The November issue of TRI’s newsletter, The TRIbune, is now available. This issue features our clinical trials services, our promotion of health sciences innovation and entrepreneurship, KL2 Awardee Ling Gao, M.D., Ph.D., published in the NEJM, and TRI-cited publications.
TRI is pleased to be able to offer Mock Study Sections for any researcher seeking review of an external grant application. Reviews are available for laboratory, animal and human
participant study proposals. New submissions and resubmissions will be considered. Interested researchers can request a Mock Study Section through the TRI Portal (TRIServices@uams.edu) and should submit draft copies of their proposal, budget, and biosketch, as well as comments from a previous submission (if applicable). The request deadline for review of February proposals is Dec. 4, 2015.
Mock Study Sections are intended to be learning experiences and investigators should plan to be present. Collaborators are also encouraged to attend. Participating investigators will be expected to provide TRI with follow-up information on grant submission outcomes, scores and funding awards.
Dec. 3, 2015 | The Medicare National Coverage Determination (NCD) for Clinical Trials outlines items and services that are not billable to Medicare. These include “items and services customarily provided by the research sponsors free-of-charge for any enrollee in the trial.” The NCD provides no further clarification for this language.
Historically UAMS has not negotiated when a sponsor offered to pay for an item or service; as a result that offer was accepted as a term of the final agreement. An item or service that is paid by the sponsor is not billable to Medicare and must be designated “research,” even if it would otherwise be considered conventional care.
Based upon a recent review of our process with the Office of Institutional Compliance, UAMS has determined that the sponsor’s offer to pay for such items and services is merely a part of the overall negotiation of the final clinical trial agreement. A number of statements, FAQs, and other language from CMS was analyzed as a part of this review, including the following from a proposed replacement Clinical Trial NCD: “Medicare does not cover usual patient care when such care is provided free to the Medicare beneficiary or when the study sponsor agreement with investigator sites or the informed consent documents provided to the patient specify that the care will be provided free to participants (§1862(a)(2); 42 CFR 411.4).”
Accordingly, investigators will be able to use the sponsor exhibit as a guide in negotiations rather than something that must be accepted exactly as written. However, once negotiations are complete and the contract is signed, the final signed contract must be followed exactly as written. Once signed, these items will be analyzed as they have been, according to language in the contract, protocol and consent.
The TRI Research Finance Team will now perform coverage analyses in which they initially do their analyses based on the protocol, consent, sponsor exhibit and CTA. However, the team will also provide notes regarding any item or service subject to a proposed sponsor payment that may be billable to Medicare or other payors as conventional care. The research team will have this information available for their negotiations with the sponsor. The final coverage determination for items and services will occur upon completion of the signed clinical trial agreement.
Caveat:
One issue has arisen under this new approach. Billing rules may limit a sponsor’s ability to pay for various activities that occur during certain visits or procedures. For example, where a visit/procedure is bundled, that is, where the services may not be itemized individually for payment, neither the sponsor nor UAMS may pick and choose which items can be invoiced to the sponsor and which can be billed as routine care. The TRI Research Finance Team will identify these instances for investigators as part of the coverage analysis.
For any questions related to this new approach please contact Kennetha Newman, TRI program coordinator, at 501-526-7665.
Oct. 22, 2015 | Behind the headlines of his breast cancer vaccine, now in a phase II clinical trial, UAMS’ Thomas Kieber-Emmons, Ph.D., tells a back story that inspires him and even draws applause from colleagues.
Kieber-Emmons peppers the story with some significant numbers: 1, 6, 28, 1,500, 4,000. The story begins in 2005 with 1, meaning Kieber-Emmons’ first-in-man, computer-designed vaccine. No researcher at UAMS had developed such a vaccine or attempted the mammoth effort to deliver a synthesized product that could be safely tested in humans.
“This is not for the faint of heart,” he said.
In addition to required preclinical safety/toxicity studies mandated by the FDA, which were firsts in their own right at UAMS, requiring a rethinking of how the institution viewed such studies, Kieber-Emmons sought assistance within UAMS to prepare his investigational new drug (IND) application for the FDA. A meeting was arranged with the then-Research Support Center, now the Office of Research Regulatory Affairs.
“There were 28 people there,” he recalled, shaking his head in amazement. “My first thought was, ‘why 28?’ So many people were part of this story, and it turns out they all had a meaningful role to play. It really did take a village.”
Having joined UAMS from the University of Pennsylvania, which has a much larger biomedical research enterprise, Kieber-Emmons was astonished that UAMS had such expertise. His previous employer would have had to hire a contract firm to handle what UAMS did by itself, he said. “It’s just phenomenal. The resources that UAMS brought to this is big-time.”
Still, getting his vaccine discovery into a form that could be tested in humans tested the limits of UAMS’ research resources, said Larry Parker, a mainstay on the project as Quality Assurance Unit manager for the Office of Research Regulatory Affairs.
“We were stretched to pull it off,” he said. “There are a lot of wheels and gears that have to be moving in the right direction to do this kind of stuff.”
Other key staff included Carole Hamon, Regulatory Affairs Unit Manager (retired, 2014), and Raymond Anderson, Quality Assurance Unit manager (retired, 2009).
In addition to numerous meetings with FDA staff, there were weekly meetings involving Kieber-Emmons and UAMS staff as they worked to meet the agency’s extensive safety requirements. Their work included writing 97 standard operating procedures (SOPs) that required the agency’s approval.
The IND application, submitted in 2011, was more than 1,500 pages, the largest IND application ever submitted by UAMS. Of all the numbers in Kieber-Emmons’ story, six may be his most prized; that’s how many questions the FDA posed after its review of the application.
“I’m almost more proud of that than the results of the vaccine, which is doing very well,” Kieber-Emmons said. “Other investigators are just amazed when I tell them there were only six questions; people clap.”
The FDA’s questions were received by Kieber-Emmons late on a Friday, and he and staff went to work that weekend drafting their responses, which went in the mail on Monday.
The experience speaks to the quality of people at the Office of Research Regulatory Affairs, he said.
“Our research support people know what they’re doing and they are very careful, so I love them, and I think they’re just the best,” he said.
The vaccine proved to be safe in a phase I trial. The phase II trial is examining if the vaccine improves the efficacy of preoperative chemotherapy. The trial includes women who are newly diagnosed with breast cancer to determine if the combination of vaccine and standard chemotherapy improves the benefit from preoperative therapy.
The heavy workload on Kieber-Emmons’ project continues for the UAMS Office of Research Regulatory Affairs. Annual reports, adverse event reporting and annual product stability testing are all part of the project’s management. Parker’s work, Kieber-Emmons said, includes working closely with the company that manufactures the vaccine, another company that tests the manufacturing process and a third company that is putting the vaccine into vials.
In his quality assurance/project management role, Parker has been the UAMS contact with these three companies. His job has included planning of testing protocols, manufacturing/testing timelines, review and approval of batch records, product labels, and testing reports. He organizes all the product information from the companies into a format required by FDA for submission.
Parker notes that he has more than 4,000 emails specific to the project dating to March 2006, and several people in his office have in excess of 1,000 emails for the project.
“We’re in the process of filing the fifth complete version of the Chemistry Manufacturing and Control (CMC) section of the IND,” Parker said. “Each of these versions has been in excess of 450 pages, and the current revision is in excess of 600 pages. This doesn’t include the filing of all protocol amendments and annual progress reports to the IND. Needless to say, we’ve killed a few trees to keep this IND up to date with FDA.”
The Office of Research Regulatory Affairs currently manages 15 active INDs that include 20 current clinical trials and 15 investigational device exemptions (IDEs). Parker urges researchers to call his office if they are planning regulated research such as for new drugs or devices.
“Call us sooner rather than later,” he said. “The later we’re involved, the more work the researcher has to redo.”
The Office of Research Regulatory Affairs can be reached at 501-526-6876.
The Patient Centered Outcomes Research Institute (PCORI) has released a series of six free CME/CE activities on its methods standards for patient-centered outcomes research. The CME/CE modules are available for viewing at: http://www.pcori.org/research-results/cmece-activities. Researchers who wish to seek funding from PCORI will want to know about these new standards. Led by highly qualified faculty, these CME/CE modules include the PCORI Methodology Standards recommendations for researchers on best practices for conducting patient-centered outcomes-oriented clinical research.
The number of AMA PRA Category 1 Credits™ are listed with each of the online activities below. All other partnering entities’ credit designation information (physician assistants, nursing, pharmacy) can be found in the Accreditation/Credit Designation statement for each individual activity.
These activities are approved for AMA PRA Category 1 Credits™.
Oct. 15, 2015 | Identifying a patient’s genetic mutation led University of Arkansas for Medical Sciences (UAMS) physician-researcher Ling Gao, M.D., Ph.D., to an existing drug that eliminated the patient’s stage IV Merkel-cell carcinoma. Gao’s findings, made in collaboration with two other UAMS researchers, were published today in The New England Journal of Medicine.
Gao is a recipient of the UAMS Translational Research Institute’s (TRI) KL2 Mentored Research Career Development Scholar Award, which provided two years of research funding and translational research training.
Metastatic Merkel-cell carcinoma is often fatal and there is no effective treatment. Gao’s 86-year-old female patient was diagnosed in 2013 with stage IIIB Merkel-cell carcinoma of the right temple. She had surgery and received radiation therapy in May 2013 and additional surgery in July 2014. In November 2014, doctors confirmed that the cancer had metastasized.
Gao, a dermatologist who treats Merkel-cell carcinoma patients from Arkansas and surrounding states, performed genetics tests on the tumor that revealed multiple mutations, including PI3Kδ.
Gao was aware that the drug idelalisib is a novel PI3K pathway inhibitor approved by the Food and Drug Administration (FDA) for treatment of B-cell lymphoma, a cancer of the blood. She was also aware of recent studies showing that disruption of the PI3Kδ mutation allows the body to mount an effective antitumor immune response.
On the basis of her laboratory work and knowledge of idelalisb, Gao began treatment of the patient with the drug on Feb. 6, 2015.
Three months after administering the idelalisib, there was no sign of the tumor in the patient’s liver, Gao said. Her findings were published in the Journal in a letter to the editor.
Based on what she’s learned, Gao said the case can be made for further study of PI3Kδ inhibitors like idelalisib in solid tumors, not just blood cancers.
“The efficacy of idelalisib in our patient provides initial clinical evidence that the targeting of PI3Kδ in Merkel-cell carcinoma is warranted,” Gao said in the letter, which was also signed by UAMS’ Fade Mahmoud, M.D., and Mallory B. Shiver, M.D.
Gao also credits support she received from Peter Emanuel, M.D., director of the UAMS Winthrop P. Rockefeller Cancer Institute, and James Suen, M.D., chair of the Department of Otolaryngology-Head and Neck Surgery in the UAMS College of Medicine.
View the article and accompanying PET-CT findings here.
Gao’s research has been supported by the UAMS Translational Research Institute through the National Institutes of Health National Center for Advancing Translational Sciences, the Department of Dermatology in the UAMS College of Medicine, UAMS Winthrop P. Rockefeller Cancer Institute, and the Arkansas Biosciences Institute.
UAMS’ Aliza Brown, Ph.D., recently received a nearly $200,000 Genentech stroke research award after she incorporated ideas in her application from the first TRI Research Forum in June 2014.
The grant was one of only three community stroke pilots funded by Genentech in the United States. The study will enable Brown to determine paramedics’ recognition of stroke and whether stroke patients are being taken to stroke-ready hospitals. In addition, she is developing an educational video for paramedics in partnership with the UAMS-led Arkansas SAVES (Stroke Assistance through Virtual Emergency Support) telestroke program and the Arkansas Department of Health’s Arkansas Stroke Registry.
Her hope is that the study will provide data to support state sanctioned stroke guidelines and practices for emergency medical services.
“The Department of Health is very interested in this project because this will help promote legislation for the stroke guidelines and to create a stroke dashboard to guide EMS agencies to the appropriate hospitals,” Brown said.
Brown, an assistant professor of radiology, joked that she was TRI’s first Research Forum “guinea pig.” The forums include established researchers and biostatisticians who provide feedback on investigators’ grant applications.
“The forum panel was excited about the application and said it was very translational,” Brown said. “They gave me some great advice. I learned a lot and I got a pretty good grant out of it.”
A key recommendation came from Jean McSweeney, Ph.D., R.N., professor and interim dean of the College of Nursing. “Dr. McSweeney suggested that the study include utilization of the Simulation Center and an educational intervention, so I did that,” Brown said.
Her study will validate the educational intervention – a training video – by measuring Pulaski County paramedics’ stroke recognition rates following training. Garland County EMS will serve as the control, where EMS workers will not receive the training video and whose stroke recognition rates will be followed concurrently.
“I hope that this study can provide data the state needs to make these stroke guidelines a reality,” Brown said.
To date, TRI has hosted nine Research Forums. To request a forum, email TRIservices@uams.edu.
Representatives from the National Institutes of Health (NIH) Clinical and Translational Science Awards (CTSA) Program and patient advocacy groups are collaborating to host four national one-day meetings in October and November to seek comment on proposals to better protect human subjects while facilitating valuable research and reducing burden, delay and ambiguity for investigators.
These meetings follow the Sept. 8, 2015, Notice of Proposed Rulemaking (NPRM) on the Federal Policy for the Protection of Human Subjects, which was promulgated as a Common Rule in 1991. The NPRM was released by federal agencies including the U.S. Department of Health and Human Services.
The goals of these meetings are to:
Attend via live webinar or join one or more of the following scheduled meetings in person:
o Nashville, TN
o Date: October 14, 2015
o Location: San Diego, CA
o Date: October 29, 2015
o Location: Chicago, IL
o Date: November 5, 2015
o Location: Philadelphia, PA
o Date: November 18, 2015
Submitted on Sept. 25, TRI’s 1,263-page renewal application for a Clinical and Translational Science Award (CTSA) was made possible thanks to the dedication of faculty and staff across UAMS and its affiliated institutions, said TRI Director Laura James, M.D.
“Faculty reviewers and writers from across all colleges tackled this project in a spirit of teamwork that allowed us to develop the strongest possible application,” James said. “This was a cross-college, cross-department, cross-institution effort that involved basic scientists, clinical researchers, community engagement researchers, etc.”
Reviewers were Larry Cornett, Ph.D., Charlotte Hobbs, M.D., Ph.D., Donald Mock, M.D. Ph.D., Mike Owens, Ph.D., Paula Roberson, Ph.D., and Nancy Rusch, Ph.D. This group’s work included nine two-hour meetings. Other major contributors to the review group were DeAnn Hubberd and Peggy Brenner from the UAMS Office of Grants and Scientific Publications (OGSP).
Meanwhile, Mary Aitken, M.D., Pedro Delgado, M.D., and Rusch spent countless hours writing the application’s two training components, James said.
Other primary writers were Beatrice Boateng, Ph.D., Barry Brady, Mathias Brochhausen, Ph.D., Cornett, Geoff Curran, Ph.D., Gloria Richard-Davis, M.D., Ellen Fischer, Ph.D., Kristie Hadden, Ph.D., Hobbs, Laura Hutchins, M.D., Greg Kearns, Pharm.D., Ph.D., Brad Martin, Pharm.D., Ph.D., Pearl McElfish, Ph.D., Jean McSweeney, Ph.D., R.N., Mock, Pope L. Moseley, M.D., Alison Oliveto, Ph.D., Owens, Tamara Perry, M.D., Fred Prior, Ph.D., James Raczynski, Ph.D., Paula Roberson, Ph.D., Kate Stewart, M.D., M.P.H., Dennis Sullivan, M.D., Billy Thomas, M.D., and Pam Williams, Ph.D.
Valuable expertise was contributed by Hari Eswaran, Ph.D., as well as Barry Brady and Phaedra Yount from the Arkansas Children’s Research Institute (ACRI), and OGSP staff. TRI’s staff was critical to the process, James said, including Pamela Christie, Amy Jo Jenkins, Donna Mattingly, Anthony McGuire, and Laura Wilson, and many others who provided information for the grant.
If the application is successful, UAMS will receive about $24.4 million over five years. The CTSA Award is funded by the National Institutes of Health (NIH) National Center for Advancing Translational Sciences (NCATS).
Over the next two months, the UAMS Office of Research Compliance is offering face-to-face classes as part of the Certified Research Specialist Program. Class participation can also be used to obtain Society of Clinical Research Associate (SoCRA) credit. TRI is co-sponsoring these activities by providing WebEx broadcast capabilities, making them available to anyone who wants to participate. You may register for these classes under Research Education Q&A. Please feel free to attend even if you do not register. Contact: Catrice Banks-Johnson crbanksjohnson@uams.edu, (501) 526-6879. Class and WebEx details are below.
Developing a Research Protocol
Date: Wednesday, October 21, 2015
Time: 12:00 PM – 2:00 PM
Presenter(s): Michael Bailey
Location: IDW 105A/B
| Meeting number: 807 541 525 Join by phone +1-855-749-4750 US TOLL FREE |
| +1-415-655-0001 US TOLL |
| Access code: 807 541 525 |
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Information Quality – Module 1: Principles of IQ
Date: Thursday, October 22, 2015
Time: 2:00 PM – 3:00 PM
Presenter(s): Dr. John Talburt
Location: IDW 115A
| Meeting number: | 803 271 381 |
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Protocol Deviations
Date: Monday, October 26, 2015
Time: 2:00 PM – 3:00 PM
Presenter(s): Darri Scalzo
Location: Walton Auditorium (Cancer Institute)
| Meeting number: | 801 659 882 |
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Reportable New Information and the IRB
Date: Wednesday, October 28, 2015
Time: 1:00 PM – 2:00 PM
Presenter(s): Edith Paal
Location: IDW 105A/B
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Advanced Research Ethics
Date: Friday, November 6, 2015
Time: 8:00 AM – 12:00 PM
Presenter(s): Dr. Micah Hester
Location: IDW 105A/B
| Join WebEx meeting | Meeting number: | 808 347 913 | Join by phone | +1-855-749-4750 US TOLL FREE | +1-415-655-0001 US TOLL | Access code: 808 347 913 | Global call-in numbers | Toll-free calling restrictions | ||||||||||||
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Writing Standard Operating Procedures
Date: Tuesday, November 10, 2015
Time: 11:00 AM – 1:00 PM
Presenter(s): Larry Parker
Location: IDW 115A
| Meeting number: | 805 263 225 |
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Research Misconduct
Date: Friday, November 13, 2015
Time: 11:00 AM – 1:00 PM
Presenter(s): Dr. Micah Hester
Location: ED II 8/121
| Meeting number: | 806 805 379 |
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