	Closer collaboration between academia and industry in the design and execution of clinical trials is vital to produce the best results, delegates were told at the European Society of Cardiology (ESC) annual meeting, held in London last month.

	Industry-funded trials have many excellent features and have convincingly demonstrated the benefit of many medicines, but challenges to the external and internal validity of pure industry trials 

must be addressed more effectively, according to Marc S. Sabatine, MD, Chairman of the Thrombolysis in Myocardial Infarction (TIMI) Study Group and a Professor of Medicine at Harvard Medical School, Boston. Government and professional society funding can fill important gaps in this area, he said during a special ESC lecture on pressures and conflicts in industry-sponsored trials.

	Problems and delays tend not to occur in Phase III trials because they are extremely well-resourced, Sabatine explained. In general, a careful central review of endpoints and safety takes place, case report forms are comprehensive, and there is a large sample size, number of events, and statistical power. Therefore, usually these trials are completed rapidly.

	“Acceptance of a new drug depends on clear and compelling evidence of helping patients,” says Sabatine, adding that pharmaceutical companies are very good at reading Phase II trial data because their future survival depends on selecting the right compounds to take through to Phase III studies. “There is intense scrutiny of every piece of data, which is picked over and checked.”

	When it comes to the questions being asked in a trial, a practical challenge is to retain a focus on commercial value, particularly when the end of a compound’s patent life approaches. Trials organizers must think about indications early on, later turning to government and academic society funding, Sabatine recommends. Furthermore, some Phase IV studies offer nominal assurance in a specific disease or patient subgroup, but are not well-powered, in which case the solution is to be more discerning about how to use such trial data.

	In the control arm of a study, two challenges are dealing with the suboptimal comparator and the need to avoid head-to-head comparisons against roughly similarly active controls. Possible solutions are to partner with academic clinical trialists and to see government and academic society funding.

	Often, there is a pressure for rapid selection of dose, leading to reliance on imperfect surrogates. Sabatine’s solution is for greater investment of time and resources in Phase II trials in order to optimize the likelihood of positive results. Also, to avoid multiple doses in Phase III studies, guidance from academic trialists and support from regulators for analyses of trials testing multiple doses can help, he says.

	To achieve composite outcomes, inclusion of “softer” components is an appealing option, but the answer is to focus on harder outcomes, Sabatine contends. When amalgamating directionally opposite components into a single composite, it is advisable to present data on efficacy and safety separately and then analyze the benefits and risks.

	To keep patients on a study drug and guarantee follow-up, thereby maximizing trial quality, sponsors should make sure those individuals directly interacting with and guiding sites understand and appreciate the importance of metrics for trial integrity, Sabatine pointed out.

	Session moderator Kim Fox, Professor of Clinical Cardiology and Head of the National Heart and Lung Institute at Imperial College London, says the major problem for trial organizers in cardiology is that the outcome in cases of stable coronary disease is so good now that it becomes impossible to test a drug for mortality because so many patients are required and it is necessary to add softer composite endpoints like admission for stable angina and revascularization.

	“In some senses, we are a victim of our own success for getting the event rates down,” Sabatine noted. “We need to accept that we will use these composites, but then we need to look at them very carefully.”

	An overall goal should be to conduct trials that give a definitive answer for all-cause mortality, but provided there is no hazard for non-cardiovascular (CV) mortality; Sabatine does not insist that a particular trial shows a reduction for all-cause mortality.

	“As long as it’s neutral for non-CV mortality, I then like to see a reduction in CV mortality," he says. "If there’s only a reduction in MI (myocardial infarction) and stroke and the trial doesn’t impact CV mortality, I’m still OK with that. I’m a cardiologist, and I want to decrease the number of patients having heart attacks and strokes.”

Articles

News

Addressing the challenges unique to purely industry-sponsored trials is explored.

Top Investigator Lays out Strategy for Avoiding Conflicts

	After years of delay, there’s renewed action to update the “Common Rule,” which protects human subjects involved in research regulated or funded by the federal government. Although clinical trials to support market approval of new drugs and medical products are governed by FDA regulations, changes in the Common Rule promise to shape policies for conducting clinical trials throughout the research community. Once the Common Rule revisions are finalized, FDA will examine where it needs to revise its regulatory provisions to accommodate certain changes, explains an FDA official. In the meantime, says David Forster, chief compliance officer for the WIRB-Copernicus Group, proposed changes in institutional review board (IRB) practices and in formats and procedures for obtaining informed consent will begin to affect all sponsors and investigators.

	The 500-page proposed rule (published in the Federal Register, vol. 80, no. 173, Sept. 8, 2015) aims to streamline requirements that add to the cost and complexity of clinical research. This latest revision from the Department of Health and Human Services (HHS) and 15 other federal agencies builds on an initial proposal issued in 201l, which drew thousands of comments and then dropped out of sight.

	The new proposal continues to promote the use of a single IRB for multi-site studies and offers significant changes in informed consent processes, with an eye to making consent forms shorter, more understandable and more transparent. Sponsors would have to publicly post consent forms as a way to encourage development of more concise formats that provide relevant details for participants and avoid burying important information in “unduly long documents.”

	More controversial is the requirement to obtain individual consent for the future use of biospecimens such as blood samples. This change reflects the emergence of genomic technologies able to identify the donor of even de-identified specimens. To head off strong objections, the policy will not be retroactive and offers a three-year implementation period.

	A parallel goal of the reformers is to reduce oversight of low-risk studies. The Common Rule would not apply to activities such as oral histories and public health surveillance, and continuing review by IRBs would be dropped for certain projects involving no more than minimal risk. There’s much to comment on, and those are due by December 7.

	Meanwhile, FDA will continue to update its good clinical practice (GCP) policies, as seen in a draft guidance issued in July 2014 that outlines extensive changes to informed consent procedures and policies for clinical investigators, sponsors, and IRBs; the stated aim was to revise FDA rules to conform more with the changes to the Common Rule proposed in 2011, and another draft now may be warranted. FDA also published draft guidance in March 2015 explaining how sponsors and investigators should use electronic systems to obtain informed consent.

	Changes in informed consent policies also will come from the Clinical Trials Transformation Initiative (CTTI) at Duke University as part of its broader program for modernizing FDA clinical research policies. And the 21st Century Cures legislation before Congress supports the use of central IRBs for government-funded multi-site studies.

	Efforts to increase transparency in FDA research policies also may be shaped by recent analyses of the application review process and how effectively FDA determines the need for more or less data for market approvals. One way to help patients understand the risks and benefits of new medicines, according to some FDA analysts, is to make public FDA Complete Response Letters (CRLs). Only sponsors-and not FDA-can disclose such “commercially confidential” information on why the agency turns down an application, but many company statements regarding CRLs differ from what is actually in a letter, according to Peter Lurie, FDA associate commissioner for public health strategy and analysis, and his staff. Their review of the content of some 61 CRLs issued by the Center for Drug Evaluation and Research (CDER) from August 2008 to June 2013 (published June 2015 in the 

) finds that many press releases from sponsors about those CRLs contain incomplete or erroneous statements.

	On the too-fast-or-too-slow review issue, a surprising critique in

 magazine (August 20, 2015) charges FDA with approving just about every application sent in, providing a “rubber stamp” approach and not being sufficiently selective. Taking a different tack, two MIT economists urge FDA to be more flexible in approving more risky therapies for serious illnesses, but more cautious with treatments for common conditions (see 

Is the FDA Too Conservative or Too Aggressive?

” by Vahid Montazerhodjat and Andrew Lo, Aug. 19, 2015). The rise of breakthrough drugs and expedited review programs largely address such concerns, as well as questions raised by other analysts as to why some CDER review divisions approve applications faster than others. 

Changes Ahead for Informed Consent, IRBs, Transparency

	What has been obvious to strategists-and to most readers of this publication-for a long time is now becoming evident to a wider population in Europe: the classic methods for evaluating new medicines are being overtaken by science. In other words, new thinking is needed on clinical trials. 

	So the autumn is seeing a wave of European initiatives to explore just how things ought to change. 

	In late September, the subject is high on the agenda of the European Society for Medical Oncology (ESMO)-European CanCer Organization (ECCO) Congress in Vienna, and one of the first into the fray is the European Alliance for Personalized Medicine (EAPM), one of the most vocal advocates of change. EAPM is holding an event under the banner of “modernizing clinical trials for the benefit of Europe’s patients,” with the aim of promoting consensus on the policy initiatives that the oncology community should focus on for the next two years.  

	Mark Lawler of Queen’s University Belfast and Anastassia Negrouk from the European Organization for Research and Treatment of Cancer (EORTC) will be among those calling for new thinking across the range of trials, biobanks, and data sharing. The group has already been energetic in promoting understanding among members of the European Parliament and other legislators of how one-time informed consent be handled to ensure that the patient understands the benefits and risks of conducting future research based on archived samples, or how access to clinical trials can be handled to prioritize the evaluation of technologies that have the highest potential for clinical utility and avoid exhausting valuable samples unnecessarily. It has also been working on exploring standards that could ensure multiple clinical trials addressing the same questions are comparable, both from a clinical and analytical perspective.

	Among the suggestions the group is now canvassing are the idea of setting the efficacy bars much higher than at present at the start of trials, and the development of a well-defined biomarker strategy embedded in the clinical trial process, with regulatory review and implementation based on best international practices.

	 Then in early October, the annual gathering of Europe’s great and good at Gastein, a village in the Austrian mountains, will pick up the reflections, with a seminar on how patients will be impacted by adaptive pathways and breakthrough designations. “While the long-awaited promise of personalized medicine is finally arriving, the regulatory structures required for their evaluation and reimbursement are still based around the blockbuster models of the last century,” proclaims the blurb for the meeting. And senior figures including Carole Longson from the National Institute for Health and Care Excellence (NICE), Gordon McVie of the European Institute of Oncology, and Barbara Kerstiens of the European Commission’s public health research department will lead the discussion.

	In late October, the next meeting of the European Commission’s expert group on safe and timely access to medicines for patients-another bizarrely concocted European Union (EU) name to permit the equally bizarre acronym of STAMP (safe and timely access to medicines for patients)-will resume its reflections on real-world data and registries, and pursue its exploration of national schemes for early links between marketing authorization applicants and authorities to reinforce dialogue and regulatory support for new medicines addressing major public health needs. It will also review possible modifications of conditional marketing authorization procedures in Europe that are now under consideration. 

	All the while, the European Medicines Agency’s (EMA) own pilot project on adaptive pathways is humming along quietly, sifting through the proposals submitted by drugmakers as possible test cases as the mechanisms are studied. So far, one of the lessons to emerge is that companies need to be better prepared to get involved with authorities, but just when the pilot phase will be completed and evaluated remains clouded in uncertainty.

	Further toward the end of the year, the EU is expected to agree on broad principles on personalized medicine that will have significant implications for clinical trials. Luxembourg, the country  currently holding the rotating presidency of the EU council of ministers, has been working with diplomats and officials over recent weeks to draft a plan, which it says will be “patient-centered” but will take account of the need for adaptations in evidence-gathering and evaluation.

	Meanwhile, another informal EU group of individuals from national authorities, academia, and industry have circulated a paper of their own on personalized medicine, which gives a flavor of how the debate in Europe is proceeding. Entitled “Ten actions to stimulate patient access to personalized medicine in Europe,” this extends across the entire range of adaptations it says are needed in what it calls “a fast-moving field.” It says “this new approach to medicine will foster more collaborative and interdisciplinary working methods amongst health professionals, induce the use of big data, and imply a change for the regulatory framework,” and calls for “disruptive change to the traditional way of working and thinking.”

	Not surprisingly, this study devotes much of its attention to trials. “A key challenge for companies investing in innovative personalized medicine is to develop compelling evidence about the added value of the personalized approach in a timely and efficient way. However, the current clinical development paradigm and the traditional rather rigid requirements for trial designs are not adapted to the specific development challenges,” it says. There will be “an increased need to endorse and accept flexible trial designs that are adapted to the type of the diagnostic-therapy relationship and allow the identification of optimal combinations,” it adds.

	In addition, “the collection of a standardized baseline biomarker data and associated treatment, and treatment outcomes in large national or supranational databases will be essential to support the future development and clinical use of personalized medicine.” Databases of this sort “would help the real-life positioning of treatments providing outcomes in specific patient subgroups.” Adaptive pathways “need to become more established and formalized,” and “it should finally be acknowledged” that comprehensive evidence about benefit and risk “is only going to be clear once diagnostic tools and medicines are on the market, based on real-life data. Evidence generation is a continuum.” Inevitably, “the lack of solid and complete evidence at the time of market authorization will require agreement on the application of principles of risk management.”

	To make all this possible, the study insists, the full introduction of electronic patient records containing all health-related data of European citizens is essential, not just for development of innovations but to observe and guide the appropriate use of innovative treatments. But it complains that current efforts to 

establish registries are still insufficient, and “greater governance is needed to speed up this process towards full capacity health informatics systems.”

	Then in December, the EMA and industry association Emerging Biopharmaceutical Entreprises is holding a conference on how to get emerging medicines from laboratory to patient, with a particular focus on how regulators should respond to the challenges posed by innovative medicines, and how regulators and developers can work together early in the development process.

	Whether this process can move forward fast enough and with sufficient coherence to keep up with the pace of change in product development is another question. But at last, there is a sense that pioneers are no longer voices crying in the wilderness, but are shifting wider perceptions that their messages are now increasingly being integrated into mainstream thinking.

 is a freelance journalist who specializes in European health affairs and is based in Brussels, Belgium.

View from Brussels

Several initiatives are focused on integrating biomarkers and personalized medicine techniques into studies.

Europe: At Last, the Hunt is On for Trials That Fit Science

	Drug safety is an especially challenging issue in emerging treatments for Alzheimer’s disease (AD), requiring pharmaceutical and biotechnology companies to refocus clinical trial design using patient-centric approaches that mitigate risk and manage adverse events. Current research indicates that AD is a complex disease with a long progression from early onset to the manifestation of clinical symptoms. Moreover, physicians can struggle with

 the clinical diagnosis of AD versus related dementias. Taken together, drug sponsors face the task of enrolling diverse patient populations, which they must carefully enrich and monitor throughout lengthy clinical trials. 

	Improvements in technology, an increased understanding of disease mechanisms, and enhanced clinical trial processes and systems are bringing new tools and resources with the potential to help researchers develop safe and effective drugs for this indication.

	In the era of personalized medicine, imaging and cerebrospinal fluid (CSF) biomarkers play an increasingly pivotal role in AD trials. The development and widespread use of positron emission tomography (PET) tracers enable clinicians and investigators to detect and measure key targets, including amyloid plaques and tau tangles, hallmarks of neurodegenerative disease. CSF biomarker assays are being developed with the goal of identifying and diagnosing patient cohorts in the earliest stages of AD, prior to structural changes in the brain and cognitive defects. 

	Biomarker approaches help direct tailored treatment options to patients most likely to respond, minimizing risk for patients unlikely to benefit from treatment. Moreover, the ability to image the brain of AD patients during the course of treatment provides a critical tool for detecting and monitoring amyloid-related imaging abnormalities (ARIA), including edema and microhemorrhages, often observed with immunotherapies targeting amyloid plaques. Early detection of ARIA in patients, combined with appropriate monitoring and management, is important for reducing patient risk during the course of a trial.

	Treating patients in the earlier stages of disease translates to treating a significantly younger population (on the order of decades), potentially decreasing the likelihood for certain adverse events and complications. Stratification of patient populations also increases the likelihood of observing disease-modifying activity, which may otherwise be obscured by overlapping patient populations in various stages of disease. 

	With over 500 open clinical trials for AD looking to enroll thousands of patients, one of the largest obstacles to developing new and safe treatments is patient recruitment.  Many AD trial participants are over the age of 65, may be undergoing treatment for other diseases (e.g., cardiovascular disease, metabolic disease), and may not meet inclusion criteria designed to ensure participant safety. Furthermore, the use of biomarkers for AD diagnoses may result in more stringent inclusion criteria for a trial.

	Today’s trials require specialized recruitment-retention strategies to enroll suitable patients, keep them safely in the trial, and minimize loss to follow up. To satisfy enrollment needs, specialized industry services aimed at ensuring the safety of patients over the duration of long, complex trials are becoming more popular among sponsors.

	Concerted patient-centric practices aligned with personalized medicine, biomarker use, and patient recruitment have already transformed the design of AD clinical trials. These efforts will continue to grow and ultimately contribute to the approval of the first disease- modifying therapy for this widespread disease.

, PhD, FCP, is President and CEO, BioClinica

A Closing Thought

Aligning patient-centric approaches with personalized medicine and biomarker use is transforming the design of Alzheimer's trials.

Developing New Alzheimer’s Drugs With a Focus on Patient Safety

	Few topics occasion the lamentations of clinical trial professionals more than the topic of patient inclusion/exclusion criteria in clinical protocols. 

 represents an important public data source to establish baseline numbers of inclusion/exclusion criteria. A review of these publicly available data shows that there is a small increase in the number of commercially funded Phase III inclusion/exclusion criteria per trial, but nowhere as dramatic as is sometimes portrayed in industry press and industry conferences.

	Every year, there is a statistically significant 0.41 increase in inclusion/exclusion criteria totals in commercially funded Phase III studies. Although the increase is not large, the mere size of the database itself helps to make even mild changes seem statistically significant. Two MedDRA therapeutic areas, renal and urinary disorders as well as gastrointestinal disorders, differ statistically significantly from the overall trend, evidencing slight declines in the total number of criteria.

A review of public data indicates a small increase in Phase III inclusion/exclusion criteria per trial over a five-year period.

Inclusion/Exclusion Criteria Show Minimal Rise

	One can’t help but marvel at the number of clinical trial technology solutions providers exhibiting at major conferences like the Drug Information Association (DIA) annual meeting or the Disruptive Innovations conference. The advent of new and potentially lower-cost technologies improved access to capital, and better access to scientific and operating data has fueled a proliferation of vendors

 and solutions categories. These categories  include mature solutions where substantial vendor consolidation has occurred, as well as nascent solutions that have attracted a vast collective of players. 

	To name but a few of the solutions categories: document exchange portals; electronic data capture (EDC); electronic case report forms (eCRFs); electronic patient-reported outcomes (ePRO); ePRO/electronic clinical outcomes assessments (eCOA); electronic trial master files (eTMFs); site-oriented project management technologies; randomization and trial supply management/interactive response technologies (RTSM/IRT); structured content management (SCM); and regulatory information management (RIM). Taken all together, according to a recent analyst report, the clinical trial technology sector will generate total global sales of $5 billion by 2018, nearly a 14% five-year annual growth rate.

	Despite the expanding depth and breadth of eClinical technology solutions during the past two decades, the drug development enterprise continues to experience long cycle times, more complex protocols, and high levels of inefficiency. The average clinical phase duration is 6.8 years, a 15% increase over levels observed 10 years ago. Only 11.3% of drugs that enter clinical testing will be approved in the U.S. and Europe, half the success rate observed 15 years ago. In addition, the total capitalized cost to develop a single drug now exceeds $2.5 billion-nearly a 9% annual increase over 2003 levels when adjusted for inflation.

	Given rising cost and high levels of risk and inefficiency, pressure on sponsors and contract research organizations (CROs) to adopt technology solutions that promise to streamline processes and accelerate management decision-making have intensified. Regulatory agency support of technology solutions adoption to improve efficiency has also increased. But there have been few reports published in the last decade  that monitor and inform industry professionals on the usage and adoption of eClinical technology solutions. It seems that as the breadth and depth of the arsenal of technology solutions has expanded, our ability to monitor usage and impact has diminished. 

	In mid-2014, the Tufts Center for the Study of Drug Development (Tufts CSDD) collaborated with the Clinical Data Interchange Standards Consortium (CDISC) and 10 biopharmaceutical companies, CROs, and eClinical technology vendors to develop an online survey to gather updated benchmark data on technology solution usage. This working group of participating companies had planned to gather study performance data to evaluate the impact of various solutions. That ambitious plan, however, was quickly aborted-a very telling sign about the ways that technology solutions are used and managed within organizations. More about that later.

	More than 550 companies completed the online survey in late 2014. Of that total, 290 sponsor companies and 146 CROs responded, representing a broad mix of large global, mid-sized, and smaller companies. Overall, the rate of adoption of nearly all technology solutions was higher among sponsor companies than CROs, with only two exceptions (see chart).

	The top five most-used technology solutions are EDC, CTMS, RTSM/IRT, and ePRO/eCOA. More than 90% of sponsors and 87% of CROs report that they are currently using EDC; two-thirds of sponsors and nearly 60% of CROs report regularly using CTMS. Usage varied by study phase with Phase III studies receiving the highest usage rates of these four solutions categories.

	Four out of 10 sponsors and CROs report that they are now routinely using eTMF and safety case management systems. As expected, a relatively small percentage of sponsors and CROs report using newer solutions regularly, such as RIM, patient portals, and SCM.

	The cost of implementing technology solutions remains the primary barrier to adoption. A similar result was shown in a 2007 survey of EDC adoption. A strong majority, 80% of sponsor companies and 70% of CROs, cited the investment required as the top constraint. Approximately half of sponsors and CROs cited having insufficient time to evaluate new systems and the challenge of having to maintain old and new systems simultaneously as major barriers to adoption. Nearly 60% of sponsors and CROs noted that, in many cases, their current processes and systems were performing adequately and there was limited incentive or a reasonable value proposition to adopt something new.

	The companies responding to our survey showed mixed experience and perceptions regarding the integration of eClinical systems. Nearly one in four (37%) sponsor and CRO companies reported that they have already integrated some of their systems or are currently working on integrating systems. About one-third (29%) of companies were uncertain about what integration steps had been implemented or were underway. Nearly one-third of sponsors (31%) and four out of 10 (37%) CROs report having integrated both front-end and back-end systems, whereas one-in-five (21%) have purchased prebuilt integrated systems.

	Looking over a short term time horizon, sponsors and CROs report concerns about accommodating a number of new technology developments. Two areas in particular were the most cited: 88% of companies said that they are looking to accommodate patients’ own devices (e.g., smart phones and other mobile devices) in clinical trials. And 80% of respondents noted that they are anticipating and evaluating the use of validated wearable devices and the collection of real-time patient data. A small number of companies also acknowledged the growing importance of management data to support predictive analytics.

	The results of this important study provide useful new benchmarks on technology solutions adoption. Sponsor and CRO companies are currently using EDC, CTMS, RTSM/IRT, and ePRO/eCOA extensively and actively. These findings are not surprising given that EDC and CTMS are relatively mature systems categories, and they have become widely viewed as common solutions. Use of RTSM/IRT within clinical supply and logistics functions is also relatively high and speaks to the growing need for more sophisticated controls as trials have become increasingly dispersed. Use of ePRO tools is also relatively high for registration and post-marketing studies. Use of investigator and patient portals, however, are only beginning to resonate. 

	Technology solutions integration appears to be occurring on a more limited basis than expected. Many factors are likely constraining integration efforts, including high costs, implementation and compatibility challenges, and insufficient use of data standards.  

	The difficulty in gathering data characterizing the impact of technology solutions on performance, efficiency, and drug development economics is disappointing. Our working group struggled on so many levels to derive a methodology that would cleanly and reasonably measure impact. The group concluded that there is too much noise from disparate practices to be mitigated.  And most participating companies can neither access nor collect a sufficient amount of performance data to make this exercise feasible.  

	The real-world practice of technology solutions usage within and between companies makes it particularly challenging to gather performance and management metrics. Company use of technology solutions is typically inconsistent as organizations juggle the use of legacy, new, and pilot solutions simultaneously. Clinical teams and contract service providers also play a role in dictating the technology solutions that will be used on a given study. 

	There is no doubt that next year, and in the years thereafter, we will continue to see a proliferation of technology solutions targeting specific areas within the drug development continuum of activity. In addition to monitoring and updating adoption trends, hopefully, we will ultimately find ways to reasonably and credibly quantify return on technology solution investment.

, MBA, is the Director of Sponsored Research at the Tufts CSDD and Chairman of CISCRP, both in Boston, MA, e-mail: 

CTI Insights

Survey provides new benchmarks on e-solutions adoption, but actual impact data remains elusive.

A New Look at the Arsenal of Tech Solutions

Human gene transfer (HGT) is defined as the transfer of genetic material (DNA or RNA) into a person. This experimental technique is being studied to see whether it could treat certain health problems by “compensating for defective genes, prompting the body to make a potentially therapeutic substance, or triggering the immune system to fight disease.”

 There are a number of different techniques for introducing the recombinant or synthetic DNA into the body, including both 

 (inside the body) integration into the human genome (See Figure 1 below). HGT research is sometimes called "gene therapy" research, although many researchers and ethicists prefer not to use the term “therapy” to refer to products which are still investigational. HGT research is now being tested in a wide number of

 therapeutic indications (See Figure 2 below).

	The first clinical trial of an HGT product was initiated in 1989, and the number of new trials started to grow quickly over the next 10 years. The field of gene transfer research was set back in 1999, after the death of 18-year-old Jesse Gelsinger in a trial at the University of Pennsylvania. Gelsinger suffered from ornithine transcarbamylase deficiency, an X-linked genetic disease of the liver. The symptoms include an inability to metabolize ammonia, which is a byproduct of protein breakdown. The disease is usually fatal at birth. But Gelsinger had not inherited the disease; in his case, it was apparently the result of a spontaneous genetic mutation. Some of his cells were normal, enabling him to survive on medication and a restricted diet. On September 13, 1999, Gelsinger was injected with an adenoviral vector carrying a corrected gene as part of a clinical trial to assess the safety of the gene transfer product. He died four days 

later, apparently having suffered a massive immune response triggered by the use of the viral vector used to transport the gene into his cells, leading to multiple organ failure and brain death. A number of concerns were subsequently raised about this clinical trial, regarding the adequacy of the consent process, his full awareness of the potential risks, and the conflict of interests of the investigator who had created and patented the gene transfer product. The resulting concerns about the field of gene transfer research slowed growth in the number of studies initiated  and, consequently, slowed progress in this area of research for several years.

	Between 1989 and the beginning of 2015, approximately 2,000 trials have begun (see Figure 3). About 195 companies have gene transfer products in clinical development at this time,

 and many of them are working with contract research organizations (CROs) on the design and conduct of studies in these clinical programs.

How is human gene transfer research different from small molecule drug development?

	In many ways, the design and conduct of clinical trials of HGT products are similar to those evaluating small molecule drugs or non-HGT biologic products. But there are some important differences to consider in the planning of HGT clinical development programs and individual studies.
	 

	In the U.S., many HGT products have been developed with support from the National Institutes of Health (NIH). This support may have been to an academic institution at which the product was first created or researched, or in some cases provided directly to the biopharma sponsor. The provision of this funding provides a mechanism for NIH oversight of this HGT research. Even if the funding period has ended, the NIH Office of Biotechnology Activities maintains authority over the development of the product. Once one dollar of NIH funding is attached to the product (which may include the technology platform on which the product was based), the NIH oversight attaches as well.

	Knowing exactly when the NIH oversight applies can be tricky. If the funding was given to the biopharma sponsor, the NIH oversight applies to all the clinical sites in the study run by that sponsor. If there is NIH funding for recombinant DNA research at an institution that is one of the clinical sites, NIH oversight applies to all recombinant DNA research done at that institution even if the research is using a different product or the funding is given to a different investigator at the institution. NIH oversight may also apply to clinical study sites in countries outside the U.S., unless that country has equivalent policies and protections for the use of recombinant DNA products. Therefore, NIH oversight may apply to all, some, or none of the clinical sites in any multi-center clinical study, and expert advice may be necessary to be certain of the appropriate regulatory obligations. 

	The specific requirements of the NIH oversight are provided in the NIH Guidelines for Research Involving Recombinant or Synthetic Nucleic Acid Molecules

 (commonly referred to as the “NIH Guidelines”). The NIH Guidelines is a dynamic document that is periodically updated with the science and understanding of recombinant and synthetic nucleic acid molecule research. In 1990, a new section was added to the NIH Guidelines, Appendix M, which describes points to consider in the design and submission of HGT trials, including the standards and procedures to which investigators must adhere. 

	The NIH Guidelines also describe the role of the NIH Recombinant Advisory Committee (RAC). The RAC makes recommendations on research involving the use of recombinant DNA and on developments in recombinant DNA technology. Gene transfer trials using recombinant DNA fall under NIH oversight and require registration and potential convened review through the RAC. The RAC’s role is to conduct risk assessment reviews of the protocols for HGT products, if it considers a specific risk assessment is necessary. The RAC applies the NIH Guidelines standards for investigators and institutions to ensure the safe handling and containment of gene therapies. As more viral vector delivery systems are becoming standard and the risks are better understood, the RAC frequently declines to review research using these more common systems and only convenes to review novel systems.

	In addition to providing risk classification information for specific biologic compounds, the NIH Guidelines outline requirements for institutional oversight of gene transfer research and for the constitution and conduct of institutional biosafety committees (IBCs). While the role of an institutional review board (IRB) in human subject research is to protect the rights and welfare of the study participant, the IBC’s role is to protect those around the study participant; the research team, the participant’s family and contacts, and the public. Although the IRB regulations allow the use of a “central” IRB (an independent IRB, not based at the research institution), the IBC must be a local committee; that is, committee members must be at or near the institution at which the research will be conducted, although the administration and management of the IBC can be “centralized.”

	The IBC reviews not only the protocol, but also the clinical site’s physical qualifications, including the policies and procedures for the safe and appropriate storage, handling, and administration of the gene transfer product, based on the product’s biosafety risk level. If a clinical site has not conducted any HGT research before, and does not conduct non-clinical research with recombinant DNA products, this may mean that an IBC needs to be created to review the protocol at the clinical site to maintain compliance with the NIH Guidelines. Like IRB approval, IBC approval must be obtained before any clinical trial of HGT research can be initiated, and approval must be maintained through periodic review during the study.

	The institution’s IBC has oversight of the practices and operating procedures governing the lifecycle of the product at the dosing institution. The IBC will review the standard operating procedures for these processes. These include receipt of the product, storage of the product on site in appropriately labeled biohazard freezers and liquid nitrogen containers, and transport from storage to the dosing preparation areas. The IBC will review the physical manipulations involved in product preparation and determine whether personal protective equipment for research staff (e.g., masks, eye shields), or engineering controls such as preparing injections inside a biosafety cabinet, are indicated. The IBC will also review the product administration process (e.g., injection, infusion, etc.).

	This oversight is in addition to the FDA regulations for the development of biologic products. FDA has also created a number of guidances and FAQs related to the development of HGT products.

 The European Medicines Agency (EMA) has drafted guidance for the development of HGT products as well.

	One of the most challenging areas for sponsors and CROs is how to evaluate a site for potential participation in a HGT trial. Most sponsors and CROs are unaware of the role that NIH has with regards to HGT trials in the U.S., along with the standards and guidelines for initiating gene transfer trials. Many institutions also have local standards which are beyond the NIH Guidelines which they consider to be “best practice.”

	The NIH Guidelines and the requirements of the Centers for Disease Control (CDC)

 require the IBC to assess a clinical site to a biosafety level which is based on the risk assessment of the biological agent (and is different from the adverse event profile of the investigational product). No standard definitions of biosafety levels have been generated for clinical settings, so IBCs default to applying the biosafety level definitions developed for laboratory work. For most gene transfer products, the IBC will require the clinical site to conform to Biosafety Level 2 requirements. These include requirements such as having eyewash stations available in case of splashing or eye exposure, bare floors (no carpet) that can be cleaned in case of spills, and enclosed spaces (as opposed to an open floor plan) that can be closed off for decontamination in the event of an accidental product release (broken or dropped vial, etc.). 

	The process of evaluating sites for participation in a HGT study has to look not only at the usual requirements for any clinical trial (experience, resources, potential subject population, basic facilities) but at their ability to meet or to become prepared to meet the additional standards required by the biosafety level assessment, additional safety controls, and IBC review process. If the site has never participated in an HGT study before, they may need to develop and document new procedures, and to train all their staff who will be involved in the study. 

	While basic guidelines for the selection of efficacy assessments in specific therapeutic areas should be followed, the timing of efficacy assessments may need to 

be modified in studies of HGT products. In many diseases, the treatment goal for an HGT product is not management of symptoms or delay of the progression of disease but, particularly in the case of genetic diseases, life-long continuation and function of the newly-added genetic sequence. Therefore, assessment of the efficacy endpoint should be evaluation with an appropriate duration of follow-up, which may even persist into post-marketing requirements.

	There are novel considerations in the safety assessment of an HGT product. Some of the potential safety effects may need to be assessed in specific non-clinical studies, but they may also have implications for safety monitoring in the human studies.

	Since many HGT products create an immune response, immunogenicity should be assessed in non-clinical studies and considered in the selection of the population and in the safety monitoring plans.  This is especially important in pediatric or elderly populations, who may have different immune responses compared to adults, based on whether or not they have had prior exposure to, or vaccination with, the viral vector being used. Instructions for the assessment of safety monitoring should specifically include the assessment of infusion-related reactions, infections, and inflammatory responses, and immune-mediated adverse events.

	When live viral vectors are used in the product, clinical trial eligibility criteria should contain an assessment of immunosuppression, including the presence of immunosuppressive illnesses (HIV infection, etc.) or concomitant use of immunosuppressive medications. After administration of the product, “shedding” of the virus is also possible. Shedding refers to the potential for the participant to whom the product has been administered to continue to secrete the virus in their bodily fluids. This can include direct leakage of the virus from the injection site after administration, when the skin puncture is still open or through a lesion that forms at the site. Viral shedding creates a safety issue not just for the participant, but creates the potential for infection of family, friends, and even casual contacts. The potential for shedding should be assessed in non-clinical studies, but human shedding studies may also be performed to assess this risk. Protocols may need to specify the use of waterproof, occlusive dressings over injection sites and/or the resulting lesions, rather than use of gauze or other common bandages.

	Human DNA contains many sequences that turn the translation of other DNA sections on and off. When DNA is introduced into the research participant with the use of a viral vector, the DNA can be incorporated into the DNA of the participant’s cell, but the precise location of that integration cannot be controlled. It is possible that the new DNA can be incorporated into a location which accidentally turns on a tumor-promoter gene (or turns off a tumor suppressor), which is called “insertional oncogenesis.”  Non-clinical studies to assess tumorogenicity may be conducted, but long-term follow-up for secondary cancers may also be necessary in clinical trials.

	Some HGT products are introduced into specific tissues rather than being administered systemically; for example, administration of a gene transfer product using an adenovirus vector into the eye for the treatment of macular degeneration.

 In such cases, safety monitoring should also watch for the distribution of viral vector beyond the intended tissues.
	 

	The NIH Guidelines provide guidance on four topics in addition to the standard required elements of informed consent that are considered necessary to include in trials of HGT products. While IBCs will review the informed consent document to see if these issues are addressed, they do not “approve” consent documents; they will provide feedback to the researcher, sponsor or the appropriate IRB if they feel that these elements are not adequately addressed. The topics are:

		Reproductive Considerations - When existing data are inadequate to rule out the possibility of inadvertent germline alteration that could be passed on to offspring, participants should be informed that the consequences to unborn children are unknown.
		 

		Long-term Follow up with rDNA- Prospective participants should be aware that they will be expected to participate in long-term follow up that extends beyond the active phase of the study. Investigators should explain the rationale for long-term follow up and describe the specific follow-up activities planned, including the desire to collect information about any new cancers, blood disorders, autoimmune diseases, and neurologic disorders encountered.
		 

		Request for Autopsy - The request to be allowed to perform an autopsy in case of the participant’s death is an aspect of long-term follow up that is unique to gene transfer, since it is still such a new area of research. It is requested because autopsies can yield important information that may enable a better understanding about the long-term effects of gene transfer intervention.
		 

		Interest of the Media and Others - This issue was added shortly after the Gelsinger case, when it was thought necessary to warn participants that there may be public interest in their trial and participation. While generally considered much less necessary now, this item has not been removed from the guidance.

	The number of HGT products in development is increasing, and the number of these clinical trials is increasing. As this trend continues, more clinical research professionals within biopharma sponsors and CROs, who may be well-versed in the details of drug and/or biologic development, may find it necessary to be aware of the specifics of the design and conduct of HGT studies. This will be necessary to ensure that these trials are conducted with regulatory compliance, scientific rigor, and the best protection for the participants as well as the researchers and the public. This paper has provided only a brief summary of some of the key challenges unique to gene transfer clinical trials. The field is constantly changing as regulatory bodies develop and evolve frameworks that will impact the conduct of these types of trials. As these products pass through proof-of-concept assessments, gain financial support, and progress into later-stage clinical trials, it is important that clinical research professionals keep up with the additional challenges of successfully conducting these trials.

	1. NIH Backgrounder on Gene Transfer; http://www.nih.gov/news/pr/nov2002/genetransferbackgrounder.htm.  Accessed 8 July 2015.

	2. Jain Biotech Gene Therapy – technologies, markets and companies.  http://pharmabiotech.ch/reports/genetherapy/.  Accessed 8 July 2015.

	3. NIH Guidelines for Research Involving Recombinant or Synthetic Nucleic Acid Molecules. 

	4. FDA Cellular and Gene Therapy Guidances; Cellular and Gene Therapy Guidance Documents.  

http://www.fda.gov/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/Guidances/CellularandGeneTherapy/

	5. Guideline on the Quality, Non-clinical and Clinical Aspects of Gene Therapy Medicinal Products.   EMA/CAT/80183/2014, draft 23march 2015.

Biological Materials Oversight in the United States

. Health Care Compliance Professionals Handbook.  2014. 

http://www.hcca-info.org/Products/Books.aspx

Trends in United States Biological Materials Oversight and Institutional Biosafety Committees

.  Journal of Research Administration. Volume XLV, Number 1. Spring 2014.  

http://srainternational.org/publications/journal/volume-xlv-number-1

	8.  U.S. Department of Health and Human Services, Centers for Disease Control and Prevention, & National Institutes of Health. (2007). Biosafety in Microbiological and Biomedical Laboratories (5th ed.). L. C. Chosewood and D. E. Wilson (Eds.). Washington, DC: U.S. Government Printing Office. Available at: 

www.cdc.gov/od/ohs/biosfty/bmbl5/bmbl5toc.htm

https://www.clinicaltrials.gov/ct2/show/NCT02341807?term=spark+therapeutics&rank=1

https://www.clinicaltrials.gov/ct2/show/NCT01494805?term=raav+sflt&rank=1

Applied Genetics Technology Corporation (AGTC). 

https://www.clinicaltrials.gov/ct2/show/NCT02416622?term=AGTC&rank=1

, PhD, MPH, BRP, CHMM, is Senior Vice President of Biosafety and Gene Therapy, WIRB-Copernicus Group, email: 

, MD, MPH, MSB, is Chief Medical Officer, WIRB-Copernicus Group, email:  

Feature Article

This experimental technique is being studied to see whether it could treat certain health problems.

Human Gene Transfer Studies: What Clinicians Should Know

	The current practice of waiver on immediate reporting of cases of death due to the main disease progression may jeopardize data quality from discrepancies in the overall number of deaths registered and documented across the lifecycle reporting of a clinical trial. This article will describe the practical aspects of reporting deaths due to the main disease progression to ensure the data quality of the drug development program.

	The International Conference on Harmonisation (ICH) E2A Guideline titled “Clinical Safety Data Management: Definitions and Standards for Expedited Reporting”

 defines a serious adverse event (or reaction) (SAE) as any untoward medical occurrence that at any dose results in death, is life-threatening, requires inpatient hospitalization or prolongation of existing hospitalization, results in persistent or significant disability/incapacity, or is a congenital anomaly/birth defect.

	Serious adverse events are critically important for the identification of safety problems that might be significant enough to lead to important changes in the way the medicinal product is developed (e.g., change in dose, population, needed monitoring, consent forms). Such reactions should be expeditiously reported to regulatory authorities if they are suspected to be related to the medicinal product and unexpected as per the applicable product information.

	Reporting of death-an SAE in its most severe form-is the No. 1 postulate of drug safety or pharmacovigilance (PVG) as per ICH E2A. However, there are a number of trials in which death of the study subjects is an expected event and likely due to the main disease progression (e.g., late stage of cancer, coma). Reporting of disease-related mortality as single events is generally uninformative, 

and neither contributes meaningfully to the developing safety profile of an investigational drug nor to human subject protection. Thus, the sponsor and regulatory authority rather frequently reach the agreement that such cases will be aggregated and compared to cases in a control group and submitted only if the event occurs more frequently in the drug treatment group.

 Many times, the study protocol or the investigator’s brochure identify cases of death due to the main disease progression as not requiring expedited reporting. Investigators will not complete and submit an SAE report form for such cases unless they are considered related to the study treatment by the investigator.

	On the other hand, at the end of the trial, the sponsor should summarize the study results in the clinical study report (CSR). The CSR is the document-above all other study information-that should include all comprehensive information of all SAEs (including all deaths) from each particular clinical trial and is reported to regulatory authorities by the study sponsor. In the ICH E3 Guideline for Industry titled “Structure and Content of Clinical Study Reports,”

 section 12.3.2 states that “there should be brief narratives describing each death, each other serious adverse event, and those of the other significant adverse events that are judged to be of special interest because of clinical importance.”

	At this stage, if there was a waiver on expedited reporting of deaths due to the main disease progression, discrepancies may occur, such as:

		Death is an SAE in accordance with ICH E2A, and without any exception, information about all cases of death should be listed in the CSR (including cases of death that do not require immediate reporting as per the study protocol or the investigator’s brochure). However, not all cases of death have been captured in the safety database, as the cases of death due to the main disease progression were not reported within the trial expeditiously. We understand that our opponents may refer to the statement “Events (of death) that were clearly unrelated to the test drug/investigational product may be omitted or described very briefly” in section 12.3.2 of ICH E3. Nevertheless, the necessity to have all safety information on hand can arise at any stage of the investigational medicinal product life cycle based on analysis of aggregated data performed both for individual studies (if there are enough events to be informative) and across all studies.

 The larger sample size provides the best chance of detecting safety signals.

		Comparison of disease-related mortality is performed during the interim and/or final analysis of statistical data derived from the clinical study database. In circumstances where the mortality rate in the study treatment group is higher than in the control group, the case would be considered a suspected unexpected serious adverse reaction (SUSAR) and investigational new drug (IND) safety reports should be prepared and submitted to regulatory authorities in narrative format for aggregated data in an expedited way. The individual cases that were analyzed should also be submitted at the same time (e.g., completed FDA Form 3500A for each case).

 However, as already discussed, not all cases of death were captured in the safety database if information about deaths due to the main disease progression were not collected within the trial.

	It is the responsibility of the study sponsor to maintain the safety database in order to monitor the safety of medicinal products and to detect any change to their risk-benefit balance (including all events of death); however, information regarding deaths due to the main disease progression will not be comprehensively captured in the safety database. The lack of clarity and consistency in reporting of deaths in clinical trials can also lead to discordance in deaths documented across reports of a trial.

	As a contract research organization (CRO) and safety provider, we have already faced situations several times when it was very difficult to collect sufficient information about the cases of death due to the main disease progression that had not required the immediate reporting as per study protocol. Such information should be collected before the CSR finalization and sometimes after the study database lock (i.e., probably a long time after the occurrence). For queries, the investigators had to recall the information of patients who discontinued months (sometimes years) ago, which was rather time-consuming and annoying for the investigators.

	From our point of view, the following steps are necessary to improve the process of cooperation between the different parties responsible for collection, evaluation, benefit/risk assessment, and regulatory reporting of deaths due to the main disease progression that are not reported by the investigator in an expedited way:

		Cross-functional operation procedure on collection of such occurrences within clinical trials should be developed by any CRO or the study sponsor (if they run clinical trials on their own).
		 

		Safety management plan should match with, or contain a reference to, safety data reconciliation guidelines. Both documents should be finalized before the first patient in.
		 

		Data management team should provide PVG team with the listings of deaths on a regular basis (e.g., monthly or quarterly). The PVG team should review the listings and reconcile them with previously reported SAE cases of death on an ongoing basis.
		 

		Additional information should be requested from the clinical/site team for all cases of death that were not reported by the investigators on an expedited basis to avoid delayed queries after the end of the trial.
		 

		Brief narratives are compiled for all cases of death either by the PVG team or by medical writers in accordance with the safety management plan.

	Such simple steps can eliminate the possibility of losing data pertaining to disease-related mortality and could significantly improve the quality of CSRs and lifecycle documentation for the investigational product.

	Because the regulations require reporting certain adverse events in the aggregate rather than as individual cases, it is important for sponsors to plan the process of collection and evaluation of such safety data in the very beginning of the investigational product life cycle. It is crucial to remember that brief narratives describing each death should be provided in CSRs and in IND safety reports in situations where the mortality rate in the study treatment group is higher than in the control group. For cases of death that are specifically defined in the protocol as the study endpoints, and that are neither collected in the safety database nor on the adverse event pages of the case report form, it also could be useful to design an additional case report form, so that the investigator could provide a brief narrative for the case in the pre-specified format.

	A participant death is a serious event in a clinical trial and needs to be unambiguously reported either in IND or aggregated safety reports. Waiver on immediate reporting of cases of death due to the main disease progression can be a challenge in situations where the process of collection and evaluation of all cases of deaths was not carefully planned by the study sponsor in the very beginning of the investigational product life cycle. Failure to report all cases of death in the safety database leads to discrepancies in the number of deaths registered and documented across reports (the development safety update report, CSR) of a trial thereafter, affecting the quality of the reports. Incomplete reporting of deaths may overemphasize health benefits when benefits and harms of the investigational medicinal product are summarized in the large sample size or may influence the timelines of expedited reporting in circumstances where the mortality rate in the study treatment group is higher than in the control group.

	1. International Conference on Harmonisation.  “Clinical Safety Data Management: Definitions and Standards for Expedited Reporting.” E2A, Step 4. October 1994. 

http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/

	2. United States Food and Drug Administration. “Final Rule: Investigational New Drug Safety Reporting Requirements for Human Drug and Biological Products and Safety Reporting Requirements for Bioavailability and Bioequivalence Studies in Humans.” 21 CFR Parts 312 and 320.  October 2013. 

http://www.fda.gov/Drugs/DevelopmentApprovalProcess/HowDrugsareDeveloped

andApproved/ApprovalApplications/InvestigationalNewDrugINDApplication/ucm226358.htm

	3. European Parliament. “Approximation of the laws, regulations and administrative provisions of the Member States relating to the implementation of good clinical practice in the conduct of clinical trials on medicinal products for human use.” Directive 2001/20/EC. April 4, 2001. 

http://ec.europa.eu/health/files/eudralex/vol-1/dir_2001_20/dir_2001_20_en.pdf

	4. European Commission. “Detailed guidance on the collection, verification and presentation of adverse event/reaction reports arising from clinical trials on medicinal products for human use (‘CT-3’).” 2011/C 172/01 Article 16(1). 

http://ec.europa.eu/health/files/eudralex/vol-10/2011_c172_01/2011_c172_01_en.pdf

	5. International Conference on Harmonisation.  “Structure and Content of Clinical Study Report.” E3, Step 4. November 1995. 

	6. United States Department of Health and Human Services, Food and Drug Administration, Center for Drug Evaluation and Research (CDER), and Center for Biologics Evaluation and Research (CBER). “Guidance for Industry and Investigators: Safety Reporting Requirements for INDs and BA/BE studies.” December 2012. 

http://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/

	7. International Conference on Harmonisation. “Statistical Principles for Clinical Trials.” E9, Step 4. February 1998. 

http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines

	8. Earley Amy, Joseph Lau, and Katrin Uhlig. “Haphazard reporting of deaths in clinical trials: a review of cases of ClinicalTrials.gov records and matched publications–a cross-sectional study.” 

2013;3:e001963. Accessed June 1, 2015. doi:10.1136/bmjopen-2012-001963.

, MD, is Medical Officer/Pharmacovigilance Physician, PSI CRO South Africa (Pty) Ltd; 

 is Director, Medical Writing, PSI Pharma Support America Inc.; 

, MD, is Senior Director, Medical Affairs, PSI CRO Deutschland GmbH; 

, MD, is Manager, Pharmacovigilance Unit, PSI Pharma Support Intl

Examining the practical significance of reporting patient deaths due to main disease progression.

Death Waivers an Incomplete Picture of Drug Safety

	An important criterion for a well-conducted clinical trial is minimization of bias in endpoint assessment. When possible, treatment assignments should be masked (or “blinded”) so the assignment is unknown to both the study participants and healthcare professionals treating the participants. Strategies for masking studies range from very elaborate, such as sham surgeries

, to the most common, which is simply providing a placebo pill that is visually identical to the active drug. While masking is a common strategy to reduce bias in randomized clinical trials (RCT), assessment of the adequacy of the treatment mask is seldom evaluated. Schultz reported that trials that were not double-blind yielded larger effects with odds ratios exaggerated by as much as 17%.

Using a specific trial, the importance of assessing the success of therapy masking is examined.

Applied Clinical Trials-10-01-2015