Notes from the 2006
Children’s Arthritis and Rheumatology Research Alliance (CARRA) Annual
Scientific Meeting
Reporter: Charles Spencer
Nature Clinical Rheumatology seeking articles for
pediatric rheumatology including clinical rheum, case reports, and series and
commentaries.
I Keynote speaker: Genomics of juvenile arthritis
David Glass
A. Basics
JIA
has a female predominance, family history of autoimmunity, predominance of some
T cell clones as well as some HLA associations. The paradox is that most
families with a JIA child usually do not have any other children with JIA
despite the HLA linkage noted; so JIA must be inherited as a complex genetic
trait inheritance as seen in other chronic diseases such as asthma and diabetes.
How
many genes might be involved? Dr. Glass suggests that 3-10 per trait is
reasonable. Modest non-HLA odds ratios are in the range of 1.2-2.0 contrasting
to odds ratio obtained in diseases with definite HLA associations which are
>3 and often up to 10. Low odds ratio gives us major power problems in JIA
studies.
Two approaches are available:
1) Candidate
gene approach by testing for a limited number of polymorphisms. It’s possible
to look at pathologic mechanisms of other diseases and then can come up with
2000 possible genes this way, e.g., gene polymorphisms for IgA
deficiency. It’s not a hopeless search as there are general autoimmune disease genes
that have been discovered, e.g., PTPN22 1p13.2, an intracellular protein
tyrosine phosphate which is seen in rheumatoid factor positive arthritis in
adults. The general autoimmune gene MIF 22qqq.23 is a mediator of inflammation.
CTAL4 also appears to be a general autoimmune gene. Low odd ratios bedevil
these genes.
2) A second approach is a global genome approach
genome-wide and utilizes
haplotype or linkage disequilibrium. Five hundred thousand
polymorphisms can
cover 90%
of the haplotype in the genome and the human genome
has 3 x109
haplotype pairs. “SNPs” can be used
to characterize small pieces of the genome.
Functional
genomics is also being pursued and an integrative approach also has
great
potential.
B. Linkage: Following inheritance
polymorphic patterns
Unfortunately
no large families with many children with JIA have been identified and so we
cannot use the linkage approach with multiple family members. An alternative is
to use allele sharing and affected sib pairs. It is less sensitive than the
linkage studies in large families with many affected members.
One
thousand sib pairs will be needed and the
C. Gene-wide association
studies using case/control studies
A considerable
number of patients are needed for this approach; You need a SNP map and one is now
available for the genome with a SNP for every 5-6 genes; 2 chipsets that cover
most of the genome will be soon available. SNPs dinucleotide variants and
SNPs per genes are analyzed. cSNPs
in coding region are a crucial area to look at searching for non-synonymous cSNPs with an amino acid change. It’s also important to look
for SNPs in promoter and regulatory regions. Two companies
are developing these chips now and are in a stiff competition.
The
D. Environmental influences
in JIA-e.g., smoking
No
clusters have been noted yet. Altered
family structure has been reported in early childhood onset JIA particularly.
Mothers with autoimmune diseases or in families with much autoimmunity often
have difficulties in pregnancy. Consider the autoimmune environment during
pregnancy. One approach was to check reproductive fitness of JIA mothers versus
best friends using a reproductive questionnaire on 227 JRA patients with 796
pregnancies and similar of pregnancies for best friends. JIA mothers had no
problems conceiving but had more problems with miscarriages, preterm delivery
and still births
Thus one should compare two
family groups having a similar number of children.
Hypothesis:
Stage I: Intrauterine
inflammation (Th1 basis) associated with increased numbers of pregnancy
complications and increased mediators of inflammation.
Stage II Maternal
inflammatory mediators pass via cord blood into the fetus resulting in
increased fetal Th1 level as well as the presence of susceptibility JIA genes.
E. Methotrexate
pharmocogenomics
Pilot SNP study involves
separating JIA DNA into pools of methotrexate
responders and nonresponders and then evaluates the SNP’s. Then it should be possible to separate out top 10 SNP’s findings Then it might eventually be feasible to have
a SNP test that will evaluate whether your patient will respond to methotrexate or Enbrel or other
drugs.
In conclusion, presently
there are extraordinary opportunities to explore the JIA genome and determine
why a child might get JIA, whether a child will do well, and whether a child
will do well on a particular drug.
II Reports from the Subcommittees of CARRA
A. JIA and spondyloarthropathy subcommittee
1. RFA for uveitis-several proposals sent in; One
was chosen from Duke that is a Multicenter
Prospective Registry of Infliximab Use in Uveitis. It will use a
The study will assess the ability
of infliximab to treat uveitis
using different parameters. It will compare
efficacy between two doses of rituximab:
5 mg/kg/dose and 10 mg mg/kg/dose, both every 4 weeks. The study
will utilize a web-based, prospective collection of data.
A child must to have been determined to need infliximab
before treatment. The study will attempt to standardize treatment using
standard ophthalmologic techniques.
These techniques include use
of a recent classification of uveitis (
Ten to 12 CARRA centers will be sought.
Each center must be motivated and reliable. Each center must have an excellent
collaborative relationship with their pediatric ophthalmologists. The goal is
for each center to recruit 4 patients over 6 month’s entry period.
Inclusion criteria include: persistent
non-infectious JIA uveitis, onset < 16 years of
age, present for 3 months and already treated appropriately. The anterior
chamber should have at least 1+uveitis by
Exclusion criteria include:
No biological drug utilized in current treatment program and must have been off
Enbrel or Humira for >60
days.
B. Long-term JIA outcome-Sue Bowyer
Presently
Cohort 1 has 347 patients. They are mostly from the middle to the late period
of the use of methotrexate (1980’s-1990’s), some even
in the time of early use of methotrexate. Cohort 2
has a goal of 500 children that will cover the era of early use of methotrexate and biologics singly or in combination. Parents
are filling out CHAQ, global assessment, etc., medications used, side effects
of medications, PT/OT, and hospital admissions. Barriers to care are now being
collected including referral source, specialists seen before, insurance
problems, etc.
Yet
new Changes being considered in JRA outcome study Some of these changes include
quality of life measure, a modified CHAQ (compare to previous CHAQ), repeat RF
level, collect remission criteria and test criteria, and possible collaboration
with DNA collection of David Glass (but no $$ yet)
C. Dermatomyositis-Brian
Feldman
The JDM priorities voted on last year include:
1) treatment for new patients
Our plan-Survey of current practice-medications,
other therapies, evaluation, and how long to treat. A consensus practice conference will be held. The
survey will be reviewed and 2-3 treatment protocols will be developed. The
funding will be provided by Friends of CARRA. Cases have been written and
reviewed-survey to be written; survey will be send out soon.
2)
It
will involve validation of disease activity measures that have been developed
as well as a basic science study of responders and non-responders. The primary
aim is the efficacy of treatment while the secondary aim remains the science,
both clinical and basic.
In
the
3)
IMACS-Ingrid Lundberg
This
project involves several aspects including a classification study of JDM, a
Twin Sib study, and a Canadian IMACs registry. See
more information on the IMACS website.
4)
Ann Reeds lab-
Dendritic cells and pathogenesis, gene profiling in JDM, and T
cell repertoire work.
5)
Lauren Pachman: Biology of calcification-Dr. Pachman needs Ca++ specimens.
6)
European PRINTO is doing a three limb treatment study for newly diagnosed JDM
comparing prednisone
alone, pred + cyclosporine, and prednisone + methotrexate.
CARRA has not given approval for
participation of US centers in this study and
PRINTO will not enroll US centers without a
coordinated approval by CARRA.
7)
PReS European JDM network in participating in a classification
of overlap
syndrome project.
D. Lupus studies-Lupus Committee Project Update Laura
Schaunberg
a) Meaning Outcomes-objective is to find minimally
clinical important differences of disease activity measures-also the validity
of SLE criteria for children and the validity of outcome measures.
b) Renal biomarkers-NGAL Neutrophil
gelatonaise
c) Development of evidence-based use of steroids in cSLE
as well
the use of steroids effect on outcome of cSLE.
d) Effect of hormonal changes in adolescents with cSLE on disease and antibodies levels
2.
Clinical Science-not approved
a) Helping educate lupus
patients-Larry Vogler
b) Lupus Registry
in
c) Tripoelin
in protecting ovaries in patients with
3.
Basic Research-approved
a) Nitric oxide in cSLE-another
researcher
b) Maternal microchimerism in cSLE-Ann Reed
4. Basic Science-not improved-multiple
studies-see CARRA website
5.
Ongoing studies-APPLE
This
study is testing the efficacy of atorvastatin (Lipitor) in preventing atherosclerosis in cSLE over 3 years. It is a placebo controlled study. The
secondary goals are to assess Limiter’s anti-inflammatory effect on
So far
22 sites have been activated with 2 sites terminated. Enrollment began in Sept
2003 and since then 143 patients have been randomized, 163 consented (169 with verbal
consents). The goal of enrollment is 280 patients. The current timeline is to
consent 180 by 6/2006 and finish all entry by the end of 2006.
About
½ of approached cSLE patients have been successfully
enrolled. There has been only a 4% dropout rate. Compliance (defined as missing
less than 25% of doses) has thus far been excellent at 90%.
APPLE
adverse events include 24 SAE's (serious adverse
events). The SAE’s
involve a lupus flares (5 patients), infections (7), related complications (3),
e.g., MAS or enteritis, and liver enzymes or muscle enzymes elevation (9).
What
have we learned?
a) Enthusiasm is necessary but not sufficient
b) Sites need enough money
c) Sites need outside support both doing things for
sites and being available for questions.
d) Sites need education of staff.
e) Sites need personal attention.
f) RCT’s (randomized control trials) need longer start up as
there are multiple regulatory groups
(NIAMS,
FDA, OMB, DSMB) and multiple IRB’s to deal with. A site
visit with the sponsor can
help.
g) Data collected;
1)
The mean for IRB approval was 25 weeks! (0-Duke-to 85 weeks)
2)
The mean time to IMT certification of scan technicians for a site was 37 weeks
(11-157)
3)
Site activation mean was 63 weeks (25-152 weeks)
4)
Even after site approved, the time to enrollment of the first patient was a
mean of 12 weeks.
How can we optimize
recruitment? The role of the patient’s physician (rheumatologist) appears to be
critical. Make sure it’s clear whose patient it is and have the primary pediatric
rheumatologist initiate the approach to the patient and family.
The importance of PI cannot
be over-emphasized. The PI must be very active in the study from the beginning
and remain so and not leave it all to the clinical coordinator.
The overall belief system
that research is good is important and that this particular trial is valuable
and worth doing is essential. Once these beliefs are in place, effectiveness in
recruitment can be taught.
Additional strategies might
include:
From the study PI’s perspective, it might be best to focus on the best
clinical study sites with the best track record. Who can provide your most
potential patients and who will follow through well?
In summary, the Apple study
has accomplished some things and learned much. Look at the study data available
on CARRA website. It includes a well developed and refined CRF. The study has established
site activation benchmarks. We have much data on cSLE
and the most experience on Lipitor in children for
any disease. In the next year Apple enrollment will be ended. A shared data
base will be available. Several other lupus studies are nearing publication;
and several other accomplishments are noteworthy. Please see the CARRA website.
E. Vasculitis/Scleroderma/autoinflammatory
disease subcommittee-Kathleen O’Neil
1. Scleroderma-Gloria
Higgins
a)
CARRA is currently indigitating with International
Inception Juvenile Systemic Sclerosis Cohort Study.
b) Investigation
of topical alprostadil for severe Raynaud’s
phenomenon.
c) COMPAQ-1H
severe immunosuppressive study-Andy Reiff
d) Vasculitis registries have been started including-Wegner's
Registry, CNS Vasculitis
e) Autoinflammatory diseases-FMF meeting occurred in
f) Registry for autoinflammatory
diseases has begun.
2. Juvenile systemic
sclerosis cohort study:
a) Disease for <18 months.
b) Collect data q 6 months for 36 months: skin and organ
involvement, lab results, quality of life
measured;
Note: Patient # will be given for confidentiality
c) Chronic
vasculitis registry-David Cabral
d) Case
report forms are being developed.
e) Diseases
are rare!-Only 64 Wegener’s and 327 unspecified vasculitis
patients have been entered in
the registry so
far.
Why important?
High
disease burden occurs and there is limited pediatric specific data available. Why
do it? Because of our belief in the need for and value of
hypothesis driven research.
The
vasculitis registry needs sufficient resources!!! Is
it feasible even if this registry remains unfunded by CARRA and non-CARRA
organizations? Yes, it is feasible! But start simple with Wegener’s granulomatosis, Microscopic angiitis,
Churg-Stauss syndrome, and CNS vasculitis
syndromes. Data Registry on internet; once at diagnosis only-many benefits,
e.g., be able to test formation and function of database and web system; It
will provide a framework for expansion of the registry and other benefits.
Things to be done: Obtain more
centers and help with IRB applications with suggested consents. Time frame for
launching is 3-4 months. There is a plan for followup
studies.
2. CNS vasculitis-Sue
Benseler-
As mentioned above and
previously at last year meeting, CARRA has envisioned developing a framework
for prospective network studies of pediatric rheumatologic diseases. Some networks
that may serve as a model for ours might include two existing research
framework of pediatric neurology: International Stroke registry (1000 children)
and a Canadian study of pediatric demyelinating
diseases; This study allows for multiple visits.
Features of this CNS vasculitis network will include:
1) A secure web based interactive repository which is
Oracle-based and easy to use.
2) A database developed in collaboration with Computer
Biology at
3) Project manager: Stacy Ou Wai who will have 2 programmers to help.
4) The browser will be hosted at Sick Kids.
5) Two CNS vasculitis
studies are planned
-CNS
vasculitis prospective outcome study-test monitoring and
outcome tools,
predictors
of adverse outcome-see website
Work to be done:
organization at this meeting for the startup-discuss data collection forms and
overall functionality of study databases; discuss and tackle all challenges
around the organization; finalize the projects, so that the programmers can
start. Fortunately, there are some startup funds available.
F. Pain and outcome and quality of life-Gary Walco
Introduction: Questions to
be discussed: Should this group continue at all? The group is small and many of
the participants have roles on other committees. You could also argue that pain
not a disease. Some good things to mention: Members of the pain group have a
major interest in pain and QOL. It would appear likely focus on pain within
CARRA would be diminished if the group was disbanded. The idiopathic pain focus
would be lost.
It has been decided to
continue.
1. Studies
2. Idiopathic pain syndromes
a.
Musculoskeletal pain registry
Last
CARRA meeting there was much discussion on beginning a longitudinal, prospective
observation study of all children presenting with chronic or recurrent
musculoskeletal pain in order to generate regression models. This would be a
registry. This project is still under discussion.
b. Taxonomy
This
is a joint endeavor of CARRA and the American Pain Society Special Interest
Group on Pain in Infants, Children, and Adolescents. A summit is planned for 2007.
The planning meeting for the summit in
Funding sources being pursued.
c.
Other studies in progress: Jennifer Weiss-Analgesia for joint injections; P Malleson, Yuki Kimura, and J Weiss are doing a pain survey;
Fibromyalgia studies begun in Cincinnati including sleep
patterns in pain syndrome children and the relationship of celiac disease and
pain syndromes.
III Committee Concurrent Sessions-JDM-Meeting #1
Brian Feldman
2. Pick
top priorities of this subcommittee
This effort will include addressing
the most commonly seen JDM as well as the most severe forms (e.g., the JDM ICU
patient). It will leverage current technology and scientific progress. It will require
multicenter collaboration. It will be pediatric
focused.
Recall some of last CARRA
meetings JDM subcommittee priorities (not complete list):
Recall the ranking list-top
8-Revisit every 2 years
A survey will be sent out
soon of 11 cases of JDM. It has been reviewed by multiple committee members. It
includes an ICU case. Hopefully it will prove to be a very user- friendly
survey. Then a conference for development of consensus treatment protocols will
be organized. Four protocols will be created and then ranked in priority. The
results of the protocol development conference will be reviewed by the
individual JDM results subcommittee. The time line will be: Cases to Brian in
next two weeks; Develop web survey with cases by July 1; Send out surveys and
analyze over 3-6 months; By January 1, 2007, Brian will choose a working group
to review the survey; A conference will then be organized (but not have
occurred) by the next CARRA.
Juvenile dermatomyositis
subcommmittee-2nd meeting. Brian Feldman
What additional studies
should be done now that we have one study (survey and development of 4
treatment protocols) ongoing?
Let’s review the priorities:
The NIH study for adults and
children (Ingrid Lundberg’s study) may help us with classification and
criteria; Everyone should read her protocol and decide
if want to participate.
PRINTO is working with JDM
activity and damage indices.
Brainstorming sessions next
occurred on ideas for the next priorities: Three groups of 8-12 subcommittee
members.
1. Group A
Priorities:
2. Group B Priorities:
Group C
Group Consensus in 2nd
meeting
Pain syndromes Committee
What study to do? Much to discuss. Perhaps a prospective study on pain
syndrome patients should be performed. Consider also a naturalistic study using
a registry that collects all the data such as temperament, early pain
experience, quality of life, taxonomy. How to fund?
We could develop a
denominator by doing a brief survey of generalists’ exposure to chronic msk pain or could you use Finnish data instead as the
denominator.
Hypotheses to be studied
might include:
-Frequency of idiopathic msk pain in primary care setting.
-Socioeconomic factors in
development of pain syndromes.
Should we collect data by
naturalistic study or intervention program or both?
It could be make easier for the physician team with the patient and
family filling out the registry or study forms. It may be best to have it
computer-based. Should the target population for a study be all children with
different types of musculoskeletal pain or just those with idiopathic pain?
Who can do this work and how
can it be paid for? The NIH is interested in observational studies, outcome
measures, and statistical measures as they apply to pain. Thus it is a
surprisingly good atmosphere for funding for pain in children. A small workshop
may further this along, perhaps in 2007 with big meeting funded by NIH.
Pain Subcommittee-2nd meeting
Again, what are we
interested in studying?
Use a model of the useful
lupus study group-answer one question and get it going.
e.g., taxonomy and
classification-classification schema, and data, then biomarkers with treatment
intervention; Have the NIH or a drug company support a conference to set up the
study initially.
First, establish a Web-based
data registry or study. Plan a conference to set up a questionnaire for
web-based registry and then establish the registry in the next 18 months.
Next pilot the registry. Second, tie in a study limb on biomarkers and
cytokines for pain sensitivity or pain response as well as genetics. Again, initial funding could be through the
NIH or a drug company. In two years ready to go for a RO-1 with biology and
intervention portions.
The plan is to set up a website
on the CARRA website and link it to SharePoint or similar commercial site; The entire subcommittee should then together put together a
form by e-mail. The versions of the form can be debated over the internet with
everyone posting comments or questions on CARRA website. Each subcommittee
member would fill out the form on 20 patients each. Deadline:
Peter Malleson
will send out e-mail to ask for input on the website; Please look for the disease
group (Pain) and give your input and monitor other’s input. Peter will
spearhead it. The Steering
group meeting in June at Pain Meeting in Vancouver-Saturday and Sunday.
Please remember the ongoing
study of the joint injection questionnaire. It has started at
The study coordinators will
send out an IRB protocol and grant application.
Transition study-Patience
White
Their group will survey the pediatric
rheumatology community and how are they following the current guidelines from the
consensus conference of 2002. The group is using the Survey Monkey. Peter Malleson will fill out the form CARRA requires-It will be
sent out thru CARRA and then sent for publication.
IV-CARRA funding sources discussions
What is the current
atmosphere for clinical research in rheumatic disease? We’ll review the current
status and describe some funding and career opportunities and new initiatives
A. NIH/NIAMS
Let’s review current status
of funding-Is there money?
1. Budget
Two hundred and forty-four
new and competing continuation applications accepted by NIAMS in 2005 (20.2%
acceptance rate); overall rate for NIH was 22%; NIAMS is usually less than the NIH
rate due to its 10% rate on high risk research applications. The
information on grants available on NIAMS website at www.NIAMS.gov.
What is the picture for 2006
and 2007 for funding? Congress has cut Fiscal Year (FY) NIAMS 2006 funding by
3.2 million dollars over FY 2005-In response,
NIAMS is decreasing non-competing continuing grants by 3.2%. The pay line for FY 2006 is 14.5%
and overall success rate of grants will be 18-19%. All program projects (e.g.,
P01) that are 10 years old or over will be eliminated.
FY 2007 is going to be
tough; NIH total budget will be cut to $28.6 billion-NIAMS will go down to a
budget of 504.5 million; NIAMS success rate will be likely be in the
neighborhood of 16% compared to 19% NIH overall.
2. New career opportunities
a. New
career funding opportunities (K99)
This
is a NIH pathway to independence award program. The program features an
opportunity for promising postdoc scientists to
receive both mentored and independent research support from the same award This
was started partly in recognition that
the mean age currently of new RO1 awardees
is now 42years. NIH will award 150-200 awards in its initial year, beginning in
fall 2006. NIH hopes to continue this level of awards for each of the following
five years. This is a major component of the NIH effort to support new
scientists as they transition to research independence. All NIH institutes and
Centers are participating in this award. Award applications will be reviewed by
K study sections. This is a career transition grant. The grant application can
be viewed at the website http://grants.nih.gov/grants/guide/pa-files. The mentored phase direct costs are $50,000
per year, with $20,000 for research costs. Independent phase requires review
and if continued, $250,000 per year is budgeted. Many submission dates are
planned including a 4/6, 10/6;
b. Exploratory/Development
Research Grants
High
risk research will major risk of failure, but if works, then it is a
significant result-2 year grant-$275,000 total. Success rate is low at 10%.
3. NIAMS Small Grant Award
for New Investigators (R03)
This grant is for funding for
a pilot study to obtain preliminary data. If you’ve had a large grant with the
NIH in the past you are ineligible. It provides 3 years of support with up to
$50,000 per year.
4. NIH Loan Repayment
Program for Clinical Research (L30) for subspecialty trainees. If the applicant’s research application is chosen (it is
competitive), the trainee must do a minimum of 2 years of research. It
is expected that the applicant for the L30 has received outside funding for the
research, though it does not have to be from the NIH. The applicant will
receive repayment of $35,000/year towards his or her loans.
5. CTSA-This program may
replace the GCRP. It is for the development of a center for translational clinical
and basic research projects so that new treatments can be developed and be
available much more quickly to patients. CTSA’s
purpose is to create a definable academic home for the discipline of clinical
and transitional science that encourage novel methods and approaches, enhance
informatics and technology, and improve training and mentoring to ensure that
new investigators can navigate the increasingly complex research system.
Other
programs are continuing:
6. Outcomes RFA; To promote the development of instruments to measure
outcomes and clinical response. ($11 million)
7. Clinical Trial Planning
Grants (PA)
8. RDCRN (RFA about to be
reissued)-rare disease center and research network-look to this RFA
9. Rheumatic Disease Core
Centers (RFA)
10. NIH wide: Gain (Genetic
association information network) and GEI (genes and environment)
B. Arthritis Foundation
Debbie McCoy
AF Vice President for Research
1. Introduction to Arthritis
Foundation
The mission activities for
the Arthritis Foundation (AF) include research, public health, and public
policy. The top priority diseases currently are OA, RA, and JIA. Peer review
includes ten study sections. On each study section, members serve 3 year terms.
Selection of the members of the study sections is based upon scientific background.
Most clinical studies are in clinical immunology, clinical outcomes and
therapeutics, and technology and biomechanics.
Grant decisions are made by
the Medical and Scientific Advisory Board of the AF. It determines funding
priorities fro any given year and allocation for award programs. The award programs
are defined by their funding mechanism. Funds are actually a bit better in
2006! Sept 1 is the deadline for these research grants.
2. Types of awards:
a. Post-doc
fellowships for MD or PhD scientists. This grant provides salary support of $50,000
for up to 3 years.
b.
Doctor dissertation. This grant awards sufficient funds to finish a dissertation.
c. Career
Development Grant-This grant requires > 3 years research experience and allows
a young I investigator to set
up own lab. The grant provides $330,000 over 4 years.
d. Established
Investigator Awards-e.g., Innovation Research Grant.
This grant is for innovative, novel, and special research opportunities to
address unique and relevant research that has substantial risk of having
negative results. Little or no preliminary data is necessary. The grant
provides $100,000 per year for 2 years;
3. How does the AF spend its
money for research every year? On developing young researchers! Eight-two
percent of AF funds are in training and career development grants. Seventeen
percent fund established investigators; Innovative research applications have a
success rate of 10% and career development/training grants are at 40%.
4. Changes in the AF: A working
group has been established
There has been consideration
of a merger of AJAO strategic goals and AF goals; e.g., AJAO goal by 2010 for 10
million dollars, AF has a 3 million dollar target for Juvenile idiopathic
arthritis funding.
Charge of the working group
is to discuss if the AJAO and the AF Strategic Initiatives can be combined-$10
million fund-raising is feasible and how these may be best utilized and how
collaborate with other organizations and funding sources. The report from this
working group is due by June- The M&S committee will make a recommendation
to Executive Board of the Arthritis Foundation.
5. Contact information
dmccoy@arthritis.org (404-965-9625)
Don’t forget the summer
fellowship meeting of pediatric rheumatology fellows at the AJAO in July which
is organized by the
C. Institute of Musculoskeletal Health and Arthritis
(IHMA)-Louise Desjardins, BSc, MSc,
PhD
IHMA is one of 13 institutes
of Canadian Institute of Health Research (CIHR)
There are 3 dimensions:
1. A focus on access
(arthritis, bone, skin, muscle, oral, musculoskeletal rehab), strategic
priorities (tissue injury and repair, physical activity, mobility, and health/pain
disability), and knowledge translation. All three areas built on ethics base.
2. All research projects are
done in concert with commercial partners.
Partnership contributions can
be diverse and include research agendas.
3. Types of grants (Go to
website for more detail on grants)
a. One
year pilot grants
b.
c. Visiting
Professorships
d. Canadian
wide science fair
e. Pfizer
summer science scholarship
f. Strategic training in health research: e.g., pain
and Inflammation (Pfizer), pain and disability; also operating grants in
arthritis, injury initiatives, regenerative medicine, and osteoarthritis
(Partners put in 5-6 parts to one part government)
g. Knowledge
Translation: Choosing new research directions, informing relevant policies,
encouraging product development-all done with partners-Doing two such
transitional knowledge projects at present.
2. Stakeholders in the IHMA:
Researchers, health care providers, policy makers, the Canadian public, private
sector, and patients/public groups.
3. Recent conferences:
a. Current
research- topics and RFA’s
b. Canadian arthritis standards of care-access to
meds, education of providers, testing innovative
models of care
c. Pain
Anyone
interested in more details may e-mail Dr. Desjardin for the 2005 IHMA annual report
and visit the IHMA website.
V Clinical Research-Advanced session Ed Giannini Cincinnati
A. Introduction
Topics today will include:
Budget, Summary of required documents, Training, Certification, and Resources,
and
Audits-types of audits, what
to do when told an audit is going to occur, what to do before an audit to
prepare, what to do during audit, possible outcomes.
B. Budget:
1) Look at your study protocol, flowsheet,
and budget and make sure all 3 match up well.
2) Some sponsors believe that study coordinators and
investigators should not be compensated. If that is the case, it may be
possible to merge costs into other areas.
3) Prepare an internal budget exactly like the one
provided by the pharmaceutical company and compare the two budgets.
4) Underestimating study coordinator time needed is a
major budget problem. Remember to include monitoring visits by the sponsor or
CRC-When the monitor is there, his or her time is totally utilized.
5) Allow for time to prepare and ship specimens in coordinator’s
time.
6) Don’t be afraid to approach the sponsor company for
budget renegotiation if some costs are not being covered. They expect you to
come back.
7) Ask for non-refundable startup funds and fees upfront
and these funds should be paid even if no patients are ever enrolled.
C. Required study documents:
1) Important points in preparing study documents:
a) Need to document delegation of authority for any
study.
b) Document everything when communicating with sponsor
or coordinating center-Have a log of contacts, especially phone calls. The
pharmaceutical companies do.
c) Act as if it’s a medical record and you have to go to
court-have all the documents you would need.
D. Training, certification,
and resources
1) Required now or soon to
be required everywhere:
a)
b)
GCP-Good Clinical Practice training-provided not at Drug study meetings but at
separate
training programs.
c)
HIPAA-training by institution you’re at.
2)
Recommended
a)
You should take
can also use
on-line training at www.citiprogram.org and follow explicit instructions as an
outside applicant,
e.g., at Cincinnati Children’s
b) Institutions are seeking AAHRAP certification and
requiring you to take
c)
You will need GCP training soon-Good clinical practice guidelines-these
guidelines give you
help in designing
and performing a study properly.
d) Training may soon be required to take GCP training
e.g., at RAN Institute, it might cost $175 for an online course by yourself and
$87.50 for a discount. Soon training at drug company investigators will not be
sufficient to the FDA as they have been tired of mistakes.
e) It is not required yet to get Certified Physician
Investigator (CPA) online through
3) Resources
There are a number of texts and references e.g., The
Research.
Other good references to use:
a) Ellenberg SS, Fleming
TR, DeMets DL: Data Monitoring Committees in Clinical
Trials: A Practical Perspective.
b) Nylen: The ultimate step
by step guide to conducting pharmaceutical studies in the
4)
HIPAA requirements-Check with your institutional requirements.
E. Audits
This discussion will focus
on FDA, Internal Audits, and Drug Company Audits.
1. What trigger audits,
internal or external?
2. If you receive notice
that you are going to be audited:
a.
Notify everyone-Sponsor, IRB (your mother, the neighbors)
b.
Get ready using an audit checklist
c.
Some "do’s and don’ts" might include:
1) No clinic for the PI or subPI’s
that day-Don’t have patients in clinic or inpatient duties. It insults the
auditors
and gets everything off on a bad foot.
2)
Answer as briefly and concisely as possible and don’t sign anything. Pretend
that you are a defendant
in
front of a judge.
3) Offer
only water, coffee, soft drinks-no special entertainment, dinner, free lunch.
4) Have
all patient notebooks, ICDs, training and source
documents, computerized records at hand for
the
audit. The auditor will try to see if all the records jibe. Have a room setup
before hand.
3. Outcomes of an audit:
a.
FDA-deviations/violations: may get form 483-shows their findings and requires a
response.
b.
Correction needed right away-You will get a warning letter if the inspector
finds something wrong that needs correction right away. Respond immediately.
c.
The official Establishment Inspection Report (EIR) comes several months later:
3 outcomes:
a)
No action indicated (NAI):
b)
Voluntary action indicated (VAI)-not signing CRF’s in
a timely manner,
unknown investigator signs CRF
c)
Official Action Indicated (OAI)-the worse-you’re put on the List of
Disqualified and
Restricted Investigator list. You will never get another study
And should resign from
research groups (CARRA, PRCSG).
Example: Patient in study not observed
overnight as indicated after study
medicine given.
Patient became sick overnight and was brought into the
institution’s ER. No one at the ER knew anything about the
study. The PI could
not be contacted.
V SUMMARY OF MEETING
A. JIA Committee
1.
Studies to mention
a. Uveitis Remicad