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In a nutshell
Issue 1.4 Fall 2004
contentsinside Adverse Event Reporting in Clinical Trials
safety of these drugs taken in death or disability for pa-
1 Adverse Event Reporting in combination. Furthermore, tients.
in Clinical Trials the safety of fenfluramine How did this happen?
use beyond one year had not How does such a problem
2 Who’s Who been established. with a known, effective drug
Problems Emerge develop? Some say it hap-
2 Upcoming Meetings On July 8, 1997, the Mayo pened because “off label”
Clinic reported that 24 pa- use was initiated without
SALLY JO ZUSPAN, RN, MSN
3 Adverse Event Reporting Cont. tients developed heart valve adequate study. Lack of ap-
CDMCC Program Manager disease after taking fen-phen. propriate reporting was also
Y
4 From Initiating to Regulating ou have heard about Fen- The cluster of these unusual a contributing factor. FDA ap-
Phen, the diet drug that cases suggested that there proval for fenfluramine was
4 Creating a Diagnosis Group- lead to reports of problems might be an association be- granted for use alone and not
ing System for Child ED Visits in women taking it for weight tween fen-phen use and in combination with another
loss. So what does this have valve disease. Further study drug. In addition, earlier tri-
5 Nodal News to do with PECARN studies? reported that 1/3 of patients als did not study long term
The Fen Phen experience who had taken the combined use for either drug. Further-
5 Intention to Treat has some important lessons drug had leaky heart valves more, there was evidence
that serve to educate every- and abnormal EKGs. Five pa- that the drug might have ad-
6 PECARN Update one conducting clinical trials. tients in this study underwent verse effects on the heart. A
What is fen-phen? valve replacement surgery. Belgian study in 1994 had
7 New Faces Fen-phen refers to the com- On the same day that this shown leaky heart valves as-
bined use of fenfluramine report was released, the FDA sociated with fenfluramine
and phentermine, prescrip- issued a Public Health Advi- use but this information did
8 Sepsis
tion medications that have sory that described the Mayo not get passed along to the
been approved by the FDA findings. The Mayo findings FDA. It is for these reasons
9 Protocol Deviations were reported in the August that the FDA requires all drug
for many years as appetite
suppressants for the short- 28 issue of the New England companies to report any se-
10 Research in Children Journal of Medicine, along rious or unexpected adverse
term management of obesity.
Phentermine was approved with an FDA letter to the edi- events regardless of their
11 Spotlights tor describing additional cas- apparent relationship to the
in 1959 and fenfluramine in
1973. In 1992, a series of es. Since then, the FDA has study drug.
11 Good Clinical Practice Tip received over 100 reports (in- PECARN Clinical Trials
studies reported that the com-
bination of these two drugs, cluding the original 24 Mayo Reporting of Adverse Events
12 CDMCC On the Road cases) of heart valve disease (AE) and Serious Adverse
dubbed Fen-Phen, reduced
certain side effects while associated with fen-phen. Events (SAE) is required dur-
12 Research in Children Cont. Based on these data, the ing a clinical trial. Failure to
maintaining weight loss in
patients. Despite the fact that FDA asked manufacturers report an adverse event is
these drugs were approved to voluntarily withdraw these a violation of federal regula-
SUPPORTED IN FULL BY GRANT for “short term use”, another drugs from the market and tions and good clinical prac-
physician studying the same recommended to the pub- tice. The Fen-Phen story
U03MC00008, MATERNAL AND lic that patients stop taking teaches us that even “safe”
drugs reasoned that since
CHILD HEALTH BUREAU, HEALTH both drugs were being taken them. The Fen-Phen lesson drugs can have unexpected
RESOURCES AND SERVICES at lower doses, patients could is clear: Nearly forty years effects. Because PECARN
ADMINISTRATION, DEPARTMENT OF take the combination drug for after phentermine received investigations by definition
many months instead of a FDA approval, the combined involve children, who are
HEALTH AND HUMAN SERVICES. use of this drug and another known in research as a “vul-
few weeks. This type of drug
drug resulted in a previously nerable population,” we must
contactinfo
use is called “off-label use”
meaning that the drug is used undocumented and unex- be extra cautious with report-
in ways other than described pected physical finding: leaky ing adverse events.
615 Arapeen Drive Suite 202
in the FDA-approved label. At heart valves. The Fen-Phen Dexamethasone was ap-
Salt Lake City, Utah 84108
the time of these decisions, experience teaches us that proved by the FDA on Octo-
Phone: (801) 587-7613
no studies were presented even well established, seem- ber 30, 1958. Since that time,
Fax: (801) 581-8686
to the FDA to demonstrate ingly “safe” drugs can cause labeling for the drug has
www.pecarn.org
either the effectiveness or unexpected results, resulting Continued on page 3
page 2 fall 2004
whoswho
Nathan Kuppermann, MD, MPH
Chairman of the PECARN Jennilyn Suhajda, RPh, MS Stacey Knight, MStat
Nodal Principal Investigator Great Lakes Nodal Admin. Biostatistician
nkuppermann@ucdavis.edu jkleins@umich.edu stacey.knight@hsc.utah.edu
Jim Chamberlain, MD Helena Rincon, MA Amy Donaldson, MS
Vice-Chairman of the PECARN PED-NET Nodal Admin. Biostatistician
Nodal Principal Investigator hr2016@columbia.edu amy.donaldson@hsc.utah.edu
jchamber@cnmc.org
Sally Jo Zuspan, RN, MSN Brian Gadoury, BS
Ron Maio, DO, MS CDMCC Project Manager Software Developer
Nodal Principal Investigator sally.zuspan@hsc.utah.edu brian.gadoury@hsc.utah.edu
ronmaio@umich.edu
Rene Enriquez, BS Drew DeMarco
Steven Miller, MD CDMCC Data Manager Computer Systems Analyst
Nodal Principal Investigator rene.enriquez@hsc.utah.edu andrew.demarco@hsc.utah.edu
szm1@columbia.edu
Jeri Burr, RNC, CCRC Brooke Millar, BS
J. Michael Dean, MD, MBA Pediatric Pharmacology Head Injury Study Coordinator
CDMCC Principal Investigator jeri.burr@hsc.utah.edu brooke.millar@hsc.utah.edu
mike.dean@hsc.utah.edu
Richard Holubkov, PhD Kym Brown, BA
Mike Shults, MA Chief Biostatistician Bronchiolitis Study Coordinator
ACORN Nodal Admin. rholubkov@hrc.utah.edu kimberlee.brown@hsc.utah.edu
mbshults@ucdavis.edu
Clay Mann, PhD, MS Christy Hansen
Tasmeen Singh, MPH, NREMT-P Director of Research Executive Secretary
CARN Nodal Admin. clay.mann@hsc.utah.edu christine.hansen@hsc.utah.edu
tsingh@cnmc.org
upcomingmeetings
The PECARN Steering Committee Meeting is The PECARN Steering Committee Meeting and
scheduled for Tuesday, September 21 through the study training sessions will be held at the
Thursday, September 23, 2004 in Chicago, IL. The Swissotel Chicago. For more information regarding
PECARN meeting will begin at 2:30 PM on Tuesday the logistics for this meeting please refer to the IQ
and will adjourn at 6:30 PM. On Wednesday the Solutions eRoom.
meeting will be from 8:30 AM to 6:00 PM and on https://www.nedarcssl.org/eRoom/nddp/IQSolutions
Thursday the meeting will begin at 8:30 AM and
adjourn at 12:00 PM. It is recommended that those Swissotel Chicago
outside of the Chicago metropolitan area arrive 323 East Wacker Drive
Chicago, IL 60601-9722
on Monday, September 20th, in the afternoon or
Phone: (312) 565-0565
evening. Fax: (312) 565-0540
www.swissotel-chicago.com
The PECARN Steering Committee Meeting will
be combined with four study training sessions. On
Tuesday from 8:00 AM to 2:00 PM the Hypothermia
Planning Grant Training meeting and the Seizure
Principal Investigator Training meetings will take
place. On Thursday from 12:00 PM to 5:00 PM
the Bronchiolitis RA Training meeting and the
Diagnostic Grouping Systems Investigator
Meeting will take place.
fall 2004 page 3
Adverse Event Reporting in Clinical Trials Continued
been changed thirteen times, most re- investigational plan”. Another Example:
cently on May 17, 2004. This most recent Finally, the guidance requires SAE re- Suppose an investigator studied head in-
label revision provides new information porting as follows: “All serious adverse jured patients’ response to a study drug.
concerning drug interactions with dexa- events (SAEs) should be reported im- One site reported that 4 out of 10 subjects
methasone. mediately to the sponsor except for those vomited after receiving the study drug.
Although it is a seemingly safe, well es- SAEs that the protocol or other document Since vomiting could be related to the
tablished drug that has been used suc- (e.g., Investigator’s Brochure) identifies underlying head trauma, the event may
cessfully in children, dexamethasone is as not needing immediate reporting. The seem insignificant. However, it is possible
a drug that may yet demonstrate unex- immediate reports should be followed that oral administration caused vomiting
pected side effects. We are using only a promptly by detailed, written reports. The in numerous of patients across multiple
single dose in our Bronchiolitis study. So investigator should also comply with the sites. This would not be revealed unless
why report seemingly benign events such applicable regulatory requirement(s) relat- all investigators reported the vomiting
as admission, vomiting, rash, or even ed to the reporting of unexpected serious events. The conclusion of the study may
relatively expected events like intubation? adverse drug reactions to the regulatory be that the drug, while effective, caused
The answer is clear: no matter how safe authority (ies) and the Institutional Review vomiting frequently enough that its use
an approved medication appears, there Board (IRB).” is not justified. This is precisely why all
is ALWAYS the possibility of a previously Can you translate that? adverse events must be reported without
unknown effect. Seemingly insignificant or An AE is an experience that takes place investigator bias.
isolated events may be viewed as a “clus- after the investigational drug is given that The protocol can define reporting re-
ter of cases” when they are analyzed to- is “untoward,” harmful, or increases the quirements for AEs and expected SAEs,
gether. It may be hard to appreciate why it risk of harm to the patient. Say your cute, but unexpected SAEs are required by
is necessary to report events that appear squalling infant, affectionately known regulations to be reported immediately.
to be completely unrelated to the study as study subject number one, suddenly The Bronchiolitis study will detail specific
drug, or are more likely related to the dis- sprouts horns after administration of the requirements for immediately reporting all
ease itself. However, we must remember, study drug. This is an adverse event (AE). unexpected SAEs.
it is impossible to determine if an event Since this was not listed in the consent We are studying vulnerable populations
is drug-related in a single patient. These form or the drug information, as a known in PECARN (and the current bronchiolitis
events must be evaluated in the context side effect of the drug, it is an “unexpected RCT) and it is important to adequately re-
of the entire study population in order to AE.” I am sure the parents would agree! If port Adverse Events. The updated Manual
determine relatedness. the development of horns requires admis- of Operations (MOO) and study guidance
A Primer for AE Reporting sion to the hospital, or surgery to remove will clearly specify how AEs and SAEs
The International Council on Harmoniza- them so the child does not suffer psycho- should be reported. If you are unclear at
tion, (ICH) Guidelines on Good Clinical logical torment, then it becomes a Serious anytime about how to report AEs, please
GCP guidelines (E6) define an adverse Adverse Event (SAE). Is this interesting contact the study PI or the CDMCC.
event (AE) as: “An AE is any untoward finding related to the study drug? Maybe, The most important things to remember
medical occurrence in a patient or clini- maybe not. Perhaps it was related to the are:
cal investigation subject administered combination of the study drug and the • Reporting: You are required to report all AEs
a pharmaceutical product and that does stress of spending 4 hours in a busy ED. and SAEs to your IRB and to the CDMCC as
not necessarily have a causal relationship Maybe you have just discovered an alien specified by the study protocol and MOO.
with this treatment. An AE can therefore life form. It doesn’t matter which; you must • IRB requirements: Each IRB has specific re-
be any unfavorable and unintended sign report this event even if it does not seem quirements about AE reporting and often has
special forms on which to report AE. It is the
(including abnormal laboratory finding), to be caused by the study drug. Reporting responsibility of the Investigator at each site to
symptom, or disease temporally associat- the event is the first step. The AE report report AE as required by the individual hospi-
ed with the use of a medicinal (investiga- will also ask the investigator to determine tal.
tional) product, whether or not related to the causal relationship of the horns to the • Forms: Complete all information on the AE
the medicinal (investigational) product.” study drug. The choices are: form.
The same guidance defines a serious • Definitely related • Site Monitoring: Site monitors will evaluate
adverse event (SAE) as “Any untoward • Possibly related how well a site has reported AE by completing
medical occurrence that at any dose: • Probably related chart abstractions.
• Results in death • Unlikely to be related AE reporting is much like a puzzle; you
• Is life-threatening • Unrelated cannot make sense of it until you have all
• Requires inpatient hospitalization or prolon- These choices require the investigator the pieces. Reporting promptly and ac-
gation of existing hospitalization to make an assessment regarding the curately is one of the keys to conducting
• Results in persistent or significant dis causal relationship between a drug or in- a safe, ethical and responsible clinical
ability/incapacity tervention and the AE. Reporting the AE trial. To report AEs accurately, you must
• Is a congenital anomaly/birth defect” is not an option; categorizing it in terms approach the process with no pre-con-
An unexpected SAE is defined by the of relatedness relies on the opinion of the ceived notions about the symptoms or
guidelines as “An adverse reaction, the investigator on site. If horns have been events that occur. Reporting ALL adverse
nature or severity of which is not consis- sprouting in babies who are not in the events is akin to dumping all the pieces of
tent with the current investigator brochure; study, then a relationship is unlikely. This the puzzle on the table and putting them
or, if an investigator brochure is not re- is an important distinction and helps the together to form a complete picture. This
quired or available, the specificity or se- Data Safety Monitoring Board (DSMB) or process will help ensure that all the infor-
verity of which is not consistent with the IRB determine the action to be taken as a mation is available to assess the safety of
risk information described in the general result of your findings. the study drug.
page 4 fall 2004
From Initiating to Regulating
T hroughout the months of May and monitoring visit. These performance
June every site involved in the indicators may include everything
Head Trauma Study received a “site from enrollment rate (below 70 % of
initiation visit.” The main purpose of eligible patients for a 4 week period),
this visit was to review study materi- to poor data quality, to unexpectedly
als, educate research personnel about high numbers of patients who meet
compliance to Good Clinical Practice, exclusion criteria, to low total num-
and to review study procedures to bers in any category (missed eligibles,
assure compliance to the protocol. A patients who meet exclusion criteria,
visit at this stage of the study was in- and enrolled).
tended to clarify confusing issues and As mentioned, these triggers initi-
assure that the study would proceed BROOKE MILLAR, BS ate a site investigation. A phone call,
in the appropriate manner. Now that Head Injury Study Coordinator email, or letter will be sent to the site
sites are familiar with study imple- prior to the monitor showing up to
conducted during the study to as- conduct a formal site visit. If the is-
mentation and have been instructed sure regulatory compliance, sufficient
on how to maintain an Essential Docu- sues are unresolved after the inquiry
patient entry, (and) data quality…” then a Site Monitoring Visit will be
ments Binder as well as how to report The policy also states that there are
clean data, a “Standard Operating scheduled. This process is intended to
“triggers” which would initiate inves- provide a means to identify systematic
Policy and Procedure for Ongoing Site tigation of site performance. Several
Monitoring” will be implemented. problems so that a resolution can be
performance indicators will be mea- instituted at the site and therefore in-
The site monitoring policy for the sured to evaluate the need for a site
TBI study states that “visits are to be crease data quality.
Welcome Back Isabelle! a 2-year Hewlett post-doctoral
fellowship in reproductive health
tee on EMSC Research, renew-
ing contacts with federal and non-
Wemer colleague,to Dr. returned
are pleased see our for-
Melese-d’Hospital has
Isabelle
strategic planning, earning both
agency recognition and a Secre-
tarial award from the DOT. Prior
policy research at UCSF’s Insti-
tute for Health Policy Studies, af-
ter which she moved to the East
federal research entities of rele-
vance to EMSC. The EMSC Re-
searcher Listserv will be revived
to the EMSC National Resource to her four years as the NRC’s Coast. She is the proud mother of as well; send your email address
Center (NRC) with a new title, Research Specialist from 1999- 3 children. Now that she is back to emscresearch@emscnrc.com
“EMSC Research & Program An- 2003, Isabelle earned her Medi- at the EMSC NRC, Isabelle will to join!
alyst.” Previously a “Social Sci- cal Sociology Ph.D. in 1993 in again assist MCHB staff to pro- You’ll see Isabelle at PECARN
entist” at the Office of Strategic at UC San Francisco, where her mote and support the PECARN. meetings, EMSC Grantee meet-
and Program Planning at NHTSA dissertation on adolescents’ per- She will also resume providing ings and at some research con-
(USDOT) from 2003-2004, Isa- ceptions of HIV prevention edu- research advice to state grantees ferences. You can also contact
belle worked closely with the Ad- cation earned her the first Anselm along with NEDARC and CPEM. her directly at imelese@emscnrc.
ministrator’s office in international Strauss Qualitative Dissertation She will resume coordination of com or 202-884-6861.
health, traffic safety policy and Award. After graduation she held the federal Interagency Commit-
Creating a Diagnosis Grouping System for Child ED Visits
1) Create a Diagnosis Group- ity and measures of EMSC re- gency medicine physicians led
ing System (DGS), driven by source utilization. by an experienced facilitator.
clinical sensibility, by grouping 3) Evaluate the Diagnosis Both the DGS and SCS will
ICD-9-CM diagnoses given to Grouping System and Severity be derived from the PECARN
children during ED visits. The of Illness Classification System Core Data Project. This pro-
goal is to create a system, by applying them to external posal advances Objective C-4
using expert consensus and data sets. The goal is to en- of the EMSC Five Year Plan
clinical judgment, in order to sure that the systems created that requires research about
EVIE ALESSANDRINI, MD, MSCE comprehensively, sensibly and as part of this project may be the quality and effectiveness of
Investigator parsimoniously describe ED applicable to data sets routine- the EMS system’s services for
S ince ED’s provide care to diagnoses. ly used by EMSC researcher, children. The first consensus
patients with a full spec- 2) Create a Severity of Illness clinicians, policy makers and meeting will convene in Chi-
trum of illnesses and injuries, it Classification System (SCS), administrators. cago on September 23rd.
is important to have a taxono- by stratifying ICD-9 diagnoses Methods used for this re- Evaline A. Alessandrini, MD,
my system and severity scale within each Diagnosis Group search include both Nominal MSCE; Elizabeth R. Alpern,
that are applicable to all pedi- into four mutually exclusive Group and Delphi Process MD, MSCE; James M. Cham-
atric emergency patients. categories of illness severity consensus techniques and will berlain, MD; Marc H. Gorelick,
The specific aims of this and to examine the relation- draw on the expertise of a panel MD, MSCE
EMSC funded project are: ship between diagnosis sever- of pediatric and general emer-
fall 2004 page 5
ACORN
• ACORN welcomes the following re-
nodalnews approval from the Residency Review
Committee on Emergency Medicine
for a Fellowship Program in Pediatric
search assistants: Virginia Koors at ness Center at the School of Health
Professions, University of Michigan- Emergency Medicine. The first fellow
St. Louis Children’s Hospital, Kateland in this re-established Fellowship pro-
Webber at Cincinnati Children’s Hos- Flint, and Assistant Professor in the
Department of Health Sciences and gram is Dr. Jennifer Mackey, a 2004
pital, Kammy Jacobsen at Primary graduate of the Pediatric Residency
Childrens Medical Center in Utah, and Administration. We wish her the best
of luck in all her future endeavors! Program at SUNY – Upstate. James
Duke Wagner at Medical College of Callahan, MD, FAAP, FACEP, Associate
Wisconsin.
PED-NET Professor of Emergency Medicine and
CARN Pediatrics has been named the direc-
• Births: to Lynn Cimpello, Site PI tor of the Fellowship Program.
• CARN welcomes Kate Barcomb as at University of Rochester, Abigail
a new research assistant and Bobbe and Luke born on July 26th; to Neil • Peter Dayan of Children’s Hospital
Thomas as a new nodal project as- Schamban, Site PI of Newark Beth Is- of New York has been awarded a K12
sistant. rael, Alexander born on April 15th; to grant for the period 8/1/04-7/30/06.
Michael Bachman, Co-Investigator at The project title is: Multicenter Emer-
GREAT LAKES Newark Beth Israel Alice Maya born gency Department Study to Assess
• Please join us in congratulating Mary on August 28th. the Risk of Intracranial Abnormalities,
Ann Gregor, DrPH on a new position Interrater Reliability of Clinical Find-
• The Department of Emergency Med- ings, and Management Patterns for
she will soon be taking. Effective Sep- icine at SUNY – Upstate Medical Uni-
tember 7, 2004, Dr. Gregor will be the Children with First, Apparently Unpro-
versity in Syracuse, NY has received voked Seizures.
Director of the Urban Health and Well-
Intention to Treat
controlled “lab setting”. For new drug had side effects side effects from the new
example, studies are done preventing its full delivery. drug; such kids might be
to see if there is a dose- the focus of a subsequent
response curve for a drug, Hopefully, it’s clear that study.
and what the maximum tol- the old drug would be pre-
erable dose is. For these ferred for use in the above One question that is of-
early studies, crunching the example, because for a child ten debated is whether “in-
data using only animals or walking into the ER, his/her tention to treat” extends to
subjects who received the overall chance of admission study entry criteria as well.
RICH HOLUBKOV, PHD drug according to protocol would be lower if the old- For example, if our study
Biostatistician often makes sense. er drug were given. From had an upper age limit of
a pharmaceutical point of 9 years, but due to a birth-
Many done data“intention
will be
study protocols say
that the
by
analysis
By the time a drug is
being studied in our net-
work, we want to know if
view, the new drug is bet- year mix up, a 10-year-old
ter than the old drug when was in “good faith” entered
both are given in a “lab into the study, should that
to treat”. What does this the drug is effective in the setting” without regard to subject be counted in the
expression mean, and why “real-world setting”. Let’s potential side effects. But, final analysis? I do not be-
is this done? “Intention to say a powerful new drug is the STRATEGY, or regimen, lieve there is a “right an-
treat” analysis is usually very effective in reducing of using the old drug is su- swer” here; I might lean
used in the setting of ran- admissions in kids who re- perior (in the “real world” towards excluding that sub-
domized trials. It means ceive a full dose, but also ER setting) to a STRATEGY ject from the main analy-
that patients assigned to has strong side effects that of giving the newer drug. I sis because a “hard” study
a treatment are counted lead to its withdrawal in a always look at “intention to entry criterion was violated
as being in that treatment large proportion of kids, treat” as a comparison of and because the study re-
group for the analysis, even before they can get the strategies rather than drugs sults will be represented as
if they wind up discontinu- beneficial effect. This drug or devices themselves, since applying to children up to
ing the treatment, and even is being compared to an all consequences of first age 9, but one could argue
if they wind up changing older, less effective agent, trying a particular treat- in the other direction just
over to the other treatment which is tolerated by most ment are counted in favor as well. Perhaps more im-
arm in the study! kids. Among kids receiv- of, or against, that treat- portant is that all enrolled
Why would you want to ing a full regimen of either ment regardless of what subjects are accounted for
look at a study in this way? drug, those getting the new the patient undergoes after in the final report (see this
Early on, when a drug or agent would show a better that. In our example, so- author’s earlier article on
device is being developed treatment effect. When all called “secondary” analyses CONSORT, which you have
using animal models or randomized kids are com- would look at if the new no doubt cut out, framed,
even in early, small-scale pared, though, those as- drug is in fact better among and put on your office wall)
research in human volun- signed to the older drug kids receiving a full dose of and that the effects of any
teers, the major interest may have lower overall ad- each, and whether well-de- enrolled subject exclusions
is if the agent works in a mission rates, because so fined subgroups of kids can on the study results are de-
many kids assigned to the be found at very low risk of scribed.
page 6
pecarnupdate
Psych Working Group: Data collection for to regulate site performance. A new site Epilepticus: A Double-blinded Randomized
the PWG Pilot Project, “Referral Patterns monitoring policy has been developed. PIs Diazepam Controlled Clinical Trial: The NIH
and Resource Utilization for Pediatric and RAs are being contacted regularly. The issued a request for proposals (RFP NICHD-
Emergency Department Patients Presenting study continues to go very well due to the 2003-10) under the Better Pharmaceuticals
with a Psychiatric or Mental Health Problem: great collaboration of the Site PIs, the Site for Children Act (BPCA) for a contract to
study the pharmacokinetics and efficacy of
The PECARN Psych/Mental Health Working RAs and the CDMCC.
lorazepam for the treatment of pediatric
Group Pilot Study” is almost concluded. status epilepticus. Lorazepam is a
Data abstraction and entry is completed Hypothermia Study: As of August 11, the commonly used drug for pediatric seizures
at all but two participating sites. Derivative study database contains 110 abstracted but is not FDA-approved for children
projects and grant development are records from 15 sites. Site investigators under 18 years of age. The BPCA has a
planned for fall 2004, including submission and abstractors will meet in Chicago congressionally mandated list of such
of abstracts in December 2004 - January drugs that require pediatric study. The
before the regular PECARN meeting. The objective of this contract is to determine
2005. A second project is near completion: application for the R34 clinical trial planning
a PECARN-wide survey of Psych/Mental the pharmacokinetics and optimal dosing
grant is under development. This grant of lorazepam for pediatric use and to
Health issues in the ED. The survey will will provide $100,000 over 1 year to write conduct a randomized controlled trial of
be presented to PECARN subcommittees the protocol and manual of operations for lorazepam with a diazepam control arm
for approval and prioritization in the the randomized controlled trial. Mary Ann for the treatment of status epilepticus. The
coming months. A survey of ED physician Gregor is leaving the project to take a new lorazepam study was the first in a series of
perception of Psych/Mental Health training position as the director of Urban Health and RFPs that will be issued by NICHD under
is next in line for development. Wellness Center at the School of Health the BPCA. Since status epilepticus is an
emergency condition and informed consent
Prehospital Working Group: Prehospital Professions, University of Michigan-Flint, is not feasible in the 5-min. therapeutic
Working Group: The working group and Assistant Professor in the Department window, this protocol was submitted
Submitted a survey to PCRADS at of Health Sciences and Administration. under an exception from informed consent
the February meeting which received Jenn Suhajda will act as the coordinator using the community consent process. Five
conditional endorsement. The survey is for the project. PECARN sites were originally submitted
designed to catalogue the EMS systems with a budget of $2.9 million. The NIH
PECARN Core Data Project: Phase I responded in Dec. 2003 informing CNMC
that serve PECARN HEDA’s to be able to electronic data are complete and analyses that we were in competitive range for the
meaningfully prepare to conduct EMS are ongoing. Phase II data (electronic and contract and requested the addition of 6
research within PECARN. We hope to chart review) are being finalized. Four sites. All of the PECARN nodes responded
finalize the survey soon and send it to manuscripts are currently in preparation and a total of 11 sites were resubmitted
HEDA sites for completion. Additionally, the based on the six abstracts presented at the in Dec. 2003 with a total budget of $4.6
C-spine proposal previously submitted to Pediatric Academic Society and Society for million. Since that time, we have been
PCRADS is forming a working group. If you Academic Emergency Medicine meetings
negotiating with the NIH regarding the
would like to be a part of the Prehospital exception from informed consent process.
earlier this year. Targeted submission of The NIH has a unique relationship with the
or C-spine Working Group, please contact manuscripts is fall 2004. The proposal for
Tasmeen Singh at tsingh@cnmc.org. FDA under the BPCA and has been working
ongoing annual collection (2003-2007) with CNMC to conduct this study without
Head Injury Study: Since the last PECARN of the electronic data was reviewed by an exception from informed consent, which
Newsletter was published, we have seen a PCRADS in June with approval to move is a long and labor intensive process. The
lot of progress with this study. The Head forward. Templates for IRB modification NIH recently asked for a revised submission
have been provided by the PCDP Working to begin the contract by conducting the
Injury Study continues to move along and pharmacokinetic portion of the study using
gather enrollment momentum. Our overall Group. Sites should be in the process of
submitting IRB renewals or addendums pre-consented neurology patients and
percentage of enrollment has gone from 74 those with seizure disorders who would
percent in June, to 80 percent at the end to reflect a change in protocol that allows volunteer for elective Lorazepam therapy.
of August. Almost 5000 patients have been annual submission of data for a five-year This proposal was submitted with a budget
enrolled thus far. Enrollment reports are period. of $1.9M for the Pk study and $5M for the
sent out each week. We have had several 3-year randomized trial using 11 PECARN
Bioterrorism Surveillance: Bioterrorism sites for both parts. Although a final award
conference calls, email discussions, and Surveillance: Historical data has been
even a PECARN wide meeting (Washington has not been determined for this contract,
sent to Children’s Hospital of Boston from the intensity of ongoing negotiations and
DC) since the last PECARN Newsletter Children’s National Medical Center and real the official response from the NIH indicate
publication. The working group will begin time data transfer has begun. Additional a competitive proposal. If funded, this will
to have their conference calls every third PECARN sites are getting IRB approval or be the largest external grant received by
week from now on. RAs had a conference are in the early planning phases. PECARN and begin October 1, 2004.
call in July to discuss common issues Use of Lorazepam for Pediatric Status
and questions. Efforts are being made
PECARN Core Data Project: https://www.nedarcssl.org/eRoom/nddp/PECARNCoreDataProjec
Room
Hypothermia: https://www.nedarcssl.org/eRoom/nddp/Study-HypothermiaPlanningGrant
Bioterrorism Surveillance: https://www.nedarcssl.org/eRoom/nddp/Biosurveillance
e
Effectiveness of Oral Dexamethasone in Acute Bronchiolitis: A Multicenter Randomized Contro
Clinical Decision Rules for Identifying Children at Low and High Risk for Traumatic Brain Injurie
page 7
newfaces Margaret Boyle, BS, EMT-D
Margaret Boyle received her BS in Biology from
Kammy Jacobsen, RA Syracuse University in 2001. After graduation,
I am so excited to be working with the PECARN Margaret began working at Upstate Medical
network! I have worked with some of the CDMCC University for the Advanced Life Support Train-
staff on the Public Access Defibrillation Trial and ing Center. She is planning to attend graduate
it is great to be involved with them again. I am
a certified EMT-Intermediate and in my “spare school in the fall of 2005 to pursue a Masters’
time”, I run a BLS training company. I am also Degree in Nursing. Margaret is very excited to
an EMT instructor and I am loving this opportuni- be part of the PECARN team and is enjoying
ty to expand my Medical vocabulary with words her first clinical research experience.
like “opacification”. I am the only girl in my
family with two adorable boys and a wonderful Virginia Koors, RA
husband that keep me active and enjoying life! I am very pleased to start my third career at Wash-
ington University School Medicine. Since graduat-
Christy Hansen, Executive Secretary ing from University of North Carolina – Chapel Hill
Christy is the new Executive Secretary for with a degree in Biostatistics, I spent over 17 years
Pediatric Emergency Care Applied Research conducting qualitative and quantitative marketing
Network (PECARN) at the Intermountain Injury research at a local telephone company. When my
Control Research Center. She has attended position was moved out of state, I decided to change
BYU for 3 years and was majoring in Marriage, careers and focused on being a mom and volunteer-
Family, Human Development and Pre-Med. She ing at my children’s school. I also became an Ad-
is currently working on completing her associated junct Faculty member at Webster University teaching
degree in Executive Administration and would marketing research and marketing statistics. As my
like to continue her Bachelors at the University children grew, I decided that it was time to pursue a full-time position. Here
of Utah. With 5 years secretarial experience she at Washington University I am the Research Coordinator for the TBI and the
is working to be a helpful addition to PECARN. Bronchiolitis studies, as well as being Program Coordinator for the Pediatrics
Christy is busy with her 2 little boys and keeping up with her husband’s Emergency Medicine Research Associates Program (PEMRAP). (By the way,
school schedule. She is very thrilled to be working with Sally Jo, Brooke my boys are now 13 and 16 years old.)
and Kym at the CDMCC.
Kate Barcomb, RA
Neysha Fletcher, RA My name is Kate Barcomb, everyone calls me
A member of the five-time Grammy Award win- KB, ‘cause it’s easier. I went to Hopkins for
ning Brooklyn Tabernacle Choir and Globe trek- undergraduate and received my BA in Public
ker, Neysha is the new Research Coordinator Health. I played Lacrosse for Hopkins and was
at Harlem Hospital Center. She did her under- an academic all-American in 2004. I am from a
graduate work at The University of Pittsburgh family of 6, of which I am the youngest and the
and at The City University of New York – So- only girl, besides my wonderful mother. My life
phie Davis Bio-Medical Program. Her ultimate long goal is to start a Lupus treatment center in
goal is to continue Globe trekking with her 18 my mother and father’s name. I am excited to
month old son until they have conquered every be a part of PECARN and to be working with a
country / island, while completing her educa- great group of people.
tion to become the next CEO of Harlem Hos-
pital Center. Good Clinical Practice Tip
Duke Wagner, RA Section 4.9.4 of Good Clinical Practice states - “The investigator/
I have a diverse background and really enjoy being a part of the research institution should maintain the trial documents as specified in Es-
team here at the Medical college of Wisconsin in Milwaukee, WI. I have sential Documents for the Conduct of a Clinical Trial (see section
degree’s in Chemistry, Human Biology and a Doctorate in Chiropractic. I 8.) and as required by the applicable regulatory requirement(s).
was in practice for 12 years in a suburb of Milwaukee and finally decided The investigator/institution should take measures to prevent ac-
to become a part of a bigger medical facility. Chiropractic practice is not cidental or premature destruction of these documents.”
out of the realm of future possibilities again, but research is engaging and If you keep trial documents in your e-mail system make sure
important (I remember this even when entering data), and I hope for a fu- you talk to your IT department about archiving/saving your e-mail
ture in it with this excellent facility. My wife Carlyn and I have two children messages.
and a new home in Waukesha county west of Milwaukee. Bottom line, you should be able to retrieve trial documents until
CDMCC informs you in writing when the trial-related records are
no longer needed (GCS section 4.9.5).
ct
olled Trial: https://www.nedarcssl.org/eRoom/nddp/BronchiolitisRCTProject
es after Mild Blunt Head Trauma: https://www.nedarcssl.org/eRoom/nddp/HeadTraumaStudy
page 8 fall 2004
Sepsis
pressors if initial fluid management (CCMC-ACORN), Clay Mann, PhD
fails to restore perfusion, and the use (CDMCC), and Rachel Stanley, MD
of steroids in patients who are resistant (UM-GLRN),
to catecholamines and suspected to
be adrenally insufficient. Figure 1. Recommendations for stepwise
The Sepsis Project Working Group, management of hemodynamic support
led by Dr. Steve Miller, has developed a in infants and children with goals of
physician survey to determine current normal perfusion and perfusion pressure
variation in practice for pediatric septic (mean arterial pressure - central venous
pressure [MAP - CVP]). Proceed to next
shock and to determine acceptance step if shock persists. PALS, pediatric
of the guideline by practitioners. The advanced life support;PICU, pediatric
Working Group includes the following intensive care unit;SVC O2, superior vena
HELENA RINCON members: Kathleen Brown, MD cava oxygen;PDE, phosphodiesterase;CI,
PED-NET Nodal Administrator (CNMC-CARN), Peter Dayan, MD cardiac index;ECMO, extracorporeal
and Dale Hesdorffer, PhD (CHONY/ membrane oxygenation. From Carcillo, et
M ortality rates due to sepsis in
children have decreased from as
much as 97% to as little as 9% over
CUMC-PEDNET), Rene Enriquez
(CDMCC), Stephanie Kennebeck, MD
al 2002 (CCM 30:6, pp 1365 – 1378).
the past 25 years. Different practices
may affect outcomes, and variations in
practice persist. Sepsis still accounts
for 4,400 pediatric deaths in the United
States each year. Standardized early
aggressive therapy in the emergency
department for adults with sepsis has
been shown to decrease mortality.
Studies in children with sepsis have
also suggested that early aggressive
fluid resuscitation and treatment in
specialized centers may decrease
mortality. These observations, among
others, led to the delineation of a
practice guideline published in June
2002 by the American College of
Critical Care Medicine, endorsed by
American Heart Association/Pediatric
Advanced Life Support (ACCM-
PALS) recommending standardized
early aggressive therapy for pediatric
sepsis. Research has demonstrated
that adherence to this guideline may
decrease mortality, yet adherence
remains variable. Additionally, the
importance of the ACCM-PALS
guideline for the management of
pediatric sepsis in the emergency
department and the commitment
of individual ED practitioners to the
guideline remain to be confirmed. The
evidence for the recommendations,
the ability of the guideline to alter
outcome and the feasibility of the
suggested approach are not definitive.
The guideline includes three major
recommendations; aggressive fluid
management with the administration
of up to 60 cc/kg of fluid within 15
minutes of presentation, use of
fall 2004 page 9
Protocol Deviations
A just-in-time-refresher...
P rotocol Deviations-the term strikes
a familiar chord in your brain. Of
course! The Bronchiolitis study last
say an investigator studying the use of
XYZ drug decides that an additional
dose of the study drug is better for the
year; it is all coming back now… patient than the dose specified in the
PECARN learned some important protocol. Will this have an effect on the
data? And could this cause a problem
lessons about protocol deviation re- in the study participant? Is it a protocol
porting during the Bronchiolitis study, deviation? The correct answer is yes
our first PECARN randomized con- to all three questions.
trolled trial. Gathering protocol devia- SALLY JO ZUSPAN, RN, MSN
tion reports early in the study helped Q: Is there a regulatory requirement to re- CDMCC Program Manager
us correct confusion regarding spe- port PD?
cific procedures, identify site specific A: Of course! Good Clinical Practice • AE or SAE not reported according to
medication administration issues, and (GCP) requires reporting of PD: ICH GCP guidelines
re-think patient communication. Pro- 4.5.3 states that the investigator or per- ex: The patient had a seizure and
active reporting by the HEDA allowed son designated by the investigator should the site did not report it as an AE
document and explain any deviation from • Premature “unblinding” of research
Dr. Corneli, Stacey Townsend, and the
the approved protocol. treatment or data
CDMCC to make clarifications so that • Loss or corruption of study data or
the study would run more smoothly. Q: What types of protocol deviations study files
When we noted confusion among par- should be reported for Bronchiolitis? ex. The patient record was left in the
ents about steroid use in their infants, A: Each HEDA IRB will have a defined list ED lobby
an updated list of steroids with com- of reportable protocol deviations that must • Other deviations as identified by the
mon names and descriptors was cir- be reported by the site personnel to the site personnel or site monitor
culated to help increase parent accu- local IRB. You must contact your IRB to
racy in identifying whether their baby see what they require, and how you must Q. Does a protocol deviation mean a site
had taken steroids before. This is just report deviations. For Bronchiolitis, the made an error?
one reason why understanding Proto- CDMCC requires the following to be re- A. Not necessarily. Deviations may result
ported to even if they are not reportable from problems on the part of the study par-
col Deviations (PD) is so important.
by local IRB standards. Standard PD and ticipant, parent, investigator or site staff.
Just in case you are a little rusty, an example of each deviation is listed be- If the mother states the baby has never
here is a quick primer on PD. low: wheezed, then it may not be avoidable.
• Enrolling subjects who do not fulfill in- On the other hand, maybe the error points
Q: What is a Protocol Deviation? clusion/exclusion criteria to a need to further describe “wheezing”
A: A Protocol Deviation is any departure ex: A site that unknowingly enrolls when speaking to parents. Furthermore,
from the defined procedures and treat- a baby with a previous history of deviations may not be attributable to any
ment plans as outlined in the protocol that wheezing because the mother states one error, and identifying them should not
was approved by the IRB. Failure to fol- child has never wheezed be a punitive process. Rather a deviation
low GCP may also represent a deviation. • Subjects receiving any study related is simply an event that does not comply
activity such as treatment, procedures, with the protocol.
So far, the concept is simple: if the or drug administration prior to obtaining
protocol states that a procedure, documented IRB approved Informed Q: How do I report PD to the CDMCC in
exam or clinical event should be done Consent the Bronchiolitis study?
a certain way, and it was not, then you ex: Study drug is administered prior A: PD reports will be reported by fax to
have a deviation. to consent being signed the CDMCC. More details will be available
• Variations in drug dosing/dispensing/ when the study starts.
Q: Why is protocol deviation reporting so storage
important in a clinical trial? ex: A drug dose is intentionally in- Q: Will the CDMCC track and report PD?
A: Protocol deviations must be reported creased above what the protocol A: Since the CDMCC is a data center, we
for several reasons: specifies. track everything! However the focus of
• Protocol deviations have the poten- • Medication errors (wrong pt, wrong these reports is to improve the quality of
tial to place participants at risk and can time, wrong dose, wrong med) the study and the more consistent the re-
also undermine the scientific integrity ex: The RN erroneously gives the porting of PD, the better the study will be.
of the study thus jeopardizing the justi- patient 2x the dose of the study
fication for the research. drug. We all need to keep on top of re-
• Consistent patterns of a particular • Use of prohibited medications porting of protocol deviations. Your dil-
deviation at multiple sites may reveal • Incorrectly performed or missing pro- igence and timely reporting will make
the need to amend the protocol, or tocol required procedures a big difference in the safety and qual-
may impact analysis of the study data. ex: The 1 or 4 hour RDAI is done ity of study. You will be hearing more
Consistent reporting helps the PI rec- late, or is not done at all. The RDAI
is done with the baby (not the RA)
about protocol deviations in the com-
ognize and correct study or clarify the ing weeks.
protocol as needed. For example, let’s laying down and on Oxygen
page 10 fall 2004
Research in Children
evant to pediatric research: in- our basic premise is equipoise from a research subject when
formed consent, and definition – that is, the clinical communi- the age of majority is reached.
of risk. Problems with informed ty truly does not know if there Unlike the situation with adult
consent have been important is benefit from the treatment research subjects, who may
in other research networks. under study. The situation is provide informed consent for
The definition of risk in pediat- worse for parents when the the future use of their genetic
ric research has been a topic of child has a serious illness such material, our consent process
controversy and a recent IOM as cancer, and studies suggest will have to adapt to the chang-
report has significantly altered that parents often do not per- ing ages of our subject popula-
J. MICHAEL DEAN, MD, MBA the landscape of debate. Both ceive a real choice or do not tion.
Principal Investigator topics are of importance to us understand the difference be- Our proposal for this prob-
as PECARN researchers. tween research and treatment lem (genetic material) is that
P ECARN research often in-
volves human subjects.
The subjects are children, a
Informed Consent
Most research subjects in en-
[5-7]. In desperate situations,
stressed parents may perceive
parental permission must be
obtained for sampling and stor-
countered in PECARN projects that study participation is part ing the material for specific or
vulnerable population, and the will be children who are not le- of “trying everything” to save non-specific purposes, and that
diseases and therapies under gally able to provide informed their child [8]. In a study of if the child is able to provide as-
study have significant mortal- consent. Thus, informed con- neonatal clinical research, par- sent, that should be obtained.
ity and morbidity. We consider sent is more complicated for ents who consented were more At the time of specific analyses
it imperative to approach the the our network than for re- likely than decliners to believe of the genetic material, the cur-
privilege of conducting human search networks dealing with that the research would prob- rent age of the subjects should
subjects research with a pro- adults. There are two issues ably benefit their infant [9]. be checked, and if the devel-
spective, thoughtful, rigorous worthy of discussion here: (1) We raise these issues about opmental status of the subject
and ethical framework. This parental permission and child parental understanding be- has changed to permit assent
framework recognizes that hu- assent; (2) informed consent cause “…the conditions for in- for the research, this should be
man subjects protection is not by minor (under age) research formed and reasoned choice obtained. If the subject has
“IRB approval”, but rather, in- subjects. are threatened when parents reached the age of majority,
volves a complex interaction Parents cannot provide in- are confronting a new diag- then the parental permission is
of organizations (e.g., sponsors, formed consent on behalf of nosis of a life-threatening no longer applicable, and the
funding agencies, academic insti-
their children. Rather, parents medical condition and a crisis subject should be approached
tutions), organizational entities
(or guardians) provide permission situation in which immediate for informed consent.
(e.g., Institutional Review Board,
for their children to participate, decisions are sought [1].” Our It is likely that the Steering-
Office for Human Research Protec-
and when appropriate, children network is likely to be dealing Committee may approve a
tions), and individuals (e.g., chil-
provide assent for their own with parents in such a stress- PECARN project or topic involv-
dren, families, investigators). In
participation, in research stud- ful situation. It is crucial that ing emergency illness in adoles-
the multi-institutional setting ies [2]. In the pediatric emer- the processes used for inform- cents. In some instances, ado-
of a research network such as gency setting, we anticipate ing parents and obtaining their lescents may be emancipated
PECARN, the human subjects that most patients will not be permission for research partici- and legally enabled to provide
protection system involves able to provide assent because pation of their child are on-go- informed consent on their own
multiple research institutions of their acute illness. However, ing and thorough, as instances behalf. However, variable state
with their local IRBs, poten- during follow up research af- of misunderstanding can have regulations will be faced. State
tially multiple sponsors and ter discharge from the ED or serious ramifications for the statutes have been summarized
funding agencies, the MCHB, hospital, issues about assent function and even the on-going in the Appendix of the Institute
NICHD and FDA, the DSMB, the become applicable. In most ju- existence of the research net- of Medicine publication “Ethical
PECARN Steering Committee, risdictions, the standard is that work (in addition to the obvious Conduct of Clinical Research
different state laws governing when a child is believed to be ethical imperative to effectively Involving Children” [1] but the
informed consent by minors, cognitively able to understand, inform the parents). We believe state statutes do not deal with
different community standards then assent should be sought. that thorough understanding research consent. The network
and interpretations of risk, and This is often translated into an of these issues, on the part of will need to consider these is-
different community cultures “age of assent” of 7 years, but the PECARN investigators and sues if we undertake a trial
and ethical norms [1]. The this age criterion differs be- CDMCC staff, is absolutely criti- likely to involve emancipated
network itself is an important tween communities. cal. adolescent populations.
component of the human sub- Research suggests parents If genetic material is obtained What Is Risk?
jects protection system, and may have a therapeutic mis- from a PECARN research sub- All research projects carried out
PECARN Principal Investiga- conception that the purpose ject and banked for future anal- by the PECARN involve children
tors and CDMCC must assure of research is treatment [3] yses, then the standards for as- (infancy through 21 years) almost
that all participants in network or that allowing their child to sent and consent may change exclusively. Research in chil-
research are fully compliant enter a clinical trial is an ave- as the child becomes older. We dren involves special protec-
with all regulatory and ethical nue to obtaining “cutting edge do not have easy solutions but tions under 45 CFR §46 Subpart
requirements, MCHB policies, therapy [4]”. It is important it will be necessary to decide D “Additional DSSH protections
and policies and procedures that the parents understand if a child’s assent will become for children involved as sub-
that have been defined by the that while there may be po- necessary in later years, and it jects in research” and 21 CFR
Steering Committee. tential benefits to their child is probable that complete in- §50 and §56. To simplify this
This article will concentrate participating in a PECARN trial, formed consent will be needed discussion, we will only refer to
on two subjects that are rel- Continued on Page 12
fall 2004 page 11
spotlights HAIPING QIAO, MS (PED-NET)
DOMINIC BORGIALLI, MD (GR LAKES) Haiping Qiao currently serves as the Research
I am an Emergency Physician and the new HEDA Director at Hurley Medical Assistant for the EMSC-NDDP project in the
Center. I graduated from the Emergency Medicine residency at Michigan Department of Pediatric Emergency Medicine at
State University-Lansing in June, 2003. Prior to medical school, I completed the Women and Children’s Hospital of Buffalo
a Masters in Public Health (Epidemiology) at San Diego State University. I (WCHOB). She graduated from the Capital
have worked as a wine maker, EMT, infectious disease epidemiologist, and University of Medicine, Beijing, China with a
researcher on injury-related studies. My research interest is the impact of MD degree in Pediatrics. She expects to get
injury on our society. I am married to Michele, and have 2 young children- her Master’s degree in Epidemiology from
Cypress and Bryce. Activities for fun are mountain biking and sailing. the State University of New York at Buffalo in
December 2004; her thesis examines the role
JULIE LEONARD, MD (ACORN) of probiotics in preventing antibiotic-associated
July 2004 marked the end of my training and I joined diarrhea. Her previous experience includes working as a research associate
the faculty of the Washington University School of in Beijing Pediatric Research Institute, Beijing, China, and in the Infectious
Medicine Department of Pediatrics. When I am Disease Department at the WCHOB. In both institutions, she served as
not manning the St. Louis Children’s Hospital ED a microbiologist and conducted microbiology and immunology research.
or working on a variety of cervical spine injury Haiping enjoys classical music and her son’s funny stories. Haiping and her
projects, I am “Soccer-Tennis-Basketball-Skating- family are happily living in Canada.
Piano-Tap-Baseball” mom to Jake and Jordan,
wife to Jeff, and dog owner of Hank and Lina (a BOBBE THOMAS, Nodal Assistant
Labrador and Chihuahua). We are originally from Tonetta Thomas - always referred to as Bobbe - is the new nodal project as-
Washington State (Go Dawgs!), so most of our sistant for CARN. She was recruited for the nodal project assistant position
vacation time is spent in the Pacific Northwest after working in the Emergency Dept. for only 4 months - thanks Dr. Atabaki!
where we enjoy cruising the sound, fishing the ocean and streams, and skiing So, PECARN being all the buzz in the ED, she immediately seized the op-
the lakes and mountains. portunity. A North Carolinian, Bobbe is a graduate of the Univ. of MD with a
BA in Communications. With a yearning to pursue pediatric advocacy and
health care, she is starting a nursing program at Howard University this fall.
Her future goal is to pursue clinical nursing and research. FYI, her favorite
movie obsession is the Sound of Music.
Informed Consent Checklist
F DA regulations require that informed consent be ob-
tained before a human subject may participate in any
clinical investigations. (21 CFR Part 50). The required ele-
• Information on whom to contact for answers to pertinent
questions about research, research subjects’ rights, and in the
event of a research related injury.
ments that must be present in an informed consent form • Statement that participation is voluntary
are as follows: • Statement that if they decide not to participate there will be
no penalty or loss of benefits to which the subject is otherwise
• Statement that study involves research entitled
• Explanation of purpose of the research • Statement that the subject may discontinue participation at
• Description of the procedures to be followed any time without penalty or loss of benefits.
• Expected duration of the subject’s participation • Statement of anticipated circumstances under which the
• Identification of any procedures which are experimental subject’s participation may be terminated by the investigator
• Description of any reasonably foreseeable risks or discom- without the subject’s consent
forts of the subject • Statement regarding any additional costs to the subject that
• Statement that there are risks that are currently unforesee- may result from participation in the study
able • Statement that significant new findings developed during the
• Description of any benefits to the subject or others reason- course of the research which may affect the subject’s willing-
ably expected ness to continue participation will be provided.
• Disclosure of appropriate alternative procedures or treatment • Statement concerning the approximate number of subjects.
advantageous to the subject • HIPAA language
• Statement that notes the possibility of FDA inspecting medi- • Any other elements that are specific to the protocol or re-
cal records quired by the institution’s IRB.
• Statement informing the subject that their medical records
may be examined by the sponsor and if so, the extent to which Many IRBs approve informed consent forms that are
those records will be kept confidential missing some of these required elements. Therefore, we
• Statement as to whether compensation is available if injury recommend that you review your informed consents to
occurs ensure that all of the above elements are included.
• Explanation as to whether any medical treatments are avail-
able if injury occurs
page 12 fall 2004
CDMCC on the Road...
ACDMCCJo excusewas the ED; walkedwarmly welcomed every
visit She and Kathy Lillis MD, familiar faces in ic training program to teach residents to
a great to were complete the forms, training medical stu-
travel to Buffalo this July. Sally visited the time they through. This might have dents to cover RA shift hours, and institut-
Children’s Hospital of Buffalo (CHOB) and something to do with the fact that Haip- ing an incentive program for attending and
welcomed Haiping Qiao, Research Associ- ing and Kathy have been providing “sweet residents. The Hypothermia project is also
ate, to PECARN. Haiping has been a whirl- rewards” to staff who have been actively up and running in the PICU. Donna Kielma
wind of activity in the few short months enrolling and identifying TBI patients. RN, and Brad Fuhrman, MD have identified
she has been involved in the network. She Haiping and Kathy have developed several appropriate patients and have completed
jumped right into the TBI project and has strategies to improve enrollment including: several charts for data entry. Donna has
already set up a very detailed highly or- providing direct feedback on enrollment extensive PICU experience and is doing a
ganized filing system for the TBI project. numbers to ED staff, developing a specif- great job on this project.
Research In Children Continued... approved (under §46.404) be-
cause it involves minimal risk.
the research may be carried
out relies on a risk to benefit
45 CFR §46 because the FDA cine released “Ethical Conduct But consider a project to study analysis by the Steering Com-
regulations (21 CFR §50 and §56) of Clinical Research Involving the metabolism of a drug in an mittee, the PCRADS, the MCHB
are sufficiently identical for Children” [1]. This publication acutely ill child. If the drug ad- and other funding agencies, the
this discussion. However, the will have significant impact on ministration presents no pos- DSMB, and each of the HEDA
PECARN needs to adhere to all pediatric research approved sible direct benefit to the spe- IRBs. If the risk to benefit ra-
applicable regulations in any under these categories of risk, cific child, then the study (which tio is considered reasonable by
particular study. and alters the interpretations of might be a simple pharmacokinet- these reviewers, the research is
Children are defined as per- minimal risk and minor increase ics study of a relatively benign, approvable under §46.405.
sons who have not reached the over minimal risk. commonly used drug) can only Studies that are likely to be im-
legal age for consent, and we Minimal risk compared to be approved if the risk of drug plemented by our network will
point out that this definition will what? This interpretive prob- administration presents only a fall under the first three catego-
vary by state laws. Research in lem has sometimes led to com- minor increase above minimal ries; the last category (§46.407)
children may only be approved parison of the risk of participa- risk compared to the average requires approval “…by…the
if the research falls within one tion in research to the risk of healthy child who is not in the Secretary…” (of Health) and the
of the following categories: the individual subject, given his emergency department or ICU. associated 407 review process
• Research not involving great- or her conditions of living or For most drugs, this is unlikely remains very unsettled [10].
er than minimal risk (45 CFR presence of disease. This “rela- to be the judgment for most IRB We would not recommend at-
§46.404). tivistic approach” might have members, since the non-zero tempting to obtain approval un-
• Research involving greater led to approval of research that risk of a serious drug reaction der §46.407 until the process is
than minimal risk but present- involves risk considered mini- is not a “minor increase above clarified and our network has
ing the prospect of direct ben- mal to a child in the intensive minimal risk”. For another ex- successfully implemented other
efit to the individual subjects care unit, for example, but not ample, consider isotopic stud- complex studies.
(45 CFR §46.405). considered minimal if compared ies of metabolism in acutely ill
• Research involving greater to the healthy child who is at children. Again, the relativistic
1.IOM, The Ethical Conduct of Clinical Re-
search Involving Children, ed. M. Field and
than minimal risk and no pros- home or at school. Similarly, a interpretation might have led to R. Behrman. 2004, Washington, DC: The Na-
pect of direct benefit to individ- minor increase above minimal approval of such studies, since
tional Academies Press. 425.
2.Kodish, E., Informed consent for pediatric
ual subjects, but likely to yield risk as sometimes been inter- the risk of isotope administra- research: Is it really possible? J Pediatr, 2003.
generalizable knowledge about preted as “compared to the tion is minimal in comparison 142(2): p. 89-90.
the subject’s disorder or condi- baseline risks of the specific with the baseline risks of criti-
3.Appelbaum, P.S., L.H. Roth, and C. Lidz,
The therapeutic misconception: Informed
tion (45 CFR §46.406). research subject”. Under these cally ill children in the ED or consent in psychiatric research. Int J Law
• Research not otherwise ap- relativistic interpretations, a the PICU. But if reviewers con- Psych, 1982. 5: p. 319-329.
provable which presents an child with intracranial pressure clude that administration of
4.Dresser, R., Patient advocates in research:
New possibilities, new problems. Washington
opportunity to understand, monitoring, ventilatory support, isotope presents more than a U J Law Policy, 2003. 11: p. 237-248.
prevent, or alleviate a serious and requirement of PA catheter minor increase above minimal
5.Levi, R., et al., Diagnosis, disclosure, and
informed consent: Learning from parents of
problem affecting the health monitoring, might be permitted risk, compared to the average children with cancer. J Ped Hematology On-
or welfare of children (45 CFR to be subjected to a different healthy child who is not ill, then cology, 2000. 22(1): p. 3-12.
§46.407). minimal risk or minor increase this research cannot legally be
6.Pletsch, P.K. and P.E. Stevens, Children
in research: Informed consent and critical
Approval of pediatric research above minimal risk than would approved. factors affecting mothers. J Family Nursing,
under the first and third cat- be permitted for a healthy Clinical trials are likely to hold 2001. 7(1): p. 50-70.
egories listed above requires child. out prospect of direct benefit,
7.Ruccione, K., et al., Informed consent for
treatment of childhood cancer: Factors af-
that the child be subjected to The relativistic interpretation and in such instances, the re- fecting parents’ decision making. J Pediatr
“minimal risk” and a “minor of minimal risk has been re- search may involve significantly
Onc Nursing, 1991. 8(3): p. 112-121.
8.Deatrick, J.A., D.B. Angst, and C. Moore,
increase above minimal risk”, soundingly rejected by the IOM greater than a minor increase Parents’ views of their children’s participation
respectively. The precise mean- report [1]. This has implications above minimal risk (the sec- in phase I oncology clinical trials. J Ped Onc
ings of minimal risk and minor for all PECARN studies that do ond category listed above). We
Nursing, 2002. 19(4): p. 114-121.
9.Zupancic, J.A.F., et al., Determinants of pa-
increase above minimal risk not present the prospect of di- believe that all interventional rental authorization for involvement of new-
have been subject to detailed rect benefit to the child. Our studies in the network will fall born infants in clinical trials. Pediatrics, 1997.
ethical analyses, and in July PCDP database does not offer in this category, in which case
99(1): p. 1-6.
10.SACHRP supports improving pediatric
2004, the Institute of Medi the prospect of direct benefit the judgment about whether research. Guide to Good Clinical Practice
to the child, but can easily be (Monthly Bulletin), 2004. 11(5): p. 4-6.
