1Greater New York City Greater New York City RDRC Meeting, December 2007RDRC Meeting, December 2007

PROGRAM UPDATE -PROGRAM UPDATE -Radioactive DrugRadioactive Drug

Research CommitteeResearch Committee

CAPT Richard Fejka, USPHS, RPh, MS, BCNPSenior Manager - Radioactive Drug Research Committee program

Division of Medical Imaging and Hematology ProductsOffice Of Oncology Drug Products

Center for Drug Evaluation and ResearchU.S. Public Health Service

2Greater New York City Greater New York City RDRC Meeting, December 2007RDRC Meeting, December 2007

OutlineOutline• History

• Regulation

• Research Under an RDRC

• Monitoring

• Reporting Forms

• Current Status of Committees, Study Summaries and Regulatory Initiatives

• Annual Report Reviews - Observations

3Greater New York City Greater New York City RDRC Meeting, December 2007RDRC Meeting, December 2007

A Little HistoryA Little History• Prior to 1975 AEC (Atomic

Energy Commission) regulated reactor produced radioactive drugs

• January 8, 1963 Federal Register notice temporarily exempted radioactive new drugs for investigational use from requirements of part 312

4Greater New York City Greater New York City RDRC Meeting, December 2007RDRC Meeting, December 2007

A Little History A Little History (continued)(continued)

• The purpose of the exemption was to allow Federal agencies to explore ways to avoid unnecessary duplication of regulatory control

• AEC and FDA concluded ALL radioactive drugs should now be subject to the same clearance procedures as other drugs

5Greater New York City Greater New York City RDRC Meeting, December 2007RDRC Meeting, December 2007

A Little History A Little History (continued)(continued)

• FDA established regulations on August 25, 1975 to regulate ALL radioactive drugs

• Determined that all radioactive drugs are either New Drugs or GRAS/E (Generally Recognized As Safe and Effective)

• ALL radioactive drugs now subject to an IND, NDA or biological product license

• EXCEPT radioactive drugs used for certain research uses

6Greater New York City Greater New York City RDRC Meeting, December 2007RDRC Meeting, December 2007

The RegulationThe Regulation

• 21 CFR 361 Prescription Drugs for Human Use Generally Recognized as

Safe and Effective and Not Misbranded: Drugs Used In Research

§ 361.1 Radioactive drugs for certain research uses.

7Greater New York City Greater New York City RDRC Meeting, December 2007RDRC Meeting, December 2007

The RegulationThe Regulation• (a) Radioactive drugs (…) are generally recognized as safe

and effective when administered, under the conditions set forth in paragraph (b) of this section, to human research subjects during the course of a research project intended to obtain basic information regarding the metabolism (including kinetics, distribution, and localization) of a radioactively labeled drug or regarding human physiology, pathophysiology, or biochemistry, but not intended for immediate therapeutic, diagnostic, or similar purposes or to determine the safety and effectiveness of the drug in humans for such purposes (i.e., to carry out a clinical trial). Certain basic research studies, e.g., studies to determine whether a drug localizes in a particular organ or fluid space and to describe the kinetics of that localization, may have eventual therapeutic or diagnostic implications, but the initial studies are considered to be basic research within the meaning of this section.

8Greater New York City Greater New York City RDRC Meeting, December 2007RDRC Meeting, December 2007

Research Under an RDRCResearch Under an RDRC• Four conditions set in § 361.1

1. Basic Science Research

2. Pharmacological dose limit

3. Radiation dose limits

4. Radioactive Drug Research Committee

9Greater New York City Greater New York City RDRC Meeting, December 2007RDRC Meeting, December 2007

MonitoringMonitoringFDA conducts periodic reviews of approved

committees by:

• Review of their annual report,• Review of meeting minutes,• Review of full protocols for certain

studies,• On-site inspections.

10Greater New York City Greater New York City RDRC Meeting, December 2007RDRC Meeting, December 2007

Monitoring Monitoring

• Submit Annual Report by January 31 for past calendar year’s activitiesconsists of

• FDA FORM 2914 Membership Summaryand

• FDA Form 2915 Study Summary for EACHEACH study overseen by RDRC

11Greater New York City Greater New York City RDRC Meeting, December 2007RDRC Meeting, December 2007

Reporting FormsReporting FormsMembership (2914) and Study Summary (2915)

available through FDA RDRC website at

http://www.fda.gov/cder/regulatory/RDRC/default.htmor1. Go to www.fda.gov2. Search on “RDRC”3. Click on Radioactive Drug Research Committee (RDRC)

Program4. Click on RDRC Forms and Checklist

or go to FDA’s Electronic Forms Numerical Listing page at:

http://www.fda.gov/opacom/morechoices/fdaforms/default.html

12Greater New York City Greater New York City RDRC Meeting, December 2007RDRC Meeting, December 2007

Reporting FormsReporting Forms

Old Forms New FormsOld Forms New Forms • No instructions

• Dates for submission of past qualifications statements lacking

• Use of “dose” confusing

“Maximum amount (i.e. mg) of nonradioactive moiety administered per subject, per single dose and/or the minimum specific activity (i.e. mCi/mg) of drug at the time of administration.”

• Terms not only confusing, but incorrect: “mR/whole body”

• Provide Instructions

• Requires a Study ID number

• Requires a study approval and termination date

• Dose terms clarified, e.g.

- Pharmacological and NOEL*dose (*No Observed Effect Level )

- Activity administeredMBq - uCi, mCi

- Radiation absorbed dose mSv - Rem

13Greater New York City Greater New York City RDRC Meeting, December 2007RDRC Meeting, December 2007

Current Status on Committees and Current Status on Committees and Study Summary ReportsStudy Summary Reports

• 201 RDRCs approved

Calendar Year # of RDRCs expected to report

# of Study Summaries submitted for review

2003 84 397

2004 81 487

2005 78 602

2006 73 671

2007 75 -

14Greater New York City Greater New York City RDRC Meeting, December 2007RDRC Meeting, December 2007

Status of RDRC Status of RDRC Regulatory InitiativesRegulatory Initiatives

• Draft Guidance – being reviewed

• Reinstituted Inspection Program

• Impact of Exploratory IND

15Greater New York City Greater New York City RDRC Meeting, December 2007RDRC Meeting, December 2007

Some ObservationsSome ObservationsAnnual Report ReviewsAnnual Report Reviews

• RDRC not associated with a medical institution.

• Medical institution did not know they had an RDRC.

• An RDRC chair who tried to convince their administration that RDRC members were surrogate FDA employees and therefore operate independently of the medical institution.

• An RDRC which believed that one of their roles was to review their institution’s IRB actions.

• Inappropriate approval of First-In-Human studies under RDRC authority.

16Greater New York City Greater New York City RDRC Meeting, December 2007RDRC Meeting, December 2007

Some ObservationsSome ObservationsAnnual Report ReviewsAnnual Report Reviews

• Failure of RDRC to meet quarterly.

• Meeting minutes which do not show RDRC members recusing themselves from voting on studies which they are associated with.

• Failure to convert RDRC study into IND.

• Special Summary Reports not filed, or not filed in timely manner.

• Reluctance to use human biodistribution data to verify animal radiation dosimetry estimates.

17Greater New York City Greater New York City RDRC Meeting, December 2007RDRC Meeting, December 2007

Some ObservationsSome ObservationsAnnual Report ReviewsAnnual Report Reviews

Membership

• Lack of timely notification of membership changes.

• Incomplete qualification documentation for membership category, especially when switching from one category to another.

Radiation Dose

• Failure to report associated x-ray doses.

• Incomplete or lack of reference for dosimetry calculations.

• Inconsistency in dosimetry among investigators within an RDRC – obvious failure of RDRC to standardize.

18Greater New York City Greater New York City RDRC Meeting, December 2007RDRC Meeting, December 2007

If you need assistance:If you need assistance:CAPT Richard Fejka USPHS, RPh, MS, BCNPSenior Manager, RDRC Program Richard.Fejka@FDA.HHS.GOV(301) 796-1353

Susan Lange, ARRT (R)(N), MPHProject Manager, RDRC Program Susan.Lange@FDA.HHS.GOV(301) 796-4117

Orhan Suleiman MS, PhD, FAAPM,Senior Science Policy Advisor Orhan.Suleiman@FDA.HHS.GOV(301) 796-1471