Radioactive Drug Research Committee December 11, 2007 New York, New York Orhan H Suleiman Richard Fejka Alex Gorovets Office of New Drugs Office of Oncology Drug Development

Radiation Dosimetry RDRC Meeting New York City December 11, 2007 Orhan H Suleiman, MS, PhD, FAAPM Senior Science Policy Advisor Office of New Drugs Office of Oncology Drug Development

Radiation Dosimetry RDRC Dose Limits Diagnostic Doses Radiotherapeutics I will briefly be discussing dosimetry and what we want reported, but I also want the audience to be aware that determining radiation dose for research under an RDRC, or estimating the dose for a conventional diagnostic is not the same as for therapy. The uncertainties associated with the stochastic risk estimation for cancer is high. However, despite this level of uncertainty, we want to be certain that those calculating these doses use the appropriate methodologies, and also be aware that this continues to be an area of ongoing research. I also want to emphasize that these methodologies may not be appropriate for determining therapeutic doses. Why do I even mention it today, because I want to draw your attention to this. As radiotherapeutics enter the marketplace, it is this community will be called upon to provide accurate dosimetry.

RDRC Radiation Dose Limits* Organ or System Single Dose Annual and Total Dose Whole body 0.03 Sv (3 Rem) 0.05 Sv (5Rem) Active blood-forming organs 0.03 Sv (3 Rem) 0.05 Sv (5 Rem) Lens of the eye 0.03 Sv (3 Rem) 0.05 Sv (5 Rem) Gonads 0.03 Sv (3 Rem) 0.05 Sv (5 Rem) Other organs 0.05 Sv (5 Rem) 0.15 Sv (15 Rem) Based on 1975 Nuclear Regulatory Commission’s occupational dose limits *21 CFR 361.1 (b) (3) Radiation doses from x-ray procedures that are part of the research study shall also be included. For research subjects under 18 years of age at his last birthday, the radiation dose does not exceed 10 percent of adult dose. 1. These are the current limits, established in 1975. Until we rewrite the regulations, these are the regulatory limits. At that time we established a 2 tier set of standards, one for the whole body, the other organ specific. 2. We also require the entire dose that the human subject receives, which will most likely include doses from adjunct x-ray procedures….that are part of the study! 3. And finally, although this is rarely done today, we stipulated that the radiation dose for research subjects under the age of 18 was limited to 10% of the adult dose.

How do I determine the radiation dose from radiopharmaceutical? Organ doses and whole body doses (as specified in 21 CFR 361.1) can only be estimated using standard adult and child mathematical reference models. For radionuclides you should use methods of the: Medical Internal Radiation Dosimetry (MIRD) committee of the Society of Nuclear medicine (SNM) http://interactive.snm.org/index.cfm?PageID=2199&RPID=1372 International Commission on Radiological Protection (ICRP) Publications. www.icrp.org So how do I determine the radiation dose, and how do I report it? When I mention radiation dose, I don’t mean administered activity, in milliCuries or Mega Becquerels, or mass dose in mg or ml, but the radiation absorbed dose in rads or rem. Since most medical radiation has a radiation weighting factor of 1, rads = rem, or Gray = Sieverts.

Biodistribution If there is insufficient human biodistribution or pharmacokinetic data, absorbed dose calculations may be based on animal data. However- FDA recommends that the RDRC investigators validate with human data on the first 5-10 subjects and begin using the human biodistribution data for subsequent calculations.

How do I determine the radiation dose from x-rays? Radiation doses from associated x-ray procedures that are part of the research study shall also be included. For x-ray, and CT: Food and Drug Administration (X-ray) http://www.fda.gov/cdrh/ohip/organdose.html British Health Protection Agency (CT) http://www.hpa.org.uk/radiation/ http://www.hpa.org.uk/radiation/publications/software/index.htm German national Research Center for Environemtn and Health(Gesellschaft fur Strahlen-und-Umweltforschung (GSF) http://www.gsf.de/index_en.php Finnish Radiation and Nuclear Safety Authority (STUK) http://www.stuk.fi/sateilyn_kayttajille/ohjelmat/PCXMC/en_GB/introduction/ So how do I determine the radiation dose, and how do I report it? When I mention radiation dose, I don’t mean administered activity, in milliCuries or Mega Becquerels, or mass dose in mg or ml, but the radiation absorbed dose in rads or rem. Since most medical radiation has a radiation weighting factor of 1, rads = rem, or Gray = Sieverts.

How do I determine the radiation dose using most recent models? Exciting research and activity in this area, with many free, and linked websites, along with commercial services, for calculating organ doses from a variety of radiation sources. Two links which will serve as a gateway to much of the ongoing research are: Radiation Dose Assessment Resource (RADAR) http://www.doseinfo-radar.com/RADARphan.html Consortium of Computational Human Phantoms (CCHP) http://www.virtualphantoms.org/ So how do I determine the radiation dose, and how do I report it? When I mention radiation dose, I don’t mean administered activity, in milliCuries or Mega Becquerels, or mass dose in mg or ml, but the radiation absorbed dose in rads or rem. Since most medical radiation has a radiation weighting factor of 1, rads = rem, or Gray = Sieverts.

Patient Phantoms Stylized versus Voxel MIRD stylized phantoms Voxel phantoms

Patient Phantoms UF 9-month male phantom

Patient Phantoms UF Pediatric Phantom Series

Stylized vs Voxel Phantom External dosimetry

Image-Based Advances in Skeletal Dosimetry

Radiation Dose Administered dose Radiation Absorbed Dose Mass dose Activity- MBq (mCi) Radiation Absorbed Dose mGy (rads) Equivalent Dose (Dose equivalent) mSv (mRem)

Radiation Dose- what to report? The fundamental radiation unit of dose we need to know is the organ (tissue) dose. 21 CFR 361.1 also requires reporting of the whole body. It is essential to know the actual organ dose estimates, especially for the organs which receive the highest doses. Effective dose, E, will be acceptable as nominally equivalent to the whole body dose. Here we describe this mathematically. READ from SLIDE…NEXT SLIDE SPEAK TO AUDIENCE, slowly, with emphasis… if you add up each organ dose times it's weighting factor (thyroid dose times its weighting factor, lung dose, breast dose, etc.), then the sum of all of the equivalent doses is the effective dose… which corresponds to what the uniform whole body dose would be in terms of risk. Let me give you an example which will demonstrate the concept.

Effective Dose ~ Whole Body Dose The effective dose (E) is the sum of the weighted equivalent doses in all the tissues and organs of the body. E = ΣT WTHT Where HT is the individual tissue or organ dose for tissue T, And WT is the weighting factor for tissue T, Here we describe this mathematically. READ from SLIDE…NEXT SLIDE SPEAK TO AUDIENCE, slowly, with emphasis… if you add up each organ dose times it's weighting factor (thyroid dose times its weighting factor, lung dose, breast dose, etc.), then the sum of all of the equivalent doses is the effective dose… which corresponds to what the uniform whole body dose would be in terms of risk. Let me give you an example which will demonstrate the concept.

Tissue Weighting Factors (wt). Organ (Tissue). ICRP ICRP ICRP Tissue Weighting Factors (wt) Organ (Tissue) ICRP ICRP ICRP 26 60 Draft - 2004 Gonads 0.25 0.20 0.05 Breast 0.15 0.12 Red BM, lung Thyroid 0.03 Bone surfaces 0.01 Colon, stomach NC Bladder, liver, esophagus Skin Salivary glands, brain Remainder 0.30 0.10 Total 1.00 Here are the original, current, and proposed tissue weighting factors. In 1977, ICRP introduced effective dose equivalent with the listed tissue weighting factors, upgraded these risk derived factors in 1991, and now, using more recent science, is proposing a new revision. Actually, if you round off to 1 significant figure, considering the uncertainty in such risk estimates, the differences are not significantly different. But the purpose of standardization is to be consistent and minimize confusion. So we need to be consistent, and respect the expertise and decision of the ICRP.

In summary Use the correct methodologies Calculate the individual organ doses from all sources, including x-ray. Use human biodistribution data. Understand the different dose metrics.

Any questions?