Pediatric Considerations Beyond Assent

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During this presentation, Dr. Charlene Sanders and Angi Robinson reviewed topics including the evaluation of study design considerations such as duration of treatment, required assessments, use of placebo, and inclusion of specific age groups; selection of appropriate sites for pediatric trials and the unique needs of these sites; identification of pediatric recruitment/retention hurdles and site specific strategies to overcome these as well as a reflection on ethical concerns related to pediatric research.

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  • Historically only 20-30% of drugs approved by the FDA have been labeled in children resulting in routine but often necessary prescription of off label drugs by the pediatric health care providers. Off label drug use in children is inherently hazardous because it relies on the research findings of trials performed exclusively in an adult population. Extrapolating findings from adult trials is risky because the physiologic response to treatment can vary with age and maturation of the child, the changes in drug metabolism over time, and the different susceptibility of children to side effects seen over time with growth and development. As you are aware, within the last decade there has been a substantial increase in the number of pediatric research studies conducted by pharmaceutical companies due to legislation within the United States (FDAMA, BPCA, PREA) and Europe (Paediatric Regulation) promoting and requiring pediatric research as a part of drug development. The progress is certainly positive and further recognizes the critical need for appropriate development and evaluation of medications in children, thus limiting off‐label use, extrapolation from adult studies, and increased risk of adverse events. And as you can see from the data on this slide, research is making a difference.
  • The regulations recognize children as a vulnerable population. Because of this, additional protections are required for them in research. IRBs/ECs play a large role in providing this protection by assessing the potential risk/potential benefit ratio of the study. In the US, this assessment results in assignment of a research category when pediatric study protocols are reviewed. This category in turn dictates the number of parental or legal guardian signatures required on the permission form.Pediatric research requires not only the permission of the parent or guardian, but also the assent of the child (as applicable to age and developmental level) is solicited. Requiring the agreement not only of the parent or guardian, but also of the child helps ensure that all parties are in agreement. The American Academy of Pediatrics cautions that a lack of dissent from a child should not be considered an assent, and strongly recommends that the dissent of a child be considered carefully when deciding to proceed.Data Safety Monitoring Boards, set up to conduct ongoing periodic review of adverse events, provide another layer of protection to study subjects.Finally, when designing a pediatric research study and performing site selection, consideration should be given to continuity of treatment after the study ends. It is beneficial to many patients to continue care with the same team that performed the research, but it may be particularly important for the establishment of trusting relationships between the child and the caregivers. For that reason, an investigator that also maintains an active clinical practice may be a good choice for pediatric research.It’s important to remember in pediatric research, the primary decision-making is done by a parent or guardian on behalf of a child, yet once the decision is made to proceed the potentials risks and inconveniences can actually affect not only the child, but potentially his or her siblings and the parents. This can add a layer of complexity to pediatric research, as situations may arise where there are competing ethical principles.
  • When two or more ethical principles are in conflict, the decision-maker must consider each carefully to see which carries greater weight in that particular situation. (Give one or two examples from slide; for example, child in an RA study might experience pain relief from investigational drug, but because drug needs to be given daily for two weeks in clinic, older sibling has to miss two weeks of basketball practice if parent can’t arrange transportation for sibling).
  • This century-old statement by Abraham Jacobi, the founding father of pediatrics in the United States, is especially relevant to clinical research.Children are not little adults – they are different in numerous ways including many anatomical and physiological differences. Including: A proportionately larger body surface area (BSA) than adultsThinner skinHigher respiratory ratesSmaller airways Faster heart ratesLower blood pressureHigher metabolic rateImmature blood-brain barriers and enhanced central nervous system (CNS) receptivityLess protective muscle around their organs Less mature immune systemDrugs will have different bioavailability due to differences in ADME: Absorption Distribution Metabolism ExcretionIn addition, it is important to make sure that drugs will not have adverse effects on children’s growth and development. Children represent a vulnerable population and relegating drugs to “off-label” use is risky.
  • Just as children differ from adults, the various pediatric age groups differ from each other and each is considered a separate labeling indication. Body compositions are different at the various ages. Pre-term newborns (defined as those born prior to 36 weeks of gestation) presents special challenges because of unique pathophysiology and responses to therapy. Important considerations include low birth weight, immaturity of renal and hepatic clearance mechanisms, protein binding and displacement issues, unique neonatal diseases ( RDS, patent ductusarteriosus, intraventricular hemorrhage, NEC, retinopathy, etc.), respiratory complications and under developed organs, and potentially other issues. The amount of blood that can be safely drawn from a pre-term baby is minimal. Newborns, up to 27 days of age – their organs are rapidly developing and have an immature blood brain barrier. Oral absorption is unpredictable.Infants and toddlers, from one month to 23 months, continue to present challenges due to their rapid growth. In addition, drug compliance can be difficult in these first three groups as they tend to spit up a lot. Children, ranging from two to 11 years old, can be difficult patients for doctors – many in this age group have fear of doctors/needles. From a medical perspective, they require monitoring of development including weight gain, skeletal growth and cognitive development.Adolescents, ages 12 to 16-18 years (depending on country) - this group has a lot more independence and may have trouble following study procedures. Privacy can be an issue, and they can be uncomfortable with discussing pregnancy tests and birth control. They need to be monitored for adverse effects associated with reproductive development – hormonal changes may influence the results of studies. Studies must be conducted in each age group in which the product will be used or the indication is relevant. Best practice is to start with adolescents then children working down in age category. This can be done via separate cohorts or trials (depending on the study indication), and requires PK data for each age group. However, it should be noted the age groups defined on the slide are not always most appropriate for your study. For example, for a study on deliberate hypotension/blood pressure control that Premier Research conducted, the FDA’s Written Request (WR) defined the age groups differently. In addition to adding an additional age-range (i.e., splitting children into two groups—older and younger), adolescents were also defined based upon biological development rather age (via Tanner stage 3), which is a more rational approach. If you need to demonstrate efficacy for each age range, then each and every age range will require a sufficient sample size to make that demonstration—which can be difficult for the younger age groups. Therefore, it will be much more practical to have a single-age range for efficacy testing. In the example, the FDA allowed us to group all patients into a single age range—only one statistical test! However, they wanted to make sure that we didn’t take the easy way out and enroll only adolescents. Therefore, the FDA placed the restrictions on enrollment age. “With respect to effectiveness, the studies …will include patients from each of the age groups, with at least 50% pre-pubertal patients of whom at least 50% are neonates or toddlers at the time of enrollment, as the course of disease and the effects of drugs in older children are less likely to differ from the course and effects in adults.” This approach is probably a lot more doable that attempting to enroll enough neonates to demonstrate efficacy in this age group—again, at least in most cases, this will depend upon the indication. 
  • You will also need to consider the formulation needed for the pediatric subpopulation children and what children can take. Consider age, physical development, illness, dosing frequency, treatment duration, route of administration and dosage. Most adult formulations will not be appropriate for younger children – you need to consider the child’s physical capabilities. Babies and young children will not be able to take pills, therefore, necessitating the use of a liquid formulation.Administration of drug combined with food/drinks should improve acceptability but compatibility, stability and bioavailability (food effect) will then also need to be investigated. You will need formulations that are:Easy to both administer and swallow Acceptable in taste and volume Tolerable with minimal and safe excipients Appropriate in dosage and strength Adequate bioavailablity Less frequently administeredDetermining the best pediatric routes of administration, whether it be oral (as a liquid, chewable, dissolvable, minitablet, etc.), transdermal, injectable, via inhaler, suppository, etc., requires substantial preclinical work. This critical timeline is often underestimated.
  • Two important issues regarding formulations that need to be considered are 1) the taste as children will refuse to take an unpleasant formulation and 2) methods to ensure safe and precise administration of the formulation.Taste masking is essential to improve acceptability of the formulation and improve compliance. Oral liquids are the most appropriate for babies and very young children. But this form is the most challenging regarding taste and stability and typically requires larger amounts of excipients. And due to immature renal and hepatic functions, there are limited suitable excipients available for neonate and infants. Solids dosage forms are more stable, and have more taste masking techniques available but have less flexibility in terms of dosing.It's really difficult to ensure that you've administered the entire dose of a liquid when the baby/child is spitting, throwing their head around, etc. But if you think you've only gotten half the dose in, do you risk overdosing by giving more?While compliance will obvious improve if a formulation is better tasting, the importance of child-proofing becomes more important—infants love cherry-flavor medicine. In addition, the child-proof bottle containing the study drug can’t be grandma proof, since many times, they are the ones who actually give the medicine. Take the time and make sure that the container is something older adults can use (e.g., if measured liquid, are the numbers big enough for grandma (or grandpa) to read.Obviously, a once-a-day formulation will be better than a twice-a-day.
  • The FDA recommends that initial doses be based on mg/kg of body weight or mg/m2 of body surface area, extrapolated from adult doses. The pharmacokinetic characterization in the adult population needs to be combined with a grasp of the physiologic development of the pediatric populations to modify the initial dose estimate (e.g., consider metabolic processes development). As safety is of paramount importance for initial doses, doses that are only a fraction of the adult dose should be considered. However, when there is existing experience in the pediatric populations, this should be taken into account. Clinical observations and real time assay of drug concentrations provides the strong basis for subsequent dose adjustment.
  • We are moving now to considerations that are key to ensuring the proper protocol is in place, the best investigative sites are selected, and that enrollment is met.
  • Finding the right balanceStrike a balance between: Regulatory approvable study design and realistic, executable clinical trials Proper statistical powering of studies and practical recruitment potential Obtaining quality data while exposing as few children to both the investigational product and invasive procedures as possible Study goals and protections provided by the IRB/EC
  • Many aspects of pediatric clinical trial design must be approached proactively to insure successful and safe enrollment of children. The trial design has to be acceptable to the referring pediatrician, the pediatrician investigator, the parents (or other caregiver) and child.Primary endpoints may be different in children. For examples, for a sickle cell anemia trial that Premier Research conducted, one of the co-primary endpoints was preservation of spleen function. This endpoint is not appropriate in adult patients because spleen function is lost in these patient before they become adults. Study design must be realistic for families to commit - try not to make the study too complex or to collect too much data.Procedures which may be simple in adults can be complicated in children. For example, MRIs of infants will require sedation, which is not an insignificant risk.
  • The protocol should be rigorously evaluated to be certain that each study visit/procedure is truly needed to insure both patient safety and scientific quality. Emphasis should be placed on limiting invasive procedures as much as possible. The protocol should clearly specify the procedure, the length of the procedure, and describe any discomfort that the procedure may cause. You should try to minimize both pain and fear. Discomfort can be further minimized if studies are conducted by investigators experienced in the treatment of pediatric patients.The type of study procedure must be understood with respect to the age of the child, both chronologic and developmental.  For example,  if a trial requires an MRI, it must be remembered that younger patients generally require sedation so an IV must be placed even if there is no gadolinium/contrast agent required.  Whenever possible, measures to limit discomfort, such as EMLA cream for IV access or other needle sticks, should be used.Allowable blood volume and frequency of blood sampling is a big issue in pediatric clinical research. Consider the blood-based analyses and incorporate microvolume blood assays and sparse sampling techniques when developing the protocol.  
  • Pharmacokinetic information is difficult to obtain in children due to small studies and large differences in body size across ages.Traditional PK approach is to conduct a study of single or multiple doses of the drug in a small number of subjects with relatively frequent blood samplingPopulation PK approach requires a larger number of subjects and utilized infrequent or sparse samplingWhile the FDA draft recommendations do not indicate which method should be used, it does describe the population PK methodology as being, “an alternate, and perhaps preferable, approach in many pediatric situations.”Included in the FDA draft recommendations are four special considerations for population studies and includeWhere feasible, the study population, sample size, and age distribution should be adequate, either in a single study or several studies, to provide information on all pediatric age groups for which the drug is intendedIf other factors affecting the pharmacokinetics of the drug are to be studied (e.g. the effect of a concomitant medication or the presence or absence of a disease), sufficient numbers of subjects with and without the factor should be included in the studyThe sampling scheme should be carefully planned to obtain the maximum information using the minimum number of samplesSome knowledge of the pharmacokinetics of the drug to be investigated from previous adult or pediatric experience may be used to develop the sampling schemeThe number of subjects required for a pediatric PK trial is not calculated statistically as it would be for a PK bioequivalence trial in adults or an efficacy study, but it is dependent upon whether a traditional or population PK methodology will be used. Generally a traditional PK method requires six to 12 evaluable subjects per age group while a population model would require a larger number of subjects. Determination of the number of subjects and samples per subject needed in a population PK trial is not a simple matter but depends on knowledge of the adult PK characterization and the information that is to be obtained for best PK characterization.
  • The use of placebos in pediatric clinical trials has been a controversial topic and should be avoided in pediatric studies whenever possible, although not at the expense of good science. Placebo-controlled trials may be acceptable if there are no approved or adequately studied therapies for the children with the condition under study. Placebos are normally not considered unethical under the principle of equipoise, that is if it is uncertain that the drug-treatment offers a significant treatment advantage or safety disadvantage over placebo.Under federal regulations, IRB approval for research involving children with a placebo control group requires either:The balance of potential harms and benefits for subjects in the placebo arm must be as favorable as those receiving active treatment, or The potential harms in the placebo arm are no more than minimal or involve only a minor increase over minimal riskThe rationale for use of placebo with random allocation of treatment is often poorly understood by parents/caregivers. Parents generally express more interest in trials with active treatment in both arms.  The use of a non-inferiority trial, although not popular with sponsors in the past, has the advantage of providing active treatment in both arms and generally less risk to the patient.Many drugs are not without considerable risk. For example, the study in sickle cell study previously mentioned used hydroxyurea in infants and toddlers. Hydroxyurea is used to treat leukemia—thought to inhibit DNA synthesis--it is not an innocuous drug. Under the principle of equipoise, this was a placebo-controlled study. Once a drug has been shown to be efficacious, the principles of equipoise can no longer be used. Therefore, long-term effects may require uncontrolled epidemiological studies.
  • If a placebo arm is absolutely necessary, exposure should be minimized including the number of subjects needed, the randomization ratio, and the duration of the study. To minimize the impact of placebo, the use of the study drug as an additional component or add-on to the standard treatment for a disorder or the use of a planned early withdrawal of the placebo in a randomized design may be more appropriate in a pediatric population.
  • In addition to the specific safety and efficacy indication endpoints. Valid outcome measures are specifically challenging in the pediatric population. Measurement of subjective symptoms such as pain may require different assessment instruments/methods for different sub-population.Additional endpoints will be needed for pediatric studies to ensure development. These endpoints can be both efficacy endpoint as well safety variables.The slide includes endpoints that are long-term outcomes, which means longitudinal studies. Efficacy may be demonstrated prior to the longitudinal studies are completed. Once the study drug is found efficacious, patients in the placebo group must be given an opportunity to switch to the treatment group. The placebo group may be on study drug for more time than they were on placebo at the end of a longitudinal study. Therefore, an epidemiological approach may be required.For cognitive function, issues to consider: Scales suitable for clinical research Age coverage of scales Verbal vs. non-verbal Availability in different languages Need for neuropsychologist vs. computerized test
  • A physical setting with furniture, play equipment, activities, and food appropriate for age.
  • In addition to typical assessments of site experience in therapeutic area of study (study indication) – you need to ensure that they are prepared for the pediatric population. Personnel need to be knowledgeable and skilled in dealing with the pediatric population and its age-appropriate needs, including skill in performing pediatric procedures.
  • The mother and father will want to do what is best for the child. Premier Research has managed pediatric studies in which the standard-of-care drug was the same as the study drug for work conducted under a government contact as the BPCA-CC for off-patent drugs. The only difference was the informed consent and blood draws. Still, we did not get 100% enrollment because of stress and anxiety.Access to free medication for families with lowincome
  • Access to free medication for families with lowincome
  • What constitutes an incentive/reward for a child varies with age. Adolescents may find some study-related items unappealing (e.g., medical alert bracelets).
  • Visits must accommodate the entire family; not just the patient but the parents/guardians, siblings, etc. You need to take into account school schedules, meal and nap times for younger children, and the work schedule of the parents.
  • For a variety of reasons, (can’t afford extra childcare for someone to watch the siblings while they bring the patient to study appointments, do not want to be apart from the other children for that extra time), parents will often bring siblings to study appointments. You also need to think about accommodations and distractions for long visits plus for the siblings (e.g. DVD with movies, toys in a safe play area) so that the parent and patient are not distracted from answering questions about potential AEs, completing study questionnaires, etc. Result: more accurate reporting, retention of patients
  • Pediatric Considerations Beyond Assent

    1. 1. 2 0 11 P E D I AT R I C C L I N I C A L R E S E A R C H W E B I N A RSERIES Pediatric Considerations beyond Assent Presented byMay 11, 2011 Charlene Sanders, M.D. and Angi Robinson
    2. 2. Charlene Sanders, M.D.  Vice President, Global Regulatory Affairs and Pediatric Strategic Consulting  15+ years of regulatory and medical affairs experience – Regulatory portfolio includes NDA approvals for 15 programs which incorporated pediatric protocol design, pediatric clinical study development, PREA discussions and/or pediatric related safety issues  25+ years of clinical patient care management experience  Trained in pediatrics and completed post-doctoral2011 PEDIATRICspecialty fellowship training in primary and critical care CLINICAL RESEARCH WEBINAR SERIES
    3. 3. Angi Robinson  Director, Clinical Trials Management  10 years of pediatric clinical research experience in pharma and government  Completed a six-year contract as the BPCA-CC for the NICHD/NIH; PM for the first study launched under the BPCA in Pediatric Sedation in the ICU  Global Project Director for Good Clinical Practice Journals (GCPj) 2008 Clinical Research Team of the Year2011 PEDIATRIC CLINICAL RESEARCH WEBINAR SERIES
    4. 4. Research is Making a Difference4 Pediatric research has resulted in:  More than 350 products labeled with new pediatric information  More than 130 products with pediatric focused post labeling safety reviews D. Murphy, MD, FAAP, In Search of Pediatric Information: Where Is It at FDA?, 2010 DIA Annual Meeting, Washington, D.C. 2011 PEDIATRIC CLINICAL RESEARCH WEBINAR SERIES
    5. 5. Ethical Considerations5  Ethics of conducting pediatric research has not been studied as extensively as ethics of adult research  Need for special protections in vulnerable populations is mandated by regulations, enacted by: – IRB assessment of research risk category – Attention to Assent/Parental Permission process – DSMBs ( Data Safety Monitoring Boards) – Assurance of treatment continuity after clinical study – Use of placebos (to be discussed later)  Pediatric research means decision-making for another and involves more than just the patient – Potential risks and inconvenience are accepted by parent, but may affect child, siblings, and parents 2011 PEDIATRIC CLINICAL RESEARCH WEBINAR SERIES
    6. 6. Ethical Questions to Consider6 Is it ethical to enroll children in:  Poorly designed studies? – According to FDA, 50% of all pediatric studies are not interpretable  Studies without the possibility of direct benefit? – Normally only allowed if risk is low – Should have access to necessary health care after being enrolled in a clinical trial – Rules and definitions differ by country – Non-therapeutic studies in children are not allowed in some countries – Definition of low risk varies by country 2011 PEDIATRIC CLINICAL RESEARCH WEBINAR SERIES
    7. 7. Potential Ethical Conflicts in Pediatric Research Weighing of ethical principles is integral part of process7 Autonomy, Self- Beneficence Determination Potential or real benefit to child vs. Child’s dissent Justice Beneficence vs. Potential costs or harms Potential or real benefit to child to other family members Beneficence, Justice Possibility of obtaining Non-maleficence vs. information that could benefit Potential risk to child many Non-maleficence Privacy, Confidentiality Potential harm from Drug testing, vs. researcher pregnancy testing results not reporting risky behavior 2011 PEDIATRIC CLINICAL RESEARCH WEBINAR SERIES
    8. 8. Pediatrics does not deal with miniature men and women, with reduced doses and the same class of diseases in smaller bodies, but ... it has its own independent range and horizon and gives as much to general medicine as it receives from it - Abraham Jacobi, 18892011 PEDIATRIC CLINICAL RESEARCH WEBINAR SERIES
    9. 9. Pediatric Subpopulations Each age group is considered an indication9 Pre-term Newborns Infants & toddlers Children Adolescents newborn 27 days 28 days to 23 2 to 11 years 12 to 16-18 years s months 2011 PEDIATRIC CLINICAL RESEARCH WEBINAR SERIES
    10. 10. Age Appropriate Formulations10 Consider age, physical development, illness, dosage, dosing frequency, treatment duration, and route of administration Need pediatric formulations that are:  Easy to both administer and swallow  Acceptable in taste and volume  Appropriate in dosage and strength  Tolerable with minimal and safe excipients  Adequate bioavailability  Less frequent administration 2011 PEDIATRIC CLINICAL RESEARCH WEBINAR SERIES
    11. 11. Age Appropriate Formulations11 Children will refuse an unpleasant formulation Foster compliance by delivering formulations with an acceptable taste Poor compliance increases the risk of therapeutic failure and emergence of resistances Need to ensure safe and precise administration Foster compliance with an easy administration Provide appropriate dosing/administration devices Important to have child-proof container for product 2011 PEDIATRIC CLINICAL RESEARCH WEBINAR SERIES
    12. 12. Drug Administration Considerations12 Dosing is more difficult to manage than in an adult population:  Often based on experience in adults and weight/BSA  Titration rates and AE monitoring need to be carefully evaluated  Administration of investigational product can pose problems Timing of dosing can also be a challenge:  If during the day and there are school-age children, schools will need to be able to appropriately store the IP, administer it, and document dosing  Strict dosing times may be difficult to adhere to 2011 PEDIATRIC CLINICAL RESEARCH WEBINAR SERIES
    13. 13. Designing and Executing Pediatric Trials13 Key factors (―PIE‖): Protocol Need scientifically rigorous protocols that are also feasible for the child/parent Investigative sites Choose sites that can handle issues unique to pediatric studies Enrollment and retention Develop parent-targeted recruiting/enrollment strategies Maximize compliance/retention using child-specific 2011 PEDIATRIC CLINICAL RESEARCH WEBINAR SERIES
    14. 14. Pediatric Study Design Considerations Scientifically Feasible for the rigorous child/parent2011 PEDIATRIC CLINICAL RESEARCH WEBINAR SERIES
    15. 15. Study Design15 Why up to 50% of pediatric studies fail  Small sample size, low enrollment  Endpoints that are not well defined or pediatric relevant  PK–PD correlations that are not established  Incorrectly identified dosages for efficacy studies  Feasibility issues  Ethical constraints in protocol development 2011 PEDIATRIC CLINICAL RESEARCH WEBINAR SERIES
    16. 16. Pediatric Study Design16 Protocols need to be designed specifically for the population and not simply re-worked from adult protocols  Design must be customized for the specific populations  Primary endpoint in children may be different or even inappropriate in adults  Developmental variability should be considered in inclusion criteria, sample size calculations, and analysis  Study design must be realistic for families to commit Unsuitable designs will lead to slow enrollment and low retention resulting in higher costs and approval delays 2011 PEDIATRIC CLINICAL RESEARCH WEBINAR SERIES
    17. 17. Child Friendly Study Procedures17  Minimize intensity and frequency of the study assessments Limit number and volume of blood draws – coincide the collection of protocol-specified blood samples with routine clinical samples Limit invasive procedure as much as possible  Minimize pain and distress Use topical anesthesia, butterfly needles, pediatric sampling tubes Indwelling catheters rather than repeated venipunctures for blood sampling  Handle pregnancy testing in minors with care  Consider not only the child but also the parents and 2011 siblings when planning the frequency and length of PEDIATRIC CLINICAL RESEARCH WEBINAR SERIES
    18. 18. Traditional vs. Population PK Sampling18  Traditional PK approach is to conduct a study of single or multiple doses of the drug in a small number of subjects with relatively frequent blood sampling  Population PK approach requires a larger number of subjects and utilizes infrequent or sparse sampling  While current FDA and ICH recommendations do not indicate which method should be used, they do describe the population PK methodology as a useful technique to minimize the number of samples obtained from each patient Guidance for Industry: E11 Clinical Investigation 2011 PEDIATRIC CLINICAL RESEARCH WEBINAR SERIES of Medicinal Products in the Pediatric Population,
    19. 19. FDA Guidance for Pediatric Studies Pediatric Study Decision Tree - Integration of19 PK-PD Reasonable to assume (pediatrics vs. adults) • Similar disease progression? • Similar response to intervention? NO YES TO BOTH • Conduct PK studies Reasonable to assume • Conduct safety/efficacy similar concentration- trials response (C-R) NO in pediatrics and adults? NO YE Is there a PD measurement S that can be used to predict • Conduct PK studies to efficacy? achieve levels similar to adults YE • Conduct safety trials • Conduct PK studies to get S C-R for PD measurement • Conduct PK studies to achieve target concentrations based on C-R • Conduct safety trials Guidance for Industry: Exposure-Response Relationships — Study Design, Data Analysis, and Regulatory 2011 PEDIATRIC CLINICAL RESEARCH WEBINAR SERIES
    20. 20. Use of Placebo20  Use of placebo typically more restricted in pediatric trials simply because children cannot consent  While not ideal, the use of a placebo may be acceptable if there is no approved or adequately studied therapies  Placebo use has to be justified scientifically and ethically 2011 PEDIATRIC CLINICAL RESEARCH WEBINAR SERIES
    21. 21. Use of Placebo21 It is important to minimize placebo exposure:  Number of subjects  Study duration  Randomization ratio  Need pre-defined discontinuation criteria 2011 PEDIATRIC CLINICAL RESEARCH WEBINAR SERIES
    22. 22. Pediatric Specific Endpoints/Follow-up22 Physiological Measures and Benchmarks  Weight  Height  Thyroid hormone, Insulin-like growth factor-1 (IGF-1)  Skeletal growth  Sexual maturation Development and Cognitive function – short and long-term effects  Attention, memory and learning  Language skill Behavioral and Psychological Maturation/Milestones  Child Behavioral Checklist (CBCL)  Quality of Life, school performance, etc.  Infants and young children – mental, motor and behavioral development 2011 PEDIATRIC CLINICAL RESEARCH WEBINAR SERIES
    23. 23. Duration of Treatment, Follow-up, and Retention23  Long-term treatment or recurrent treatment may necessitate: – Tracking of growth and development changes – Potential need for patient to sign multiple assent forms/consent form over time  Outline process for study drug delivery during school days, with alternate caregivers, etc…  Working parents and school attendance issues will present additional practical problems 2011 PEDIATRIC CLINICAL RESEARCH WEBINAR SERIES
    24. 24. Pediatric Investigative Site Selection Operational Medical consider Factors Factors2011 PEDIATRIC CLINICAL RESEARCH WEBINAR SERIES
    25. 25. Operational Considerations for Pediatric Investigative Site25 Selection  In general, use same principles as selecting sites for adult trials: – Expertise and experience – Therapeutic area – Clinical research – Pediatric studies – Adequate number of appropriate patients – Easier to recruit from and gain trust of families who know PI/SC/nurse than referrals – Degree of interest expressed by the site  Facilities need appropriate equipment and activities and that can accommodate children/families  Consider using a Pediatric Research Network 2011 PEDIATRIC CLINICAL RESEARCH WEBINAR SERIES
    26. 26. Medical Considerations for Pediatric Investigative Site26 Selection  Absolutely MUST have person experienced in pediatric lab draws  Depending on protocol, may also need personnel with expertise in catheterizing small children, pediatric IV starts, placing pediatric NG tubes, etc.  Sites that are not pediatric based must have access to resources needed for the pediatric population 2011 PEDIATRIC CLINICAL RESEARCH WEBINAR SERIES
    27. 27. Pediatric Enrollment and Retention Patient really means family2011 PEDIATRIC CLINICAL RESEARCH WEBINAR SERIES
    28. 28. Enrollment Strategies28  Remember that ethical decision-making in pediatric research is not always the same as it is for adult research  Conduct studies in familiar environments such as hospital or clinic where participants normally receive their care  Studies have shown that most parents/guardians gave consent for their child to learn more about their child’s disease  References typically through a primary care provider or another physician  Family counseling by independent advisor 2011 PEDIATRIC CLINICAL RESEARCH WEBINAR SERIES
    29. 29. Enrollment Strategies29 Each age group has it own issues with enrollment  Teenage girls may decline to participate once they learn that a pregnancy test is required  The use of cartoons to explain the study may be useful for younger patients – Some countries are requiring pictorial information sheets for young children  Time missed from school may be important – Not an issue with the very young Assume about 50% of approached families will agree to participate 2011 PEDIATRIC CLINICAL RESEARCH WEBINAR SERIES
    30. 30. Enrollment Strategies30 Avoid coercion or even its appearance  Advertisements – Consider different media – TV, radio, internet, parenting publications, etc. – Ads need to target the parent, not the child – Not always appropriate  Payments to patients/parents – Reimbursements for travel expenses may be better approach – AAP recommends to not disclose payment/reimbursement information to children until they have completed the study 2011 PEDIATRIC CLINICAL RESEARCH WEBINAR SERIES
    31. 31. Retention Strategies31  Provide resource materials for patients and families  Make sure the stipend is appropriate and that families are compensated for expenses associated with their child’s participation  Appointment reminder and missed appointment postcards, emails or text messages  Close, ongoing assessment of discontinuation reasons – One-page retention questionnaire to help determine reason for withdraws 2011 PEDIATRIC CLINICAL RESEARCH WEBINAR SERIES
    32. 32. Retention Strategies32  Consider appropriate strategies for the different age groups – Example: For adolescents, consider a study subject blog; this group loves technology and it is appealing to communicate with other kids around the country who also have the same condition  Depending on indication, conduct a webcast with famous person with condition including education segment and ability to submit questions  Incentive/Rewards – For milestone achievements, depending on age consider reward certificate with 10 free music downloads or movie theatre passes – Organizer folder/portfolio with place to carry medication to and from visits that includes calendar with stickers for appointments as well as books and materials to educate on condition and making living with 2011 PEDIATRIC CLINICAL RESEARCH WEBINAR SERIES it not only possible, but FUN!!
    33. 33. ―Patient‖ really means ―Family‖33 Parents/guardians are vital to retention and compliance – you need to have their support for visits and drug administration Must remove barriers to trial participation including: • Clear instructions for drug administration and compliance • Difficult visit schedules – include appropriate windows • Scheduling – parent’s job, school attendance, nap times • Transportation costs 2011 PEDIATRIC CLINICAL RESEARCH WEBINAR SERIES
    34. 34. ―Patient‖ really means ―Family‖34 Siblings are frequently brought along to study appointments distracting both the parents and patients This can cause:  Missed reporting of AEs and con meds  Potentially incorrect responses on questionnaires  Early termination if siblings are not made to feel welcome Plan to address this with:  Secure area for siblings to wait  Personnel available to ―babysit‖ younger children during study visit  DVD player with children’s movies/shows  Snacks for longer visits  Making siblings feel welcome and parents comfortable with 2011 their decision to bring them along PEDIATRIC CLINICAL RESEARCH WEBINAR SERIES
    35. 35. Take Home Message With experience, pediatric studies can be easy as PIE Protocol Need scientifically rigorous protocols that are also child/parent friendly Investigators Choose sites that can handle issues unique to pediatric studies Enrollment and retention Develop parent-targeted recruiting/enrollment strategies2011 PEDIATRIC CLINICAL RESEARCH WEBINAR SERIES Maximize compliance/retention using child-specific
    36. 36. Past Webinars36 Recordings available at www.premier-research.com/webinars ▪ Developing a Feasible Pediatric Plan for PREA/PMDSIA Compliance Speaker: Charlene Sanders, M.D. ▪ Planning your Paediatric Investigation Plan (PIP) Submission in Europe Speaker: Susan Bhatti, Ph.D. ▪ Guidelines for Effective and Appropriate Pediatric Assent and Parental Permission Speakers: Angi Robinson and Elizabeth Jay, RN, MA 2011 PEDIATRIC CLINICAL RESEARCH WEBINAR SERIES
    37. 37. Questions? Charlene Sanders, M.D. Vice President, Global Regulatory Affairs and Pediatric Strategic Consulting charlene.sanders@premier-research.com Angi Robinson Director, Clinical Trials Management angi.robinson@premier-research.com Centre Square West 1500 Market Street, Suite 3500 Philadelphia, PA 19102 Telephone: 215.282.55002011 PEDIATRIC CLINICAL RESEARCH WEBINAR SERIES

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