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 subjectsgroupsincludes;; childern;; women;;the elders to gain drug development approchin these groups.

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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 ofquestions.

-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 preciseobjectives?

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

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 )

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PRE-TERM NEW BORN INFANTS

The study of medicinal products in pre-term newborn infants presents special challenges because of the unique pathophysiologyand 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.

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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, primarypulmonary hypertension)

Unique susceptibilities of the preterm newborn (e.g., necrotizingenterocolitis, intra-ventricular hemorrhage, retinopathy ofprematurity)

Rapid and variable maturation of all physiologic andpharmacologic processes leading to different dosing regimenswith chronic exposure; and

Transdermal absorption of medicinal products and otherchemicals.

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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.

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;;;;;;;;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 lesssusceptible to some types of adverse effects(e.g.,aminoglycoside nephrotoxicity) than are patients inolder age groups.

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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.

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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).

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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.

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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.

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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 theirparent(s)/legal guardian to assume responsibility for their participation inclinical studies.

Fully informed consent should be obtained from the legal guardian inaccordance with regional laws or regulations. All participants should beinformed to the fullest extent possible about the study in language andterms they are able to understand.

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Informed consent

Phase I studies are usually avoided in paediatrics because the risk to achild 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.

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 }