Pediatric Nuclear Medicine and the RDRC Regulations

1
Pediatric Nuclear Medicineand the RDRC
Regulations

• Michael J. Gelfand M.D.
• Cincinnati Childrens Hospital
• Cincinnati, OH
• And Past-President,
• Society of Nuclear Medicine

2
Pediatric Nuclear Medicine

• Nuclear Medicine is sidely used at childrens
  hospitals
• Nuclear medicine procedure volumes in 2003
• Boston CH 8061
• Philadelphia (CHOP) 6539
• Cincinnati CH 4780

3
Pediatric Nuclear Medicine

• At Cincinnati Childrens Hospital (CCH), we have
  experienced continued growth in Nuclear Medicine
  volumes, but at a somewhat slower rate than the
  total number of imaging examinations.

4
(No Transcript)
5
Pediatric Nuclear Medicine at CCH

• GU studies 56
• Bone 20
• Tumor studies 8.2
• including
• I-123-MIBG approx 2.4
• F-18-FDG PET 2.3

6
Pediatric Nuclear Medicine

• Radiation exposure from diagnostic pediatric
  nuclear medicine procedures is acceptable
• Comparisons between different radiographic
  procedures, and between radiographic procedures
  and nuclear medicine procedures, is accomplished
  by use of effective dose (ED) calculations

7
Effective Dose How to Compare Apples and Oranges

• Effective dose (ED), therefore, is defined as
• ED S WTHT
• T
• where WT is weighting factor for tissue T and HT
  is the calculated dose for tissue T

8
Tumor Imaging

• ED (rem)
• CT of the chest, abdomen and pelvis
• (low dose technique) 0.6
• Ga-67 (0.100 mCi/kg) 1.8 -2.5
• I-123-MIBG (0.140 mCi/kg) 0.26-0.29
• F-18-FDG (0.140 mCi/kg) 0.50-0.86
• Ware DE, Huda W, et al. Radiology 1999210645
  -650.
• Stabin MG, Gelfand MJ. Q J Nucl Med 1998
  4293-112.

9
An Important Regulatory Limitation on Pediatric
Nuclear Medicine Research

• 21CFR361.1 (b) (3) (i) states with reference to
  studies performed under approval by a Radioactive
  Drug Research Committee
• Under no circumstances may the radiation dose to
  an adult research subject from a single study or
  cumulatively from a number of studies conducted
  within 1 year be generally recognized as safe if
  such dose exceeds the following

10
An Important Regulatory Limitation on Pediatric
Nuclear Medicine Research

• 21CFR361.1 (b) (3) (i)
• Whole body, active blood forming organs,
• lens of eye and gonads
• single dose 3 rem
• annual and total dose commitment 5 rem
• Other organs
• single dose 5 rem
• annual and total dose commitment 15 rem

11
An Important Regulatory Limitation on Pediatric
Nuclear Medicine Research

• 21CFR361.1(b) (3) (ii) states
• For a research patient under 18 year of age at
  his last birthday, the radiation dose shall not
  exceed 10 of that set forth in paragraph (b) (3)
  (i).

12
An Important Regulatory Limitation on Pediatric
Nuclear Medicine Research

• The pediatric limits, therefore, become
• Whole body, active blood forming organs,
• lens of eye and gonads
• single dose 0.3 rem
• annual and total dose commitment 0.5 rem
• Other organs
• single dose 0.5 rem
• annual and total dose commitment 1.5 rem

13
An Important Regulatory Limitation on Pediatric
Nuclear Medicine Research

• This greatly limits the ability to study new PET
  agents in children with cancer or other life
  threatening or life shortening diseases
• Absorbed radiation doses for most PET
  radiopharmaceuticals far exceed 0.3 rem whole
  body and 0.5 rem to any organ
• The limits may also pose a problem for studies
  using SPECT radiopharmaceuticals

14
Pediatric Nuclear Medicine ResearchPET Dosimetry

• F-18 2-fluoro-2-deoxyglucose
• For 9.8 mCi in a 70 kg adult
• ED 0.88 rem bladder wall 6.8 rem
• For 4.5 mCi in a 10 year old
• ED 0.64 rem bladder wall 3.6 rem
• For 2.6 mCi in a 5 year old
• ED 0.56 rem bladder wall 3.0 rem
• Stabin MG, Gelfand MJ. Q J Nucl Med 1998
  4293-112.

15
Pediatric Nuclear Medicine ResearchPET Dosimetry

• F-18 fluorocholine -- for 7.7 mCi in a 70 kg
  adult
• ED 1.0 rem kidney 2.46 rem
• DeGrado TR, et al. J Nucl Med 2002 43509.
• F-18 fluorodopa -- for 9.0 mCi in a 70 kg adult
• ED 0.60 rem bladder wall 5.1 rem
• Dhawan V, et al. J Nucl Med 1996 371850-1852.
• F-18 fluorothymidine for 5.0 mCi in a 70 kg
  adult
• EDE 1.0 rem bladder wall 3.26 rem
• Vesselle H, et al. N Nucl Med 20031482-1488.
• C-11 methionine for 20 mCi in a 70 kg adult
• ED 0.33 rem bladder wall 1.73 rem

16
Pediatric Nuclear Medicine ResearchPET Dosimetry

• Why not reduce the administered activity another
  50 and double the imaging time?
• Even with an additional 50 reduction in
  administered activity, absorbed radiation doses
  still exceed the limits for F-18 labed
  radiphamraceuticals.

17
Effective DoseNot Whole Body Dose

• Effective dose (ED) takes into account the risk
  associated with radiation dose to each organ and
  tissue, but the RDRC regulations set an arbitrary
  standard that no target organ dose shall exceed
  the whole body dose by more 67.
• Whole body absorbed radiation dose is no longer
  widely used.
• The target organ dose for most radiopharmaceutical
  s is usually much more than 67 above the whole
  body dose or the ED.

18
Problems with the Current RDRC Regulations

• The radiation exposure limits are expressed in
  terms of whole-body dose, which is an obsolete
  concept. The current concept of effective dose
  (HE) is more appropriate.
• The pediatric dose limits hold the investigator
  to 10 of the permitted adult absorbed dose.
  This limit does not allow needed research in
  patients who have cancer, and other diseases that
  are life-threatening or shorten life expectancy.
  
•  Target organ dose is inappropriate in relation
  to the HE or whole body dose.

19
Recommendations for Pediatric Studies Under New
RDRC Regulations

• The HE concept should replace the concept of
  whole body dose.
• An upper limit for target organ dose may not be
  necessary. The HE calculation takes into account
  almost all of the risk associated with exposure
  to individual organs. If an upper limit is set
  for target organ dose, it should be 10 times
  higher than the HE, not 1.6 times higher than the
  whole body dose.

20
Recommendations for Pediatric Studies Under New
RDRC Regulations

• The upper limit for HE should be higher for
  children with cancer and other chronic life
  threatening and life shortening diseases. These
  children are at much higher risk from the disease
  itself than from the theoretical risk of exposure
  to a diagnostic radiotracer.
• An upper limit for HE of 2.0 rem for single dose
  and 5.0 rem for annual and total HE research
  related should be considered in these patients.
  This will facilitate needed research with
  positron emitting radiopharmaceuticals. 

21
RDRC regulations Must Encourage Research in
Pediatric Populations with Cancer and Life
Threatening Diseases

• Unless current RDRC regulations, molecular
  imaging technology will not be readily available
  for the study of pediatric cancer or other life
  threatening or life shortening diseases. With no
  action, use of molecular imaging technology in
  these children will be delayed by many years.
• An up to date standard should be developed, based
  on effective dose, with limits that permit the
  study of children with cancer or other life
  threatening diseases.

22
RDRC regulations Must Encourage Research in
Pediatric Populations with Cancer and Life
Threatening Diseases

• The RDRC mechanism should clearly permit use of a
  wide variety of labeled molecules, as long as the
  molecule is a non-biologic and is given in doses
  that are far below pharmacologic doses.