New clinical trial data sharing requirements for publications: comment period opens

The International Committee of Medical Journal Editors (ICMJE) is proposing changes in clinical trial data sharing requirements for publishing. The new rules would require investigators to include data sharing plans, and share de-identified data. The ICMJE is currently accepting feedback through their website (www.icmje.org). Changes will go into effect one year after formal adoption. The ICMJE defines a clinical trial as “any research project that prospectively assigns people or a group of people to an intervention, with or without concurrent comparison or control groups, to study the cause-and-effect relationship between a health-related intervention and a health outcome.”

Data sharing plans: When studies are registered in a database like clinicaltrials.gov, a data sharing plan will need to be included. Clinicaltrials.gov allows posting of such information. This requirement would need to be completed prior to the first participant being enrolled, a time when you may not necessarily know in which journal you will publish your work.

Data sharing: When a manuscript is accepted for publication for a clinical trial, the raw de-identified individual participant data will need to be shared within six months. This includes any data that was used to generate tables, figures, and appendices or supplementary material. In addition, when the manuscript is submitted for review, authors will be required to explain how the de-identified participant data will be shared.

The ICMJE also proposes certain safeguards to protect investigators: “First, ICMJE editors will not consider the deposition of data in a registry to constitute prior publication. Second, authors of secondary analyses using these shared data must attest that their use was in accordance with the terms (if any) agreed to upon their receipt. Third, they must reference the source of the data using a unique identifier of a clinical trial’s data set to provide appropriate credit to those who generated it and allow searching for the studies it has supported. Fourth, authors of secondary analyses must explain completely how theirs differ from previous analyses.”

Journals that belong to ICMJE include the Annals of Internal Medicine, the Lancet, the New England Journal of Medicine, JAMA and PLOS Medicine, just to name a few. Many other journals follow ICMJE publishing requirements.

Proposed “Common Rule” changes could stifle research; Jan. 6 deadline for feedback

SteveDewhurstProposed changes to the federal regulations that protect those who participate in research are aimed at improving the protection of human subjects, but researchers fear the adjustments could stifle human subject research and, ultimately, progress against preventing and treating disease. Changes to the regulations known as “The Common Rule” would complicate consent requirements for the secondary use of biospecimens and data, and mandate  single IRB approval for multi-site studies.

Wednesday’s town hall, hosted by Steve Dewhurst, Ph.D., Vice Dean for Research at SMD; Kelley O’Donoghue, Associate Vice President for Human Subject Protection; and the leadership team of the Clinical and Translational Science Institute; focused largely on these two issues, though the proposed changes cover a myriad of other topics as well.

“The policies will transform the way human subjects research is conducted,” said Dewhurst. “They may also have unintended negative consequences – including limiting who can contribute biospecimens for research, and making work with biospecimens far more onerous for researchers. So it is very important that our faculty understand the proposed changes and that they comment on them if they would prefer that the policies be revised before they become finalized.”

The federal government is accepting comments on the proposed changes until Jan. 6, and researchers are encouraged to submit feedback.

Secondary use of biospecimens and data

Research goes on every day in the U.S. with anonymous biospecimens.  Blood, urine, tissue, and other biospecimens collected and used for clinical purposes, and would otherwise be discarded are de-identified and used for laboratory research to advance science and discover new treatment opportunities.  Currently, study of these biospecimens is not considered human subject research because the tissues are anonymous. As these samples can’t be linked back to an individual, investigators aren’t required to come to their Institutional Review Board (IRB) for approval of their research, and there’s no requirement for individual consent for secondary use of those biospecimens.

The federal government’s proposed changes, if implemented, will classify secondary research on de-identified biospecimens as human subject research and requiring “broad consent” from patients. This means an individual must provide written consent to allow their biospecimens to be stored, maintained, and used for future unspecified research.

Consent must be re-obtained every 10 years for the patient’s biospecimens collected for clinical purposes to continue to be stored and used for research. This timespan applies to the pediatric population as well, who must also provide an additional consent when they reach the age of 18. Whether this re-consent will apply to specimens collected before the child turned 18, or whether it will only apply to the storage and use of specimens collected after that point is not clear.

“If this regulatory requirement is enacted, the University of Rochester will follow it. We will develop a policy and track individual decisions and maintain all of the proper forms,” said O’Donoghue. “But we’re a large academic medical center. We can come up with the resources to do this. Smaller hospitals and clinics that contribute anonymous biospecimens for secondary research will have to stop if they don’t have the means to establish what’s necessary to obtain broad consent.”

There will be consent and notification requirements for storage and secondary research use of de-identified data also, but the application is slightly less stringent than it is with biospecimens.

“The secondary use of data remains a little more unclear” said O’Donoghue. “The proposed regulations place data and the requirements for notification into a couple different buckets depending upon how it is identified, but for identifiable data broad consent is required.”

Single-IRB approval for multi-site studies

The proposed federal regulations also mandate the use of a single IRB for multi-site studies. This proposal has good intentions; rather than having each site’s IRB review and approve a study, investigators will be mandated to use a single IRB for any multi-site research conducted in the United States. (The reviewing IRB is selected by the funding agency, or defaults to the institution of the Lead Principal Investigator conducting the study.)

But in practicality, this will place a large burden on the lead PI. For example, the lead PI for a 4-site study, will be required to create a coordination center-type infrastructure with oversight plans to ensure compliance at the other 4 sites. The lead PI will be required to oversee adverse event reporting and collecting data for continuing review from the other 4 sites, so that information can be submitted to the reviewing IRB. Or alternatively, if the Lead PI doesn’t take responsibility for overseeing and managing the other 4 site, the 4 sites will be responsible for familiarizing themselves with the reviewing IRB at the alternate site.  This might mean that an active Investigator collaborating with colleagues at other institutions could be responsible for submitting to 10 or 12 different IRBs.

“I’m not against this. I think there are a lot of settings and research studies where this would make sense and potentially streamline research,” said O’Donoghue. “The problem is the mandate across every single study with more than one site. For studies with three or four sites and an expedited review, it might be quicker and less burdensome to just perform a local review rather than set up the infrastructure required for a single IRB.”

Get involved

O’Donoghue, Dewhurst and other university leaders will draft a series of comments regarding the proposed changes. However, an administrative objection to some of the proposed changes is only a small piece of the puzzle. Dewhurst strongly encouraged other researchers to get involved as well, saying that grassroots objections could be a major influence, and said that those with strong connections to organizations that do research with biospecimens or recruit research subjects should make sure those organizations are aware of the proposed changes.

“Sheer numbers and individual comments matter,” said Dewhurst. “Showing there’s concern in the community about this — from both researchers and potential human subjects — I think, is the most important thing.”

All feedback must include viable alternatives to the federal government’s proposed regulation changes. More information is available on the CTSI website: resources include the slide deck O’Donoghue presented at the meeting, a fact sheet on the proposed Common Rule changes, and a one-page guide to writing effective comments. Contact Kelley O’Donoghue for assistance or more information.

Director’s Update – August 2015

Every month, the CTSI Stories Blog will post excerpts from ongoing conversations with the institute’s co-directors. This month, Nana Bennett discusses the recently-released Program Announcement from the National Center for Advancing Translational Sciences (NCATS) for its Clinical and Translational Science Awards (CTSA) program. The CTSI is pursuing its second five-year renewal.NanaBennett

By now, anyone who works in or around the CTSI probably knows that the NCATS has released the criteria for the new CTSA awards. What can you tell us about them?

Yes, the new RFA is out! And I’m happy to discuss it, but first, a brief bit of background for people who aren’t familiar with the history. URMC was one of the first dozen institutions to receive a CTSA award when the program launched in 2006. These are five year grants that support much of the CTSI. We’ve been renewed once – this is the second time we’re applying for renewal. In terms of total dollars, it’s one of the largest grants at URMC.

The good news is that we thought that the RFA would be similar to the one was that was released last year, and for the most part, it is. The format is a bit different — it’s actually a bit better, a bit more straightforward, than before.  We began preparing based on last year’s so we’re in relatively good shape.

It’s interesting though – taking the longer view, several things have changed and several things are similar to the CTSI as it was years ago. There used to be “key functions,” and then those were eliminated, and now we’re back to what they call “cores,” which are very similar to key functions. But there are also several key themes which are more specific than in the past.

Can you talk about those themes?

Population health is a major one for us. NCATS has been tasked with improving and speeding the impact of research on improving health as a whole, and that’s why our overarching theme here at the CTSI is “from molecules to populations.” We want to help advance basic research – research at the molecular level – and help facilitate its growth and translational potential so that it can be used to improve human health across a population.

In order to span that full spectrum, team science is vital – and that’s another key theme.  Science has reached the point where it’s very difficult for a single investigator to take a discovery all the way from the bench to the bedside to community. In addition, input from community stakeholders is critical to science being responsive to the greatest health challenges facing our nation. Quality and efficiency of research is an important theme – we must show how the URMC can contribute to the national network of CTSAs in ways that speed and improve the conduct of research.

And another key theme is innovative education. Our CTSI educational programs are innovative in content and process. We recently launched a doctorate program called, “Infection and Immunity: From Molecules to Populations” which is specifically designed to train scholars in interdisciplinary research – combining the basic sciences and the population health sciences.  While this is not part of the CTSI, it dovetails with it and is illustrative of our approach.

How many people are working on the renewal grant? What else are we doing to prepare?

The three CTSI co-directors – Karl Kieburtz, Martin Zand, and I – are leading the renewal efforts, but we have more than 50 people involved in the process. We’ve engaged people across the university to ask for feedback and/or contributions to the grant-writing process, and we’ve also asked a group of internal and external experts to review the application before it goes out.

Our deadline is mid-September, so things may be a little frantic for the next 5 or 6 weeks. But we are confident that when we’ve finished the process, we’ll have made a strong case to NCATS for renewal.


Previous Director’s Updates:
July 2015 – Karl Kieburtz seeks feedback in the wake of the CTSI Town Hall meeting.
June 2015 – Martin Zand gives an overview of what will likely be different about the next CTSA renewal application.
May 2015 – Nana Bennett discusses the enhanced role of the Strategic Leadership Group.
April 2015 – Karl Kieburtz talks about how the leadership is preparing for the Clinical and Translational Science Award renewals.
March 2015 – Martin Zand introduces himself and discusses his interest in informatics and population-based research.
February 2015 – Nana Bennett discusses the CTSI’s Seminar Series on population health.
January 2015 – Harriet Kitzman reflects on her time as a CTSI co-director.
More…

Director’s Update – June 2015

Every month, the CTSI Stories Blog will post excerpts from ongoing conversations with the institute’s co-directors.

Below, Martin Zand talks about how the Clinical and Translational Science Awards are changing and how the CTSI is working towards the renewal.MartinZandNEW

Hello Martin. We’ve heard that the CTSA awards are going to be a bit different than they were in the past.

First, a bit of background. The Clinical and Translational Science Institute at the UR was one of the first in the country to be funded 9 years ago, and the grant was renewed 4 years ago. Every 5 years we have to compete with other current centers, and new center proposals, to renew our NIH funding through the National Center for Advancing Translational Sciences (NCATS). Our grant is coming up for its third competitive renewal this year.

What can you tell us about the changes, and why are they happening?

In the past, the awards were basically individual center awards, where a center puts out a plan for what it was going to do locally that was within the description and requirements of the grant requirements from NIH. Those activities included growing and providing services to support translational research, workforce training, pilot programs to help young investigators, and so on. In the past, there wasn’t much emphasis on collaborations and networking between the 62 centers funded across the country. But over the last two years, there’s been a dramatic shift. The expectation over the next funding period will be that all the CTSAs across the country will collaborate with each other, and create a cohesive nationwide research network. The goal of this is to accelerate clinical and translational research across the country.

One of the things that has motivated the National Center for Advancing Translational Science (NCATS) is that somewhere close to 30 percent of all NIH sponsored clinical trials are never completed. It’s not that they finished and weren’t published, they were just never even finished. So that’s a startling and very worrisome figure. We’re talking about hundreds of millions, if not a few billion dollars, that went into funding studies where, in the end, no usable results come out. Why does this happen?  A small portion of the answer turns out to be scientific: the problem was different than people thought, or they had to close down a trial because of early findings.

But that doesn’t account for all of them.

Unfortunately, no. Many studies never finish for structural reasons. And by that, I mean there are vast differences in how each research center handles the trial. All the centers currently have separate institutional review boards, contracting policies, cost structures. Some centers would negotiate for more funding because expenses were higher there than elsewhere. So if you’ve got a dozen institutions that agree conduct a clinical trial, you have to negotiate a dozen modifications to the consent form, which the other centers all then have to agree to. Then, you might need a dozen different contracts to pay for the trial, one with each center. Then you have the usual operational issues of enrollment, standardization of record keeping, and so on.  So, you can imagine that this process can take years. So, many studies didn’t even get started until the second or third year, and then funding finishes in year five.

What about the studies that actually finish?

Of the studies that actually finished, only about a 60-70 percent of them are published. The reasons for that are a little harder to ferret out. Negative studies often do not get published, and some end up having design flaws that become apparent in the statistical analysis after they were finished. But whatever the reason, if you’ve got scientific ideas you’re trying to take from the bench to the bedside, and in a large percentage of cases it doesn’t happen, then you should fix it. So Congress has been putting pressure on the National Institutes of Health, as they should. And NIH has tasked NCATS with creating a viable clinical trials network based on the CTSA centers. Overall, this is a really positive direction, and we all hope it leads to better, faster, and more scientifically insightful clinical trials.

What else has changed?

The other big change in the CTSA renewal is an increasing emphasis on team science. Scientific investigation has gotten very complex, with all the genomics, proteomics and other -omics technologies. Our ability to generate very, very large amounts of data has far outstripped our ability to analyze it. It’s really hard for any one investigator to do it all. The days when you could run your lab independently, without collaborators, and do all the statistics on an Excel spreadsheet or small statistical program are gone. Now you really need informatics databases, more sophisticated statistical collaborators, technical experts in RNA sequencing, and many other experts in complex methods and data analysis techniques that didn’t exist two decades ago..

Isaac Newton said “If I have seen further than others, it is by standing on the shoulders of giants.” Today, there continues to be an increasing recognition that no person can be doing discovery in isolation. So the nature of how we train people to be clinical researchers and scientists also has to change. Recognizing this, the coming CTSI renewal has a much greater emphasis on educating collaborative teams and fostering collaboration. These skills help Ph.D. researchers and clinicians collaborate and benefit from each other’s expertise, insights, and skills to take something from the bench to the bedside. So NCATS is placing less of an emphasis on funding individual projects and more of an emphasis on training scientists to work in teams.

If there’s less emphasis on individual projects, what will happen to the pilot program?

The pilot programs are an integral part of what the CTSI does, and will continue to be supported. You’re right that less of the funding will come from NCATS than in the past. But we are very fortunate that the Medical Center and the School for Medicine and Dentistry have recognized the importance of these programs, and provide other funds to help us keep them alive. In addition, the co-directors of the CTSI, Karl and Nana and I, are actively exploring ways of invigorating the funding program, so you might see more funding initiatives that ask for matching funds from divisions or departments, industry, and University wide partnerships.

I think one message for investigators is that we are all going to need to be more entrepreneurial. The more creative you can be in terms of finding matching funding and partnering with others, the greater your chances of success. A second message is to collaborate. Fortunately, the UR is a very collaborative institution, and it’s easy to find research partners. That’s also one of the roles of the CTSI – connecting people with common research interests.

Anything else you wanted to mention?

Well, writing the renewal itself is a team effort!  We have an incredible staff here at the CTSI, and there are individuals throughout the institution that are very dedicated to working on the renewal. We have over 40 authors right now for the renewal project. So it’s an industrial-sized undertaking. I think that all of us in leadership know that while it’s going to be a lot of work, I have no doubt that it’ll be done to an extraordinarily high level.


Previous Director’s Updates:

May 2015 – Nana Bennett discusses the enhanced role of the Strategic Leadership Group.
April 2015 – Karl Kieburtz talks about how the leadership is preparing for the Clinical and Translational Science Award renewals.
March 2015 – Martin Zand introduces himself and discusses his interest in informatics and population-based research.
February 2015 – Nana Bennett discusses the CTSI’s Seminar Series on population health.
January 2015 – Harriet Kitzman reflects on her time as a CTSI co-director.
December 2014  – Karl Kieburtz offers his takeaways from the CTSI all-hands retreat.
November 2014 – Nana Bennett speaks to the expansion of the role of the CTSI’s Community Advisory Council.
October 2014 – Harriet Kitzman discusses the science of team science.
September 2014 – Karl Kieburtz talks about why the CTSI is beefing up its informatics team.
August 2014 – Nana Bennett discusses the new Population Health pillar.
July 2014 – Harriet Kitzman offers her takeaways from the Mini Summer Research Institute.
June 2014 – Karl Kieburtz gives an overview of the CTSI’s six pillars.

URMC joins NIPTE, strengthens pharmaceutical science and engineering

The University of Rochester Medical Center has gained admission to the National Institute for Pharmaceutical Technology and Education (NIPTE), a collaborative organization dedicated to research and education in the field of pharmaceutical science and engineering.

URMC becomes the 14th member institution of NIPTE.

Cornelia Kamp, M.B.A.

Cornelia Kamp, M.B.A.

URMC’s Clinical Material Services Unit (CMSU), a core research unit of the Center for Human Experimental Therapeutics (CHET), was the key to the university’s admission. CMSU provides investigational drug and device services for many large, multi-center clinical trials conducted at URMC and elsewhere, and acts as the central pharmacy for the National Institutes of Health’s NeuroNEXT network. CMSU also works closely with the CTSI and CHET on drug development research.

“This membership in NIPTE expands the resources available to CMSU, and to researchers at the University of Rochester,” said Cornelia Kamp, M.B.A., executive director for strategic initiatives at CMSU. “A researcher can ask us a question, and if we don’t have an immediate answer, we can work on finding a solution through NIPTE.”

There is minimal overlap of expertise within the NIPTE member organizations, as each university brings something different to the table, said Kamp. Through CMSU, URMC is able to bring expertise in back-end pharmaceutical distribution — such as packaging, labeling, kitting, and drug destruction — to NIPTE. In turn, CMSU leaders hope to gain experience from other member collaborators, which could lead to gains for Rochester researchers.

Karl Kieburtz, M.D., M.P.H.

Karl Kieburtz, M.D., M.P.H.

“Through NIPTE, we have a better chance of making or procuring certain drugs that researchers might be interested in studying,” said Kamp.

The membership could also strengthen a future application that involves the Clinical and Translational Science Award program, said Karl Kieburtz, M.D., M.P.H., co-director of the CTSI, who will serve on the NIPTE Board of Directors.

“The National Center for Advancing Translational Science is developing this vision of improving the efficiency of clinical research and focusing on clinical trials,” said Kieburtz. “So we’re looking at what strengths we have that would apply towards these various centers, and CMSU’s affiliation with NIPTE is definitely one of them.”

CTSI revamps leadership structure

The Clinical and Translational Science Institute has reorganized itself to broaden the range of expertise among the institute’s top leadership.

Karl Kieburtz, M.D., M.P.H., senior associate dean for clinical research at the School of Medicine and Dentistry, who has served as director of the CTSI since October 2013, has been joined by Nancy M. Bennett, M.D, M.S,., and Martin S. Zand, M.D., Ph.D., and the trio are serving as the Institute’s co-directors.

MartinZand

Martin S. Zand

KarlKieburtz

Karl Kieburtz

NanaBennett

Nancy M. Bennett

The leadership change became effective on January 1.

“Karl has enormous experience in clinical trials, Nana brings her community perspective and population health expertise, and Martin brings informatics and data science, as well as a basic science background,” said Stephen Dewhurst, Ph.D., vice dean for research at the School of Medicine and Dentistry. “So they have different clinical interests, research interests and expertise, and put together, they make an extraordinarily broad and effective leadership group.”

This team approach is becoming increasingly common within the Clinical and Translational Science Award network. In Rochester, the diverse skill sets of the three co-directors allows for CTSI leadership to encompass the research spectrum, starting with basic science discovery and continuing through clinical trials and implementation on the population level.

“It really does bridge the molecules to populations theme that we’re trying to express. And the truth is, no single person can bridge all that — it has to be a transdisciplinary, multidisciplinary effort,” said Kieburtz. “So we’re doing it the leadership level, and showing that you can lead an institute effectively with a team.”

For the past year, Bennett served as a CTSI co-director alongside Kieburtz and Harriet Kitzman, Ph.D., but in a more limited capacity. Now her role comes with increasing importance, as the CTSI recently placed a renewed emphasis on improving the health of the population as a whole.

“As we try to accentuate the theme of population health in the CTSI, the new leadership structure will make it much easier for me to contribute in a meaningful way,” said Bennett.

Zand, meanwhile, brings informatics expertise, paramount when it comes to analyzing the big data needed for impactful research into population health.

“We want to use data science to identify questions that we’re not asking and identify data we don’t yet have. This will allow us to be in that space of discovery,” said Zand. “That way, we can translate data into real clinical and community interventions that improve the health of a population as a whole.”

The new structure also fosters an environment that will allow the CTSI to more easily integrate with several other centers within the university. Kieburtz also has strong ties to the Center for Human Experimental Therapeutics, Bennett heads the Center for Community Health, and Zand is the director of the Rochester Center for Health Informatics and co-director of the Center for Biodefense Immune Modeling.

In terms of operations, Kieburtz will remain the CTSI’s liaison to university leadership and to the National Center for Advancing Translational Sciences (NCATS), while Bennett will be the main interface with the community through the Center for Community Health, and focus on overall CTSI strategy and developing the population health science theme for the CTSI.

Zand will take on integrating informatics activities throughout the Medical Center and the newly created Institute for Data Science, have responsibility for the CTSI’s day-to-day operations, and will lead the grant-writing process when NCATS releases its call for renewal applications.

“Promoting” team science — URMC on the leading edge

During the lunch break at the Mini Summer Research Institute in mid-June, Beau Abar, Ph.D. and KL2 scholar, sat at a table in the Saunders Research Building lobby, swapping ideas with Harriet Kitzman, Ph.D., co-director of the CTSI.

“As a younger researcher, I want to be a team player, because the best science seems to come from strong collaborations,” said Abar. “But the best way to move up is to win those grants on your own — to be the P.I., to be the lead author. How can one do both?”

“That’s an issue that we talk about all the time,” acknowledged Kitzman.

As it turned out, the university was only weeks away from implementing updated tenure and promotion criteria specifically designed to reward talented team scientists for their contributions to collaborative research groups.

JeffLyness

Jeffrey M. Lyness, M.D.

The new policies, which went into place on July 1, allow recognition for scientists who lead a defined portion of the work done by collaborative teams. Department chairs are encouraged to ask referee letter-writers to comment specifically about the unique role on the team played by such scientists. These materials are given serious weight in tenure and promotion considerations.

This allows talented team scientists to further their careers, even if they are not always in roles such as principal investigators for grants or lead authors for publications.

“Science has gotten too complicated and requires too many different types of expertise for one person. These days, groundbreaking science of almost every discipline happens in collaborative teams,” said Jeffrey Lyness, M.D., senior associate dean for academic affairs. “Tenure systems, however, were established to recognize the achievement of an individual, and in team science not everyone can be first author, senior author, P.I., or co-P.I.”

The new system, which was established following ample input from faculty across the Medical Center, received overwhelming support from department chairs before it was put into place.

Outside organizations have appreciated the changes, too: When Lyness exchanged emails about the new system with the staff of Ann Bonham, Ph.D., Chief Scientific Officer at the Association of American Medical Colleges, he received word that the university’s policies were on the “leading edge” in this area.

Karl Kieburtz, director of the CTSI

Karl Kieburtz, director of the CTSI

Since its inception, the CTSI has also played a lead role in supporting team science. Co-director Kitzman is currently working with several others within the Institute to learn more about what traits or characteristics make one team of researchers more successful than another. The Institute’s largest grant, the Incubator Program, is specifically designed to support research efforts that involve multiple investigators or departments.

“Translation of discoveries at the bench into care — maybe that hasn’t gone so well because people are pursuing individual awards,” said Karl Kieburtz, M.D., M.P.H., director of the CTSI. “So people may need to be educated about the benefits of team science and rewarded for that interdisciplinary approach.”

The various efforts are supportive of an environment that many faculty say sets the university apart from other academic institutions.

“Collaboration has always been key to the culture here. It’s part of what I loved about the school as a student, and part of why I came back as a faculty member,” said Lyness. “As Dean Taubman has noted publicly, our faculty turnover rate is low compared to our peer institutions, and I think that’s because of our culture.”