# Presentation: 476755

## Radiation Dose Limits in Human Research:The FDA Radioactive Drug Research Committee (RDRC) 

**49****th**** Annual Meeting of the **
**Health Physics Society**
** ****Washington D.C.**** **
**July 11 – 15, 2004**
**O H Suleiman, R Fejka, R Farkas, M Walsh, **
**L Panholzer**

**Notes:**
I want to thank you for giving us the opportunity to discuss one of FDA’s oldest radioactive research program, the Radioactive Drug Research Committee.  The current team consists of the following members, Richard fejka, a nuclear pharmacisit, Maria Walsh, one of our program managers, Maria is a nurse, Lynn Panholzer our other Program Manager, she is a pharmacist, and Ray Farkas, who ran the program until he retired recently.  I am Orhan SUleiman, and I am a physicist.

## Radioactive Drug Research Committee

**Established in 1975**
**Formally codified in 21 CFR 361.1**
**Allows human research with radioactive drugs without an IND when:**
**Research is basic**
**RDRC approves**
**There is no clinically detectable pharmacologic effect from the administered drug**
**and radiation dose limits as specified are met**

**Notes:**
In 1975 the RDRC committee was established and formally codified in the Code of Federal Regulations Title 21, Part 361.1.

The intent of the regulations was to allow human research to continue without the burden of obtaining an FDA Investigational New Drug Application, or IND, if certain conditions were met.

The research protocol would have to be approved by the committee, and the administered pharmacologic dose would show “no clinically detectable effect”, and certain radiation dose limits could not be exceeded.

This enabled radiotracer research to be conducted in humans.

## Provisions within 21 CFR Part 361.1

**Membership qualifications**
**Specific Responsibilities of RDRC to**
**assure research is basic in nature and does not require IND**
**review and approve protocol, human subjects**
**report adverse reactions**
**seek approval of Institutional Review Board (IRB)**
**file required reports with FDA**** **

## Slide 4

## Most frequently used radionuclidesIn 2002, 83 FDA approved RDRC’s conducted 280 studies with 2872 human subjects             					

| Imaging
nuclides (75%) |  | Non-imaging nuclides (21%) |
| --- | --- | --- |
|       positron      | gamma | beta |
| C-11 (32%) | Tc-99m (2%) | H-3 (15%) |
| O-15 (20%) | I-123 (1%) | C-14 (6%) |
| F-18 (18%) |  |  |
| N-13 (2%) |  |  |
| Other nuclides (4%): Cu-60, Fe-59, Ca-41, F-17, Fe-55, I-125, I-131,  Ca-45, Ca-47, Cu-62, In-111, Tc-94m, Xe-133 |  |  |

**Notes:**
Looking at the data from a different perspective, there were 280 studies in 2002, using almost 2900 human subjects.

72% of these studies consisted of 4 PET radionuclides, while 3 % used conventiona gamma emitters technetium-99m  and I-123.   Another 21% used tritium and carbon 14.

## 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)**
- For **subjects under 18 years of age**: Radiation dose does not exceed 10 percent of dose set forth above.

## Organ Dose is the intermediary metric for risk estimation

- Radiation dose can be related to probability
-  of cancer detriment (risk) for a given tissue (organ)
-    e.g.	   breast risk is 1.04 x 10** -2** Sv **-1**
- 	      ~ 1 lifetime fatality per 0.01 Sv;
- 	or for screening mammography, where breast dose is  ~1.8 mSv per view, and 2 views yield a 3.6 mSv breast dose.
- 	The stochastic risk of lifetime cancer is 3.6 x 10 **-5, **
- 	or 1 in 27,778

## Effective dose (E): A homogenized single metric of radiation risk

**Effective Dose (E)***
**“****Equivalent” to whole body dose**
**Risk based metric, relating partial body irradiations (individual organ or tissue, limited x-ray field) to uniform whole body irradiation.**
**	*********International Commission on Radiological Protection (ICRP Report 60, 1990)**
** **

**Notes:**
Now, in the name of standardization, I will review one more raidation metric, having just discussed entrance exposure, and that is effective dose.

It is an internationally accepted unit, and is a homogenized single metric which is equivalent to a total body dose an individual may receive, in terms of risk.

It factors in the actual radiation dose individual organs receive, and uses a weighting factor for each organ which incorporates that  organ’s individual sensitivity to radiation in terms of cancer incidence, and mortality.

For example............................... 

## 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****** ******= ******Σ******T****** ******W******T******H******T***
**Where W****T  ****is the weighting factor for tissue T, and**
**H****T   ****is the individual tissue or organ dose for tissue T**

## 	Tissue Weighting Factors (ICRP    Organ (Tissue)   ICRP 26      ICRP 60  2005) 							

| Gonads | 0.25 | 0.20       (0.05) |
| --- | --- | --- |
| Breast | 0.15 | 0.05       (0.12) |
| Red Bone M | 0.12 | 0.12       (0.12) |
| Lung | 0.12 | 0.12       (0.12) |
| Thyroid | 0.03 | 0.05       (0.05) |
| Bone Surfaces | 0.03 | 0.01       (0.01) |
| Remainder | 0.30 | 0.05       (0.10) |
| Colon, Stomach |  | 0.12       (0.12) |
| Bladder,Liver,
Esophagus |  | 0.05       (0.05) |
| Skin |  | 0.01       (0.01) |
| Total | 1.00 | 1.00       (1.00) |

## Radiation dose (E) 

**Radiation                              Effective  ****	****Equivalent to****	****   Equivalent time from **
_**Source**_**	****                            **_**Dose (E)**_**          **_**# of chest x-rays**_**          **_**natural background radiation **_
**Background**
**U.S. - 1 year                ****	****          3 mSv         ****	****   150****	****    ****	****                1 year**
**Medical**
**Chest x-ray             ****	****      0.02 mSv            ****	****      1****	****                                2.4 days**
**Mammogram**
**(1 view)****	****                        0.09 mSv    ****	****     4.5****	****                                11 days****	**
**CT- head****	****                            2  mSv   ****	****    100****	****	****             8 months**
**Upper GI fl                             3 mSv   ****	****    150****	****	****               1 year**
**CT- abdomen                      10 mSv   ****	****    500****	****	****             3.3 years**
**Tc-99m-lung perf       ****	****          1 mSv****	****      50****	****	****             4 months**
**Tc-99m-bone              ****	****          4 mSv****	****    200****	****	****             1.3 years**
**Nuc Med –FDG         ****	****        10 mSv   ****	****    500****	****                               3.3  years**
**Regulatory Limits**
**Annual RDRC – adults        50 mSv****	**** 2500 chest x-rays****	****            16.7 years**
**Annual RDRC < 18 ****	****          5 mSv****	****   250 chest x-rays****	****            1.67 years****	**
**General public individual    1 mSv****	****     50****	****	****             4 months****	**
**Annual occupational****	****       50 mSv****	****  2500****	****	****            16.7 years**
**Emergency worker****	****     500 mSv                   25,000  ****	****  ****	****             167 years**

## In the “near” future FDA is planning a meeting

**Purpose of this meeting will be to discuss current and future status of RDRC process**
**Specifically......**

**Notes:**
At this meeting FDA will review research where an IND is not required.  All of the RDRC’s have been notified of this meeting, and we hope that they can share their experiences with us regarding the advantages and limitations of this program. 

For more information please go to the following website.
The meeting will be in Gaithersburg, MD.

## FDA issues and concerns

**Are 1975 radiation dose limits appropriate today?**
**Are RDRC studies conducted when an IND is required?**
**Should First in Human research of New Molecular Entities (NME’s) be allowed under RDRC? **
**If so, what safeguards are needed?**
**What is meant by “no clinically detectable pharmacologic effect?”**
**Should RDRC be reengineered with regard to membership, relationship to Institutional Review Boards (IRB’s), and reporting requirements?**

**Notes:**
Our concerns...........?

Are RDRC studies conducted when an IND is clearly called for?  We need to reeducate our community to understand when RDRC research ends, and the IND process takes over.

What do we mean by no clinically detectable pharmacologic effect?  When this line is crossed, the investigated drug now requires an IND.

Are the 3/5/15 rem dose limits for the whole body and certain organs still appropriate today?  Should these limits remain the same?

Should we reengineer the RDRC process, should a nuclear pharmacist be required, should reporting requirements be changed?

........and should new molecular entities be allowed? 

These are questions we are asking ourselves, and will discuss in a public meeting next month..............[NEXT slide]

## The FutureFDA Campus @ White Oak, Silver Spring, Maryland