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  1. 1. What is a Clinical Research? 1;Any investigation in human subjects intended to discover or verify the clinical, pharmacological and other pharmacodynamic/kinetic;;adr;;toxicity & efficacious effects of an investigational product(s) Clinical research may need to conduted in certain study subjectsgroups includes;; childern;; women;;the elders to gain drug development approch in these groups. 1 2;Clinical trials translate results of basic scientific research into better ways to prevent, diagnose, or treat disease The more people take part, the faster we can: - Answer critical research questions - Find better treatments and ways to prevent disease 3;This process of stating must consider a series of questions. -What data / decision is neede -Is a specific trial required? -Which trial design will deliver what is required? -What use will be made of the results? -What hypothesis is being tested or what are the precise objectives?
  2. 2. Children are not just “little adults,” and lack of data on important pharmacokinetic and pharmacodynamic difference has led to several effectable situations in paediatrics . The rate and extent of organ function development and thedistribution, metabolism, and elimination of drugs differ not only between pediatric versus adult patients but also among paediatrics age groups . The effectiveness and safety of drugs may vary among various age groups and from one drug to another in pediatric versus adult patients
  3. 3. PEDIATRICS AGE CLASSIFICATION ;  Preterm newborn infants  Term newborn infants {neonates} (0 to 27 days)  Infants and toddlers (28 days to 23 months)  Children (2 to 11 years)  Adolescents [12 to 16/18 years ) 3
  4. 4. PRE-TERM NEW BORN INFANTS The study of medicinal products in pre-term newborn infants presents special challenges because of the unique pathophysiology and responses to therapy in this population. The complexity of and ethical considerations involved in studying pre-term newborn infants suggest the need for careful protocol development with expert input from neonatologists and neonatal pharmacologists. 4
  5. 5. Important features that should be considered for these patients include ;  Gestational age at birth and age after birth (adjusted age)  Immaturity of renal and hepatic clearance mechanisms  Protein binding and displacement issues (particularly bilirubin)  Penetration of medicinal products into the (CNS)  Unique neonatal disease states (e.g., respiratory distress syndrome of the newborn, patent ductus arteriosus, primary pulmonary hypertension)  Unique susceptibilities of the preterm newborn (e.g., necrotizing enterocolitis, intra-ventricular hemorrhage, retinopathy of prematurity)  Rapid and variable maturation of all physiologic and pharmacologic processes leading to different dosing regimens with chronic exposure; and  Transdermal absorption of medicinal products and other chemicals. 5
  6. 6. NEONATES (O TO 27 DAYS )  Although, term newborn infants are developmentally more mature than preterm newborn infants, many of the physiologic and pharmacologic principles also apply to term infants.  Vd of medicinal products may be different from those inolder pediatric patients because of different body water and fat content and high body-surface-area-to-weight ratio.  BBB is still not fully mature and medicinal products and endogenous substances (e.g., bilirubin) may gain access to the CNS with resultant toxicity. 6
  7. 7. ;;;;;;;;Cntnu  Oral absorption of medicinal products may be less predictable than in older pediatric patients.  Hepatic and renal clearance mechanisms are immature and rapidly changing; doses may need to be adjusted over the first weeks of life.  Many examples of increased susceptibility to toxic effects of medicinal products result from limited clearance in these patients (e.g., chloramphenicol grey baby syndrome).  On the other hand, term newborn infants may be less susceptible to some types of adverse effects (e.g.,aminoglycoside nephrotoxicity) than are patients in older age groups. 7
  8. 8. INFANTS AND TODDLERS (28DAYS TO 23MONTHS) ;  Oral absorption becomes more reliable.  This is a period of rapid CNS maturation, immune system development and total body growth.  Hepatic and renal clearance pathways continue to mature rapidly.  By 1 to 2 years of age, clearance of many drugs on a mg/kg basis may exceed adult values.  The developmental pattern of maturation is dependent on specific pathways of clearance. 8
  9. 9. CHILDREN (2 TO 11 yrs):  Most pathways of drug clearance (hepatic and renal) are mature, with clearance often exceeding adult values. Changes in clearance of a drug may be dependent on maturation of specific metabolic pathways.  The onset of puberty is highly variable and occurs earlier in girls, i.e. as early as 9 years of age.  Puberty can affect the apparent activity of enzymes that metabolize drugs, and dose requirements for some medicinal products on a mg/kg basis may decrease dramatically (e.g., theophylline). 9
  10. 10. ADOLESCENTS:12 TO 16-18yr ;  This is a period of sexual maturation; medicinal products may interfere with the actions of sex hormones and impede development. In certain studies, pregnancy testing and review of sexual activity and contraceptive use may be appropriate.  This is also a period of rapid growth and continued neurocognitive development.  Many diseases are also influenced by the hormonal changes around puberty (e.g., increases in insulin resistance in diabetes mellitus, recurrence of seizures around menarche, changes in the frequency and severity of migraine attacks and asthma exacerbations). Hormonal changes may thus influence the results of clinical studies. 10
  11. 11. Major Physiologic Variations In Pediatrics  Generally, in children and elderly people, drugs and biological products behave similarly than in 18-65 year-old population. The important pharmacokinetic variables such as immature or aging enzyme metabolism systems as well as elimination rates affected by immature or aging organs of excretion must be properly adjusted.  In neonates, the gastric pH is biphasic- High in first few days of birth and decreases by 30th day, but takes 5-12 years for the adult pattern and a constant value to emerge.  On the other hand, methylation pathway, which is not important in adults, is well developed in children.  Furthermore, Acetaminophen is less toxic to children than adults, because it utilizes sulphate metabolic pathway. 11
  12. 12.  The informed consent process is the foundation ofany ethical research.Researchers should have a clear understanding of the process on a theoretical and practical level to conduct ethics studies, to improve parents’/patients’ understanding and expectation, and to improverecruitment rates.  in accordance with the Declaration of Helsinki on ethical principles In any research on human beings, each potential subject must be adequately informed of the aims, methods, anticipated benefits and potential hazards of the study and the discomfort it may entail. He or she should be informed that he or she is at liberty to abstain from participation in the study and that he or she is free to withdraw his or her consent to participation at any time.  As a rule, a pediatric subject is legally unable to provide informed consent.  Therefore, pediatric study participants are dependent on their parent(s)/legal guardian to assume responsibility for their participation in clinical studies.  Fully informed consent should be obtained from the legal guardian in accordance with regional laws or regulations. All participants should be informed to the fullest extent possible about the study in language and terms they are able to understand. 12 Informed consent
  13. 13.  Phase I studies are usually avoided in paediatrics because the risk to a child is more than minimal. The chance of having a significant clinical is minimal. Institutional Review Board/Independent Ethics Committee (IRB/IEC): The roles and responsibilities of IRB’s/IEC’s as detailed in ICH E6 are critical to the protection of study participants. When protocols involving the pediatric population are reviewed, there should be IRB/IEC members or experts consulted by the IRB/IEC who are knowledgeable in pediatric ethical, clinical, and psychosocial issues When studies are conducted in the pediatric population, an attempt should be made to include individuals representing the demographics of the region and the disease being studied, unless there is a valid reason for restricting enrollment. Investigators should be fully aware before the start of a clinical study of all relevant preclinical and clinical toxicity of the medicinal product. To minimize risk in pediatric clinical studies, those conducting the study should be properly trained and experienced in studying the pediatric population, including the evaluation and management of potential pediatric adverse events.
  14. 14. Types of paediatric clinical trials •Paediatric formulation studies. •Pharmacokinetic studies •Pharmacodynamics studies •Efficacy & safety study •Cohort study •Case control study •Trail design for rare diseases;;{ involves open protocol design;;Cross over design;;suurogate end point study;;meta analysis }
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