Rám N. Sukhai

Stimulation programs for pediatric drug research – do children really benefit?

Most drugs that are currently prescribed in pediatrics have not been tested in children. Pediatric drug studies are stimulated in the USA by the pediatric exclusivity provision under the Food and Drug Administration Modernization Act (FDAMA) that grants patent extensions when pediatric labeling is provided. We investigated the effectiveness of these programs in stimulating drug research in children, thereby increasing the evidence for safe and effective drug use in the pediatric population. All drugs granted pediatric exclusivity under the FDAMA were analyzed by studying the relevant summaries of medical and clinical pharmacology reviews of the pediatric studies or, if these were unavailable, the labeling information as provided by the manufacturer. A systematic search of the literature was performed to identify drug utilization patterns in children. From July 1998 to August 2006, 135 drug entities were granted pediatric exclusivity. Most frequent drug groups were anti-depressants and mood stabilizers, ACE inhibitors, lipid-lowering preparations, HIV antivirals, and non-steroidal anti-inflammatory and anti-rheumatic drugs. The distribution of the different drugs closely matched the distribution of these drugs over the adult market, and not the drug utilization by children. Many drug studies in children have been performed since the introduction of the FDAMA. However, children infrequently use the drugs granted pediatric exclusivity. The priorities for pediatric drug research should be set by the need of the patients, not by market considerations.

How Best to Define the Concept of Minimal Risk

Some studies necessary for improving pediatric care cannot directly benefit the children involved. For example, pharmacokinetic studies and studies into pathophysiological mechanisms often do not directly benefit their subjects. From an ethical point of view, involving children in such studies is complex: when considering the assumption that children cannot give informed consent, it is not easy to justify research risks that are faced solely for research purposes. Yet a total ban on such studies would seriously harm future sick children. As a compromise, the drafters of the US Federal Regulations and those of many other rules and regulations have chosen to allow review boards to approve research that does not directly benefit the children involved only when the risks are minimal or, under certain conditions, constitute a minor increase over minimal risk. 1 The concept of ‘‘minimal risk’’ was not drawn from common language. Thus, it is not clear how pediatric researchers, when designing studies, and review boards, when reviewing them, should understand and use this concept. How should one judge whether, for instance, a lumbar puncture, an anorectal manometry, or a bronchial provocation test can be considered minimal risk? An adequate definition of the concept seems vital, not only to support those involved in designing and reviewing pediatric studies but also to appropriately protect children from research risks and to let research that involves acceptable risk levels be approved. The approach in the United States was to define minimal risk in relation to other situations with risks that one may regard as minimal. The definition reads as follows: ‘‘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 examinations or tests.’’ 2 Thus, to determine whether certain research risks are minimal, researchers and review boards are supposed to comparethemwiththerisksofdailylifeandofroutineexaminations.

Detection of respiratory pathogens by real-time PCR in children with clinical suspicion of pertussis

The use of a multiplex respiratory real-time PCR in patients clinically suspected of pertussis increases the number of pathogens detected.

Drug development for children: how adequate is the current European ethical guidance?

It is unacceptable that many drugs prescribed to children have not been proven safe and effective for them. Yet some of the necessary drug studies do not directly benefit the participating children. Involving children in such studies is ethically complex: because there are no direct advantages, the possible disadvantages must be strictly limited. A European ethical framework that provides guidance regarding these limits and that can and will be consistently applied by all European countries is essential for facilitating a harmonised approach to paediatric clinical trials across Europe. Limits for paediatric research without direct benefit are defined in two European documents. According to the Council of Europe’s European Convention on Human Rights and Biomedicine, such research may be approved only if it entails “minimal risk and minimal burden”. In contrast, in a more recent document offering guidance on the application of the clinical trials directive with regard to trials with minors, the European Union recommends allowing “a minor increase over minimal risk” in case of benefit for the group of children with the same disease. On the basis of an example, this paper shows that the inconsistency between these two documents may either prohibit important research or expose participants to unjustified risks of harm. We recommend that the two documents use the same terminology and that the European Union recommendations emphasise that exposing children to higher levels of risk and burden that cannot be compensated for by direct benefits must always be considered a last resort. The European Union (EU) Regulation on medicinal products for paediatric use (Paediatric Regulation) (2007) is based on the growing insight that it is unacceptable that drugs prescribed to children have often not been proven safe and effective for them.1 Yet some studies necessary for drug development do not directly benefit the participating children. …

Regulating “Higher Risk, No Direct Benefit” Studies in Minors

(Goodyear-Smith et al. 2002). Significant difference across the judgment of ERCs without good reasons may itself be unfair and cause further confusion. The concept of minimal risk and its purposes may require further discussion. Providing a clear definition of minimal risk or its optimal and consistent interpretation may certainly be desirable. Nevertheless, it may not necessarily solve all the difficulties related to risk assessment. In practice, ERCs must grapple with a variety of research protocols to ensure that the ethical requirements including risk determination are fulfilled. What is important in the future may be more comprehensive and specific guidance on the ethics review process so that the participant’s well-being and social justice will be secured not only in terms of the level of risk involved but also with respect to other requirements for research to be ethically conducted. Much is left to be solved.

Acceptable risks and burdens for children in research without direct benefit: a systematic analysis of the decisions made by the Dutch Central Committee

Objectives To evaluate whether the requirement of “minimal risk and burden” for paediatric research without direct benefit to the subjects compromises the ability to obtain data necessary for improving paediatric care. To provide evidence-based reflections on the EU recommendation that allows for a higher level of risk. Design and setting Systematic analysis of the approval/rejection decisions made by the Dutch Central Committee on Research involving Human Subjects (CCMO). Review methods The analysis included 165 proposals for paediatric research without direct benefit that were reviewed by the CCMO between January, 2000, and July, 2007. A separate, in-depth analysis of all drug studies included 18 early phase drug studies and nine other drug studies without direct benefit. Results 11 out of 165 studies were definitively rejected because the CCMO did not regard the risk and/or burden to be minimal. In three of these 11 cases (including two early phase drug studies) the requirement of minimal risk and burden was cited as the only reason for rejection. Four other early phase drug studies also involved risks and/or burdens that were not regarded to be minimal but were nevertheless approved. Conclusions The requirement of minimal risk and burden, aiming to protect research subjects, occasionally leads to rejection of protocols. Early phase drug studies relatively often do not comply with the requirement. Committees may find ways to approve important studies that formally should be rejected, but that is not a desirable solution. The regulatory framework should be revised to make such occasional exceptions to the requirement legitimate and transparent.

A string of pearls.

And how this book will influence you to do better future? It will relate to how the readers will get the lessons that are coming. As known, commonly many people will believe that reading can be an entrance to enter the new perception. The perception will influence how you step you life. Even that is difficult enough; people with high sprit may not feel bored or give up realizing that concept. Its what a string of pearls will give the thoughts for you.