Description
The Food and Drug Administration (FDA) is announcing the availability of a guidance for industry entitled ``Nonclinical Safety Evaluation of Drug or Biologic Combinations.'' This guidance provides recommendations on nonclinical approaches to support the clinical study and approval of fixed-dose combination products (FDCs), co-packaged products, and some adjunctive therapies.
Key Topics
Terms and concepts identified from this document
Scope & Applicability
Product Classes
8Products combining drug, device, or biological constituents; Generally recommended for Enhanced Documentation; Requires 14971-based framework incorporating ICH Q9; A drug-device combination where the device constituent part detects ingestion.
Products for which batch/lot information is particularly important
New Molecular Entities requiring assessment
Two or more separate drug components combined in a single dosage form
Products involving drug and device components like injector and vial
Second drug product used together with primary treatment
A situation requiring additional pediatric safety data collection.
Product of biological origin applicable to prevention or treatment of disease.
Stakeholders
2Entity responsible for submitting applications under section 524B
Inclusion in clinical trials supported by pEFD data
Regulatory Context
Regulatory Activities
2IND phase of drug development
Proceed with doses derived from toxicology studies
Document Types
1Clinical safety and efficacy described in labels
Attributes
4PLLR requires the removal of pregnancy categories
Significant risk for developmental toxicity
Significant risk for developmental toxicity
PLLR requires the removal of pregnancy categories
Technical Details
Substances
4Combinations involving one or more NMEs
nonsteroidal anti-inflammatory drugs that may be more toxic in animals than humans; Example of drugs more toxic in animals than humans
Pharmacologic class for heart failure; Class of drugs with well-established safety profiles
Concomitant medication used to manage bacterial MVGT risks.
Testing Methods
8Used to support combinations of drugs or biologics
Pharmacokinetic study conducted if metabolic interaction is identified
determine if a new GVHD drug is a substrate, inhibitor, or inducer
general toxicity bridging study of 3 months' duration for a chronic indication
conducted per the timing described in ICH M3
Section VII of the guidance.
Carcinogenicity studies are relevant to the safety assessment of FCSs and their constituents.
Conducted early in drug development to assess interactions
Processes
10Standard nonclinical safety evaluation
Conducted on the combination product
Conducted for up to 90 days on the combination
Study of up to 90 days on the combination
Nonclinical in vivo studies to be summarized in the DSUR.
Toxicology studies for combinations involving NMEs; Evaluation of embryo-fetal development and fertility
assessment of the potential effect of the pharmaceutical on vital organ functions
Pharmacokinetics and metabolism studies; Studies to assess potential for PK interaction
General considerations in the assessment process; Evaluation of Cmax and AUC in relation to dose; Substantial differences in PK were noted; PK data available in various rat strains; Assessment of drug exposure in animal models; Assessment of systemic exposure in toxicity studies; Extrapolation of Cmax and AUC values from animal data.; PK data are also available on GD8
Toxicology studies for NME combinations; Generally not needed for biologic or drug/biologic combinations
Clinical Concepts
4Infectious disease risk factor discussed in relation to donor eligibility.
observed at a new organ or tissue site
Potential safety concern/adverse effect of some antiemetic drugs.
Patient condition increasing risk of aluminum toxicity.; Patient population sensitive to aluminum exposure
Identified Hazards
Hazards
3target organs for toxicity are similar for each drug/biologic
A safety concern that triggers specific testing pathways
one drug may oxidize, methylate, or ethylate the other
Standards & References
Specifications
2toxicologic interaction may result in lowering of previously determined no-effect doses
concern if drugs have a narrow margin of safety
ICH References (3)
International Council for Harmonisation cited for scientific standards
Preclinical Safety Evaluation of Biotechnology-Derived Pharmaceuticals
Nonclinical Safety Studies for the Conduct of Human Clinical Trials
Related MFDS Guidelines
Korean regulatory guidelines covering similar topics
See Also (8)
- DSCSA Implementation: Product Tracing Requirements — Compliance Policy
- E6(R3) Good Clinical Practice: Annex 2
- Consumer Antiseptic Rub Final Rule Questions and Answers Guidance for Industry: Guidance for Industry
- Best Practices for Communication Between IND Sponsors and FDA During Drug Development
- Botanical Drug Development: Guidance for Industry
- Prescription Requirement Under Section 503A of the Federal Food, Drug, and Cosmetic Act Guidance for Industry
- Reformulating Drug Products That Contain Carbomers Manufactured With Benzene
- ANDA Submissions -- Refuse-to-Receive Standards Rev.2