Understanding Challenges in Gene Therapy Clinical Trials

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Transcript Understanding Challenges in Gene Therapy Clinical Trials

BEST AND WORST PRACTICES IN GENE
THERAPY RESEARCH
Gwen Anderson, RN, Ph.D.
Associate Professor &
Associate Director for Nursing Research
San Diego State University
&
Adjunct Assistant Professor
University of California, San Francisco
[email protected]
(619) 473-0185
Gene Therapy Clinical Trials Worldwide
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)
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 Practices
Pilot Study I
Survey:
Characteristics of
Study Coordinates
Main Study
Institutional Ethnography
Communication Patterns &
Clinical Decision Making within
the Cultural Complex of Gene
Therapy Clinical Research
Pilot Study II
Interviewing Nurse
Study Coordinators:
Clinical Challenges
Outcomes
Types of Cultural Milieus
Types of Practices that promote or
compromise Research Integrity
Policy Recommendations
Redress
IRB
Protocols
&
Policies
Redress
Institutional &
Research
Ethics Policy
Design
Educational
Programs for
Study
Personnel
Pilot Study I
Making the Role of Study Coordinators Visible in
Gene Therapy Clinical Trails
Pilot Study II
Understanding Challenges in Gene Therapy
Clinical Trails: Listening to
Nurse Study Coordinators
Making the Role of Study Coordinators Visible in
Gene Therapy Clinical Trails
 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
Making the Role of Study Coordinators Visible in Gene
Therapy Clinical Trails
Certification
22 % hold no certification
25.5 % (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 Coordinators
35/55 were nurses = 71%
31% master’s degree
34 % BSN prepared
35 % diploma in nursing
Experience as a Clinical trials Coordinator
12.7 % (7) had less than 2 years
70.9 % (39) had 2 to 14 years
16.4 % had 15 to 25 years of experience.
Making the Role of Study Coordinators Visible in
Gene Therapy Clinical Trails
What is the primary way study coordinators are
oriented to their role?
 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
Making the Role of Study Coordinators Visible in
Gene Therapy Clinical Trails
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
Making the Role of Study Coordinators Visible in
Gene Therapy Clinical Trails
 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
Making the Role of Study Coordinators Visible in
Gene Therapy Clinical Trails
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
Understanding Challenges in Gene Therapy Clinical
Trials: Listening to Nurse Study Coordinators
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
Understanding Challenges in Gene Therapy Clinical
Trials: Listening to Nurse Study Coordinators
Getting a protocol approved and ready to roll
“ 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…”
Organizational Chart of Components of Gene Therapy Clinical Trials
Industry Sponsor
Pharmaceutical Company
University Medical
Hospital
University
Clinical Research
Department
OBA
FDA
Principal
Investigator
Study
Coordinator
RAC
Physicians
Fellows
Community Hospital/
Physician Clinic
Attending
Physicians
IRB
GCRC
Infection
Control
Investigational
Pharmacy
IBC
CRC
Study Monitor
Investigational
Pharmacy
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 Trials
Industry Sponsor
Pharmaceutical Company
University Medical
Hospital
University
Clinical Research
Department
OBA
FDA
Principal
Investigator
Nurse Study
Coordinator
RAC
Physicians
Fellows
Community Hospital/
Physician Clinic
Attending
Physicians
IRB
GCRC
Infection
Control
Investigational
Pharmacy
IBC
CRC
Study Monitor
Investigational
Pharmacy
Nature of the
Relationship between the
Study Coordinator and
the PI
Scope of Practice Issues
 Outside influence by the
type of Research
Partnership
Understanding Challenges in Gene Therapy Clinical
Trials: Listening to Nurse Study Coordinators
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.
Understanding Challenges in Gene Therapy Clinical
Trials: Listening to Nurse Study Coordinators
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”
Understanding Challenges in Gene Therapy Clinical
Trials: Listening to Nurse Study Coordinators
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.”
Understanding Challenges in Gene Therapy Clinical
Trials: Listening to Nurse Study Coordinators
“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
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 Environment
Social cultural morality
Organizational structure
 Nature of Relationships
Communication
Moral Courage
Feeling comfortable speaking your
moral voice
Advocate patient holism & Protect
research integrity
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
Moral Distress
Lack of clinical knowledge, moral
courage, self confidence
Conflict & distress within setting
Initial Distress
Frustration, Anger, Anxiety
Stress & Chaos
Internalized Distress
Self Deprecation
Loss of self esteem
Burnout, Guilt
Externalized Distress
Bitching & Complaining
Unloading to others
Moral Residue
Emotional Strain and Stress
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
Clinical Decision Making about Ethics and Research
Integrity is Multi-layered and Complex
Biomedical Ethical Principles
Informed
Consent
IRB, FDA,
RAC
Regulations
Narrative Ethics: Descriptive Ethics
Expressive Communicative
Social Construction of
Moral Conversations in
Communities
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?
BEST AND WORST PRACTICES IN GENE
THERAPY RESEARCH
Gwen Anderson, RN, Ph.D.
Associate Professor &
Associate Director for Nursing Research
San Diego State University
&
Adjunct Assistant Professor
University of California, San Francisco
[email protected]
(619) 473-0185