Break Down Why do we need to be even talking about research in children? What makes kids different? How can research benefit my child? Research Basics Research vs. clinical care, risks vs. benefits, safety Types of research Examples of new clinical trials currently or soon to be enrolling Other ways of contributing/getting involved
Sir William Osler, 1903 ―the most influential physician in history‖ ―Who can tell of the uncertainties of medicine as an art? The science on which it is based is accurate and definite enough… but no two individuals react alike and behave alike under the abnormal conditions which we know as disease‖ ―The good physician treats the disease; the great physician treats the patient who has the disease‖ His description of the inadequacy of treatment methods for most disorders was a major factor leading to the creation of the Rockefeller Institute for Medical Research in New York
Startling facts… • By age 5 yrs, 95% of children have been prescribed a medication, with an average of 8.5 prescriptions and 5.5 different medications • Medicines, devices and treatments are often NOT tested in children – In fact, 70% of medicines prescribed to children have been tested ONLY IN ADULTS • ―Off-Label‖ use of drugs in children is commonplace – 79% of hospitalized children received at least 1 off label drug – Utilize a weight based dose adjustment for children – Necessary… but NOT ENOUGH!!Loebstein R et al, Pediatr Rev, 1998 (19)12:423-428, Shah S et al, Arch Pediatr Adolesc Med, 2007 (3) 161: 282-90
Children are not little adults! Lucas at The Magic House– St Louis, MO
Stages of growth: Makes pediatric patients unique at every stage • Differences in digestion and enzyme function • Differences in muscle mass and organ size • Differences in the effect of therapies upon a growing body – Are there long term consequences? • Differences in how the disease acts in kids compared to adultshttp://www.nhlbi.nih.gov/childrenandclinicalstudies/whyclinical.php
And don’t underestimate the effects of hormones… yikes!Courtesy of Greg Kearns, PharmD, PhD
Why should children be included inresearch? If we don’t include children in research, we leave them vulnerable to: Incorrect drug dosing Sideeffects Doesn’t work Not being prioritized for: research targeted at disease CURE genetic risk studies and counseling for future risk Understanding the role of disease prevention Understanding how complementary approaches may affect disease Identification of biomarkers to guide disease activity or inactivity
Examples of HOW research can help my child?• Find the best doses of medicines to prevent harmful effects or under treatment• Making safe and easily administered medicines for kids (chewables, liquids, yummy tasting!)• Finding treatments to conditions that are expressed differently in kids compared to adults (Juvenile arthritis)• Finding treatments for new or existing diseases to improve health in the future (vaccines)• Understand how medicines affect growing children and their development
Research vs. Clinical Care• Research is done to help find out if a treatment or procedure is good for a large group of people with a certain disease or condition. Research helps to answer questions for the future health of those populations. Standard medical care, however, focuses on individual needs in the present• Similarities: – Researcher and your healthcare provider can be the SAME person – Setting may be in your regular clinic – The treatments may seem the same
Research vs. Clinical Care: questions to ask• How is this different from standard care? – Will I see different doctors and nurses for the study? – Will I go to a different hospital or clinic for the study? – Will the doctors and nurses ask me a lot more questions about my childs condition? – Will there be more paperwork or additional tests when we are in the study? – Will there be more rules and deadlines in the study?
Will my child benefit? Research is done to gain information about a disease, condition, drug or treatment that will benefit children in the future– different than regular medical treatment that is given to help a specific child However- there are potential benefits: Helping future generations Having access to new drugs or treatments, doctors or other families with same condition Getting closer monitoring or additional testing
How will my child be protected? http://www.nhlbi.nih.gov/childrenandclinicalstudies /safety.php
How will my child be protected? Research team Investigator, doctors, nurses, statistical experts, pharmacists Determine the right study, performed in the right number of patients, done in the right way, with the right participants Institutional Review Board an independent committee that reviews research plans and consent forms to make sure that people in a study are informed and protected. They review studies both before they start and throughout the study.
Protection of study participants, cont. Informed consent/Patient assent Parent is given details about a study so that you can decide if your child should join a study. You are "informed" so that you can give your "consent" or okay. Nothing can happen until you consent to it. Most children from age 7 can understand basic information if it is given at their level. So, in most studies, children are now asked if they agree (assent) to be in a study and are asked to sign an assent form. Data and safety monitoring board/medical monitor impartial Board/person that oversees studies and says if a study should be changed or closed at any time for safety issues.
And remember your rights… Ask as many questions as you’d like You can say NO at any time, for any reasonwww.rfried.info
Research Organizations Specific toPediatric Rheumatology CARRA: Childhood Arthritis and Rheumatology Research Alliance Typically manages investigator-initiated studies PRCSG: The Pediatric Rheumatology Collaborative Study Group Handles drug industry-initiated research
Types of Research Observational Studies Translational Studies Clinical Trials Comparative Effectiveness Research (CER)
Observational studies Retrospective In the past Likely no consent will be obtained Combine clinical data (without identifiers) to look for associations This is a big part of the research we have to go on from the past Ex: Arthritis Rheum. 1977 Mar;20(2 Suppl):327-31. Drs. Sullivan, Cassidy and Petty evaluated the charts of 33 patients with JDM treated with steroids, and found that the outcomes of these children were infinitely better than children NOT treated with steroids
Observational Studies Prospective: Current/future Collect specific information on patients, often over time Registry Ex. CARRAnet registry (CARRA= Childhood Arthritis & Rheumatology Research Alliance) observational retrospective and prospective study that enrolls children and adolescents with major rheumatic diseases followed at participating study sites. All patients with defined rheumatic diseases who are 21 years of age or younger and who are seen/followed at a CARRA site for medical care will be approached for participation in the registry.
Translational Studies Used as a bridge linking bench/basic scientific research with the patient Multiple disciplines often involved Goal for faster application of knowledge to patient Usually a combined collection of clinical information and biologic sample(s) (blood, urine, tissue, hair, etc) Ex. Arthritis Rheum.2010 Jun;62(6):1803-12. My work is in measuring methotrexate metabolites in cells to determine if different patterns or genetic associations are predictive of better or worse response to the medicine
Clinical Trials Compares 1 or more treatments Often randomized Means your child may NOT get active drug/therapy Treatment follows very exact guidelines protocol Not all patients will qualify Inclusion and exclusion criteria Most scientifically rigorous and most expensive
Clinical Trials Phase 1 Safety doses Phase 2 Efficacy doses Phase 3 Compare drug to placebo, or current treatment- does it work? Is it safe? Phase 3 OLE Open label extension gathers additional safety data and longer term info about treatment effects Phase 4 Large observational registries to Basic Science/bench experiments explore medication safety once drug approved by FDA
What do we have going on in clinicaltrials in the US?
TRial of Early Aggressive Therapy inPolyarticular Juvenile Idiopathic Arthritis 2 arms Methotrexate subcutaneously OR Methotrexate subcutaneous, enbrel, steroids Both arms had patients who achieved clinically inactive disease at 6 months Methotrexate only: 23% Triples (M+E+S): 40% Both arms (although fewer) had patients who reached clinical remission on medication Methotrexate only: 7% Triples (M+E+S): 21%
RAPPORT: IL-1 TRAP in systemic JIA Closed to enrollment Last patient will finish in December 2012 3 translational studies are attached to this trial Analysis will begin in January 2013
Biologics: CIMZIA ClinicalTrials.gov Identifier: NCT01550003 Pediatric Arthritis Study of Certolizumab Pegol (PASCAL): Phase 3 with OLE- all patients receive drug Anti-TNF-α monoclonal antibody—fragmented Given subcutaneously every 2 weeks Inclusion Criteria: Diagnosis of Polyarticular-course Juvenile Idiopathic Arthritis (JIA) for at least 6 months prior to Baseline Children and adolescents, aged 2 to 17 years (inclusive); weight ≥ 10 kg Inadequate response or intolerance to at least 1 Disease-Modifying Antirheumatic Drug (DMARD) (previous exposure to a maximum of 2 biologic agents will be allowed) Methotrexate (MTX) and oral Corticosteroids will be allowed at stable doses prior to Screening Inadequate response or intolerance to Methotrexate (MTX)
Biologics: SIMPONIClinicalTrials.gov Identifier: NCT01230827 Safety and Efficacy of Golimumab in Children With JIA and Multiple Joint Involvement Who Have Poor Response to Methotrexate (GO KIDS) Phase 3 (randomized placebo arm after 16 weeks on therapy through 48 weeks) Anti-TNF-α monoclonal antibody--Given once a month injection Inclusion Criteria: Diagnosis must have been before the patients 16th birthday Disease duration of at least 6 months before study entry Must have >=5 joints with active arthritis Must be taking a stable dose of methotrexate May take a stable dose of prednisone less than 10 mg/day 4 weeks prior to entry or may take a stable dose of NSAIDS (non-steroidal anti- inflammatory drugs) 2 weeks prior to entry Must have qualifying laboratory values at the first visit.
Biologics: ActemraClinical Trials.gov Identifier NCT01603355 Tocilizumab (anti IL-6 receptor antagonist) in the Management of Juvenile Idiopathic Arthritis Associated Uveitis Phase 1 and Phase 2, pharmacokinetics study (will measure blood levels of Tocilizumab, and assess safety ) Tocilizumab given IV every 4 weeks (dose depending on weight) JIA- associated Uveitis (ages 2-17 yrs) Oregon Health and Science University (not yet recruiting) Inclusion Criteria: Subjects with Juvenile Idiopathic Arthritis Subjects with vision-threatening autoimmune uveitis. Failure to respond to methotrexate or at least one other systemic immunosuppressive or intolerance to such medications due to side effects. bilateral eye disease. If subjects are on oral corticosteroids, the dosage must be stable for 2 weeks prior to baseline and not exceed 10 mg per day or 2mg/kg/day (whichever is less) of prednisone Must have a chest radiograph within 3 months prior to enrollment
Biologics: ActemraClinical Trials.gov Identifier NCT01455701 A Study of Tocilizumab in Patients Less Than 2 Years Old With Active Systemic Juvenile Idiopathic Arthritis Phase 1 and Phase 2, pharmacokinetics study (will measure blood levels of Tocilizumab, and assess safety in this age group) Tocilizumab (Anti IL-6 Rab, IV every 2 weeks x 12 weeks) Inclusion Criteria: Patients, less than 24 months old at baseline Diagnosis of systemic juvenile idiopathic arthritis (sJIA) Duration of systemic juvenile idiopathic arthritis (sJIA) lasting at least 3 months since the onset of sJIA symptoms Presence of active disease Uncontrolled disease despite treatment with non-steroidal anti- inflammatory drugs and corticosteroids
Vaccine safety in JIA: Gardasil Clinical Trials.gov Identifier NCT00573651 Safety and Efficacy of Gardasil in Females With Juvenile Idiopathic Arthritis (JIA)/Seronegative Arthritis (CHASE) Phase 4 safety observational study after vaccine administered at 0, 2 and 6 months Inclusion Criteria: Female patients, age 9-26 years, with polyarticular JIA, pauciarticular JIA, and sero-negative arthritis.
Biologics: General- when to stop? Clinical Trials.gov Identifier NCT00792233 Determining Predictors of Safe Discontinuation of Anti-TNF Treatment in JIA Ages 4-20 years Phase 4 study (but also a translational component) Looking for predictors of safe discontinuation of anti-TNF therapy Inclusion Criteria: Diagnosis of polyarticular JIA or extended oligo JIA Receiving therapy with one of the currently available anti-TNF biologic Receiving slit lamp exams performed at regular intervals Absence active arthritis/active disease (several criteria included) Exclusion Criteria: Diagnosis of a type of JIA other than polyarticular JIA Diagnosis of another inflammatory disease that may affect laboratory results or ability to discontinue anti-TNF biologic therapy previous treatment with rituximab concurrent treatment for JIA with corticosteroids >0.2 mg/kg/day OR >10 mg/day
Behavioral: Jointstrong Clinical Trials.gov Identifier NCT01166750 Jointstrong Intervention for Juvenile Arthritis Computer based intervention for 8 weeks CD-ROM intervention (randomized) for behavioral modification techniques for controlling symptoms of arthritis. Weekly modules with ―homework‖, daily questionnaire for patient for 2 week time period University of Kansas Medical Center Inclusion Criteria 8-12 years of age diagnosis of JA by a pediatric rheumatologist using established criteria have JA-related (joint) pain occurring on an average of at least once per week
Behavioral: WebSmart Clinical Trials.gov Identifier NCT01541917 Efficacy of Web-based Pain Self-management for Adolescents With Juvenile Idiopathic Arthritis (WebSMART) test of online coping skills training program for English- and Spanish-speaking adolescents with JIA experimental group :12-week interactive online multi-component treatment protocol including targeted disease education, training in empirically supported cognitive-behavioral coping skills, and social support augmented by monthly telephone contact with a nurse control group:12 weeks of guided access to extant online resources for disease education and additional attention to own best efforts at managing JIA via monthly telephone contact with a nurse. Inclusion Criteria: 12-18 years of age (inclusive) diagnosed with JIA by a pediatric rheumatologist able to speak and read English and/or Spanish able to complete online measures reporting pain in at least one joint over the past 6 months
For those interested in the newest drugtargets…Photograph: Ruth Orkin/Hulton Archive/Getty Images
Kinase Inhibitors: Block cytokine effectsJak 3(CP-690,550; Tofacitinib) Pharmacokinetics Of CP-690,550 In Pediatric Patients With Juvenile Idiopathic Arthritis (JIA) ClinicalTrials.gov Identifier: NCT01513902 Long-Term Safety Study Of CP-690,550 In Patients With Juvenile Idiopathic Arthritis ClinicalTrials.gov Identifier: NCT01500551 Pfizer: Czech Republic
Kinase Inhibitors: Block cytokine effectsSyk Kinase Inhibition (R935788) Nothing I could find in JIA Three completed Phase 2 studies in RA ClinicalTrials.gov Identifier: NCT00326339 ClinicalTrials.gov Identifier: NCT00665925 ClinicalTrials.gov Identifier: NCT00326339
New Cytokine Targets Anti IL-17: monoclonal antibody Phase 2: Psoriasis, Crohn’s disease, RA Anti IL-12/IL-23: monoclonal antibody: Ustekinumab Phase 2: Psoriatic arthritis Phase 3: Psoriatic arthritis (ongoing in adults)
Comparative Effectiveness ResearchAgency for Healthcare Research and Quality definition “A type of health care research that compares the results of one approach for managing a disease to the results of other approaches. Comparative effectiveness usually compares two or more types of treatment, such as different drugs, for the same disease. Comparative effectiveness also can compare types of surgery or other kinds of medical procedures and tests. The results often are summarized in a systematic review.” What does this actually mean??
Comparative Effectiveness ResearchWikipedia Comparative effectiveness research (CER) is the direct comparison of existing health care interventions to determine which work best for which patients and which pose the greatest benefits and harms. The core question of comparative effectiveness research is which treatment works best, for whom, and under what circumstances These clinical research trials measure effectiveness—the benefit the treatment produces in routine clinical practice. This is different than many regular clinical trials, which measure efficacy--whether the treatment works or not in a controlled environment such as a clinical trial
Comparative Effectiveness Researchwhy useful for JA? Randomized Clinical Trials: CER: Expensive and time More generalizable: ―real consuming world‖ YEARS to complete and Easier recruitment (less millions of dollars inclusion/exclusion Complex (inclusion/exclusion restrictions) criteria) ―head to head‖ comparisons Hard to recruit, especially in Can assess patient-relevant rare conditions outcomes, and clinically meaningful outcomes Can be less expensive Potential to compare treatments at an individual and population level
CER in Juvenile Arthritis: the time isNOW… or soon! CARRA Consensus Treatment Plans (CTPs) Observational CER within the CARRA registry Formulated for several pediatric rheumatic diseases CTPs developed over the past 1-2 years by polling the CARRA community of pediatric rheumatologists and reaching consensus about the most prevalent/agreed upon treatment plans for specific diseases Now, ready to implement and study what plans are best! Using the CARRAnet registry as the vehicle to collect clinical information on response/improvement, safety, patient quality of life, etc.
Role of the Arthritis Foundation Direct research grants AF support for CARRA through the foundation to and CARRA sponsored support research that: research biomarkers that predict http://www.arthritis.org/ disease outcome, measure carra.php response to treatment in http://www.arthritis.org/ JA. ja-research.php Develops and/or assesses new drugs and non- pharmacologic methods to improve JA. Assesses comparative effectiveness of different interventions for JA using the CARRA network.
Fundraising AF- sponsored events Friends of CARRA Jingle bell run/walk raises money through Arthritis walk private donations, grants and various fundraisers put on by parents and Locally sponsored friends across the country fundraisers All of money raised goes Can be designated to be directly to CARRA to used in childhood fund research to find the arthritis research only cause and cure for rheumatic diseases in children.
Children in Clinical Studies:No More Hand Me Downs! YouTube video for Families