Gwen Anderson, RN, Ph.D. Associate Professor & Associate Director for Nursing Research San Diego State University & Adjunct Assistant Professor University

Gwen Anderson, RN, Ph.D.Associate Professor & Associate Director for Nursing Research San Diego State University&Adjunct Assistant ProfessorUniversity of California, San [email protected]

(619) 473-0185

BEST AND WORST PRACTICES IN GENE THERAPY RESEARCH

mailto:[email protected]

The United States conducts the largest percentage (66 %) with 708 ever funded protocols since 1989.

UK conducts 11 % (123)

Germany 6.6 % (71)

Switzerland 3.6 % (39)

France 21.7 % (18)

Australia 1.4 % (15)

Canada 1.1 % (12)

This website currently lists 65 active ongoing trials in the US. (http://www.wiley.co.uk/genetherapy/clinical/ July 2005)

Gene Therapy Clinical Trials Worldwide

http://www.wiley.co.uk/genetherapy/clinical/



Ethical Concerns Raised by

Gene Therapy Clinical Research

Cline 1980

University of Los Angeles two patients suffering from B Thalessemia treated in Israel and Italy:

Wilson 1999

Jesse Gelsinger treated for ornithine transcarbamylase (OTC) deficiency

Fishcher 2002

10 children in France treated for X-SCID

Are Nurses Moral Voice Absent or Merely Silent in Gene Therapy Clinical Research?

Looking into Gene Therapy Clinical PracticesLooking into Gene Therapy Clinical Practices

Institutional Ethnography

Communication Patterns & Clinical Decision Making within

the Cultural Complex of Gene Therapy Clinical Research

Pilot Study I

Pilot Study II

Types of Cultural MilieusTypes of Practices that promote or

compromise Research IntegrityPolicy Recommendations

Redress IRB Protocols & Policies

Redress Institutional &Research Ethics Policy

DesignEducational Programs for Study Personnel

Survey: Characteristics of Study Coordinates

Main Study

OutcomesInterviewing Nurse

Study Coordinators:

Clinical Challenges

Pilot Study IMaking the Role of Study Coordinators Visible in Gene Therapy Clinical Trails

Pilot Study IIUnderstanding Challenges in Gene Therapy Clinical Trails: Listening toNurse Study Coordinators

A web-based survey November 2004

List of Study Coordinators from OBA, websites, American Society of Gene Therapy, national associations for hereditary diseases, biotechnology companies

Convenience national sample of 136

55 coordinators responded

40 % response rate

Making the Role of Study Coordinators Visible in Gene Therapy Clinical Trails

Descriptive Analysis Types of Clinical Settings Characteristics of the Sample of Study Coordinators Years of Clinical Research Experience and Type of

Specialty Role Title and Characteristics Orientation and Training to be a Study

Coordinator Role in Gene Therapy Interest in Continuing Education Confidence with being prepared to deal with

Clinical Situations Involving Ethics and Research Integrity


Certification22 % hold no certification25.5 % (14) hold certification in clinical research 18.2 % (10) hold certification in a nursing specialties: pediatric nurse practitioner, adult nurse practitioner, oncology, CNS

Nurse Study Coordinators35/55 were nurses = 71%31% master’s degree34 % BSN prepared35 % diploma in nursing

Experience as a Clinical trials Coordinator12.7 % (7) had less than 2 years70.9 % (39) had 2 to 14 years 16.4 % had 15 to 25 years of experience.


25.90 % (14) mentoring by the Principal Investigator

18.2 % (10) self-taught by independent reading

12.2 % (7) self-seeking of mentorship from other study coordinators

12.2 % (7) on the job training by other research staff


What is the primary way study coordinators are oriented to their role?

What are the 5 Top Priority Clinical Skills?

Protecting Human Subjects and the Research Protocol

Organizational skills Communication skills Recruitment

Ability to identify ethical issues


60 % (33) had no formal training about ethics or research integrity

36.4 % (20) had taken an ethics course in a university based clinical research certificate program

9.1% (5) had taken a university graduate course that had some research ethics

54 % (30) had attended an ethics or research integrity oriented conference

32.7 % (18) had taken a university-based or NIH-based online course on research integrity


Confidence with being prepared to deal with Clinical Situations Involving Ethics and Research Integrity?

“ It is the weekend and you are the on-call research team leader for a group of PIs involving more than one gene therapy research protocol. A staff nurse is requesting that you come to the unit to respond to questions asked by the patient and family member about the science behind a brand new research protocol.”

They are prepared, but are they Qualified?

Do they have the knowledge they need?


Understanding Challenges in Gene Therapy Clinical Trials: Listening to Nurse Study Coordinators

The purpose of this Phenomenology study is to understand the lived experience of the nurse in the role of study coordinator including:

recruiting patients into a study

coordinating a calendar of events unique to each patient and each protocol, and

negotiating relationships and responsibilities with a wide variety of health care providers to do necessary tests and collect research data

ethical issues


A non probability sample of 10 nurses from diverse settings and geographic locations in the US were randomly selected from a list of study coordinators obtained from the Office of Biotechnology at NIH after obtaining informed consent from the IRB at San Diego State University

Data Collection

Private Voice Recorded interviews (90-120 minutes)

Transcribed verbatim and cleaned of identifiers


“ We will get our internal paperwork started to go before our IRB and our IBC. Once that is in the process, then we have to identify which unit in the hospital that would be involved, so that we can do the IBC-required documentation of training for that unit. We also get our infectious disease folks involved with this, so that they always know what’s going on, in case there is any issue, they work with us, and they feel pretty comfortable with everything. We have an investigational pharmacy here that prepares all of our test articles, so that’s kind of… I’m trying to think of who else would be involved. The IRB and IBC both have templates of things, but, typically, the sponsor company will send us their protocol and their investigator’s brochure, and using our template I am able to usually pull out from the protocol and investor’s brochure what’s necessary to go into that. And then, along with that, they usually send me a draft consent document, and then I have to adapt it to fit what our IRB requires. And, you know, we submit simultaneously to the IRB and the IBC…”

Getting a protocol approved and ready to roll

Organizational Chart of Components of Gene Therapy Clinical TrialsIndustry Sponsor

Pharmaceutical Company

University

Community Hospital/ Physician Clinic

Clinical Research Department

Study Coordinator

CRCStudy Monitor

FDA

Infection Control

Investigational Pharmacy

GCRC

IRB

IBC

Attending Physicians

OBA

RAC

PhysiciansFellows


University Medical Hospital

Principal Investigator

Are some research partnerships more at risk than others? The PI, or a study coordinator and the research team write a

research protocol that is funded by a national funding agency such as NIH in collaboration with a university/ medical center

Industry Sponsor approaches an acute care medical center and sponsors a clinical trial at a per patient fee used to buy supplies, salaries, operating costs, education

Industry Sponsor provides the Clinical Research Organization service of data entry and data monitoring; they may or may not offer Regulatory Affairs Services

The NIH initiates a major grant to fund special disease organization research networks and these grants are distributed to PIs. NIH and perhaps Specialty National Disease Organization Funding

These are NIH funded centers of excellence which fund an interconnected program of research in the same institution. The grant is held by a Medical Center a Director and there are 3 more PIs that conduct studies.

Organizational Chart of Components of Gene Therapy Clinical TrialsIndustry Sponsor

Pharmaceutical Company

University

Community Hospital/ Physician Clinic

Clinical Research Department

Nurse Study Coordinator

CRCStudy Monitor

FDA

Infection Control


GCRC

IRB

IBC

Attending Physicians

OBA

RAC

PhysiciansFellows


University Medical Hospital

Principal Investigator

Nature of the Relationship between the Study Coordinator and the PIScope of Practice Issues Outside influence by the type of Research

Partnership


Ethical Challenges

“Why put very sick patients who are already vulnerable through the rigors of a protocol if the likelihood of helping the patient is minimal?”

“I’m always looking out for the patients best interest; I’m looking for other studies for them to try”

So I think it’s different in gene therapy, if you find out it doesn’t work or it’s not working long-term, it’s almost a personal thing now, because now it’s like, ‘Oh, this sucks! These people don’t feel better. I really thought, you know, we had something to offer.’

So I think they might get unblinded soon, and I’m going to have a hard time with the unblinding, I think, just as hard as the patients might have. They may do better than me, because now we’ve all just… you know, you’ve been involved with these patients’ care for now two, three years. You know, you’re hoping for the best for them.


Research Integrity Issues

“Everyday is chaotic, stressful, wearing many hats; I’m always trying t stuff 5 pounds of working into a 2 pound bucket, so you learn to cut corners”

“It is a big mistake if you enroll a patient into a study if they don’t meet all the criteria; if you have to tell your boss and the industry sponsor, maybe you just might not draw it to their attention”

“ I disagree that this department has used non RNs as coordinators…I don’t think a non RN should have the key to a drug cabinet and be handing out to patients…Where in their schooling were they taught how to do education, how to know reactions, to know drugs effects…They are just handing them [patients] a box …I don’t know where you can do that at a hospital besides research, where you just hand a patient a box of meds and say see you later. I think that’s scary”


Research Integrity Issues

“If there is something on the line, I will tell [the PI] my opinion of it…You’re putting me in a bad position here. If I know for sure it’s not right, then I will send the [PI] a copy of the protocol with that page highlighted, so [s/he] can have it refreshed. The [PI] is use to being right and not being that that [s/he] is wrong and doesn’t always want to accept how I interpreted it [the protocol]. I follow it all the way through. I see what the company has to say about it so we get into some pretty heated discussions, you know, who should be enrolled and who shouldn’t and why. So that at times, you know, we almost fight, you know saying, ‘no not doing it that way. [PI] says, ‘you’re suppose to do what I say. Well no, not at that far right… Most of the time [PI] lets is die at that point.”


“I just think… are we at the point… are you doing what’s best for the patient? If I have a coordinator who has been pushed and pushed and pushed to meet her numbers, and hasn’t been, and now this month she is just so sick of being yelled at or, you know, pointed out, and she’s going to meet those numbers no matter what. How do I know she’s giving appropriate informed consent? How do I know she’s not leaving something out? How do I know she’s not leaving something out, in her talk, in her approach to the patient, inadvertently influencing that patient? You have just put in… you know, everything has some type of… every incentive has a type of behavior that is going to promote good or bad, you know, and usually both. You know, and so by putting this type of incentive there, which is, I think you could get, you know, people are going to try to get to it.”

Nurse’s Moral Voice in Gene Therapy Research Clinical Research

Moral Agents•Moral sensitivity to self morality and ethics•Desire for promoting patient advocacy & Research Integrity•Knowing the difference between right

Negative Outcomes•Compromised data•Mistrust •Nurse & pt Drop out of Study•Compromised PI/Nurse / Pt. Relationships•Making mistakes•Patient safety is back stage not able to have moral voice hushed or ignored •Betrayal of values and beliefs

Positive Outcomes•Trust •Faith•Feeling Well•Increasing the Placebo Effect •Pt. Committed to study & long term follow up•Patient safety integrated front stage & holistic•Emotional exhaustion

Clinical Decision Making•Experiencing ethical dilemmas•Potential for violations of research integrity •Conflicts b/t nurses and physicians scope of practice & degree of involvement• Potential for patient harm vs. benefit• Meeting patient quota vs. reluctant consent• Intra-personal struggle over values• Moral & ethical certainty•Sponsor driving the protocol •Organizational structure Regulators (IRB, GCRC

Background Social-Cultural Context of Clinical EnvironmentSocial cultural morality Organizational structure Nature of Relationships Communication

Moral CourageFeeling comfortable speaking yourmoral voiceAdvocate patient holism & Protect research integrity

Moral DistressLack of clinical knowledge, moral courage, self confidenceConflict & distress within setting

Internalized DistressSelf DeprecationLoss of self esteemBurnout, Guilt

Externalized DistressBitching & Complaining Unloading to others

Moral Residue

Emotional Strain and Stress

Initial DistressFrustration, Anger, AnxietyStress & Chaos

Biomedical Ethical Principles

Informed ConsentIRB, FDA, RAC Regulations

Narrative Ethics: Descriptive EthicsExpressive Communicative Social Construction of Moral Conversations in Communities

Clinical Decision Making about Ethics and Research Integrity is Multi-layered and Complex

ARE THERE BEST AND WORST PRACTICES IN GENE THERAPY RESEARCH?

Would we recognize them if we saw them?

Do they look any different in Gene Therapy Research as compared to any other type of clinical research?

Would it help if IRBs, hospital administrators, or industry sponsors involved in each research partnership did something different?

Do hospital environments create the kind of cultural milieu for all team members to exercise their moral voice?

Gwen Anderson, RN, Ph.D.Associate Professor & Associate Director for Nursing Research San Diego State University&Adjunct Assistant ProfessorUniversity of California, San [email protected]

(619) 473-0185

BEST AND WORST PRACTICES IN GENE THERAPY RESEARCH

mailto:[email protected]

Documents

Gwen Anderson, RN, Ph.D. Associate Professor & Associate Director for Nursing Research San Diego State University & Adjunct Assistant Professor University