	With the rise in gene therapies entering clinical trials, it is important to address the operational challenges associated with these types of trials. Some gene therapy trials necessitate centralized dosing like those that require patient samples to derive the investigational medicinal product (IMP), which call for a limited number of dosing centers.

	In this case, the patient may initially be seen at one center for evaluation, dosing, and initial follow-up, and subsequently seen at another center for their longer-term follow-up activities-in some cases, these may be in different countries. Because the prevalence of patients in the rare disease space are just that-rare-special considerations must be made to ensure patient access to the clinical trials.

	This creates significant logistical challenges not only from a patient and family standpoint but from a regulatory and data collection standpoint as well. We must make sure we consider all facets of these activities to make participation in this type of trial seamless to the patient and their family.

	From a regulatory perspective, country-specific requirements must be assessed from the outset. For example, when subjects are dosed in a country other than their originating country we must understand and be conscious of the requirements of both the originating and dosing nations. Even though there is no IMP and no dosing in the subject’s originating country, the regulatory authority may request to review everything related to the IMP. Unless a patient relocates for the full duration of the study, regulatory and ethics approvals will be needed in both the patient’s originating country as well as the dosing country.

	Also, informed consent forms (ICFs) specific to patient travel and reimbursement are necessary. In the dosing country, regulatory and ethics may require approval for foreign patients to travel to the dosing country. Study documents must be available in the patient’s native language, including the dosing country ICF. For both nations, there is shared hospital liability and country specific insurance requirements.

	From a patient and family travel or relocation perspective, there are many points to consider, including travel logistics and relocation assistance. Imagine what must go into uprooting your family to another country or region to participate in a drug development program. There are passport or visa requirements; language barriers; and the need for an interpreter, school support, support for the rest of the family, including financial support, social support, insurance, etc. Additionally, given the length of gene therapy follow-up requirements, patients and their families will likely go through many changes (i.e., changes with family dynamic, relocation, etc.). Planning for all of these logistics at the outset are imperative for success in these types of trials to attract patients and ensure they remain in the study for the entire trial.

		Lastly, because patient data will need to be monitored at the originating site as well as the dosing site, different sites will need access to the same patient data; and that access could cross country lines. Collaboration between the dosing center and originating center physicians is imperative to ensure continuity of care and, ultimately, for patient safety. Prior to participating in this type of study, a site must ensure that their data collection capabilities allow for such scenarios.

		In summary, gene therapy adds additional complexity to clinical trials given the logistical challenges for specialized therapies, but it also allows for great scientific gains. When embarking on this type of study, we must always prepare for the regulatory intricacies and data needs early on and consider the patients, their caregivers, and their families to ensure that every enrolled patient stays enrolled throughout the entirety of the study.

 is Executive Director, General Medicine, Syneos Health, and co-leads the company’s Health Rare Disease Consortium. She can be reached at 

Articles

Feature Article

A look at home and dosing site considerations.

Gene Therapy in Rare Disease Research

	Unfortunately, there is no end to the number of people affected by disease-be they rare, unmet therapeutic needs, 

or chronic but manageable. But, everyday, scientists uncover yet another gene, or biomarker, or mechanism of action that leads to the next step in uncovering the true nature of a specific disease, and getting us one step closer to a healthier, longer, or higher quality life.

	In addition to advancements in science, are the advancements in drug testing. In this issue, we unveil the results of our trial design survey, conducted with our research partner SCORR Marketing. In that survey (see page 16), respondents shared the types of innovative or flexible trial designs being implemented, primarily but not limited to oncology and rare diseases. By using adaptive or innovative trials, sponsors can theoretically deliver more efficient and faster trials. The FDA and EMA, and other regulatory authorities play a big part in getting rare or orphan drugs through the review process. Starting with scientific advice before a trial is initiated, then offering priority review or other incentives to help sponsors get to the finish line faster.

	I wanted to share two recent examples about rare disease in children. The first was my research and interviews with BioMarin for its drug Brineura, approved in April 2017, for the treatment of a specific form of Battan’s disease, CLN2. I wrote about it for 

http://www.pharmexec.com/brands-year-promise-and-challenge

, and I encourage you to watch the documentary BioMarin posted on YouTube at 

	With Battan, children develop normally until ages two or three, when they experience seizures and progress rapidly to losing the ability to walk and talk by six years of age. After that, symptoms are followed by dementia and blindness; feeding and everyday needs become extremely difficult, and then death occurs between the ages of eight and 12. The video outlines in detail what BioMarin and scientists achieved to get a protein-replacement therapy approved, using one trial of 24 patients with a natural history cohort completed in four years. The drug has only shown to halt the progression, but BioMarin works with commercial lab Invitae to offer a 125-gene panel tests for different types of seizures free of charge. It not only helps diagnose what type of epilepsy may be present, but also diagnose CLN2 in those that were previously undiagnosed.

	At the recent Pop-Up Star event, which highlighted programs to increase clinical research awareness, parent Allison Greiner spoke of her son’s journey to date with Duchenne Muscular Dystrophy. After observing his lack of hitting developmental milestones, Matthew was enrolled in physical therapy classes, routine medical exams, and more until his diagnosis almost 16 months later. The first clinical trial ended for lack of efficacy, but now he is enrolled in a Pfizer trial and showing tremendous improvement. Greiner is sure that Matthew will continue to thrive and outlast the expected disease timeline of death in the late 20s, early 30s. Greiner said clinical research offer the hope that these parents and patients need. 

From the Editor

Editor-in-Chief Lisa Henderson speak about therapeutic needs, rare diseases in children, and the SCORR Marketing survey on innovative or flexible trial designs.

Hope. The Power for the Rare Disease Journey

, the authors explored master protocols and their increasing use in oncology. “The term master protocol is well accepted to represent an ongoing trial intended for the addition or removal of drugs, arms, and study hypotheses. Master protocols may or may not be adaptive, umbrella, or basket studies. They may be a collection of sub-studies or a complex statistical design or platform for rapid learning and decision-making. Whether umbrella, basket, or platform, a master protocol seeks to update the randomized clinical trial model for the genomic age,” the authors state.

	While this article specifically focuses on oncology, asking the question, “what will it take to make the master protocol a standard in oncology research?” master protocols and other innovative or adaptive designs are beneficial for many rare diseases.

	With our survey partner, SCORR Marketing, 

asked respondents about their use and knowledge of clinical trial design, not specific to oncology or rare diseases. (The survey is available here to download: 

). Suffice to say, many respondents who indicated they used master protocols also conducted oncology and/or rare disease research. While master protocols may not be adaptive, adaptive trials, as well as basket trials, ranked first overall in implementation of trial designs.

	Adaptive trial design allows for modifications to the clinical development program based on how patients are responding, without undermining the trial’s validity and integrity.

	The primary goal is for a more flexible, efficient, and faster study. Adaptive clinical trials have come into their own since the FDA issued

	Basket trials, on the other hand, have multiple arms (baskets) and can include a single drug evaluated in multiple malignancies or tumor site with the same target; a single drug evaluated as in the previous, but some may have different molecular targets; or multiple baskets representing multiple targeted agents that are evaluated in the same malignancies or tumors.

	The basket trial design has limitations, primarily around the complexity of addressing multiple questions in a single protocol.

	With the increased use and acceptance of innovative and adaptive trial designs, both the FDA and the European Medicines Agency (EMA) offer scientific advice meetings for sponsors. In our survey, all respondents who said they conducted master protocols also said they solicit regulatory authority advice prior to designing their trials. A full 70% for all trial designs said that they do solicit that advanced scientific advice.

	Recently, FDA Commissioner Scott Gottlieb highlighted past and future changes at the agency’s Center for Drug Evaluation and Research (CDER) (http://bit.ly/2J7MoCl). Specifically, he noted “...the FDA has introduced many fundamental advances in how it evaluates drugs for safety and effectiveness, as well as the manner in which clinical trials are guided. These include adaptive approaches to clinical development such as the introduction of seamless trial designs or master protocols or tissue agnostic product approvals.”

	Gottlieb continued regarding the specific changes to organizational structures and processes at the FDA, which are intended to “allow our review staff to have more time for reviewing and providing feedback to sponsors on clinical protocols. One goal is to engage sponsors earlier in the development process to ensure that trial designs are efficient and structured in the most effective way to identify risks and measure benefit. Equally important, there will also be more ability to engage external stakeholders, such as disease specialists, academic researchers, and regulatory partners at other agencies. And with patient-focused drug development becoming a reality, ongoing relationships and interactions with patient groups are becoming an important part of our regulatory practices.”

	The EMA also offers scientific advice, and for 487 clinical trials hosted between 2009 and 2015, 244 requests for scientific advice were received by July 2017.

, SGS Life Sciences offers expert insight into scientific advice with regulators, for EMA, FDA, and the individual, national European Union authorities. While experts explained sponsors can ask for advice at anytime during the drug’s development, different points will offer different scenarios. For example, a European biotech with a compound in Phase IIa for women’s health had meetings with both FDA and EMA. The discussion centered on:

	• Set-up of the further clinical program

	• Assessments to be done in the Phase IIb study

	• Further non-clinical testing, in particular carcinogenicity testing

	• Development plan for specific sub-indication

	The company left with a clear outcome for its Phase IIb study, as well as improving assessments to its Phase III study. Other discussion points that SGS advised early in development included study design, development program, CMC aspects, and pediatric development.

	In addition to designs, we asked respondents about the trial innovations they are using or plan to use. The majority responded that they are using EHR data (63%), followed by siteless studies (31%), blockchain (17%), and semantic technology (14%).

	At a recent conference, CEO of Sarah Cannon Research Institute, Dee Anna Smith, presented the components of its cancer data warehouse. Those included its “systems” such as Epic; bone marrow transplant solution; radiation oncology EHR; cancer registry; and cancer navigation system. Data from the molecular profiling labs and affiliated medical oncologists EMR were also included in the warehouse.

	Sarah Cannon is part of the larger HCA health network, and using the data from the warehouse, Smith said the company was able to identify 17,383 patients with breast, colon, gastrointestinal, and lung cancer. Of those, 6,092 were newly diagnosed and were navigated through Cannon and retained as patients. Keeping patients within the HCA system helps them access to the clinical trials through Sarah Cannon, and not be referred out of the system for care.

	Siteless studies, also called remote, decentralized or virtual trials, have been an increasing choice for clinical operations in looking for more patient-centric choices. Siteless trials use digital technology to allow some or all aspects of a clinical trial to be carried out at a participant’s home or local physician’s office, rather than at a central trial site such as a large hospital.

	In early March, Novartis announced that its alliance with Science 37 would initiate up to 10 new clinical trials over the next three years. The studies will blend virtual and traditional models, with increasing degrees of decentralization toward a mostly siteless model. Novartis was an early investor in Science 37, a decentralized clinical trial technology and design provider that uses its proprietary Network Oriented Research Assistant (NORA®) technology), which enables patients to participate in studies using mobile devices and telemedicine services. To date, Novartis and Science 37 have initiated virtual trials for cluster headache, acne, and nonalcoholic steatohepatitis (NASH). The decentralized trials are expected to begin later this year in the US in the areas of dermatology, neuroscience, and oncology. In May, UCB also announced the use of NORA in its trials.

	Our survey did tackle a number of other questions, including gains or benefits expected by using innovation or different trial designs. All received about a 70% score in the following: better quality data; better recruitment/retention; cost savings; faster executive and regulatory compliance.

	Respondents also noted that adaptive trials and studies that use EHR data provide the highest return on investment.

Findings from a new ACT and SCORR Marketing survey reveal the most actively used flexible design approaches in clinical research-many with application in rare disease.

Clinical Design: A Deep Dive

	Devinder Poonian, CEO of Rockville, MDbased CRO DP Clinical, discusses changes in clinical trial practice over the years, and the company’s experiences with complex spinal cord injury trials. 

Q: Your CRO has been in business over 24 years. What specific changes have you seen in the industry?

 A great deal has changed in the CRO/drug development industry over the last 24 years. Patient participation as a result of greater awareness through advocacy groups and social media have had a significant impact on how patient recruitment is handled. We are now able to identify potential trial participants so much easier than before, and with difficult-to-enroll patient populations, this is extremely important.

	Technology changes have also had a significant impact on the industry. Whether you look at how data management was handled in the past (paper case report forms, or CRFs) and the move to electronic data capture or the use of other trials tools-clinical trial management systems (CTMS) and electronic master file (eTMF) systems, there is no doubt that we have come a long way in how we conduct clinical trials. Other industry changes include product licensing, mergers and acquisitions of both pharma and CROs, as well as the development of creative approaches to the financial challenges of many startup companies pursuing new therapies.

Q: What specific changes have there been to clinical trials?

 Technology has had the biggest impact on clinical trials. When DP Clinical started, data was captured on paper CRFs, monitored onsite, collected, and brought or shipped back to the CRO for data entry into the study database. Today, everything is electronic-EDC systems, remote and onsite monitoring, and almost real-time access to data. All this provides sponsors with the information they need to make informed decisions regarding their studies quickly, ultimately minimizing risk and reducing cost.

Q: As a small CRO, how do you respond to the big CRO/big pharma, little CRO/little pharma discussion?

 To some extent, I agree. We have found that small pharmaceutical companies and biotechs have needs that can’t typically be met by large CROs. Small/mid-sized CROs have much more flexibility to meet sponsor requests and can adapt quickly to their ever- changing requirements.

	Having said that, we work well with large pharma also. They appreciate our focus, experience, and reputation; and they know we can deliver. At DP Clinical, we have successfully managed studies for all types/sizes of companies. We develop true partnerships with our sponsors and offer the personal attention they often don’t get with larger CROs.

	We’ve found that the CRO’s experience, knowledge of the therapeutic area, quality of work, and reputation are more important than the size of the CRO or pharma. Finding a partner that you trust, is knowledgeable in the type of study to be conducted, and has a reputation for delivering are key.

Q: How did you get involved with spinal cord injury trials?

 I started my clinical career with Fidia Pharmaceuticals, which specialized in products for neurological disorders. There I initiated the first acute spinal cord Injury (SCI) study at 32 neurotrauma centers in North America. I then went on to start DP Clinical, which combines a strong neurology/CNS research heritage with over 24 years of experience in conducting acute

	and chronic SCI clinical trials. Since 1994, we have worked on almost all of the major acute and chronic SCI studies conducted, starting with the benchmark study of Sygen® (GM1)-considered the gold standard in SCI treatment-as well as studies using autologous cells, stem cells, and devices.

Q: How difficult are these trials to conduct? What is involved?

 Because of the small potential market size, large pharmaceutical companies have not invested in SCI research; however, small pharmaceutical and biotech companies have displayed an increased interest in SCI clinical trials, and it’s a good fit for them.

	SCI studies are very difficult, because they have an added level of complexity-sites must wait for someone to experience a life-altering event. It’s traumatic, literally, for the patient; and study sites must wait for an event to occur as opposed to actively seeking patients. With improvements in car safety (airbags and seatbelts), fewer people are injured in car accidents, thus reducing the number of SCI patients each year.

	Potential patients are often treated at a hospital and would have to be transferred to a study site. This typically cannot be done within the study timeline which often require therapies to be administered within a few hours or days of the SCI. Additionally, many acute SCI patients are seen at Level II trauma centers and are not transferred to Level I centers where studies are actively enrolling. As a result, enrollment takes longer than some clinical trials and must be managed carefully by the CRO.

	Finding the right trauma centers, with experienced staff able to conduct the necessary assessments is critical. Because there is variability among study sites and assessors, additional training must be provided to ensure consistency. CRO oversight is very important to these studies to maintain assessment and data accuracy. We have worked with numerous centers to train and support them in patient enrollment.

	Many companies interested in conducting SCI research are small and funding can be difficult, because SCI studies are costly. To meet enrollment requirements, especially for larger SCI clinical trials, it may take several years to recruit and enroll the needed number of SCI patients needed. So, long-term funding becomes an important element in SCI trials. To date, there have been no FDA approved treatments for SCI and only a few trials have shown patient improvement.

News

Leader of one longtime CRO discusses the marked changes in clinical trial practice from past to present-and the company’s unique focus.



Clinical Trial Evolution: A CRO’s Perspective

	The Patient-Focused Drug Development (PFDD) program at FDA has progressed over the last decade to achieve a more systematic approach to incorporating patients’ experiences and priorities into the clinical testing process. 

Efforts to identify what is most important to patients regarding burden of disease and treatment preferences have become important in designing protocols and research strategies most likely to address medical needs and risks.

	Congress has signaled strong support for such initiatives: the latest Prescription Drug User Fee Act (PDUFA VI) authorizes additional strategies for utilizing the “patient’s voice” in assessing the burden of disease and treatment most important to patients. And the 21st Century Cures Act calls on FDA to develop guidance on methods for collecting “relevant, objective, accurate, representative, and meaningful patient experience data” throughout drug development. In finalizing FDA’s budget for 2019, the House Appropriations Committee specifies the importance of considering patient experience information in the review of new medical products and relevant product labeling to inform treatment decisions and “payer determinations.”

	FDA is responding with initiatives to better coordinate patient input activities for drugs, biologics, and medical devices. A new Patient Affairs Staff (PAS) in the Office of Medical Products and Tobacco (OMPT) is collaborating with the National Organization for Rare Disorders (NORD) to hold a series of listening sessions to further incorporate patient experience with rare diseases into regulatory decision-making. PAS also has launched the Patient Engagement Collaborative with the Clinical Trials Transformation Initiative (CTTI) to establish an outside group able to provide regular patient views to FDA. The CTTI collaborative is similar to the Consumers’ Working Party of the European Medicines Agency (EMA). Separately, FDA and EMA formed a Patient Engagement Cluster in 2016 to discuss best practices and experiences in this area on a more formal, regular basis.

	PDUFA and the Cures legislation both instruct FDA to issue multiple guidances on collecting and submitting patient experience data to FDA to enhance how the agency uses it to inform decision-making. The advisories will assist sponsors in assessing burden of disease and burden of treatment most important to patients, how best to identify measures in clinical trials that matter most to patients, and how to use such measures as endpoints significant for regulatory decision-making. These and other topics will be discussed at FDA public workshops in the coming months.

	The new PAS initiatives reflect a shift at FDA from expanding on the 24 PFDD meetings conducted since 2014 to strategies to incorporate more clearly the wide range of patients’ perspectives gained from these meetings into credible evidence that can support product development and regulatory decision-making. The aim is to identify best practices for identifying meaningful patient data and new programs and policies to utilize this information.

	Insight and advice for achieving this goal may arise from an initiative to advance the science of patient input to achieve more rigorous, credible evidence for use in medical product R&D. At a workshop in May, organized by the Forum on Drug Discovery, Development and Translation of the National Academies of Sciences, Engineering and Medicine (NASEM), experts from industry, disease organizations, academic research centers, and government agencies discussed optimal methods for collecting patient experience reports, barriers to this process, and how these initiatives relate to the drive to tap real-world evidence and other information sources useful to decision makers (see 

	Theresa Mullin, associate director for strategic initiatives in the Center for Drug Evaluation and Research (CDER) and head of the PFDD program, noted that many drug development programs do not ask patients early enough about setting eligibility criteria, avoiding barriers to trial participation, and what endpoints are most meaningful in dealing with a disease. Mullin outlined how FDA seeks to better understand those aspects of a disease that matter most to patients and whether such attitudes vary by age, culture, or severity of disease. A related question is which commonly measured endpoints are most relevant to different patient subgroups. FDA seeks ideas for dealing with clinical trials that exclude patients who want to participate and with study protocols that are intolerable or unworkable for some individuals. And the agency wants information on measures that may increase the likelihood of patient enrollment and retention in a study and what challenges patients may face in trying to adhere to a prescribed drug regimen.

	Workshop participants discussed a range of strategies for improving the measurement and collection of patient experience data, including the use of registries to identify in advance those patients who meet enrollment criteria. The goal is to outline in a report where further research may advance methods for soliciting patient input in research processes that reflect the needs and preferences of affected populations.

	Jill Wechsler is the Washington Correspondent for 

Jill Wechsler details the continued rise of incorporating the “patient experience” in drug development measures.  

Patient Experience Moves to Center Stage in Medical Product Development

As patients take more active roles in decision-making about health, healthcare, clinical trials, and regulatory activities, their influence has changed how sponsors and researchers view patient involvement in clinical research. Once regarded as “subjects” who had research performed on them, patients are now contributing across the spectrum of clinical development, including in the design and planning of research protocols, selection of outcomes and endpoints, development of recruitment and retention strategies, and dissemination of research results. The unique perspectives afforded by patients’ lived experiences can inform researchers’ approaches and help identify knowledge gaps. By sharing their experiences of the daily burden of disease and their perspectives regarding unmet needs, therapeutic burdens, the balance of benefit and risk, and the types of research questions most important to them, patient partners can transform the clinical development process from one directed by sponsors and investigators to one driven by the needs of patients and their caregivers.

	While the concept of patients as partners in clinical research is gaining momentum, recent research points to room for improvement.

 The development and validation of partnership models to engage patients in the design and governance of clinical research programs is still in its infancy, and approaches that can ensure meaningful and effective patient participation in research are needed.

 For this reason, the Duke Clinical Research Institute (DCRI) and our research partners are exploring models of patient engagement to determine what works best for patients, their caregivers, research sponsors, and investigators, with the ultimate goal of enhancing the speed and quality of clinical research.

	In this article, we describe three different patient partnership models to help researchers evaluate which method of engagement could work best for their clinical program or study. These models integrate patients and their caregivers into the governance structure of the clinical research program or study to ensure continuous partnership throughout the project life cycle. The models of patient engagement and studies profiled include:

		Patients as advisory board members: the ADAPTABLE aspirin study and CONNECT-HF trial

		Patients as steering committee members: Industry-sponsored Phase II study

		Patients as co-investigators: the PCORnet obesity studies

	We discuss these models, the methods used to implement them, and outcomes to date. We also share lessons learned and explore future possibilities for patient engagement in clinical research. This paper is written from 

the perspective of communication professionals who work alongside research sponsors and study teams-including faculty, operations staff, researchers, clinicians, and patient advisors-to facilitate patients as partners in clinical research. We fully recognize that a commitment from all parties, including our patient partners, is necessary to a successful, lasting engagement.

	PCORnet (the National Patient-Centered Clinical Research Network) is an initiative funded by the Patient-Centered Outcomes Research Institute and is designed to build patient partnerships and harness health data to improve clinical research. PCORnet ensures that patients are directly involved in the development and execution of research by weaving requirements for patient involvement directly into the network’s governance structure. Patient members are represented on each of the overarching 

, where they play an integral role in overseeing decision-making and leadership, stakeholder engagement, PCORnet’s data network, and research partnerships.

	The DCRI serves as the coordinating center for PCORnet and also leads its first demonstration project, ADAPTABLE (Aspirin Dosing: A Patient-centric Trial Assessing Benefits and Long-Term Effectiveness; NCT02697916). A pragmatic clinical trial designed to answer an important clinical question in the “real-world” setting of patient care, ADAPTABLE is comparing the effectiveness and safety of two different daily doses of aspirin, both of which are widely used for secondary prevention of heart attack and stroke in persons living with heart disease. However, the study is also implementing a new model of patient engagement in clinical research by integrating patient partners (the 

) into the study team to provide patient voices and perspectives in all aspects of the trial. The Adaptors team is facilitated by 

, a PCORnet Patient-Powered Research Network.

 are involved in the identification and recruitment of study participants. At the onset of the study, each CDRN invited a patient to join the Adaptors team. Some Adaptors have previous clinical research experience through personal or professional experiences; all consider themselves healthcare experts through their lived experiences battling chronic diseases.

	By participating in ongoing study meetings, Adaptors hear firsthand about recruitment challenges and barriers to enrolling up to 15,000 patients in the 

ADAPTABLE study. Working with their local network researchers, Adaptors play a key role in tailoring the recruitment messages. Adaptors help develop and review recruitment materials, anticipating questions and identifying potential points of confusion. They offer input on study materials that facilitates understanding and enhances appeal to a broad audience, such as incorporating graphics and white space, reducing jargon and legalese, and using language that emphasizes the importance of clinical trials, the role of patients in the process, and the value of the patient voice in transforming healthcare. Adaptors have also contributed as authors in peer-reviewed literature.

Better health outcomes for all when patients partner with researchers 

	In addition to spreading awareness of ADAPTABLE, Adaptors are dedicated to educating others on the importance of clinical research. Their motto, 

Better health outcomes for all when patients partner with researchers

conveys how patient participation in research can help answer health questions that matter most to patients and their doctors. This motto is part of the 

, a touring art exhibit developed by Eli Lilly to honor clinical trial participants and raise awareness of clinical research.

	Through the ADAPTABLE patient-research partnership, patient partners have come to appreciate how their experiences can inform research questions, protocol design, and the collection of patient-reported outcomes. Researchers have come to understand that patients may have their own perspectives on what study outcomes or endpoints are most important. For example: an investigator might assume that the most important question to ask during a therapeutic trial is whether the intervention results in an improvement in mortality. However, a patient might be more concerned with quality-of-life issues-if they experience a stroke, will they have to live with a disability, and what will the impact on their family be?

	The Care Optimization Through Patient and Hospital Engagement Clinical Trial for Heart Failure (

; NCT03035474) is a nationwide pragmatic clinical trial funded by Novartis and coordinated by the DCRI. CONNECT-HF employs digital and quality improvement approaches to enhance care for patients with heart failure, with the goal of improving outcomes and reducing the number of hospital readmissions. The CONNECT-HF trial team worked closely with a team of patient advisers while designing the study. To establish the patient advisory group, physicians on the trial steering committee were asked to nominate patients from their practices who they felt would be engaged and interested in giving back to help others with heart failure. Although there were no official requirements for selection, the team aimed to identify advisers who had similar characteristics to the expected trial population, including a similar degree of diversity with regard to age, sex, race/ethnicity, and geographical location.

	The resulting group of eight patient advisers-the “

”-were not professional patient advocates, and most had never participated in a clinical trial. A DCRI patient engagement liaison facilitated interactions between the trial team and the Cardi-Yacks by orienting them to their roles, outlining expectations, answering questions, scheduling meetings, and conveying requests for input from the trial team. The Cardi-Yacks, in turn, offered their experiences and advice on aspects such as eligibility criteria and the follow-up phone call schedule to help researchers design a trial that would be both useful for patients and easy for them to participate in.

	An in-person meeting was organized for the Cardi-Yacks at the trial coordinating center, where they met with the project team and gave feedback on the trial enrollment process and patient-facing educational materials. The meeting included individual mock enrollment sessions with each Cardi-Yack to replicate the patient experience of enrollment. The Cardi-Yacks then participated in a facilitated focus group to provide input on the enrollment process and draft patient-facing materials that would make them more useful and patient-friendly. In addition, the Cardi-Yacks piloted patient-facing mobile applications that are part of the trial interventions and gave input directly to the application designers. The Cardi-Yacks expressed positive feelings about being partners in the trial and helping others with heart failure through their involvement. After trial enrollment began, the Cardi-Yacks continued to work with the trial team on recruitment, adherence, and retention.

	DCRI is spearheading an engagement initiative for a patient to serve as a member of a Phase II study’s steering committee. The selected individual would give input on protocol design, anticipated burden for study participants, recruitment and retention tactics, and other key areas. DCRI would be responsible for the engagement and education of this patient representative, whose views would carry as much weight as those of other steering committee members. 

	The DCRI team, working in close collaboration with the principal investigators and other study stakeholders, has developed a customized internal process according to the therapeutic area, patient population, and protocol (see table below). This customized process enabled us to establish a profile for an “ideal” patient representative, develop selection criteria, identify potentially suitable candidates, and clearly define the role of nominated persons.

	While this patient engagement initiative is still in the early stages of the nomination process, the DCRI is optimistic about the benefits the patient representative could bring to the study. The study team believes this additional layer of patient engagement could strengthen partnerships between patients and study staff, demonstrating the value of patients’ viewpoints in clinical research. It could also facilitate effective communication between the patient representative and the steering committee members. 

	In addition to the ADAPTABLE aspirin study, PCORnet is also conducting a pair of observational studies on obesity. Like many PCORnet demonstration projects, these studies require a patient or caregiver to be included as a co-principal investigator (PI).

, led by Harvard Pilgrim Health Care, examines the relationship between antibiotic use in the first two years of life and weight gain in later childhood. The parent co-PI for the study is a special education teacher and the parent of a teenage son who has experienced childhood obesity for most of his life. As a co-PI, he oversees patient engagement efforts and works to address potential barriers to patient involvement by openly discussing concerns about data security and anonymity and by creating a patient- and family-friendly glossary of acronyms commonly used within the medical community. 

, led by Kaiser Permanente Washington Health Research Institute, is building evidence on which of three different bariatric surgical procedures results in the best outcomes for specific patient communities. A church pastor, community advocate, and bariatric surgery patient herself, the patient co-PI shares her story, “

Why patients need a louder voice in medical research

,” which explores her experience of being part of an underrepresented patient community seeking bariatric surgery, the knowledge gaps that exist in the current medical literature, and the importance of patient partnership in clinical research. 

 have built strong collaborations between patients, clinicians, and healthcare system leaders. One of the unifying messages shared by both co-PIs is how they have learned that these partnerships benefit not just patients but all stakeholders-everybody wins. The model has demonstrated the power of patients’ unique voices when they are thoughtfully integrated into the fabric of decision-making and governance. PCORnet and the DCRI plan to continue to share news on patient engagement strategies, best practices, and lessons learned, highlighting personal stories from throughout the PCORnet partner networks and studies.

The future of patient engagement in research

	The DCRI has been exploring approaches to patient engagement for some time. Large-scale initiatives with DCRI involvement, such as PCORnet, have been characterized by extensive partnerships with communities and individuals to shape, inform, and improve research design and conduct.

	More recently, the DCRI appointed Bray Patrick-Lake, MFS, as director of stakeholder engagement in June 2017. A former trial participant who later became a patient advocate, Patrick-Lake led a multi-stakeholder team of experts from industry, academia, patient groups, the NIH, and the FDA to develop 

Best Practices for Effective Engagement with Patient Groups around Clinical Trials

 for the Clinical Trials Transformation Initiative (CTTI). She also developed successful patient engagement models and strategies for PCORnet studies, co-chaired the Advisory Committee to the NIH Director responsible for authoring the vision of the Precision Medicine Initiative Cohort Program (now called 

), and served as the interim director of engagement during the program’s pilot phase. Under her leadership, DCRI faculty, investigators, and operational teams are working to institutionalize a set of guiding principles for involving patients as partners in clinical research (see table).

	The DCRI is working to catalyze the adoption of a gold standard of partnership with patients in research design, conduct, oversight, and dissemination, while raising the bar on participant experience in research. Although including patients in the governance of clinical studies is just one approach to advancing patient partnerships in clinical research, we have found it to be an effective tool for supporting high-quality, efficient, patient-centered research. Patient input in clinical research has many potential benefits, such as making it possible to achieve higher rates of retention and compliance through enhanced value and improved participant experience; improving data quality by minimizing patient dropout and enhancing participant adherence to protocol; and inspiring scientists to pursue research opportunities and approaches that might not have been obvious. Finally, we anticipate that continuous patient input could drive more rapid research innovation cycles and accelerate the development and appropriate scaling of novel methods and tools. Effectively integrating patient partners into clinical research requires thoughtful approaches and bidirectional learning. Their participation throughout the clinical development life cycle is proving invaluable to improving clinical studies and forging new paths in biomedical research.

Associate Director, Clinical Research Communications; 

Clinical Research Communications Specialist; 

Clinical Research Communications Manager; 

Clinical Research Communications Specialist; and 

Clinical Research Communications Specialist, all with Duke Clinical Research Institute (DCRI)

* The authors would like to acknowledge the following individuals for their leadership in implementing the models of engagement profiled in this paper: Adrian F. Hernandez, MD, MHS; Matthew T. Roe, MD, MHS; William Schuyler Jones, MD; Holly Robertson, PhD; Madelaine Faulkner, MPH; the Adaptors; Jane Anau, BS; David Arterburn, MD, MPH; Jason Block, MD, MPH; Doug Lunsford; Juliane Reynolds, MPH; Neely Williams; Beth Martinez, PMP; Adam DeVore, MD; Linda Davidson-Ray; Tracy Hofmann; Renee Leverty; the Cardi-Yacks; and Susan Landis. 

	1. Calaprice-Whitty D, Byrne J, Gilbert J. Bridging the gap for better patient engagement. 

http://www.appliedclinicaltrialsonline.com/bridging-gap-better-patient-engagement

	2. Domecq JP, Prutsky G, Elraiyah T, et al. Patient engagement in research: a systematic review. 

	3. Hernandez AF, Cruz HP. Engagement, research, and evidence: Leveraging the National Patient-Centered Clinical Research Network for better cardiovascular health. 

Exploring three distinct patient partnership models to help researchers assess which methods of engagement could work best for their clinical programs.

Models of Engagement: Patients as Partners in Clinical Research

	In the earliest days of science, researchers thought that if you had cancer, you just had cancer. Then, as classifications evolved, they thought if you 

had lung cancer, you just had lung cancer. But now, advanced molecular profiling has necessitated a more complex analysis: You not only have lung cancer, you have EGFR mutated, KRAS mutated, or ALK gene rearrangement non-small cell lung cancer.

	Welcome to the driving force behind the precision medicine movement. We’ve taken a general disease, narrowed that down to a specific disease classified by its organ of origin, and further classified the cancer by one or more defining genomic defects.

	The process has turned the term “rare cancers” on its head. You might not consider lung cancer, which is diagnosed in 234,030 patients a year, a rare cancer. But what about ALK+ nonsmall cell lung cancer, which is diagnosed in just under 10,000 patients every year?

	Because those 10,000 patients have a specific type of lung cancer, they don’t respond to the standard treatments that work for most people. Instead, they need drugs made specifically for their genomically defined cancer.

	The same thing goes for those who have other cancers few people have heard of, like small intestine cancer, which also affects about 10,000 people a year. Small intestine cancer is a “rare cancer,” but so are certain types of more commonly diagnosed cancers-because cancer “rareness” means more than cancer incidence. It’s about the molecular makeup of each tumor.

	That’s why the future of research for any cancer is entirely, and unequivocally, molecular. Drugmakers have caught on-and it has changed the calculus for cancer research.

	Investigators should no longer pack as many patients as possible into a global clinical trial just to find responses to a new medicine in a few patients. Instead, they need to identify patients whose cancers share molecular defects, and match those molecular defects with a medicine that targets that particular defect.

	You might think that finding very specific people with very specific diseases slows down research. And in a way, it can…at the start.

	But here’s the reality: Targeted clinical trials yield the most dramatic results. When tumors rely on a single genetic mutation, medicines that target those mutations see response rates as high as 100%.

	And if you’re a drugmaker, clinical investigator, or patient, once a new medicine makes headlines touting its benefit in nine of 10 patients, any slowdown is quickly reversed. People get excited and there is a singular focus on getting the medicine approved quickly by the FDA.

	Then, it’s not about finding the right patients-the right patients find the right medicines.

	That’s what happened with Gleevec, the milestone drug that marked the first step in molecular

	profiling. Built for patients with chronic myeloid leukemia (a rare subset that affects about 10% of leukemia patients), Gleevec saw an 88% response immediately. These were the patients for whom other drugs had failed.

	In many of these cases, you don’t need a lot of patients to respond in order to get a drug approved. They’re rare cancers, after all. This kind of drug discovery means that researchers can spend less time in development, get their drugs approved faster, and start helping patients immediately. It just requires a sound clinical strategy that targets the right people.

	When I think of the impact that one small change could make on the lives of patients, it gives me hope. I think of patients with uveal melanoma, which has zero drugs approved for treatment. I think of patients with fibrolamellar hepatocellular carcinoma that impacts young adults and has no drugs approved for treatment.

	Each is a rare cancer in its own right. Each has known molecular or genetic defects. We need to

	find the right drugs to match to these cancers. Precision medicine provides physicians with the opportunity to avoid less effective treatments and focus on rationally selected medicines that improve clinical outcomes for patients. 

A Closing Thought

With more common cancers now increasingly broken down by specific genomic defects, the future of research for any cancer is entirely, and unequivocally, molecular.

Any Cancer Can Be a 'Rare Cancer'

Antibodies, also called immunoglobulins (Igs), are large proteins used by the immune system to identify and neutralize foreign objects such as bacteria and viruses. Several monoclonal antibody (mAbs) drugs have been approved, or are at the late stage of clinical development within various therapeutic indications. The amount of mAbs making it to the market will continue to increase thanks to their characteristics, including good solubility and stability, long persistence in the body, high selectivity and specificity of action, and low risk of toxic metabolites.

	However, mAbs still have complex pharmacokinetic (PK) and pharmacodynamic (PD) properties compared to small chemical molecules. These include poor bioavailability, slow distribution, both linear- and non-linear elimination processes, and other factors influencing PK and PD such as immune reactions/immunogenicity.

	Before planning a first-in-human (FIH) study, robust preclinical data should be available providing sufficient insight into the full PD pathways, and used to select the most appropriate animal species from both PK/PD and safety considerations. Challenging steps in designing FIH studies with mAb drugs, therefore remain, and the appropriate selection/exclusion criteria of healthy volunteers, a carefully selected safe and appropriate starting dose; the choice of dose escalation steps to achieve the goal of FIH study; the planning of sufficient and correct follow-up procedures; and the safety monitoring necessary, considering both the short term site related reactions and delayed PD effects.

	In addition, due to incidents in the past, authorities look more rigorously toward mAbs, considering many of them as high-risk medicinal products. A sound early clinical development plan, including appropriate justifications, might help regulatory bodies with their evaluation of what they view as high risk.   

	Initial monoclonal antibody drugs were generated from mouse and rat hybridomas, and these first-generation antibodies had only limited clinical success because of their short half-lives and high immunogenicity. Several approaches have been developed to humanize these rodent antibodies, and technological advances during the past four decades have allowed mAbs to be developed and produced at commercial scale. The FDA and the European Medicines Agency (EMA) have approved many mAbs in various therapeutic areas, and it is estimated that several hundred mAbs are currently in development.

	As noted above, (PK/PD) analyses are essential steps in the early drug development process. Antibody drugs often exhibit PK/PD properties that are much more complex than those typically associated with small-molecule drugs (i.e., organic compounds with molecular weight <1,000 Da).

	Most of the marketed antibodies are labeled for intravenous administration, but several mAbs are under development or have been approved for intramuscular or subcutaneous injections. The subcutaneous route is of growing interest as an administrative method, however, factors affecting the bioavailability, such as catabolic first-pass clearance, subcutaneous transport processes, and translation of subcutaneous animal data to humans require further research.

 Oral administration of mAbs for systemic therapy is not indicated, because of their size, polarity, and gastrointestinal degradation, which preclude adequate bioavailability.

	The bioavailability of mAbs after intramuscular or subcutaneous administration varies between 50% and 80%.

 As a rule, after subcutaneous administration, biologicals with molecular weight >16kDa are largely absorbed into the lymphatic system (slow absorption rate), while those <2kDa are absorbed into the blood circulation.

mAbs and their derivative drugs are large biologicals with a molecular weight of around 150kDa; therefore, after intramuscular or subcutaneous injection, absorption of these drugs into the lymphatic system proceeds slowly, and the time to reach maximal plasma concentrations typically ranges from two to eight days.

	There is a relatively new interest in the development of aerosolized mAbs for pulmonary delivery, as the lungs have a very large surface area and a high perfusion rate. In addition, pulmonary epithelial cells are known to express neonatal Fc-receptor (FcRn), which may facilitate efficient systemic absorption of antibody delivered to the lung. However, similar to, or even more than, intramuscular or subcutaneous administration, the feasibility of pulmonary delivery of mAbs is limited to those with very high dose potency, as only small volumes of fluid can be administered.

	Analysis of antibody distribution is much more complicated than the analysis of the distribution of most small molecule drugs. mAbs are often designed to bind with high affinity to tissue sites containing the target antigen; however, because of their large size and hydrophilic nature, they have a slow distribution to peripheral tissue.

 Unlike small molecules, the paracellular movement of biologics is mainly via convective transport instead of passive diffusion.

	Higher mAb concentrations have been observed in body tissues that are highly perfused with relatively leaky vascularization such as the spleen, liver, and bone marrow; but very little distribution to the brain. This may be because of the blood-brain barrier with its “tight junctions,” the rapid turnover of brain intestinal fluid, or potentially because of the active involvement of the FcRn in mAb efflux from brain tissue.

Experimentally, and by using a physiologically-based PK (PBPK) model, the tissue to blood ratio of mAbs was estimated to be in the range of 0.1 to 0.5, but only 0.02 for the brain.

	If the target of the mAb is localized in tissue, slow and/or low distribution to tissue from the systemic circulation may be an obstacle to achieving clinical responses. Alternatively, antibody fragments, consisting of only an antigen-binding part (Fab fragments) or single-chain variable fragments, can cross the blood-tissue barrier more easily and, hence, are less hindered by this “binding-site barrier” and poor distribution compared to intact mAbs.

	Additionally, for macromolecular protein drugs such as mAbs, it is likely that a significant fraction of drug elimination occurs from tissue sites that are not in rapid equilibrium with plasma. In such situations, non-compartmental analysis of plasma data will lead to an underestimation of the distribution volume (V

). When significant drug elimination occurs from “peripheral compartments,” it is not possible to obtain precise estimates of V

 from analysis of plasma data alone. Plasma concentrations may be used to define the range of possible values for the distribution volume, but the determination of tissue concentration by biopsies or imaging techniques would provide more insight into distribution.

	Because of their molecular size, mAbs are not generally excreted into urine, but are metabolized to peptides and amino acids that can be re-used in the body for the 

 synthesis of proteins, or are excreted by the kidney. A few mAbs with a molecular weight <69 kDa are mainly cleared by renal excretion, and thus the clearance of these biologics can be compromised in patients with renal impairment.

 Several elimination mechanisms are reported to be involved in mAbs elimination, of which the three most commonly observed are proteolysis by the liver and the reticuloendothelial system, target-mediated elimination, and nonspecific endocytosis.

	First, phagocytic cells such as macrophages and monocytes are expected to play a role in the elimination of mAbs, as they are also key factors in the elimination of endogenous IgG. Internalization and subsequent degradation of IgG by lysosomes in these cells occurs predominantly after binding of the Fc part of the antibody to Fcg-receptors expressed on these cells.

	A second elimination route is degradation of the mAb within the target cell after internalization and subsequent intracellular degradation in its lysosomes. For mAbs targeting an antigen located on cells, degradation by target cells after binding of the Fv-part to the target antigen (target-mediated elimination) is probably the most important elimination route. As this route is saturable as a result of the confined amount of target antigen, non-linear elimination has often been reported for mAbs.

The rate of uptake and elimination of antibodies by target-mediated pathways is a function of dose, the expression level of the target, the kinetics of receptor internalization, and intracellular catabolism.

	Finally, mAbs may also be taken up into cells in different tissues by non-specific pino- or endocytosis. After uptake in the slightly acidic environment of the endosomes in endothelial cells, the immunoglobulins bind to the FcRn. After binding, the IgG-FcRn complex is transported back to the cell surface, where it is released again into the circulation. In contrast, unbound IgG is degraded into amino acids by lysosomes present in the cell.

 In the absence of target-mediated drug clearance, most IgG-based mAbs exhibit long half-lives, typically three or four weeks, mainly as a result of FcRn-mediated antibody recycling.

	Another distinction between small molecules and biologics is that biologics can be immunogenic, leading to the formation of neutralizing anti-drug antibodies (ADA). It has been shown that the change in elimination rates resulting from immunogenicity may be either increased or decreased, depending on the number of sites on the therapeutic mAb that the endogenous anti-mAb are directed against. Because of individual differences in the immune response to mAb administration, it is difficult to predict how immune response influences the elimination rate of therapeutic mAbs and whether a change in the elimination rate has clinical implications.

The degree of humanization, route of administration, duration of therapy, and dose level can also impact immunogenicity.

	A complication with any ADA response found in preclinical species is that it does not accurately predict the ADA response in humans. Therefore, it is essential to assess the ADA response in FIH studies and evaluate this information with respect to its impact on PK and/or PD, when possible. If there is an effect on PK (and related to that to PD), it is frequently that the elimination of the affected mAb drug is increased, resulting in a reduced systemic exposure; this additional clearance pathway should be considered when establishing a PK or PK/PD model, and when designing the further clinical evaluation studies.

	Since the 1980s, mAbs are increasingly being incorporated into clinical practice as therapeutic options, particularly in oncology and immunology, and several are still under development. While these targeted therapies are predicted to be highly selective and specific, protein-based drugs such as mAbs, like all drugs, can have unpredictable safety profiles.

	One of the reasons for the revised EMA guidance released in 2007 was a FIH trial in 2006 with a new mAb drug.

 All subjects receiving the first dose of active drug TGN1412, a superagonist mAb against CD28, developed a life-threatening, severe adverse reaction, caused by an uncontrollable cytokine release. The maximum recommended starting dose (MRSD) was, nevertheless, determined by the conventional allometric approach from the no-observed adverse effect level (NOAEL) with a large safety factor of 160, resulting in 0.1 mg/kg. However, when using the receptor occupancy to reinvestigate this dose, it was found that 0.1 mg/kg would elicit greater than 90% receptor occupancy. So, in this situation, not only was the pharmacodynamic effect unacceptably high, producing a cytokine storm, the increased receptor occupancy could also have altered the pharmacokinetics of the antibody by decreasing its clearance, thereby further increasing the peak concentration and prolonging its effect.

	This tragic incident highlighted the importance of, and difficulties in, selecting the safest MRSD in FIH studies with mAbs. One of the lessons learned from this tragedy is that once receptor occupancy starts to increase, the PD and PK response to further dose escalations becomes non-linear. The TGN1412 incident led to the recommendation that the MRSD should also be calculated based on the minimal anticipated biological effect level (MABEL). It is important to determine in preclinical studies whether target-mediated elimination occurs, which should be considered when deriving the MABEL.

	MABEL is useful for protein drugs because it defines a dose at which receptor occupancy is low. Per the revised EMA guideline, the FIH doses need to be calculated from both NOAEL and MABEL, and the lowest value is recommended for the clinical trial.

For biotherapeutics, such as mAbs, with potential agonistic modes of action on key body systems, no more than 10% receptor occupancy is proposed as starting dose in a FIH trial.

Outlining the unique pharmacokinetic factors that should be considered when designing and running early stage clinical trials for monoclonal antibodies.

Applied Clinical Trials-06-01-2018

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Hope. The Power for the Rare Disease Journey

Clinical Design: A Deep Dive

Clinical Trial Evolution: A CRO’s Perspective

Patient Experience Moves to Center Stage in Medical Product Development

Models of Engagement: Patients as Partners in Clinical Research

Any Cancer Can Be a 'Rare Cancer'

Monoclonal Antibodies: Clinical Pharmacology Keys

The Need and Opportunity for a New Paradigm in Clinical Trial Execution

Policy and Practice Come Together on EU Vaccine Thrust

Applied Clinical Trials, June 2018 Issue (PDF)

Enrollment Cycle Times Can and Should Be Optimized