PharmacologyToxicology information to submit an IND for an anticancer drug

1
Pharmacology/Toxicology information to submit an
IND for an anticancer drug

• Haleh Saber-Mahloogi Ph.D.
• Pharmacologist
• Division of Oncology Drug products
• FDA/ CDER
• haleh.mahloogi_at_fda.hhs.gov

2

• This presentation is not an official FDA
  guidance or policy statement. No official
  support or endorsement by the FDA is intended or
  should be inferred

3
Disciplines involved in the review process of
applications for oncology drug products

• Project Manager (to coordinate meetings, respond
  to sponsors, provide regulatory insights)
• Pharmacology/Toxicology
• Chemistry
• Medical
• Clinical Pharmacology
• Biostatistics (usually not at the initial IND
  stage)

4
Pharmacology/ ToxicologyNonclinical Development

• A compound is tested in cell cultures and whole
  animals in order to make educated guesses about
  how it should be used in people.
• Pharmacology Studies (efficacy, mechanism)
• Toxicology Studies (safety)
• Pharmacokinetic studies (ADME)

5
Pharmacology Studies

• Used to evaluate desirable effects, but may give
  additional insight into toxicity
• Exact mechanism of action may never be determined

6
Toxicology The search for the unexpected
7
Toxicology Studies

• Review the nonclinical (animal) studies to
• estimate the safe starting dose for clinical
  studies
• assess toxic effects with respect to target
  organs therefore, potential organ toxicities
  to be monitored in the clinical studies
• assess potential reversibility

8
Toxicology Studies (contd)

• assess dose dependence
• assess relationship to exposure
• assess hazards that cannot be evaluated in
  clinical trials (e.g. carcinogenicity and
  teratogenicity)
• To identify hazards and estimate the relatively
  safe starting dose

9
Toxicology Studies (contd)

• While risks for humans cannot be eliminated, they
  may be anticipated, ameliorated, and/or avoided

10
Common Types of Toxicity Studies

• General Toxicity (repeat dose), can have
  incorporated in it
• Safety Pharmacology
• TK
• Genotoxicity (later in the development unless
  disease-free subjects are entered)
• Reproductive Toxicity (later in the development)
• Carcinogenicity (for disease-free subjects later
  in the development)
• Immunotoxicity (occasionally required)

11
Pharmacokinetic (ADME) Studies

• Not required, but strongly encouraged
• Assists the interspecies comparison of toxicity
  and extrapolation to humans
• May suggest modifications in the intended dose,
  route or schedule for the clinical trial
• Can contribute to optimal dose escalation in
  early clinical studies

12
Nonclinical Information (Item 8 of the IND)

• Line listed data
• Interpretation of the data- The output is
  information, not report

13
Interpretation of the data

• Integration of intra-species findings
• Clinical signs, clinical pathology, histopath...
• Exaggerated pharmacologic effect? Intended or
  toxic effects?
• Cross-species extrapolation
• Allow educated guesses about the implications of
  nonclinical findings for human
• Are findings consistent across species?
• Correlate toxic doses with exposure

14

• Estimation of the starting dose in cancer
  patients

http//www.fda.gov/cder/cancer/docs/doseflow.pdf
15
Good Laboratory Practices (GLP)21CFR 58

• The purpose of the GLPs is to assure the quality
  and integrity of the nonclinical safety data
  submitted to the regulatory agency

16
Good Laboratory Practices (GLP)http//www.access.
gpo.gov/nara/cfr/waisidx_00/21cfr58_00.html
17
Plan in AdvanceEstimated Costs of Toxicology
Studies
Anticancer Drug Development Guide BA Teicher and
PA Andrews
18
Example of Poor Planning!
Acknowledge that planning is a dynamic process
19
User Fee

• No IND fee
• NDA user fee is waived for Small Business (employees) for the 1st human drug application
  that a small business or its affiliate submits
  for review.
• http//www.fda.gov/cder/about/smallbiz/Econonic.ht
  m
• http//www.fda.gov/cder/about/smallbiz/pdufa.htm
• http//www.fda.gov/orphan/faq/index.htm

20
Resources

• Guidances and Guidelines
• ICH- http//www.fda.gov/cder/guidance/index.htm
• S1 Carcinogenicity
• S2 Genetic toxicity
• S3 Toxicokinetics
• S4 Duration of Chronic Toxicity Testing
• S5 Reproductive toxicity
• S6 Biotechnology
• S7 Safety Pharmacology
• M3 Nonclinical Safety Studies for the conduct of
  Human Clinical Trials

21
(No Transcript)
22
Resources (contd)

• CFSAN Redbook http//www.cfsan.fda.gov/redbook/r
  ed-toca.html

23
(No Transcript)
24
Resources (contd)

• Articles/Books (regulatory technical )
• DeGeorge et al. Regulatory considerations for
  preclinical development of anticancer drugs.
  Cancer Chemother Pharmacol 1998, 41 173-185

25
(No Transcript)
26
Resources (contd)

• Diehl et al A good practice guide to the
  administration of substances and removal of
  blood, including routes and volumes- Journal of
  Applied Toxicology 2001, 21 15-23

27
(No Transcript)
28
FDA /NCI Joint Effort

29
Resources (contd)

• Training Courses/ Workshops
• PERI Courses (www.peri.org) (Phone
  703-276-0178)
• Basic Training Course in Drug Development
• Biologics Drug Development
• Good Laboratory Practices
• Advanced Course in Cancer Development and
  Clinical Trial Methods for Oncologic Products
• PK concepts in drug development

30
Resources(contd)

• DIA Courses (www.diahome.org)
• Regulatory Affairs Training Course
• Part I The IND
• Part II The CTD/NDA Phase
• DIA Workshops (same site)
• GLP
• PK
• OTC

31
Pre-IND Meeting

• Not sure if the ongoing and/or planned
  nonclinical studies are adequate to support your
  IND?
• Ask for a pre-IND meeting