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Pediatric Nuclear Medicine and the RDRC Regulations

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  1. Pediatric Nuclear Medicineand the RDRC Regulations Michael J. Gelfand M.D. Cincinnati Children’s Hospital Cincinnati, OH Past-President , Society of Nuclear Medicine

  2. Pediatric Nuclear Medicine Nuclear Medicine is widely used at children’s hospitals Nuclear medicine procedure volumes in 2003 • Boston CH 8061 • Philadelphia (CHOP) 6539 • Cincinnati CH 4780

  3. Pediatric Nuclear Medicine • At Cincinnati Children’s 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. 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%

  5. 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

  6. Effective Dose — How to Compare Apples and Oranges • Effective dose (ED), therefore, is defined as: ED = Σ WTHT T where WT is weighting factor for tissue T and HT is the calculated dose for tissue T

  7. 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 1999;210:645 -650. Stabin MG, Gelfand MJ. Q J Nucl Med 1998; 42:93-112.

  8. 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:”

  9. 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

  10. 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).”

  11. 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

  12. 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

  13. 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: 42:93-112.

  14. 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; 43:509. [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; 37:1850-1852. [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 2003;1482-1488. C-11 methionine – for 20 mCi in a 70 kg adult ED 0.33 rem bladder wall 1.73 rem Deloar HN, et al. Eur J Nucl Med Mol Imag 1998; 25:629-633.

  15. 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 labeled radiopharmaceuticals.

  16. 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 radiopharmaceuticals is usually much more than 67% above the whole body dose or the ED.

  17. 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.

  18. 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.

  19. 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.

  20. 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.

  21. 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.