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 purposes), 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 a 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 the pediatric population is specifically a concern and has been discussed extensively. Stephen RC Howie (2010) reviewed blood sample volumes in child health research: a review of safe limits in the 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 the 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, the 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 minimize 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, pediatric enabled 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.

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

• How Much Blood is too Much Guideline including the maximum volumes from several institutes
•  Clinical Translational Research Center TraCS Institute Approved by: Administrative Director and Nursing Director SOP Title and #: Pediatric Blood Draw: includes a table for “NIH Pediatric Blood Volume for Research Guidelines”
• Blood Sampling Guidelines from Partners Human Research Committee  Blood volume taken from children must be less than 3 cc/kg body weight per 8 week period.
•  BLOOD VOLUME COLLECTED PER VENIPUNCTURE
  The maximum volume for single phlebotomy is:
  Term newborn – Age 18: 3 mL/kg, up to a maximum of 150 mL
  Age 18 – 85: Maximum of 150 mL
  Age 86 and above: Maximum of 100 mL
  Repeated Phlebotomy over Acute Periods: Where possible, blood collection over a 24- hour period should be limited to 5 mL/kg with a balanced consideration of patient safety and clinical needs
• Different institute IRB or EC committees may have different policies regarding the blood draw and volumes. For example, here is the policy Blood drawing for human subject research by Duke University Health System

In EU, there are specific guidelines on "ETHICAL CONSIDERATIONS FOR CLINICAL TRIALS ON MEDICINAL PRODUCTS CONDUCTED WITH THE PAEDIATRIC POPULATION"

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