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Year : 2014  |  Volume : 46  |  Issue : 2  |  Page : 145-146

Clinical trials for children: Some concerns

Department of Pharmacology, SCB Medical College, Cuttack-753007, Odisha, India

Date of Web Publication24-Mar-2014

Correspondence Address:
Trupti Rekha Swain
Department of Pharmacology, SCB Medical College, Cuttack-753007, Odisha
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/0253-7613.129300

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How to cite this article:
Swain TR. Clinical trials for children: Some concerns. Indian J Pharmacol 2014;46:145-6

How to cite this URL:
Swain TR. Clinical trials for children: Some concerns. Indian J Pharmacol [serial online] 2014 [cited 2023 Sep 28];46:145-6. Available from: https://www.ijp-online.com/text.asp?2014/46/2/145/129300

India has 440 million children, and every fifth child in the world is an Indian. Child-specific medicines are the most cost-effective tools to reduce morbidity and mortality. Out of the total medicines prescribed for the sick children, 50% to 90% are "off label" i.e. these have not been evaluated for their safety and efficacy in children. [1] It has been realized that the normal practice of extrapolation of adult data for children is unethical as pharmacokinetic (PK) and pharmacodynamic (PD) properties differ considerably in children from their adult counterparts. A greater incidence of adverse drug reactions and therapeutic failures have been confirmed due to use of off label or unlicensed medicines in children. [2],[3] Unlike adults, children are not homogeneous population; hence safety and efficacy data is required at all stages of their development The difference in body composition and developmental process makes extrapolation of adult data appropriate for only 6% of drugs. [4] In order to meet children's right and demand for highest attainable health, the General Assembly of United Nation (Convention on the Right of the Child 1989) has emphasized the need to study new and existing therapies specifically in children. [5]

The number of clinical trials carried out in children is relatively few worldwide. There are a number of reasons for this. The high developmental cost and low expected returns from new paediatric drugs usually do not attract the pharmaceutical industry to invest in these areas. The lack of suitable trial subjects due to the heterogeneity of the pediatric population requires stratification of samples. Ethical concerns about inclusion of children in clinical trials have been disproportionately high, resulting in strict laws and ethical "guidelines" and phobia for drug trial in children (Belmont report 1979, [6] Declaration of Helsinki [7] ). However, well-designed clinical trials make a significant contribution to advancement in medical knowledge and improved therapeutics by bringing cost-effective and therapeutically superior drugs or formulations over existing ones for all, including children. Understandably there is a fear of exploitation of children for unnecessary drug trials especially in transitional countries. A recent review of pediatric trials submitted to the US Food and Drug Administration between September 28, 2007 and December 21, 2010 revealed that the United States conducts a maximum number of pediatric trials. The involvement of developing countries in pediatric drug development is not increasing. These countries however participate significantly in vaccine trials. [8]

In December 2008, the WHO reviewed the existing evidences on appropriate drug formulations for children. The members of the above meeting which included pediatricians, pharmacists, clinical pharmacologists, representatives of the European Medicines Agency, International Federations of Pharmaceutical Manufacturers and Associations, UNICEF and the Bill and Melinda Gates Foundation identified the requirement of future research to improve the development of preferred dosage forms. The significant result of the meeting was the proposal that WHO would promote flexible solid oral dosage forms as the preferred formulations. One of the important questions in the discussion was on the stability of the active ingredients when dissolved in breast milk which needs to be addressed through clinical trials. Recently conducted studies on availability and pricing of children's medicines in Odisha and Chhattisgarh have revealed that availability of essential pediatrics medicines is poor. [9],[10]

Developed countries have already done a lot to improve access of medicines for children. In the initial phase, Food and Drug Administration Modernization Act (FDAMA) was passed for providing financial incentives for pediatric drug development. Other measures include grant of additional period of market exclusivity for pharmaceutical company that submitted pediatric studies of a particular medication. The Food and Drug Administration also introduced the pediatric rule to encourage drugs for new therapies and indications to be studied in children. In another important development, The National institute of Health (NIH), USA, formulated a policy that requires inclusion of children in all research on humans if no scientific or ethical issue exists to exclude these populations. Because most pharmaceutical companies do not prefer to conduct clinical trial in children, the USA has now introduced a legal obligation for Pharmaceutical companies to conduct drug trials in children if the medication is a good therapeutic option. Best Pharmaceuticals for Children Act (BPCA, 2002) provides financial incentives to companies that undertake clinical trials to improve safety and efficacy of products used in children. Importantly, the act enforces research on older off-patent medicines through a special list developed by the NIH. Also, the contributions of European Medicines Agency are significant towards strengthening safety and efficacy of medicine use in children. The methods adopted by the agency include use of efficacy data and Safety Monitoring Boards as a standard requisite, promoting sparse sampling, granting permissions for novel designs and methodologies to reduce the number of children exposed for trial and maximizing drug information. The agency also initiated its own clinical trial registry which was made publicly accessible

Even though the need of clinical trial in children is evidently high because of our own marketing environment and genomics, resource-limited countries like India face several challenges. The ethics committees function sub-optimally though they are formed to comply with national guidelines. Members of the ethics committees usually lack the knowledge and skills required to process clinical trial applications in children. Children are seen as a group with diminished autonomy and clinical trials in this age group are automatically rejected, though they may be scientifically sound, ethically acceptable and address an issue which has important clinical implications in practice. The pool of well-trained clinical investigators is also small. Lack of proper database is another hurdle in conducting pediatric trials in our setup. Trials that may have been done are not registered and a majority of them go unpublished. The Clinical Trial Registry of India (CTRI) has been in place since 2007. More than 200 completed clinical trials in children have been registered. However, the information provided about these is insufficient. [11]

Fear of exploitation of children as trial participants poses a big challenge that may be aggravated by poverty and lack of education. Parents can rarely make informed choices. More often than not, parents may give consent for a modest amount of "incentives". Thus, recruitment in pediatric trials needs a cautious and vigilant approach.

The scenario of clinical trials among children in India can be improved by addressing these issues. It would be reasonable to conduct clinical trial in children if sufficient proof of efficacy and safety has already been generated in adults. It would be prudent to recommend that ideally pediatric trial should be deferred till adult testing has reached Phase III of drug development or beyond. [12] However, the above criteria may be relaxed if the research involves disease that affects children exclusively (genetic or metabolic diseases). Risk minimization strategy should be adopted for all clinical trials involving children. Data safety monitoring committee involving pediatricians should be formed in all institutions where these trials are undertaken. As blinding in trials poses risks, special precautions must be taken for such trials. The informed consent process and conduct of the trial should be done in a clear and transparent manner. As per ICMR guidelines, assent should be obtained from children aged 7-18 years irrespective of parent's nod. [13] In case of neonatal trials that involves recruitment immediately after birth, seeking consent from parents adds distress to the whole process and sometimes violates the process of autonomy. The "opting out" is a kinder option than just persuading parents to decide whether or not to participate in the trial. A robust study design including optimum sample size and well-defined outcome measures would ensure that the benefits of conducting the trials outweigh the risk involved.

All stakeholders like investigators, regulators and sponsors should be well trained to conduct trials in children. The most effective and challenging step would be to strengthen our laws that will ensure that all the guidelines are adhered to, in the interest of this special population.

  References Top

1.Ernest TB, Elder DP, Martini LG, Roberts M, Ford JL. Developing pediatric medicines: Identifying the needs and recognizing the challenges. J Pharm Pharmacol 2007;59:1043-55.  Back to cited text no. 1
2.Committee on Bioethics. Ethics and the care of critically ill infants and children. Pediatrics 1996;98:149-52.  Back to cited text no. 2
3.Morales-Olivas FJ, Morales-Carpi C. Clinical trials in children. Rev Recent Clin Trials 2006;1:251-8.  Back to cited text no. 3
4.Dunne J, Rodriguez WJ, Murphy MD, Beasely BN, Burckart GJ, Filie JD, et al. Extrapolation of adult data in pediatric drug development programme. Pediatrics 2011;128:e1242-9.  Back to cited text no. 4
5.General Assembly of United Nations. Convention on the rights of the child. 20 Nov 1989. Available from: http://www.unicef.org/crc/crc.org [Last accessed on 2014 Jan 2].  Back to cited text no. 5
6.The Belmont Report. Ethical Principles and Guidelines for the Protection of Human Subjects of Research. The National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research April 18, 1979.  Back to cited text no. 6
7.Declaration of Helsinki. Ethical Principles for Medical Research Involving Human Subjects.  Back to cited text no. 7
8.Dunne J, Murphy MD, Rodriguez WJ. The globalization of pediatric clinical trials. Pediatrics 2012;130:1-9.  Back to cited text no. 8
9.Available from: http://www.who.int/child medicines/countries/ODISHA_PRICING.[Last accessed on 2014 Jan 1].  Back to cited text no. 9
10.Available from: http://www.who.int/childmedicines/countries/PRICING_CHHATTISGARH [Last accessed on 2014 Jan 1].  Back to cited text no. 10
11.Pandey A, Aggarwal AR, Seth SD, Maulik M, Bano R, Juneja A. Clinical Trials Registry India: Redefining the conduct of clinical trials. Indian J Cancer 2008;45:79-82.  Back to cited text no. 11
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12.Shaddy RE, Denne SC. The Committee on Drugs and Committee on Pediatric Research. Pediatrics. 2010;125(4):850-60.  Back to cited text no. 12
13.Guidelines for Biomedical Research on Human Participants. New Delhi. Indian Council of Medical Research; 2006. Available from http://www.icmr.nic.in/Guidelines/pdf [Last accessed on 2014 Jan 4].  Back to cited text no. 13

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