FDA Genetic Toxicology Workshop: How Many Doses of an DNA Reactive (Ames-positive) Drug can be Safely Administered to Healthy Subjects?
November 4, 2019
- November 4, 2019
Onsite Check-In will begin at 8:00 am
The Food and Drug Administration (FDA) is announcing the following public workshop entitled “How many doses of an DNA-Reactive Drug can be safely administered to Healthy Subjects?". The following topics will be discussed:
- Healthy subjects receive no benefits from treatment with a DNA-reactive drug and they could be potentially exposed to significant health risks.
- Does this safety concern of a DNA-reactive drug apply only to chronic administration or does it also extend to administering a small number of doses?
There is a general lack of published scientific literature or guidance directed toward the cancer risk or other potential health concerns associated with a small number of doses of a DNA-reactive drug. This workshop seeks to discuss and potentially address the question of how many doses of a DNA-reactive drug could be administered to healthy subjects without significantly increasing their cancer risk. Additional details are provided below.
FDA Staff and Scientists in the areas of genotoxicity and carcinogenicity from academia and industry are invited to attend.
FDA White Oak Campus
Building 2, Room 2031
10903 New Hampshire Ave
Silver Spring, MD 20993
Entrance for the public meeting participants (non-FDA employees) is through Building 1. Please allow time for routine security checks, as procedures will be performed. For parking and security information, please refer to Public Meetings at the FDA White Oak Campus.
If you require special accommodations due to a disability, please contact Dr. Timothy Robison Timothy.Robison@fda.hhs.gov or Dr. Aisar Atrakchi Aisar.Atrakchi@fda.hhs.gov, no later than October 21, 2019, at 4:00 pm EST.
This meeting will be available for online viewing, on the day of the meeting. The link will be provided at a later date.
If you have never attended a Connect Pro event before, test your connection at https://collaboration.fda.gov/common/help/en/support/meeting_test.htm. To get a quick overview of the Connect Pro program, visit https://www.adobe.com/go/connectpro_overview
Additional Details of Workshop
Early phase 1 clinical trials are typically conducted in healthy subjects. The advantages of conducting studies in healthy volunteers include investigation of bioavailability/pharmacokinetics, data not confounded by disease, reduction in patient exposure to ineffective drugs or doses, and rapid subject accrual into a study.
For phase 1 clinical trials, at least two in vitro genetic toxicity tests per the ICH S2 (R1) Guidance are required. At least one in vivo test, in addition, is desirable and should be available prior to the start of phase 2 clinical trials. In the USA, a drug with positive in vitro genotoxicity may still be administered to healthy volunteers for single-dose studies if it does not belong to a known carcinogenic class (structurally or mechanistically), and the trial participants are appropriately made aware of the results in the Informed Consent.
Pharmacokinetic studies generally require two or more doses (e.g., cross-over study). Potential treatment of healthy subjects with a DNA-reactive drug in a clinical trial could consist of: 1) A single dose clinical trial (no repeat dosing of subjects); 2) A crossover design with up to 4 doses of the DNA-reactive drug (each dose may be separated by a washout period [e.g., up to 5 half-lives between each dose]); or 3) Consecutive daily treatment that might go up to 14 days (this example is included as the longest duration/greatest number of doses).
Use of a DNA-reactive drug raises many safety questions, particularly in the case of healthy subjects. Healthy subjects receive no benefits from treatment with a DNA-reactive drug and could potentially be exposed to significant health risks. Does this safety concern of a DNA-reactive drug only apply to chronic administration or does it also extend to a small number of doses? There is a general lack of published scientific literature or guidance directed toward the cancer risk or other potential health concerns associated with administering a small number of doses of a DNA reactive drug. For the purposes of the discussion, DNA reactive drugs will primarily refer to those drugs that tested positive in the in vitro bacterial mutagenicity assay.
The workshop seeks to discuss and potentially address the question of how many doses of a DNA-reactive drug could be administered to healthy subjects without significantly increasing their cancer risk. In the morning there will be several presentations of the relevant issues. In the afternoon, a panel of experts will discuss the issues in detail.
Persons with disabilities having problems accessing the PDF file(s) below may call (301) 796-3634 for assistance.
|2019 FDA Genetic Toxicology Workshop - Agenda and Biographies_Final||pdf (79.70 KB)|
|Considerations on Genotoxic APIs in clinical trials||pdf (433.86 KB)|
|Crump Nov 2019 presentation||pdf (739.07 KB)|
|Drugs targeting the epigenome||pdf (272.50 KB)|
|FDA Talk Slides Brash||pdf (1.81 MB)|
|Gene Tox Workshop Prohaska||pdf (789.22 KB)|
|Meeting_Transcription||pdf (4.39 MB)|
|November 4 2019 Genetic Toxicology Workshop Agenda||pdf (121.27 KB)|
|Petibone Gentox Presentation||pdf (942.88 KB)|
|TWR-Introductory Presentation for Workshop||pdf (621.61 KB)|
|Workshop Questions_10-28-19||pdf (14.83 KB)|