1. Translational Research
Responsible Conduct of Research
- Cells to Animals to Humans -
Compliance Assurance Specialist
Carrie Parinandi, RBP
7 December 2016

2. Objectives & Agenda Definitions Framing the problem Case studies
Decision Trees
Institutional Resources
Institutional Experts
Mark Douse, PhD – Office of Research Committee Support
John Heldens– Director, COMIRB
Alison Lakin, PhD – Associate Vice Chancellor, Regulatory Compliance

3. Do you know what you are getting in to?

4. What is Translational Research?
The purpose of translational research is to test, in humans, novel therapeutic strategies developed through basic research and experimentation. This is the foundation of the NIH’s Bench-to-Bedside Awards which encourage the collaboration between clinicians and basic scientists. NIH launched the Clinical and Translational Science Award (CTSA) Consortium in Our institution has been a CTSA awardee since Translational research can occur in these formal, structured environments or in informal collaborations.
In 2012, the NIH expects to fund 60 CTSA-funded academic centers.
By no means is translational research restricted to NIH CTSA awards. In fact, most translational research at our institution is conducted outside of the CTSA funding framework.
This presentation is looking broadly at the “bench-to-bedside” aspect of translational research (T-1) and will not address a second aspect in the TR paradigm (T-2) – namely research that aims to close the gap and improve quality by improving access, reorganizing and coordinating systems of care, helping clinicians and patients to change behaviors and make more informed choices, and strengthening the patient clinician relationship. The federal responsibility for T-2 is arguably with the Agency for Healthcare Research and Quality and not the NIH.

5. Why Conduct Translational Research?
Complexity - Basic mechanisms of disease must be studied in more simple platforms - cells and animals.
Expertise – No one person or research group possesses all of the skills required.
Safety - Novel modalities must be tested safely before being used in humans.
Efficiency – Well-coordinated translational research can conserve resources and speed the delivery of treatments and cures to human disease.
The reasons and the power of translational research are somewhat self-evident but the major points bear stating and repeating.
Why use cells and animals to study human disease?
Cells are very simple and clean. In addition, cells research allow for adherence to at least one of the three R’s – “Replace”
Reduce - Employ appropriate statistical analysis of number of animals needed
Refine - Use of new techniques, analgesics/anesthetics
Replace - In vitro methods, computer models, appropriate animal model
In many cases, underpinning these points are federal laws or international agreements as the next slide illustrates. With respect to animals – per the Helsinki Agreement (late 1950’s), testing in animals must occur before human testing (Advance to next slide)

6. Bidirectional Translational Research
Clinical
Investigation
Clinical Trials
Practice
In the
Community
Basic
Research T1 T2
The first area of translation, from laboratory findings to clinical practice (and visa versa—from clinical observations back to the laboratory for further testing) is often called “bench to bedside and back” or T1 translation.
The second area of translation, to the community and back, is called T2 translation.
Again - this presentation is looking broadly at the “bench-to-bedside” aspect of translational research (T-1) and will not address a second aspect in the TR paradigm (T-2) – namely research that aims to close the gap and improve quality by improving access, reorganizing and coordinating systems of care, helping clinicians and patients to change behaviors and make more informed choices, and strengthening the patient clinician relationship. The federal responsibility for T-2 is arguably with the Agency for Healthcare Research and Quality and not the NIH.
Bench
Bedside
Trench
Molecules & Cells,
Animal Models
Patients
Community & Population
Courtesy of Ron Sokol, MD

7. NIH CTSA Awards: A Home for Clinical and Translational Science
Trial Design
Clinical
Research
Ethics
Industry
Biomedical
Informatics
Advanced
Degree-Granting
Programs
CTSA
HOME
Other
Institutions
Clinical
Resources
Participant
& Community
Involvement
Biostatistics
Regulatory
Support
Housed in a Department, Center or Institute
Courtesy of Ron Sokol, MD

8. Why is translational research an RCR topic?
The foundation of translational research is to foster and promote multi-investigator and multi-institutional collaboration and sharing.
Multiple methods and technologies are used.
Numerous federal regulations, institutional policies and best practices govern cell, animal and human research.
Federal Regulations - CFR’s;
FDA regulations (GCP, GMP, etc);
HHS privacy (HIPAA);
Export controls, shipping
NIH Grants Policy
Inter-entity Material Transfer Agreements
Institutional oversight committees
Industry agreements
Translational research is one of the required modules for mandatory RCR training. Institutions can tailor the curriculum to fit their specific needs. In our case, we are focusing on the T-1 area that bridges basic science to the bedside/clinical investigation. NIH Grants Policy Section specifically calls out the requirement for RCR training at all career levels.
During collaboration and sharing, not all parties may be well-versed in all of the regulatory aspects associated with this collaboration. In addition, the collaboration could involve public academic institutions, private academic institutions, government partners, institutions in foreign countries, and industry partners.
These regulations and policies are frequently put together in isolation of translational research implications. In addition, regulatory “creep” has become common place.
List is an example of stakeholders and regulatory bodies. This diverse group of stakeholders and interested parties is a regulatory and compliance minefield. Our institutional resources are listed on the next slide.

9. Do you know all of the rules and regulations in your operating environment?

10. Translational Research & Compliance
Institutional Oversight of Translational Research
Colorado Multi-Institutional Review Board (COMIRB) – reviews all human subjects research
Institutional Animal Care and Use Committee (IACUC) – reviews all research using animals
Institutional Biosafety Committee – reviews all research using rDNA, Select Agents, Dual-use Research and infectious material
Department of Environmental Health and Safety
Office of Regulatory Compliance – oversees DURC, EC, COI and HIPAA compliance; Clinical Research Support Center (CRSC)
Clinical Research Administration Office (CRAO)– oversees the protection of intellectual property and material transfer agreements (MTAs)
Colorado Clinical & Translational Sciences Institute (CCTSI) – has a Regulatory Knowledge & Support Core (RKSC)
Our regulatory framework largely resembles what is an every major academic research institution.
CCTSI’s RKSC has a variety of resources to integrate and facilitate compliance with respect to translational research. This includes training and education, compliance consultation services, human research participant advocacy, safety monitoring, etc

11. Translational Research & Compliance
Review of several scenarios or hypothetical case studies that represent commonly occurring situations in translational research

12. Scenario #1
A colleague here at the Anschutz Medical Campus is in the middle of a clinical study collecting liver biopsy samples from subjects to study liver enzyme function in alcoholics (40 out of 60 subjects enrolled). Your lab is interested in exploring liver function during bipolar disorder. You would like to use both the stored 40 samples and upcoming 20 samples to be collected. What, if anything, needs to be done for you to access these samples?

13. Scenario #1 - Discussion
If the samples are de-identified, with PI approval you can access the stored biopsy samples. The PI must ensure you do not have access to the key. For the future samples, the informed consent must be modified and COMIRB notified that you will be looking at aspects beyond the initial scope of approval. Question to ask: Can an identifiable group be stigmatized by new research?
Very complex scenario with a multitude of potential pitfalls and correct answers.

14. Scenario #2
A colleague at University of Iowa created a novel cDNA probe and has agreed to share this with you. You want to use this probe to evaluate gene expression and intracellular location in macrophages you collected from bronchoalvelar lavage (BAL) fluid. What, if anything, needs to be done for you receive this probe and use it in your studies?
This scenario has two potential regulatory triggers:
Materials transfer
Human subjects

15. Scenario #2 - Discussion
Because the probe is the intellectual property of the University of Iowa investigator, a Material Transfer Agreement (MTA) will need to be executed between the two institutions. If the gene of interest in the macrophages was previously covered in the informed consent with COMIRB, no additional action is needed. If not, COMIRB should be contacted. In general, our Institutional policy is that an MTA must be executed for the exchange of ALL scientific material with external entities.
Our institutional policy for MTA’s applies to ALL research materials – not just patented or “intellectual property” . Frozen rat tissue, chemicals, etc.

16. Scenario #3
You have an approved IACUC protocol to investigate cardiovascular function in aging rats. Five drugs were approved for use in this protocol. A clinical colleague approaches you about treating your rats with a FDA approved drug that she had very interesting observations in some of the patients in her clinic. What, if anything, needs to be done for you to treat your rats with this drug and give your colleague the hearts and aortas from these rats?

17. Scenario #3 - Discussion
If the goals of the colleague’s work is the same, you must file an IACUC amendment requesting to add this additional drug to your protocol. No work can begin until this protocol is approved.
If the colleague’s goals are distinctly different, she will have to submit her own protocol for review. No work can begin until this protocol is approved.
What if your colleague just needs the untreated tissue for controls ?
Harvested from an anesthetized, but alive animal ?
Harvested from a properly euthanized animal ?
Doing additional work, not previously reviewed and approved, is a common violation that is reportable to the NIH. Institutional, this needs to be avoided by ensuring that ALL animal work has been reviewed and approved.

18. Scenario #4
You have purchased a stock of kidney (MDCK) cells from American Type Cell Culture (ATCC). In addition to experiments on untransfected cells, you will also be transfecting these cells with various sodium channel constructs. Your colleague across the bench would like a couple of plates of these cells to conduct their own, unrelated research. What, if anything, needs to be done for you to give him several plates of cells?

19. Scenario #4 - Discussion
Per our Institutional Materials Transfer Agreement (MTA) with ATCC, material purchased from ATCC may only be used by the purchaser. Exception: Transfer of material is authorized if the collaborator is doing work directly tied to the original purchaser’s project.
Although this is our MTA executed with ATCC, the reality is that it would be very difficult to enforce. Nevertheless, as recipient of federal dollars (our tax dollars) it is incumbent upon us to hold our research to the highest level of scrutiny. Don’t be cheap – buy your own cells.

20. Scenario #5
You are interested in studying the pathogenicity of the influenza virus, to include exploring the mechanisms that could enhance human to human transmission. Published work from University of Florida and Beijing University indicate possible collaborators on this project. You have secured space in our BSL-3 lab for this work. What, if anything, should be your considerations for this work?

21. Scenario #5 - Discussion
Research involving the manipulation or enhancement of the pathogenicity of infectious agents may fall under federal “Dual Use Research of Concern” (DURC). DURC regulations include a variety of other areas, as well. In addition to DURC, shipping material such as high path influenza also falls under new federal regulations pertaining to “Export Controls”. Finally, if biological materials will be shipped between collaborating institutions FAA/IATA shipping training must be taken by the shipper.

22. RCR Decision Trees www.ucdenver.edu/safety
Several decision trees will be placed on the RCR website
Overall Translational Research
Cellular Research
Animal Research
Human Subjects Research
Bio-Banking
Show and review the overall TR Decision Tree

23. Summary Translational research can be a formal or informal process.
Translational research is complicated with a multitude of compliance decision points.
Numerous institutional resources exist to facilitate the research and collaboration.

24. Institutional Resources
Office for the Vice Chancellor for Research
Other Depts/Resources
Office of Regulatory Compliance
AVC Alison Lakin, PhD
Environmental Health & Safety
Ethan Carter, PhD, Director
Office of Research Committee Support (ORCS) IACUC, IBC, Radiation Safety
Mark Douse, PhD, Director
Office of Laboratory Animal Resources (OLAR)
Jori Leszczynski, DVM, Institutional veterinarian
Colorado Multi-Institution Review Board (COMIRB)
John Heldens, Director
Dual Use Research of Concern and Export Controls
Christine Ahearn, JD
Office of Grants & Contracts
Amy Gannon
1. Clinical Research Administration Office
CU System –
AMC –
2. CCTSI