1. Pediatric Nuclear Medicine and 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 CH8061 Philadelphia (CHOP)6539 Cincinnati CH4780

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.

5. GU studies56% Bone20% Tumor studies 8.2% including I-123-MIBGapprox 2.4% F-18-FDG PET2.3% Pediatric Nuclear Medicine at CCH

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 =Σ W T H T T where W T is weighting factor for tissue T and H T 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 1999;210:645 -650. Stabin MG, Gelfand MJ. Q J Nucl Med 1998; 42:93-112.

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 commitment15 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 dose0.3 rem annual and total dose commitment0.5 rem Other organs single dose0.5 rem annual and total dose commitment1.5 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 Research PET Dosimetry [F-18] 2-fluoro-2-deoxyglucose For 9.8 mCi in a 70 kg adult ED0.88 rembladder wall 6.8 rem For 4.5 mCi in a 10 year old ED0.64 rembladder wall 3.6 rem For 2.6 mCi in a 5 year old ED0.56 rembladder wall 3.0 rem Stabin MG, Gelfand MJ. Q J Nucl Med 1998: 42:93-112.

15. [F-18] fluorocholine -- for 7.7 mCi in a 70 kg adult ED1.0 remkidney 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 ED0.60 rembladder 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 rembladder 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 ED0.33 rembladder wall 1.73 rem Deloar HN, et al. Eur J Nucl Med Mol Imag 1998; 25:629-633. Pediatric Nuclear Medicine Research PET Dosimetry

16. 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. Pediatric Nuclear Medicine Research PET Dosimetry

17. Effective Dose Not 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.

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 (H E ) 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 H E or whole body dose.

19. Recommendations for Pediatric Studies Under New RDRC Regulations 1.The H E concept should replace the concept of whole body dose. 2.An upper limit for target organ dose may not be necessary. The H E 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 H E, not 1.6 times higher than the whole body dose.

20. Recommendations for Pediatric Studies Under New RDRC Regulations 3.The upper limit for H E 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. 4.An upper limit for H E of 2.0 rem for single dose and 5.0 rem for annual and total H E 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.