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Sep 3, 2018

The purpose of this guidance is to provide advice to sponsors regarding the design and conduct of first-in-human (FIH) clinical trials intended to efficiently expedite the clinical development of cancer drugs, including biological products, through multiple expansion cohort trial designs. These are trial designs that employ multiple, concurrently accruing patient cohorts, where individual cohorts assess different aspects of the safety, pharmacokinetics, and anti-tumor activity of the drug.

The key points of the guidance are:

• FIH should be in patients’ population with no available therapies, patient population for expansion cohorts always need to be justified
• Multiple expansion cohort trials usually better with drugs where CMC changes can be more easily controlled/bridged – e.g. small molecules
• Products with steep toxicity indices and high inter-/intra-patient variable PK not suitable
• Strong emphasis on prespecified statistical design of expansion cohorts – randomized, non-randomized and corresponding analyses required
• If sponsor adds a disease specific cohort and intends to further develop the specific indication then a new IND should be submitted
• In exceptional cases expansion cohorts can be used for regulatory filing, but need high quality incl. IRC, optimal dose determined, prespecified statistical plan
• Reminder to asses need for ID exemption assessment when IVD/biomarker used
• Need for IDMC, central IRB preferred
• Pre-IND meeting recommended and sponsor can request FDA a meeting (TC) within the 30-day review period

This guidance provides recommendations to industry regarding the use of placebos and blinding in randomized controlled clinical trials in development programs for drug or biological products for the treatment of hematologic malignancies and oncologic diseases.

This guidance is intended for sponsors of drugs and biological products who are considering submitting requests for orphan-drug designation for their drugs under section 526 of the Federal Food, Drug, and Cosmetic Act (FD&C Act). The Food and Drug Administration (FDA) does not expect to grant any additional orphan-drug designation to drugs for pediatric subpopulations of common diseases (i.e., diseases or conditions with an overall prevalence of 200,000 or greater). Pediatric-subpopulation designations that have already been granted will not be affected by this change.

This guideline defines scientific principles and provides guidance for the development and evaluation of medicinal products containing genetically modified cells intended for use in humans and presented for marketing authorization. Its focus is on the quality, nonclinical aspects and safety and efficacy requirements of genetically modified cells developed as medicinal products.

The aim of this question-and-answer document is to supplement the CHMP Data Monitoring Committee Guideline (Doc Ref. EMEA/CHMP/EWP/5872/03) by providing clarification on the role and necessity for a Data Monitoring Committee (DMC) in different phases of drug development and throughout the product lifecycle as well as with regard to the responsibilities for implementing DMC decisions.