1. The ethical princiles of paediatric studies

The fundamental pillar of paediatric research is ethical principle of “scientific necessity. The description for scientific necessity is following:

The Principle of Scientific Necessity

The ethical principle of “scientific necessity” has been operationalized in the scientific principle of “extrapolation.” The EMA regulation (2001), ICH guideline E6 (1996), E11 (2000) and the Declaration of Helsinki (2008) states paediatrics should not be enrolled in any investigation unless their involvement are necessary to answer a scientific objective relevant to the health. FDA regulations require that risks to subjects are minimized by eliminating unnecessary procedures (21 CFR 56.111(a) (1)), and that the selection of subjects must be equitable (21 CFR 56.111(b)). According to the Paediatric Research Equity Act (2007) “if the course of the disease and the effects of the drug are sufficiently similar in adults and paediatric patients, the Secretary may conclude that paediatric effectiveness can be extrapolated from adequate and well controlled studies in adults, usually supplemented with other information obtained in paediatric patients, such as pharmacokinetic studies” (7-10). Based on the ethical principle, a number of concepts arise in paediatric studies;

A. Minimising risk of harm

Minimal risk means the probability and magnitude of harm or discomfort anticipated in the research are not greater in and of themselves than those ordinarily encountered in daily life or during the performance of routine physical or psychological exams or tests. The degree of risk (potential harm) may vary based on the level of physical, psychological or social vulnerability in the study population or sample. Ethics committees, investigators and reviewers of protocols should be consider the evaluation of the potential risk or discomfort posed for paediatrics, interpreting minimal risk in relation to the normal experiences of average healthy child participant. They should also ensure that measures are in place to mitigate potential harm arising from the research process, including suspension of the research project if a child participants’ safety or well being is negatively affected.

B. Informed consent and assent

A parent is generally defined as a child’s biological or adoptive parent, and a guardian is defined as an individual who is authorized under applicable state or local law to consent on behalf of a child to general medical care. The parental permission requirement is intended to protect the child from assuming unreasonable risks. Assent must be obtained from paediatric patients who are competent to understand; and the purpose, risks and benefits of a study should be explained to them. They are not treated as autonomous decision makers; paediatric participants have the same basic human rights as adults. The dissent of a child participant capable of understanding the information presented to them should be honoured (11, 18). The requirement for child assent emerged in a 1978 report by The National Commission (1978b).

William Bartholome had defined some considerable fundamental elements of a child assent:

· A developmentally appropriate understanding of the nature of the condition

· Disclosure of the nature of the proposed intervention and what it will involve

· An assessment of the child understands of the information provided and the influences that impact on the child’s evaluation of the situation, and a solicitation of the child’s expression of willingness to accept the intervention. (12-13)

· Competency: Paediatric participants are legally unable to give informed consent, and can only ‘assent’. They are dependent on their parents to consent to their participation in the trial. Depends on age, the child’s assent is required but not sufficient allowing participation in a trial.

Information/understanding: Paediatric participant does not yet have the decision making capacity to fully comprehend all information on study details, its nature, implications, related risks and benefits. The parents are required to make an informed decision on their child’s study participation and must represent the child’s will. Clinical investigators are held responsible for ensuring adequate informed consent and they should discuss the potential risk or discomfort to the parent and paediatric participants in relation to duration of the trial period and whether the interventions or following trial procedures are reasonably comparable to past tests or treatments undergone by the children and their knowledge and understanding of the treatments that they might undergo in the future and the evaluation of the contribution to knowledge about a particular disorder or condition, especially if the study child has the disorder or condition. (14-15)

C. Confidentiality and anonymity

The principle of anonymity is that individual participants should not be identifiable in research documentation, unless agreed to by the participant. Obtained clinical data from the trial that include identifiable information on participants should not be disclosed to others without the explicit consent of the participants. The clinical data should be collected with only the consent of the participant and the investigators should also inform who would have access to their data (except in the case of a child protection concern).

2. Issues and Challenges for Designing and Conducting Paediatric Studies

· Clinical Equipoise

The term clinical equipoise is defined as “genuine uncertainty on the part of the expert medical community about the comparative therapeutic merits of each arm of a trial.” Equipoise is based on these two fundamental principles; the scientific principle of “uncertainty”. The uncertainty of the individual clinician is not decisive, but rather the uncertainty of the relevant community. The morally problematic area is where sufficient data have been developed such that clinical equipoise is disturbed, but insufficient data exist to justify a scientific conclusion. The second principle is an ethical norm that no person enrolled in the trial should receive an inferior treatment. The role of equipoise is primarily about whether the “duty of care” carried over from the clinical setting based on the fiduciary duty of a physician to act in a patient’s best interest, should be ethical framework for the clinical trial. No any child should be disadvantaged by participation in the clinical trial bears some resemblance to clinical equipoise. An affirmation of the child patient’s right to competent medical care and to protection from undue risk of harm when participating in a clinical investigation does not require nor entail the principle of clinical equipoise. The nature of the scientific uncertainty to be resolved by the study design should be specified, and the comparability of alternatives namely, the ethical and scientific argument in favour of the chosen control group should be justified. (16)

· Choice of Control Group and Placebo Controls

The enrolment of a subject in the placebo group does not offer that subject a PDB. No direct medical benefit will be available from the placebo itself, and the avoidance of exposure to an unknown risk of the experimental intervention cannot be considered a direct medical benefit. Direct benefits are limited to good clinical effects arising from receipt of the experimental intervention. The Declaration of Helsinki (D.O.H.) states that “a placebo controlled trial may be ethically acceptable, even if proven therapy is available, under the following circumstances; where no current proven intervention exists; or where for compelling and scientifically sound methodological reasons the use of placebo is necessary to determine the efficacy or safety of an intervention. The patients who receive placebo or no treatment will not be subject to any risk of serious or irreversible harm”. The ICH E10 Choice of Control Group guidance states that a placebo controlled trial may be ethically when there would be “no serious harm” from withholding known effective treatment. (15-16)

· Placebo Controlled Trials

In a randomized withdrawal trial, all eligible patients with a particular disease are initially treated with the investigational drug. Patients that have a successful initial response are then randomized in a double-blind fashion to remain on the drug or be switched to placebo. Primary endpoint of the study is time to relapse, defined as the duration of time before which clinical sign and symptoms of the disease recur. These trial designs are useful when a trial of medication withdrawal or change in therapy may be clinically indicated, particularly if the investigational drug is similar to those already marketed. Any child that relapses may immediately be provided with “rescue” medication to reduce the harm or discomfort to no more than a minor increase over minimal risk. If any exposure to placebo is unacceptable, actively controlled trials may be an alternative. These trials can be designed to test either superiority or non-inferiority of the experimental intervention relative to the control. Non-inferiority (NI) trials are described the effect of a new treatment is not worse than that of an active control by more than a specified margin. The trials do not assure that the investigational drug is “at least as effective” as the active regimen unless superiority of the experimental agent is demonstrated. Experimental intervention may be inferior to the active control and still demonstrate non inferiority.

· Compensation to Paediatric participants

Payments to parent for their child’s trial participation could potentially influence parent to decide in favour of participation without regard for the child’s wishes, because there is no personal risk to them. The obligation to treat all participants fairly might include compensating them for their time, effort, and discomfort and for their contribution to the social good. These concerns must be carefully weighed to ensure that paediatric research can continue without unduly influencing a parent to enrol a child in a protocol that is not consistent with the best interests of the individual child. (16-17)

· Early testing

The lack of healthy volunteers for Phase I studies is a big problem and makes the planning of therapeutic studies in paediatric population difficult. The requirements for paediatric research study designs are for this and other reasons different from studies in adults. Alternative study designs and alternative statistical methods are required.

· Study management

To obtain a sufficient number of paediatric subjects requires a large number of study centres. The cost for each individual step of a paediatric study is usually higher than for studies in adults- both to pharmaceutical companies, as sponsors of the research studies, and to the participating physician. Explaining the nature of a research to obtain permission from parent and ensure their cooperation during the course of the trial is a lengthy and time consuming process. Explanatory material and information has to be prepared not only for parents, but also adapted for the child patients.

· Subjects requirement

Insufficient enrolment of paediatrics is the commonest reason for discontinuing paediatric studies. Some reasons for the poor recruitment rate in paediatric studies include: (i) strict inclusion and exclusion criteria for participation (ii) less number of the paediatrics available (iii) each age group has to be considered separately (iv) fear of making one’s own child available as a ‘guinea pig for research’ (v) doctors are wary of jeopardising the physician-patient relationship (v) inconvenience for the parents in having their children participates in the trial.

· Child Assent and Parental Permission

The child’s involvement in the decision process and ability to give assent increases with their age; in the US, the age of assent is endorsed to be seven years, whereas in the EU, nine years is considered reasonable. According to the Declaration of Human Rights, a child is to be considered as a person with all basic human rights from the day of birth. (18-21)

In the US, the Food and Drug Administration (FDA) Modernization Act and the Best Pharmaceuticals for Children Act, provide companies a six-month patent extension in recognition of adequately conducted paediatric trials. The EU Directive 2001/20/EC states that the following conditions must be met for any paediatric trial:

o A consent must represent the minor's presumed will and may be revoked at any time, without detriment to the minor and the minor has received information according to its capacity of understanding regarding the trial, the risks and the benefits

o Explicit wish of a minor who is capable of forming an opinion and assessing this information to refuse participation or to be withdrawn from the clinical trial at any time is considered by the investigator” (European Parliament and the Council 2001).

o Childhood has various age (s) and stages, and trials must be performed on specific age groups such as premature newborns, full term newborns, infants and toddlers, older children, and adolescents. The associated risks and benefits of the study setting need to be discussed in description with their parents. (7, 14)

1. Obtaining assent from the newborn and infants/toddlers

Study considerations should include the vulnerability of the participant and the development status of critical organs e.g. skin, liver, kidneys, heart, lungs gastrointestinal tract, immune system, and central nervous system. Clinical investigators need to provide sufficient time with the parents to discuss their concerns and doubts at the beginning and throughout the trial, so the parents are comfortable with their decision throughout the trial.

2. Obtaining assent from the children (2-11 years)

Ethics Committees usually do not request assent in this age group (2-6 years) and parent consent is sufficient, although signs of unwillingness from the child or objections to specific procedures need to be respected and handled appropriately by the investigator by continuously evaluating further study participation of the child. At this age group may be able to understand the purpose of trial procedures.

3. Obtaining assent from the adolescents (12-17 years)

They are able to independent decision making and capable of discussing hypothetical situations by considering personal experiences and other external factors. Adolescents go through hormonal and emotional development b/w the ages of 12-17 having issues with accepting authority, sexual development and possible exposure to drugs of abuse. The assent form should be separate from the parents’ information sheet and consent form and should be directed to the child, personally asking the child of agreement to participate. (20)

CONCLUSION:

Recruitment of paediatric patients into the clinical studies is still a challenging job. One of the important challenges is the protection of paediatric patients from harm or the limitation of risk of harm, because the autonomy and competence of paediatrics to give informed consent is less than that of adults. During the paediatric drug development, some more challenges are finding about the first dose of investigational drug with appropriate sampling strategies in paediatrics. How to choose the right methods for data collection and analysis, and generating the information about safety, efficacy, pharmacokinetics, and pharmacodynamics of investigational drug in paediatrics for determination of the right dose and dosing regimen is also considered.

REFERENCES:

1. ICH (2000) International Conference on Harmonisation Guidance on E11 clinical investigation of medicinal products in the pediatric population. Available viaHSR.http://www.fda.gov/downloads/RegulatoryInformation/Guidances/ucm129477.pdf.

2. United States Food and Drug Administration, Department of Health, Education, and Welfare. Guideline for the study and evaluation of gender differences in the clinical evaluation of drugs. Washington, DC: Government Printing Office; Report No. HEW 77-3040, 1993

3. American Academy of Pediatrics (1977) Committee on Drugs. Guidelines for the ethical conduct of studies to evaluate drugs in pediatric populations. Pediatrics 60 (1):91-101

4. Food and Drug Administration, Department of Health and Human Services, The Pediatric Exclusivity Provision January 2001 Status Report to Congress.

5. Food and Drug Administration (2001) Additional Safeguards for Children in Clinical Research. Federal Register 66 (79):20589-20600

6. Ethical considerations for clinical trials with medicinal products with the paediatric population: Recommendations of the ad hoc group for the development of implementing guidelines for Directive 2001/20/EC relating to good clinical practice in the conduct of clinical trials on medicinal products for human use. European Commission, 2008.

7. European Medicines Agency. The European paediatric initiative: History of the PaediatricRegulation(EMEA/17967/04Rev1).http://www.ema.europa.eu/docs/en_GB/document_library/Other/2009/09/WC500003693.pdf/

8. Department of Health Education and Welfare (1978b) Research Involving Children: Report and Recommendations of the National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research. Fed Register 43 (9):2083-2114

9. The National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research. The Belmont Report. Washington, DC: OPPR, US Government Printing Office; 1983.

10. CDER/CBER. Guidance for the Industry: General Considerations for Pediatric Pharmacokinetic Studies for Drugs and Biological Products. Rockville, MD: Food and Drug Administration. November 1998.

11. United States Department of Health and Human Services. Protections for children in research, a report to Congress, Section 1003 of P.L. 106-310, May 2001

12. Bartholome W (1996) Ethical Issues in Pediatric Research. In: Vanderpool HY (ed) The Ethics of Research Involving Human Subjects. University Publishing Group, Fredrick, MD,

13. The National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research. The Belmont Report. Washington, DC: OPPR, US Government Printing Office; 1983.

14. Clinical Trials Directive 2001/20/EC of the European Parliament and the Council, 2001

15. International Conference on Harmonization (ICH) Guideline E11: Clinical investigation of medicinal products in the pediatric population, July 2000

16. Shaddy RE, Denne SC (2010) Clinical report-Guidelines for the ethical conduct of studies to evaluate drugsin pediatric populations. Pediatrics 125 (4):850-860. doi:peds.2010-0082 [pii] 10.1542/peds.2010-0082

17. Bagley SJ, Reynolds WW, Nelson RM (2007) Isa "wage-payment" model for research participation appropriate for children? Pediatrics 119 (1):46-51. doi:10.1542/peds.2006-1813

18. Department of Health Education and Welfare (1978b) Research Involving Children: Report and Recommendations of the National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research. Fed Register 43 (9):2083-2114.

Received on 05.03.2014 Modified on 02.05.2014

Res. J. Pharm. Dosage Form. and Tech. 6(3):July- Sept. 2014; Page 156-160

Organization	Initiative
European Medicines Agency (EMEA)	Paediatric Regulation (2007) Patent extension in return for paediatric data Penalty Marketing Authorisation may not be granted.
Food and Drug Administration (FDA)	1) Best Pharmaceuticals for Children Act (2002) Voluntary : 6 month exclusivity 2) Paediatric Research Equity Act (2003)Mandatory (may qualify for BPCA incentive)
Japanese Ministry of Health, Welfare and Labor (MHLW)	Ordinance allowing acceptance of foreign data pertaining to off label use of medicines in children. Ordinance on registration renewal: Extension of renewal period from 6 to 20 year if clinical data in children available
World Health Organization (WHO)	Better Medicines for Children Safer Medicines for Children Make Medicines Child Sized