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Radioactive Drug Research Radioactive Drug Research Committee Committee

December 11, 2007December 11, 2007New York, New YorkNew York, New York

Orhan H SuleimanOrhan H SuleimanRichard FejkaRichard FejkaAlex GorovetsAlex Gorovets

Office of New DrugsOffice of New DrugsOffice of Oncology Drug DevelopmentOffice of Oncology Drug Development

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Radiation DosimetryRadiation Dosimetry

RDRC MeetingRDRC MeetingNew York CityNew York City

December 11, 2007December 11, 2007

Orhan H Suleiman, MS, PhD, FAAPMOrhan H Suleiman, MS, PhD, FAAPMSenior Science Policy AdvisorSenior Science Policy Advisor

Office of New DrugsOffice of New DrugsOffice of Oncology Drug DevelopmentOffice of Oncology Drug Development

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Radiation DosimetryRadiation Dosimetry

RDRC Dose LimitsRDRC Dose Limits Diagnostic Doses Diagnostic Doses RadiotherapeuticsRadiotherapeutics

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RDRC Radiation Dose Limits*RDRC Radiation Dose Limits*Organ or SystemOrgan or System Single DoseSingle Dose Annual and Total DoseAnnual and Total Dose

Whole bodyWhole body 0.03 Sv (3 Rem) 0.03 Sv (3 Rem) 0.05 Sv (5Rem)0.05 Sv (5Rem)Active blood-forming Active blood-forming organsorgans 0.03 Sv (3 Rem) 0.03 Sv (3 Rem) 0.05 Sv (5 Rem)0.05 Sv (5 Rem)Lens of the eyeLens of the eye 0.03 Sv (3 Rem)0.03 Sv (3 Rem) 0.05 Sv (5 Rem)0.05 Sv (5 Rem)GonadsGonads 0.03 Sv (3 Rem)0.03 Sv (3 Rem) 0.05 Sv (5 Rem)0.05 Sv (5 Rem)Other organsOther organs 0.05 Sv (5 Rem)0.05 Sv (5 Rem) 0.15 Sv (15 Rem) 0.15 Sv (15 Rem)

Based on 1975 Nuclear Regulatory Commission’s occupational dose limitsBased on 1975 Nuclear Regulatory Commission’s occupational dose limits

*21 CFR 361.1 (b) (3)*21 CFR 361.1 (b) (3)

Radiation doses from x-ray procedures that are part of the research study shall Radiation doses from x-ray procedures that are part of the research study shall also be included.also be included.

For research subjects under 18 years of age at his last birthday, the radiation For research subjects under 18 years of age at his last birthday, the radiation dose does not exceed 10 percent of adult dose.dose does not exceed 10 percent of adult dose.

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How do I determine the radiation dose How do I determine the radiation dose from radiopharmaceutical?from radiopharmaceutical?

Organ doses and whole body doses (as specified in 21 CFR Organ doses and whole body doses (as specified in 21 CFR 361.1) can only be estimated using standard adult and child 361.1) can only be estimated using standard adult and child mathematical reference models.mathematical reference models.

For radionuclides you should use methods of the:For radionuclides you should use methods of the:

Medical Internal Radiation Dosimetry (MIRD) committee of the Society of Medical Internal Radiation Dosimetry (MIRD) committee of the Society of Nuclear medicine (SNM)Nuclear medicine (SNM)

http://interactive.snm.org/index.cfm?PageID=2199&RPID=1372http://interactive.snm.org/index.cfm?PageID=2199&RPID=1372

International Commission on Radiological Protection (ICRP) Publications. International Commission on Radiological Protection (ICRP) Publications. www.icrp.orgwww.icrp.org

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BiodistributionBiodistribution

If there is insufficient human biodistribution or If there is insufficient human biodistribution or pharmacokinetic data, absorbed dose pharmacokinetic data, absorbed dose calculations may be based on animal data.calculations may be based on animal data.

However- FDA recommends that the RDRC However- FDA recommends that the RDRC investigators validate with human data on the investigators validate with human data on the first 5-10 subjects and begin using the human first 5-10 subjects and begin using the human biodistribution data for subsequent calculations.biodistribution data for subsequent calculations.

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How do I determine the radiation dose How do I determine the radiation dose from x-rays?from x-rays?

Radiation doses from associated x-ray procedures that are part Radiation doses from associated x-ray procedures that are part of the research study shall also be included. of the research study shall also be included.

For x-ray, and CT:For x-ray, and CT:

Food and Drug Administration (X-ray)Food and Drug Administration (X-ray)http://www.fda.gov/cdrh/ohip/organdose.htmlhttp://www.fda.gov/cdrh/ohip/organdose.html

British Health Protection Agency (CT)British Health Protection Agency (CT)http://www.hpa.org.uk/radiationhttp://www.hpa.org.uk/radiation//

http://www.hpa.org.uk/radiation/publications/software/index.htmhttp://www.hpa.org.uk/radiation/publications/software/index.htm

German national Research Center for Environemtn and German national Research Center for Environemtn and Health(Gesellschaft fur Strahlen-und-Umweltforschung (GSF) Health(Gesellschaft fur Strahlen-und-Umweltforschung (GSF) http://www.gsf.de/index_en.phphttp://www.gsf.de/index_en.php

Finnish Radiation and Nuclear Safety Authority (STUK)Finnish Radiation and Nuclear Safety Authority (STUK)

http://www.stuk.fi/sateilyn_kayttajille/ohjelmat/PCXMC/en_GB/introduction/http://www.stuk.fi/sateilyn_kayttajille/ohjelmat/PCXMC/en_GB/introduction/

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How do I determine the radiation dose How do I determine the radiation dose using most recent models?using most recent models?

Exciting research and activity in this area, with many free, and Exciting research and activity in this area, with many free, and linked websites, along with commercial services, for linked websites, along with commercial services, for calculating organ doses from a variety of radiation sources.calculating organ doses from a variety of radiation sources.

Two links which will serve as a gateway to much of the ongoing Two links which will serve as a gateway to much of the ongoing research are:research are:

Radiation Dose Assessment Resource (RADAR)Radiation Dose Assessment Resource (RADAR)

http://www.doseinfo-radar.com/RADARphan.htmlhttp://www.doseinfo-radar.com/RADARphan.html

Consortium of Computational Human Phantoms (CCHP)Consortium of Computational Human Phantoms (CCHP)

http://www.virtualphantoms.org/http://www.virtualphantoms.org/

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Patient PhantomsPatient PhantomsStylized versus VoxelStylized versus Voxel

MIRD stylized phantoms Voxel phantoms

1010

Patient PhantomsPatient PhantomsUF 9-month male phantomUF 9-month male phantom

1111

Patient PhantomsPatient PhantomsUF Pediatric Phantom SeriesUF Pediatric Phantom Series

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Stylized vs Voxel PhantomStylized vs Voxel PhantomExternal dosimetryExternal dosimetry

1313

Image-Based Advances in Skeletal DosimetryImage-Based Advances in Skeletal Dosimetry

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Radiation DoseRadiation Dose

Administered doseAdministered dose Mass doseMass dose Activity- MBq (mCi)Activity- MBq (mCi)

Radiation Absorbed DoseRadiation Absorbed Dose mGy (rads)mGy (rads)

Equivalent Dose (Dose equivalent)Equivalent Dose (Dose equivalent) mSv (mRem)mSv (mRem)

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Radiation Dose- what to report?Radiation Dose- what to report?

The fundamental radiation unit of dose we need to know The fundamental radiation unit of dose we need to know is the organ (tissue) dose. 21 CFR 361.1 also requires is the organ (tissue) dose. 21 CFR 361.1 also requires reporting of the whole body.reporting of the whole body.

It is essential to know the actual organ dose estimates, It is essential to know the actual organ dose estimates, especially for the organs which receive the highest especially for the organs which receive the highest doses.doses.

Effective dose, E, will be acceptable as nominally Effective dose, E, will be acceptable as nominally

equivalent to the whole body dose. equivalent to the whole body dose.

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Effective Dose ~ Whole Body DoseEffective Dose ~ Whole Body Dose

The effective dose (E) is the sum of the The effective dose (E) is the sum of the weighted equivalent doses in all the weighted equivalent doses in all the tissues and organs of the body.tissues and organs of the body.

EE = = ΣΣTT WWTTHHTT

WhereWhere HHTT is the individual tissue or organ dose for tissue is the individual tissue or organ dose for tissue

T,T,

And And WWTT is the weighting factor for tissue T,is the weighting factor for tissue T,

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Tissue Weighting Factors (wTissue Weighting Factors (wtt)) Organ (Tissue) Organ (Tissue) ICRP ICRP ICRP ICRP ICRPICRP 26 60 26 60 Draft - 2004Draft - 2004

GonadsGonads 0.250.25 0.200.20 0.050.05

BreastBreast 0.150.15 0.050.05 0.120.12

Red BM, lungRed BM, lung 0.120.12 0.120.12 0.120.12

ThyroidThyroid 0.030.03 0.050.05 0.050.05

Bone surfacesBone surfaces 0.030.03 0.010.01 0.010.01

Colon, stomachColon, stomach NCNC 0.120.12 0.120.12

Bladder, liver, esophagusBladder, liver, esophagus NCNC 0.050.05 0.050.05

SkinSkin NCNC 0.010.01 0.010.01

Salivary glands, brainSalivary glands, brain NCNC NCNC 0.010.01

RemainderRemainder 0.300.30 0.050.05 0.100.10

TotalTotal 1.001.00 1.001.00 1.001.00

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In summaryIn summary

Use the correct methodologiesUse the correct methodologies Calculate the individual organ doses from Calculate the individual organ doses from

all sources, including x-ray.all sources, including x-ray. Use human biodistribution data.Use human biodistribution data. Understand the different dose metrics.Understand the different dose metrics.

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Any questions?Any questions?