Toxicology

 

• Selection of appropriate toxicology CROs, management of toxicology studies, develop protocols, study monitoring, review and evaluation of draft and final study reports

  • CRO selection and qualification, includes favorable cost, timeline negotiations and past experience with CROs

• Able to place studies at the CRO of the client's preference if requested

• Perform on-site CRO inspection on behalf of the client as needed

  • This may include technical meetings with scientific staff, ensure GLP compliance and scientific integrity

• Design appropriate pharmacology/toxicology program to support the intended route and duration of treatment in the clinic to enable successful regulatory filings

• Custom design of non-GLP (including investigative) and GLP  toxicology studies (acute and chronic)

  • Bioanalytical method development and validation

  • General Toxicology

  • Genetic Toxicology

  • Safety Pharmacology

  • Reproductive Toxicology

  • Carcinogenicity

• Identify and address key pharmacology/toxicology issues unique to compound, the indication, and patient population in accordance with regulatory guidance

• Design follow-up studies to clarify toxicology study findings 

• Able to review client's existing nonclinical programs and provide advice on potential refining

  • Develop gap analysis of nonclinical packages with assessments of strengths, weaknesses, opportunities and threats

• ISO 10993 biocompatibility testing and program management

• Literature searches and review

 

 

Impurity Assessment

 

• Perform regulatory compliant assessment of potential genotoxic impurities

  • Assess the genotoxic potential of impurities according to ICH guidelines using QSAR analysis and/or genotoxicity tests

• Resolve impurity and degradant/metabolite issues and qualifications

• Impurity qualification based on literature when applicable, and/or by testing the impurity in the appropriate studies

Regulatory

 

• In depth knowledge and understanding of FDA expectations, regulations and ICH Guidelines

• Authoring of nonclinical sections of Investigator Brochures, pre-INDs, INDs and similar regulatory documents (eIND or paper)

• Periodic safety reports: DSUR

• Represent client at regulatory agency meetings and respond to any nonclinical regulatory questions/issues

  • Plan and conduct pre-IND, end-of-Phase I and II, and special meetings with FDA to discuss nonclinical pharmacology/toxicology issues

• Provide team leadership and project management for the nonclinical aspects of drug development programs

Discovery Toxicology

 

• Evaluation and optimization of the Toxicology and ADME profiles of drug candidates early in the drug discovery process

• Discovery toxicology involves determining the potential toxicology, as well as safety pharmacology profiles of compounds during the discovery stage (before lead optimization).  These studies help eliminate molecules that might have high risk to benefit ratio and involve both in vitro/in vivo testing and predictive modeling

• Examples of early Discovery Toxicology activities:

  • In vitro ADME studies

  • In vivo PK studies (rodent and non-rodent species and routes of administration)

  • In vitro hERG and cardiovascular studies

  • Early genetic toxicology studies

  • Early Cardiovascular, Pulmonary, CNS, Gastrointestinal and Renal studies

  • CEREP/Kinase Panels to flag off-target activity of compounds

  • Cell culture, tissue slices, 3D tissue models and Organ on a Chip

  • Literature Review for early safety prediction of drug targets to provide insight into any potential future toxicology concerns

 

 

Pharmacology Studies

 

• Identify appropriate CROs to perform desired studies

• Pharmacology and efficacy study design and management

• Pharmacology proposed mechanism of action identification and secondary pharmacologic effects

Mechanistic Toxicology

 

• Provide preclinical services and expertise specializing in investigative toxicology, exploratory/discovery toxicology

• Design and oversee studies to help elucidate mechanism of toxicity (in vitro, in vivo, genomic, proteomic, etc.)

• Understand the pathways that define the sensitivity of organs and cells to chemicals

  • Data can aid in understanding toxicology findings and potential risk to humans

• Mechanism studies are helpful as compounds progress through development

  • Regulatory agencies place increased value on mechanistic data 

  • Aid in establishing the relevance of animal data to human, and species specificity

  • Mechanistic data typically included in IND and NDA applications

 

 

 

Preclinical Biomarker Studies

 

• Identify appropriate CROs to perform biomarker studies or review client’s current toxicology/biomarker data

  • Potentially use tissues and biofluids from past in vivo studies for biomarker studies

• Establish a comprehensive plan for biomarker exploration, selection and development based on preclinical toxicology data

• Possible biomarkers to investigate:

  • Toxicity biomarkers, target engagement biomarkers, efficacy biomarkers

• Preclinical biomarkers linked with histopathology are able to investigate a compound’s impact on organs or tissues before  injury is evident

  • The ultimate goal is translating nonclinical biomarkers into clinical programs to demonstrate pharmacological activity, early indicators of toxicity, enable a safe starting dose and dose escalation

 

 

Due Diligence

 

• Perform due diligence review of preclinical data for potential in-licensed and out-licensed compounds

  • Identify critical issues, interpret data, prepare and provide assessment

  • Participation in client's due diligence meetings (serve as nonclinical representative)

 

 

ADME

 

• Evaluation of ADME CROs to support particular phase in development

• Pharmacokinetics and ADME study design and management (in vitro or in vivo)

• Providing advice and expertise to assist discovery and early development challenges

• Help design and implement studies for maximum impact while making the most of existing data

  • Pharmacokinetic study planning, placement and monitoring

  • Evaluation and integration of toxicokinetic results into the overall toxicology data package

  • Metabolism and drug-drug interaction studies