Tuesday, February 08, 2011

Guidelines for Blood Volumes in Clinical Trials (Especially in Pediatric Clinical Trials)

Nowadays, the clinical study protocols are becoming more and more complicated and require more and more blood sample draws for various purposes. The blood samples are needed for testing the hematology, chemistry, immunogenicity (for biological products), biomarkers (for diagnostic or other purpose), pharmacogenomics,… In some clinical trials, additional blood samples (sample retains) may be drawn for future studies (even though we may not know what the future study will be). If the study has the component of pharmacokinetics, the many more samples (series blood samples) will be drawn within short period to characterize the pharmacokinetic profile, estimate the total drug exposure (AUC), and calculate other pharmacokinetic parameters.

With increasing in the number of blood draws or the blood volumes, the ethic issue often arises, especially in clinical trials with children.

US FDA and EMA do not really regulate the maximum blood volume that can be drawn from a subject during the clinical trials. The requirements for limiting the blood sample volume may come from the National Institute of Health (NIH), American Academy of Pediatrics, World Health Organization (WHO), and European Union (EU) and are typically enforced by the ethic bodies such as Institute Review Board (IRB) and Ethics Committee (EC). The requirements on blood volume during the clinical trials may be different depending on the country and local IRB.

The blood volume drawn for pharmacokinetic studies in pediatric population is specifically a concern and has been discussed extensively. Stephen RC Howie (2010) reviewed blood sample volumes in child health research: review of safe limits in Bulletin of the World Health Organization (BLT) . WHO also has its guidelines on drawing blood: best practices in phlebotomy. The guidelines are not specifically for clinical trials, rather for general blood donations. The guidelines contain specific technical requirements for blood drawn in pediatric and neonatal subjects.

In US, Code of Federal Regulations has a specific chapter (Part 46) to discuss protection of human subjects and the chapter contains a subpart D to address additional Protections for Children Involved as Subjects in Research. While there is no specific requirement on the limit of blood volume, the CFR indicated that the research involves no more than minimal risk to the subjects and IRB should take into account the purposes of the research and the setting in which the research will be conducted and should be particularly cognizant of the special problems of research involving vulnerable populations, such as children, prisoners, pregnant women, mentally disabled persons, or economically or educationally disadvantaged persons. Similarly, American Academy of Pediatrics has its policy on Guidelines on Ethical Conduct of Studies to Evaluate Drugs in Pediatric Populations. The policy requires “…with the growing number of pediatric drug studies, IRBs need to be familiar with the various research-design methods that inimize risk to the child. Examples include limiting research under some circumstances to pharmacokinetic and safety data, combining this approach with pharmacodynamic data, and minimizing the volume of blood withdrawn through the use of sensitive assays, pediatricenabled laboratories, and population pharmacokinetic approaches"

National Institute of Health Clinical Center has a guideline M95-9: Guidelines for Blood Drawn for Research Purposes in the Clinical Center, however, the guideline is only accessible for NIH internal use.

Two articles from the web actually reflect the limit of blood volume in US.

"13.2 Volume of blood

Preterm and term neonates have very limited blood volume, are often anaemic due to age and frequent sampling related to pathological conditions. The fact that children, especially in this age group, receive blood transfusions (or iron or erythropoietin supplementation) should not be used as a convenience for increased volume or frequency for blood sampling.

The following blood volume limits for sampling are recommended (although are not evidence-based).
If an investigator decides to deviate from these, this should be justified. Per individual, the trial-related blood loss (including any losses in the manoeuvre) should not exceed 3 % of the total blood volume during a period of four weeks and should not exceed 1% at any single time. In the rare case of simultaneous trials, the recommendation of 3% remains the maximum. The total volume of blood is
estimated at 80 to 90 ml/kg body weight; 3% is 2.4 ml blood per kg body weight."

The guidelines on blood volume are usually based on the amount of blood in percentage of total blood volume (BLV). BLV varies depending on the age and body weight. A good reference for BLV for pediatrics can be found in pediatricareonline.com.


clinnovator said...

very very informative

hangrt said...

A phlebotomist must quickly learn how to do that all. Since blood contamination is probably one of the major ways of getting contaminated with diseases like AIDS and hepatitis, the training will also cope with laboratory security. phlebotomy training

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Amy Krussell said...

Really informative and useful information.

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