if the cancer ever decides to come back where it wasn’t found the last time. Having a little army of these things surveilling the body might be a very good thing.” What Is the Drug? All of these questions are variables, Demetri says. “Sometimes we are used to clinical trials where there is one variable. Here’s the drug. You take it. And then we monitor the response to that drug. There are many variables in these complex gene and immune therapy approaches.” He points to a statement on the National Cancer Institute website about some of these CAR T-cell approaches: Genetically engineered immune cells are a “living drug.” “I love that phrase,” he says. “I think it really captures it because the infused engineered cells from the patients ARE the therapy, along with the patient’s own response to the cells themselves. This is a living situation in which the therapy is not only the living drug…the cells that are living… but also the host response to those cells. As these infused cells grow in the patient, they will themselves release bioactive substances, expand in a continuous manner, and do other effects in the patient’s own body.” … researchers have to consider how much is enough to wipe out a cancer by turning on Typically these cells really “grow up” and increase their numbers after they are given back to the patient. “They wake up and hopefully they do their job to kill tumors,” Demetri says. “Then we can monitor the patient. We can see how much the disease might be responding.” Researchers also can monitor the patient for side effects because the immune system, if “turned on” in an uncontrolled way, can be a “dangerous thing.” “We all know from being very sick that the immune system when it’s revved up causes high fevers, shaking, and chills. If the immune cells get revved up, they can get into places they don’t ordinarily go,” he says. “That’s what’s wrong with some of the reactions to terrible encephalitis viruses where the immune system tries to wipe out the virus but then wipes out some other part of the central nervous system and can cause a great deal of trouble.” the immune system and how much is too much, in which the patient gets damaged by the immune response. The therapy may be as permanent as the cells, too. “The cells are in the patient’s body and they may not go away,” Demetri says. Many of these cells have built-in kill switches. “There may be clever ways of getting rid of them. Maybe you don’t want to get rid of them – yet another variable. I point this out because the number of variables can be mind-bogglingly large. There is beyond just drug formulation, beyond just delivery, and beyond just exposure. There are so many dimensions to this work.” September–October 2015 | Research Practitioner 107 Altering of Human Embryos in China Sparks Fierce Debate Among Scientists By Sue Coons, MA The announcement that a Chinese research team had altered the genetics of human embryos sparked a fierce debate among scientists around the world. Not only did the experiments cross an ethical line that could affect future generations, they argued, but the resulting mutations in the genes show the serious issues surrounding this kind of gene editing. The research was published on April 18 in the online journal Protein & Cell.1 On April 22, Nature published an article about the genetic modification, bringing worldwide attention to the controversial research. 2 In the experiments, the researchers used the genome editing tool called the clustered regularly interspaced short palindromic repeat (CRISPR)-associated system (Cas) to edit the hemoglobin-B gene (HBB) in human embryos. The team had hoped to modify the gene since it is responsible for ß-thalassaemia, a blood disorder that can be fatal. These 86 “non-viable” embryos used in the experiment were donated for research by couples at an in vitro fertilization clinic. Two days after injecting the embryos, Risks and Safety Issues Gene therapy risks also vary according to where the different gene is placed into the organism, Demetri says. For example, there may be a desirable anti-angiogenic effect in and around the tumor so the tumor doesn’t grow its own blood supply or so that the body can’t feed the tumor. “But if were to happen in the heart, it may have an adverse effect on the heart muscle. The heart might need to grow more blood supply if blood supply was being compromised by cardiovascular disease, and this might adversely impact that. So there could be these organ-specific risks,” he says. “Also, what is the natural history of the vector itself? What is the natural history of the transgene that is inside the vector that you are trying to do the therapy with? Where does the vector go? Do it all go to the liver? Does it all go somewhere else? Does it go into the organ systems?” A unique side effect of gene therapy is the risk of insertional oncogenesis, which has already been documented with older vectors in humans, Demetri continues. Proto108 Research Practitioner | September–October 2015 the researchers genetically tested 54 of the 71 embryos that survived. Just a few of the embryos showed any of the “desired” genetic changes and only in some of their cells. More concerning was the number of inadvertent and potentially harmful DNA damage to genes other than HBB. The mutations were greater than had been observed in previous studies of mouse embryos or adult cells in humans. 2 And even Huang admitted that the mutations noted were just a subset since the researchers had only looked at a portion of the genome. Huang says he plans to try to improve the results of his research. Nature reports that more Chinese researchers are working on this approach as well. Some researchers expressed alarm at this fact. “The ubiquitous access to and simplicity of creating CRISPRs,” says Edward Lanphier, CEO of Sangamo BioSciences in Richmond, California, “creates opportunities for scientists in any part of the world to do any kind of experiments they want.” While many scientists argued that such experiments should be discouraged, others argued that using discarded IVF embryos in research is acceptable. However, Jennifer Doudna, professor of chemistry oncogenes are normal cells that could if turned on in an abnormal way cause cancer. Proto-oncogenes have other functions, often unknown, he says. “But they are quiet or tightly regulated in normal physiology. Now let’s say a patient or a person gets virally transduced. A gene gets put in. It’s somewhere in the proto-oncogene and it’s now sending a signal to turn the reading of that gene on. There can be an insertional event that turns on that gene in an abnormal way. By doing that, there is a risk that you could actually cause cancer.” Then there is the issue of germ-line transmission. In many of the gene therapy trials, researchers are trying to get genes into normal parts of the immune system but not into the egg and sperm, which can pass those genes on to subsequent generations. “The risk of germ-line transmission continues to be a major concern in early preclinical and early clinical studies,” Demetri says. “When one is testing a vector or a way of transferring a gene in, you want to make sure that gene you are moving around does not move into the egg or the sperm. Many of the preclinical models should give us some hope of safety for that. So and of molecular and cell biology at the University of California, Berkeley, argued that the research was not even necessary since the CRISPR gene-editing method is not close to being perfected. In addition, she wondered if the research had been peer-reviewed since it was accepted by Protein & Cell only two days after it was submitted.3 On April 8, two Nobel laureates weighed in on the issue in a commentary in the Wall Street Journal. The advent of CRISPR/Cas9 challenges norms and raises concerns, they say “It may be possible to make these alterations quite precise, with no undesired changes in the genome. Nevertheless, such changes would be inherited not only by the next generation but by all subsequent generations. Thus the decision to alter a germline cell may be valuable to offspring, but as norms change and the altered inheritance is carried into new genetic combinations, uncertain and possibly undesirable consequences may ensue,” say David Baltimore and Paul Berg.4 Baltimore is the president emeritus and Robert Andrews Millikan Professor Biology at Caltech, Pasedena, Calif. Berg is the Robert W. and Vivian K. Cahill Professor of Cancer Research, Emeritus, at Stanford School of Medicine, in Stanford, Calif. Science does not know the “total range of consequences of a given gene alteration, potentially creating unexpected physiological alterations that would extend down through generations to come,” they continue. far there have not been cases of vectors seen in isolated sperm or egg. These are typically assessed in the preclinical animal modeling safety studies. “ Another issue IRBs must consider is the risk of patient “shedding.” When researchers give a vector containing a gene to a human so that the virus will reproduce in that patient, the possibility exists that it can spread just by that patient breathing, sneezing, or sweating. “Shedding is the release of the virus or the bacterial progeny from the patient after the patient gets a virus or a bacterial vector and it successfully reproduces in that patient. You want it to reproduce so it actually infects the patients’ cells.” But if the patient is going to shed, what is the risk to family members or others who come into contact with the patient? Federal Oversight FDA has the responsibility of overseeing drug safety and efficacy, but again, in this case, what IS the drug? “If we said “For these reasons and others, voluntary genome alteration might well be outlawed, at least at the present stage of knowledge.” The Nobel Laureates propose convening an international meeting to consider the best way to proceed. “Those of us in the scientific community need to think carefully about the implications of our actions in both practical and ethical dimensions. Biomedical research offers hope for the alleviation of human disease, yet to address complex diseases like cancer we must carry our investigations to the most fundamental elements of living systems,” they conclude.”4 This gives researchers powerful capabilities that can be used for reaching desired goals. We need to ensure that we have widespread agreement about what is desirable.” References 1. Puping L, Yanwen X, Xiya Z, et al. CRISPR/Cas9-mediated gene editing in human tripronuclear zygotes. Protein & Cell. 2015,6:363-372. 2. Cyranoski D, Reardon S. Chinese scientists genetically modify human embryos. Nature. Published April 22, 2015. Available at http://www.nature.com/news/chinese-scientistsgenetically-modify-human-embryos-1.17378. 3. Kaiser J, Normile D. Chinese paper on embryo engineering splits scientific community. Science Published on April 25, 2015. Available at http://news.sciencemag.org/asiapacific/2015/04/chinese-paper-embryo-engineering-splits-scientific-community. 4. Baltimore D, Berg P. Let’s Hit ‘Pause’ Before Altering Humankind. WSJ April 8, 2015. Available at http://www.wsj.com/articles/lets-hit-pause-before-altering-humankind-1428536400. that the CAR-T cells are a living drug, is the drug the stuff that infects the cells with the chimeric antigen receptor gene? Is it the solution they are bathed in?” Demetri says. “The drug is many things, and that is part of the complexity for the FDA and the biologics branch of the FDA, to say this is a process and not just a drug. That’s also what makes all of these companies so complicated to understand. Everyone might be doing things a little bit differently.” Separately, the National Institutes of Health’s (NIH’s) Recombinant DNA Advisory Committee harmonizes its efforts with FDA. It regulates essentially through the threat of funding restriction to investigators, he says. “It is a significant, but future, threat.” Many of these studies to this point have been carried out in the rarefied environment of top-notch academic centers. What happens when they move into multicenter studies? “There is a lot of concern about how we keep the quality control high, keep the patient risk under some control, and figure out what the regulatory oversight is, both on the local as well as the national and even international level,” Demetri says. September–October 2015 | Research Practitioner 109 Along with the institutional review board, which fundamentally has the protection of the rights and welfare of the human subjects at the site, there is the institutional biosafety committee (IBC). “It is extremely important for the institution to think about how this study in that institution can protect the welfare of everyone around the patient…the team itself, the doctors and the nurses, the family, the facility, even the public health. The random people the patient may be exposed to in the grocery store. How is that taken into account and how is the institution complying with all of the NIH guidelines?” The IBC is required for institutions receiving funds from NIH for research with recombinant DNA or studies by NIH-funded sponsors, Demetri says. “The roles are to assure compliance with the NIH guidelines, to approve specific research protocols, to approve facilities, to set biocontainment levels — different levels of safety that have to be known about and to be respected for the institution to process these things safely — and to advise the institution on policies.” The IBC works in tandem with the IRB in complementary roles and has to be comprised of experts on required topics relevant to the protocol as well as representatives of the institutions and local members of the public not affiliated with the institution, he explains. However, while the IBC can work with a central IRB, the biosafety committee must be local review. “This has a logistical, boots-on-the-ground local review,” Demetri says. “Then [the IBC] deliberates and votes on specific research proposals at convened public meetings.” Final Thoughts In conclusion, the introduction of complex new technology (immune-activating agents, gene therapy, and genetically engineered cell therapies) into clinical anticancer studies in patients has immense promise as well as substantial risks and must be put into context, Demetri says. The number of variables involved in this kind of research can be huge and not easy for the potential study participant to understand. In addition, the institutional processes for review of risks and safe implementation is not as straightforward as for traditional “drug studies” in cancer. “We can respond to this by having the best education and expert advice to serve the best interests of patients, families, the investigators and institutions, as well as the public at large,” he says. “IRBs and IBCs need to collaborate for the review of human gene transfer research. Certainly, the IRBs need to be prepared through education, training, being aware of the complexities, and selection of board members, to review this novel and very 110 Research Practitioner | September–October 2015 challenging field of research.” With all of the complexity, does this mean Demetri believes these therapies are moving too quickly through clinical trials? No, he actually believes the movement is “just right.” “Remember that most of this has been done in the rarefied academic medical center environment where we have a lot of infrastructure, with a ton of safety that might not exist in smaller, community hospitals. That is one of my concerns. I just think this is something we need to be cognizant about. What kind of an institution are we working at? What kind of institution is our IRB serving? That institutional capability has to be taken into account in the risk-benefit profile.” “I actually think a lot of this stuff is so incredibly promising that it is good to move this through clinical trials,” he continues. “Participating in a clinical trial is a job for pioneers…. The fact that we have so many patients lined up for so many trials I think means both there’s promise and probably just the right amount of balance of risk and potential benefit to move the field forward. I think that the fact we are doing clinical research in the context of much learning over decades of clinical investigation with rigorous safety profiles has helped us.” References 1. New Therapeutic Innovations in Oncology Research: Is Your IRB Ready? WIRB-Copernicus Group. June 30, 2015. Available at https://goto.webcasts.com/viewer/event.jsp?ei=1067866. 2. Giants of Cancer Care. Available at http://giants.onclive.com/current/26. 3. Hacein-Bey-Abina S, Hauer J, Lim A, et al. Efficacy of gene therapy for x-linked severe combined immunodeficiency. N Engl J Med 2010;363:355-364. 4. Horvath CJ, Milton MN. The TeGenero incident and the Duff Report Conclusions: A series of unfortunate events or an avoidable event? Toxicol Pathol 2009;37:372-383. 5. Mills D. Experts say Vice may have overstated case in “Killing Cancer.” Healthline News March 6, 2015. Available at http://www.healthline.com/health-news/vice-may-have-overstated-casein-killing-cancer-030615#1. 6. Maxmen A. Easy DNA editing will remake the World. Buckle up. Wired July 2015. Available at http://www.wired.com/2015/07/crispr-dna-editing-2/. Is There Really a Shortage of Study Volunteers? Participation and Willingness High, but Awareness, Access Low By Karyn Korieth Learning Objectives: P atient recruitment remains one of the biggest challenges facing the clinical research enterprise today. Forward-thinking industry leaders recognize the need for rethinking the common view that patient recruitment is difficult primarily due to a shortage of study volunteers. Instead, these experts believe the industry needs to focus the discussion on practices that limit access to clinical trials and how to build support systems needed to better engage patient communities and the public in clinical research. Ever since the National Cancer Institute (NCI) presented data during a 2009 Institute of Medicine (IOM) workshop indicating that only 3% of adult cancer patients participate in clinical trials, many conference speakers and authors have pointed to the statistic as proof that clinical trial volunteers don’t exist and the industry has a crisis on its hands. The NCI statistic has been misinterpreted. Many stakeholders throughout the clinical research enterprise cite the statistic as proof that patient recruitment is an external threat that can’t be controlled. 1. Define challenges related to patient recruitment 2. Discuss strategies for ef fective recruitment. 3. Identif y ways to increase trial par ticipation. 4. List obstacles that prevent patients from enrolling in trials. A recent study from the nonprofit Center for Information & Study on Clinical Research Participation (CISCRP), however, suggests that there isn’t a shortage of patients willing to participate in clinical research. An overwhelming majority (87%) of the public reports a willingness to participate if research made sense for them. “There isn’t a shortage of patients; it’s just finding the pathway for them to participate. How do we take that energy or interest and turn it into actual people participating in trials?” says Gretchen Goller, senior director of patient access and retention services at PR A International. “Ultimately, the issue is lack of access. It’s a lack of education about the benefits of clinical research, a lack of access to finding out about trials and a clear pathway to get patients into those trials. There are all types of obstacles in that pathway linking patients to trials.” “Our enterprise really needs to think about it in a different light. We have to think about it more as an implementation challenge that requires building all of the necessary pieces that can help raise awareness, ensure easier access, and establish a higher foundation of understanding, trust, and literacy,” says Ken Getz, director of sponsored research programs at the Tufts Center for the Study of Drug Development (CSDD) and chairman of CISCRP. “When we think of it as an implementation and health literacy challenge, we see that there are many opportunities that require investment to build infrastructure and support. But reaching and engaging patients is no longer seen as an insurmountable problem.” September–October 2015 | Research Practitioner 111 Fig ure 1: Public W illingness to Pa r ticipate in Clinica l Tria ls Percent of total “very” and “somewhat” willing to participate 87% Fig ure 2 : E stimated Tota l Number of Volu nteers Completing Clinica l Tria ls in 2013 Number of study volunteers 875,000 93% 73% 58% 750,000 700,000 64% Overall North Europe South Asia AmericaAmerica Pacific Source: CISCRP, 2013 Perceptions & Insights Study; n = 5701 respondents Building Awareness and Trust The disconnect between the low participation rates and a high degree of willingness among the public to join studies suggests that the industry needs to better raise awareness about clinical research and how to access study opportunities. “Patients don’t take part in clinical trials because they don’t know about them,” says Paul Evans, vice president and global head of feasibility and enrollment solutions at Parexel. “There are two aspects that we need to focus on. How do we make the case for clinical research? It’s a good, positive story that should be told and not hidden. We as an industry should also make it easy for patients to be able to access clinical trials and get the information that they need. Neither of those things happens at present.” Grassroots outreach and education efforts implemented by CISCRP and other organizations, along with campaigns run by individual site networks, have begun to raise public perceptions about the research enterprise. But costs are too high for a single organization or site to support outreach efforts alone, and there is a growing call for a more widespread, shared effort to increase general knowledge and public perceptions about clinical research. “We need a hard, heavy-hitting national/global campaign to educate the public about clinical research. We need to 112 Research Practitioner | September–October 2015 Government-funded clinical trials Industry-funded Phase 1-3 clinical trials Industry-funded Phase 4 clinical trials Source: CISCRP give potential patients a better understanding of what we do and why it’s important,” says PR A’s Goller. “It would do a tremendous amount of good for everything that we do in this industry. For patients, healthcare providers, families and caregivers, it would put what we do and why it’s important in a whole different light.” Drug sponsors and contract research organizations (CROs) spend a great deal of energy on patient recruitment advertising, yet these campaigns will continue to have limited impact until the clinical research enterprise raises fundamental knowledge about clinical research and trust in the industry among both prospective volunteers and the general public. “At the moment, we tend to push clinical trials toward the patients we identify. What we need to encourage is more of a pull-approach where patients want to take part in clinical trials because they understand the benefits and the opportunities they present to them. That change of mindset would benefit the industry greatly,” says Parexel’s Evans. Getting Health Providers on Board Sponsors and CROs have a range of tools and technologies that can be used to make clinical trials more convenient and identify those who would most benefit from clinical research. Underlying these approaches, however, is the Fig ure 3 : Top Five Rea sons for Choosing Not to Pa r ticipate Percent of total patients Too much risk 26% 23% Difficulty getting to the research center Did not want to take a chance on my overall health 21% 20% Too much time required Could not afford time away from my job 18% Source: CISCRP, 2013 Perceptions & Insights Study; n = 2647 respondents need to improve access and support by engaging physicians and other healthcare providers as partners — both to help spread the word as educators and also to help patients and their families navigate the research system when a trial is appropriate for them. Although CISCRP found that more than half of survey respondents would be most receptive to hearing about clinical research when the information came from their primary physicians, only 20% of the public learns about studies from their healthcare providers. “Not even all physicians understand the dynamics and the process of how research is done. Yet they are the biggest source of referrals and patients trust them,” says Mohammad Millwala, chief executive officer of DM Clinical Research, a Texas-based site network that won an innovation award last year from the Society for Clinical Research Sites (SCRS) for a pediatric vaccine study recruitment campaign that helped raise education levels about clinical research in the community. “Throughout the entire healthcare ecosystem, awareness about research — particularly among physicians — needs to go up.” The Florida-based Atlantic Clinical Research Collaborative (ACRC), which operates a network of research divisions that conduct clinical trials in different therapeutic areas, has based its business model on building direct relationships between its research team and physicians in the community who are committed to supporting clinical trials as a care option for their patients. Network physicians are kept up-to-date about local study opportunities, including inclusion/exclusion criteria for the protocol. ACRC also identifies appropriate patients in their prac tices for specific trials; prescreens potential study volunteers; and helps connect them to the dedicated research site. “It’s taken us a number of years to develop this infrastructure. The key is engaging with our network physicians and building awareness in the community that quality research is going on. Recruitment becomes easier once that is established,” says Debra Weinstein, chief medical officer and lead principal investigator, ACRC. “The involvement with the doctors not only helps with recruitment, but also with retention. The patients feel that it’s all part of their care.” The need to develop stronger referral bases with physicians is particularly acute in minority communities. While the proportion of minorities in clinical research remains low, a peer-reviewed study published in PLOS Medicine found a higher willingness among minority patients to participate in clinical research than white patients (48% compared to 42%). Yet minority patients lack access to clinical trials because a disproportionately low number of minority physicians participate in clinical research. Tufts CSDD also has found that minority physicians are less likely to refer their patients into clinical studies than white doctors. “The industry should be focusing on minority participation,” says PR A’s Goller. “If an African-American patient has a tendency to have an African-American primary care provider, we need to test the limits of what we have been doing and try to expand our network of investigators. We September–October 2015 | Research Practitioner 113 Fig ure 4 : Study Volu nteers’ Preferred a nd Actua l Sources for Clinica l Resea rch Information Preferred 52% Actual 46% 41% 39% 32% 20% 32% 30% 20% 22% 22% 21% 20% 20% 11% 15% 13% 8% Primary Specialty Care Internet Email Media Mail Pharmacist physician physician Advocacy groups Family Source: CISCRP, 2013 Perceptions & Insights Study; n = 4425 respondents need to try to put ourselves in the place of patients and understand where they get their information.” When patients don’t learn about clinical research from their healthcare providers, CISCRP found almost half (46%) turn to the Internet, which can be difficult to navigate when looking for credible, objective, balanced, and user-friendly information about clinical trials. “There are obstacles that are put into place,” says PR A’s Goller. “Unless you have a super-motivated patient seeking information about the trial, we are making it harder for people to reach out.” Easing Participation Burden Some obstacles to patient participation are a direct result of legacy drug-development practices implemented by sponsor companies. Industry veteran John Needham, managing director of Patient Recruitment Strategy, notes that sponsors and CROs often choose investigators who have a great deal of experience but lack sufficient numbers of potential study volunteers. Needham adds that many protocol designs are extremely 114 Research Practitioner | September–October 2015 demanding and complex, making clinical trials unfeasible and inaccessible for a majority of patients. CISCRP found that among patients willing to participate in clinical research, the top reasons for deciding not to participate included difficulties getting to the research center (23%), too much time required (20%), and an inability to take time away from their job (18%). “In some cases there are plenty of patients, but there may be so many extra tasks in the protocol that the study is not viable,” says Needham. “We have to make sure the study we offer appeals to patients and doesn’t connote that we really don’t care about them, that we just want their body for our experiment. We have to stop that [perception], because that is the image that the public and patients have of our industry.” Needham says it’s often difficult for the industry to rethink patient recruitment challenges because many clinical teams at pharmaceutical companies work in a “cloistered” environment. “Managers involved in study design or protocol development, for example, often have never visited an investigative site, don’t belong to industry organizations, or take time for training,” he says. “They don’t know how unviable their studies are,” says Needham. “How can we rethink patient recruitment when nobody has been trained to really drill down and look at the problems?” around the needs of a patient, so it has the potential to result in faster patient recruitment and overall development timelines. Building Bridges “In this collaborative environment, patient communities can help with connecting trials to their patient community, and also contribute to a larger sense of trust and joint ownership in the development of these potential new medicines,” says DiBiaso. Refocusing the patient-recruitment challenge to address literacy and access speaks to the mission and philosophy of a patient-centered approach designed to engage patients and their communities. Patient advocacy groups have passionate memberships; they are a critical and trusted source for health and clinical research information. CISCRP research found that 20% of the public wants to learn about clinical trials through advocacy groups, but only 11% do so through this channel. Sanofi has created new processes and practices that involve patients and advocacy groups in its R&D processes. The firm has found that patient groups are grateful for the opportunity to talk about their disease with researchers and to collaborate with a drug sponsor on developing medicines. When Sanofi worked with a patient panel recently for feedback on ways to simplify a protocol, the president of the advocacy association told Sanofi’s team that when the study opened, the entire community would be informed. “The advocacy groups understand that the community needs to get behind this and participate in the clinical trials themselves,” says Vicky DiBiaso, head of Sanofi’s Office of Patient Participation & Preferred Partnerships. The company chose to develop the new processes with input from the patient advocacy community. An important element was to “lower the barrier” to patient access so that everyone in the organization, including scientists and physicians involved in early protocol development, had a quick way to request patient feedback and wouldn’t think it was easier to proceed without it. A web-based patient engagement portal was created to connect anyone in the organization seeking patient expertise on a project with an internal advocate who could facilitate a meeting with appropriate patient representatives. CISCRP research found that 20% of the public wants to learn about clinical trials through advocacy groups, but only 11% do so through Anthony Yanni, global head of Medical Intelligence and Patient Perspectives at Sanofi, says vehicles also have been developed to ensure patient perspectives are made actionable by incorporating learnings and insights into project plans and overall strategy throughout the development cycle. this channel. Sanofi has moved beyond concentrating on patientrecruitment tactics alone and has created a more holistic approach that addresses many of the issues around limited access to clinical trials. Sanofi’s model incorporates collaboration with patients and patient advocacy groups in the development of new medicines from preclinical research through registration. Patients are directly involved in activities across the entire R&D paradigm including early asset identification, study design, and outreach. This comprehensive approach improves Sanofi’s ability to build development programs and individual studies Sanofi began to develop the new model to incorporate patient insights into R&D discovery and clinical development programs in 2011 after it acquired Genzyme. “We think these things are critically important to create this continuum of patient input into asset development and creating a portfolio that is completely driven to satisfy needs of patients,” says Yanni. Sanofi Patient Network manager Pat Roselle says the program’s success also has been built on establishing long-term partnerships with patient advocacy groups, which may exist after the clinical development program ends, and exploring mutual benefits to avoid the appearance of collaborating with patient advocates and groups September–October 2015 | Research Practitioner 115 only to fulfill recruitment for trials. The company has established a network of patient advocacy group leaders in 60 countries. “The key to any partnership starts with relationshipbuilding. It’s not only establishing relationships with our patient advocacy communities but also how we keep them sustainable. True to any relationship is establishing trust — we build trust between ourselves and the partner group,” says Roselle. Early metrics demonstrate that Sanofi’s approach has contributed to improving R&D efficiencies. According to an international industry benchmarking survey, which compared the median duration of patient-enrollment periods for 23 companies, Sanofi’s ranking improved by six points from 2012 to 2013, moving from the 18th position to 12th; metrics from 2015 show the trend continues to move in the right direction. In addition, costly protocol amendments, which often are the result of an inability to recruit a study, have been cut by more than one-half as a result of patient feedback about ways to reduce study burdens. patient community. If we are doing it together, we are all pushing the momentum forward in a much more efficient manner.” Looking Ahead There is a widespread belief throughout the clinical research enterprise that there is a critical shortage of study volunteers. Yet this emphasis on the lack of participants has been misplaced. CISCRP data shows the public has a high general willingness to participate in clinical research, yet access to clinical trial opportunities often is limited. … data show that the public has a high general willingness to participate in clinical research, yet access to clinical trial opportunities often is limited. “We have a significantly large patient population waiting for us to come forward with medications. At the same time, we are under pressure to do things faster. We all have the same goals in mind,” says DiBiaso. “By giving patients a seat at the table from the very beginning, they can help us improve things such as our study design and how we communicate with the 116 Research Practitioner | September–October 2015 Gaining insight into factors that limit access to clinical trials and make it difficult for patients to participate gives sponsors and CROs the opportunity to modify practices and ultimately improve participation rates. There are many opportunities to improve support systems and better engage patient communities and the public in research. “I don’t think there is a silver bullet when it comes to patient recruitment,” says Evans. “Successful patient recruitment is about doing a large number of small things very well. I’m not sure there is any one thing that is going to transform it. But there is no question that there is a lot we can do to improve it.” Requirements for Successful Completion To receive contact hours, participants must register, read the full journal, then go to: http://thci.org/researchpractitioner/ welcome.aspx. Follow the instructions on that page to register with your account number, select this issue, complete the evaluation, successfully complete the post-test with a minimum score of 70%, and view and print your certificate. Exam for Continuing Education Research Practitioner 16.5, 3 Contact Hours Therapeutic Treatments in Oncology Rife with Unknown Variables 1. The Chinese team of researchers who decided to use the CRISPR/Cas9 genome editing tool to alter “non-viable” human embryos announced this result: A. All of the embryos showed a desired effect B. None of the embryos showed a desired effect C. All of the embryos had DNA damage D. A and C 2. Clinical researchers are developing a thorough understanding of what might happen in humans during immunotherapy, genetically engineered cell therapies, and other human gene transfers. A. True B. False 3. What is NOT considered to be a benefit of human gene transfer right now? A. The ability to address the root cause of a genetic disease B. The ability to prevent future disease C. The ability to resist or even cure cancer D. The ability to correct genes for subsequent generations 4. Television shows such as HBO’s VICE series do this, according to some researchers? A. Overstate the potential benefits of gene therapy B. Understate the potential benefits of gene therapy C. Overly dramatize the risks of gene therapy D. Make gene therapy less attractive for potential study subjects 5. CAR T-cell immunotherapy can result in a “revved up” immune system that attacks and damages other parts of the body. A. True B. False 6. What is the “drug” in Car T-cell immunotherapy? A. The engineered cells B. The patient’s response to the cells C. The bioactive substances released by the therapy D. Still to be determined 7. The A. B. C. D. number of variables in gene therapy is: Controllable Incredibly large Determined by the investigator The same as random drug trials 8. Inserting a transgene into a human organ has the same effect, regardless of the organ involved. A. True B. False 9. After a virus or bacterial progeny successfully reproduces in a patient, that patient can “shed” that bacteria or virus by: A. Sneezing B. Sweating C. Breathing D. Any of the above 10. An institutional biosafety committee must have: A. Central review B. Local review C. A central IRB D. A local IRB Is There Really a Shortage of Study Volunteers? 11. Statistics indicating that only 3% of adult cancer patients participate in clinical trials mean that most people do not want to be in them. A. True B. False 12. What is NOT considered an obstacle for people to participate in clinical research? A. Lack of access B. Lack of education C. Lack of information D. All of the above 13. “People don’t participate in clinical research trials because...” A. they don’t know about them. B. they hear negative things in the media. C. they don’t believe participating is worth their time. D. they worry about possible side effects. September–October 2015 | Research Practitioner 117 14. Who/what is considered to be a major factor in engaging potential research participants? A. Friends and family B. Sponsors C. Media outlets D. Physicians and health care providers 15. What are ways to keep physicians apprised of local study opportunities? A. Providing inclusion/exclusion criteria for the protocol B. Identifying appropriate patients in the practices for specific trials C. Prescreening potential study volunteers D. All of the above 16. What does research show about minority patients and access to clinical trials compared to white patients? A. Higher willingness to participate but lower access to trials B. Lower willingness to participate and lower access to trials C. Higher willingness to participate and higher access to trials D. Lower willingness to participate but higher access to trials 17. What is NOT considered to be an access obstacle relating to clinical trial participation? A. Getting to the research center B. Too much time required C. Can’t take time off work D. No compensation for travel 18. Sanofi developed a network of __________ to improve its R&D efficiencies. A. IRB advisors B. Nurse advisory groups C. Provider focus groups D. Patient advocacy groups 19. The industry has difficulty rethinking patient recruitment challenges because many clinical teams at pharmaceutical companies work in a cloistered environment. A. True B. False Subscribe to Research Practitioner and earn up to 18 nursing contact hours a year Please send me Research Practitioner (6 issues annually): o Individual subscription with nursing Contact Hours o Print – $185 o Digital – $139 To subscribe, e-mail [email protected]. To pay by credit card, please go to: http://store.centerwatch.com/p-118-research-practitionersubscription.aspx To inquire about multi-reader or corporate discount rates, call (866) 219-3440 or email [email protected]. International subscribers, please add $30 for shipping. Payment (must be in U.S. funds): o Check enclosed o P.O. # Mailing Address (please print): Name Company/Institution Address City/State/Postal code/Country PhoneFax E-mail Subscribe: Phone: (866) 219-3440 118 Research Practitioner | September–October 2015 Fax: (617) 948-5101 Mail: Customer Service 10 Winthrop Square, Fifth Floor Boston, MA 02110 Regulatory Update CRO Warning Letter from FDA Instructional to Sponsors on Overseeing CROs On June 16, 2015, a contract research organization (CRO) received an FDA Warning Letter (WL) for violations of FDA regulations observed during a September 2014 inspection. Many sponsors lack the resources to fully manage their clinical trials in-house and outsourcing to CROs is common, whether for a few trial activities or a full service CRO to manage essentially all trial activities. Sponsors are responsible for the adequacy of the CROs they choose and are expected to oversee their performance. Sponsors can review the violations in this WL as a “lessons learned” exercise and use those violations for help in assessing their own CROs. Excerpts are provided below but the entire WL is available for interested readers at www.fda.gov/ICECI/EnforcementActions/WarningLetters/2015/ucm453979.htm. The inspection covered three protocols for an investigational drug being studied under an Investigational New Drug (IND) application. 1. Failure to ensure proper monitoring and failure to ensure that the investigations are conducted in accordance with the general investigational plan and protocols contained in the IND [21 CFR 312.50 and 312.56(a)]. As a result of “your inadequate monitoring, you did not identify, and did not correct in a timely manner, the clinical investigators’ failure to report serious adverse events (SAEs) according to protocol-specified timeframes and failure to perform protocol-required laboratory tests.” SAEs, whether or not considered related to study drug, were to be reported to the sponsor within 24 hours of occurrence or the investigator’s knowledge of the event, even if the event did not appear to be treatmentrelated. Furthermore, the WL states these SAEs were not identified by the monitor in monitoring visit reports, which is of significant concern, as it suggests the CRO’s monitors may not have been qualified to perform their monitoring tasks. As examples, one SAE (thrombocytopenia) occurred on May 4, 2009, but the site did not report it to the sponsor on an SAE form until April 30, 2013. In another example (leukopenia and neutropenia), the SAEs occurred on June 8, 2010, but the site did not report them until May 2, 2013. The long delay between occurrence and reporting of these SAEs is worrisome on its own but it also suggests the unreported SAEs may have been discovered during a late-stage audit; clearly the SAEs were described somewhere in the subjects’ medical records. Shorter delays also were cited, including one subject’s surgery for knee arthritis that was complicated by phlebitis. The investigator noted the subject’s surgery in a progress note dated March 15, 2013 but the site did not report the hospitalization to the sponsor on an SAE form until April 10, 2013. Regarding laboratory tests, “Your monitoring failed to identify and correct a clinical investigator’s failure to perform protocol-required laboratory tests.” One protocol required hematologic laboratory tests at many time points and included an array of routine hematologic tests. These were important safety assessments to monitor for study drug-related adverse events such as neutropenia. The WL cited five subjects whose testing was not done at various times. It also cited an example of failure to perform urine dipstick testing and 24-hour urine collection to measure protein. These were safety assessment to monitor for study drug-related renal disorders. Similarly, these missed tests also were not noted in monitoring reports. Missed protocol-specified tests and delayed SAE reporting are frequent problems in clinical trials, but in the author’s experience, monitors are usually qualified and their reports generally capture these protocol violations; that is the “easy part.” Securing investigator compliance is the “hard part.” In this case, it appears the CRO’s selection of monitors may have been inadequate. Options to consider for preventing this include: (a) Conduct a robust vendor qualification of the CRO before you sign a contract to assess your desired services and the senior staff to be assigned your services; (b) Require the CRO to submit CVs to you for all prospective monitors (whether employees or contractors) for your prior approval; (c) Conduct a re-qualification audit if many CRO team members delegated to your study (managers, monitors) are reassigned or quit the CRO; (d) Conduct co-monitoring with a senior level sponsor employee early in the study to focus on SAEs and protocol violations, as an assessment of the monitor(s); and (e) Conduct audits at (a) early- and (b) middle-stage time points of a clinical trial, to (a) identify problems before they have affected all your study data and (b) evaluate September–October 2015 | Research Practitioner 119 the effectiveness of audit-required corrective actions. Call for Papers (f ) When preparing corrective actions, always include effectiveness checks. Research Practitioner invites submissions of high-quality research papers describing original and unpublished work. 2. You failed to ensure proper monitoring of the investigations contained in your INDs because you did not follow the monitoring guidelines you developed. FDA expects all regulated entities to follow their own standard operating procedures and any other written instructions (such as protocols and monitoring guidelines or plans). This CRO’s monitoring guidelines required that monitoring reports be written by the Clinical Research Associate (CR A) and approved by the Clinical Project Manager (CPM) within specific timeframes, but some monitoring reports were not completed and approved within those timeframes, and in some instances, were not completed at all. FDA provided many examples. The CRO’s monitoring guidelines required that interim monitoring reports be prepared by the CR A within 5 business days after the visit and approved by the CPM within 10 business days after receipt of the report. The CRO’s report creation, review, and approval timeframes were very aggressive, and sponsors and CROs should think carefully about imposing such requirements on staff who are routinely very busy (consider each monitor’s/CR A’s visit and travel schedule, and the number of projects the CPM may be juggling). In addition, it is well known in the CRO industry that the monitoring role experiences significant turnover as monitoring is a very demanding and difficult job. Often, a monitor leaves a CRO before completing his or her reports and these may “fall by the wayside” while the CRO finds a suitable replacement. A more reasonable approach might be to: (a) Have the monitor send the monitoring visit follow-up letter to the site within 5 business days (so the site can quickly proceed with corrections and queries); (b) Allow the monitor 10 business days to write the report; and (c) Allow the CPM an additional 5 to 10 business days for review and approval. 120 Research Practitioner | September–October 2015 Research Practitioner focuses on the methods and practice of clinical research, from in vitro studies to statistical analysis. Continuing education articles for Research Practitioner should be between 4000 and 6000 words and can include original research and review of articles about protocol design and implementation, research methodology, research practice management, ethical considerations, or regulatory requirements and research trends. For preparation and submission of a manuscript for publication, please contact J. Michael Whalen at (617) 948-5182 or by e-mail at michael.whalen@centerwatch. com. FDA Issues Two Final Guidance Documents Since the last issue, FDA released two final guidance documents in the Federal Register. Interested persons may submit electronic or written comments on final FDA guidance documents at any time. Submit electronic comments www.regulations.gov/. Submit written comments to the Division of Dockets Management (HFA-305), Food and Drug Administration, 5630 Fishers Lane, Rm. 1061, Rockville, MD 20852. Identify comments with the associated Docket number (in parentheses). Uncomplicated Gonorrhea: Developing Drugs for Treatment On August 18, 2015, FDA announced availability of a guidance titled Uncomplicated Gonorrhea: Developing Drugs for Treatment. The purpose of this guidance is to assist sponsors in the clinical development of drugs for the treatment of uncomplicated gonorrhea. This guidance makes final the draft guidance of the same name issued on June 19, 2014. The guidance focuses on the non-inferiority trial design and describes an efficacy endpoint for which there is a well-defined treatment effect. The guidance also provides the justification for the non-inferiority margin. It includes a brief discussion of the potential for pregnant women to be included in specific populations for drug development. In addition, this guidance ref lects recent developments in scientific information that pertain to drugs being developed for the treatment of uncomplicated gonorrhea. (Docket No. FDA-2014-D-0640) Design and Analysis of Shedding Studies for Virus or Bacteria-Based Gene Therapy and Oncolytic Products On August 27, 2015, FDA announced availability of a guidance document titled Design and Analysis of Shedding Studies for Virus or Bacteria-Based Gene Therapy and Oncolytic Products. The document provides sponsors of virus or bacteria-based gene therapy products (VBGT products) and oncolytic viruses or bacteria (oncolytic products) with recommendations on how to conduct shedding studies during preclinical and clinical development. VBGT and oncolytic products are derived from infectious viruses or bacteria. In general, these product-based viruses and bacteria are not as infectious or as virulent as the parent strain of virus or bacterium. Nonetheless, FDA issued this guidance because the possibility that infectious product-based viruses and bacteria may be shed by a patient raises safety concerns related to the risk of transmission to untreated individuals. To understand the risk associated with product shedding, sponsors should collect data in the target patient population in clinical trials before licensure. The guidance makes final the draft guidance of the same title dated July 2014. (Docket No. FDA-2014-D-0852) FDA Issues Several Draft Guidance Documents Since the last issue, FDA released six draft guidance documents in the Federal Register. Interested persons should submit electronic or written comments on draft FDA guidance documents by the date specified (in parentheses) to have their comments considered for preparation of the final document, but comments will be accepted at any time and may be used in the future. Submit comments as instructed above. Identify comments with the associated Docket number (also in parentheses). Clinical Evaluation of Drugs for Treatment of Gastroparesis On July 23, 2015, FDA announced a draft guidance titled Gastroparesis: Clinical Evaluation of Drugs for Treatment. This draft guidance is intended to provide sponsors with FDA’s current thinking regarding clinical trial design and clinical endpoint assessments to support development of drugs for treatment of diabetic and id iopathic gastroparesis. (Docket No. FDA-2015-D-2479; September 21, 2015) Common Issues in Drug Development of Rare Diseases On August 17, 2015, FDA announced a draft guidance titled Rare Diseases: Common Issues in Drug Development. The purpose of this draft guidance is to advance and facilitate the development of drugs and biologics to treat rare diseases. Drug development for rare diseases has many challenges related to the nature of these diseases. This draft guidance is intended to assist sponsors of drug and biological products for treating rare diseases in conducting more efficient and successful development programs through a discussion of selected issues commonly encountered in rare disease drug development. Although these issues are encountered in other drug development programs, they are frequently more difficult to address in the context of a rare disease than a common disease for which there is greater and more widespread medical experience. These issues are also more acute with increasing rarity of the disorder. A rare disease is defined by the Orphan Drug Act as a disorder or condition that affects less than 200,000 persons in the United States; however, most rare diseases affect far fewer persons. Most rare disorders are serious conditions with no approved treatments, and rare disease patients have considerable unmet medical needs. Early consideration of drug development issues allows sponsors to efficiently and adequately address them during the course of drug development, from drug discovery to confirmatory efficacy and safety studies, and to have productive meetings with FDA. (Docket No. FDA2015-D-2818; October 16, 2015) Biomarker — Plasma Fibrinogen in Studies Examining COPD On July 7, 2015, FDA announced a draft guidance titled Qualification of Biomarker — Plasma Fibrinogen in Studies Examining Exacerbations and/or All-Cause Mortality in Patients with Chronic Obstructive Pulmonary Disease. This draft guidance provides a qualified context of use (COU) for plasma fibrinogen in interventional clinical trials of chronic obstructive pulmonary disease (COPD) subjects at high risk for exacerbations and/or all-cause September–October 2015 | Research Practitioner 121 mortality. This draft also describes the experimental conditions and constraints for which this biomarker is qualified through FDA’s Biomarker Qualification Program. This biomarker can be used by drug developers for the qualified COU in submissions of INDs and other applications without the relevant FDA review group reconsidering and reconfirming the suitability of the biomarker. This draft guidance provides qualification recommendations for the use of plasma fibrinogen, measured at baseline, as a prognostic biomarker to enrich clinical trial populations of COPD subjects at high risk for exacerbations and/or all-cause mortality for inclusion in interventional clinical trials. This biomarker should be considered with other subject demographic and clinical characteristics, including a prior history of COPD exacerbations, as an enrichment factor in these trials. FDA concluded that analytically valid measurements of the biomarker can be relied on to have a specific use and interpretable meaning. (Docket No. FDA-2015-D-2244; September 8, 2015) Biomarker — Total Kidney Volume in Studies for Treating ADPKD On August 17, 2015, FDA announced a draft guidance titled Qualification of Biomarker — Total Kidney Volume in Studies for Treatment of Autosomal Dominant Polycystic Kidney Disease. This draft guidance provides a qualified COU for total kidney volume (TKV), measured at baseline, to be used as a prognostic enrichment biomarker to select patients with autosomal dominant polycystic kidney disease (ADPKD) at high risk for a “progressive decline” in renal function, defined as a confirmed 30% decline in the patient’s estimated glomerular filtration rate (eGFR), for inclusion in interventional clinical trials. This biomarker may be used in combination with the patient’s age and baseline eGFR as an enrichment factor in these interventional clinical trials. This draft also describes the experimental conditions and constraints for this biomarker and can be used as described above for other such biomarkers. (Docket No. FDA-2015-D-2843; October 16, 2015) 122 Research Practitioner | September–October 2015 Qualification of Testicular Toxicity: Evaluation during Drug Development On July 17, 2015, FDA announced a draft guidance titled Testicular Toxicity: Evaluation during Drug Development. This draft guidance is intended to help sponsors identify nonclinical signals that raise concern regarding the potential for human testicular toxicity and to evaluate those signals appropriately in human studies. The draft guidance describes the standard battery of nonclinical studies that are used to assess the effects of pharmaceuticals on the male reproductive system. It discusses findings in nonclinical studies that may increase the level of concern for drug-related testicular toxicity. Examples of nonclinical studies that could be used to further evaluate initial signals of testicular toxicity are also described. The draft guidance then provides a general approach on how to weigh the relevance of nonclinical findings, taking into account factors that can confound the interpretation of these findings. (Docket No. FDA-2015-D-2306; October 15, 2015) EMPLOYERS VALUE ACRP CERTIFICATION SET YOURSELF APART 62.5% ACRP Certification elevates you above the crowd. The recognition and confidence that result from your commitment will prepare you for greater responsibility and open the door to career advancement. Employers and colleagues will notice your dedication, giving you an edge in a competitive market. 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