The US Food and Drug Administration (FDA) on Thursday finalized guidance on how sponsors can design clinical pharmacology studies to support the safety and efficacy of antibody-drug conjugates (ADCs).
The final guidance makes some revisions to the draft version issued in February 2022.
FDA defines ADCs as a combination of a small-molecule drug, also known as a payload, and an antibody or antibody fragment, conjugated together by a chemical linker that are used together to treat cancer. They are regulated as biologic-drug combination products, and the guidance directs sponsors to consult existing guidance in many areas of ADC clinical development.
The guidance specifically addresses the use of bioanalytical methods, dosing strategies, dose- and exposure response analysis, QTc assessments, immunogenicity, and drug-drug interaction (DDI) studies in assessing the safety and efficacy of these treatments.
The agency has approved more than a dozen ADCs, including Kadcycla (ado-trastuzumab emtansine) for metastatic breast cancer and Adcetris (brentuximab vedotin) for treating relapsed or refractory Hodgkin’s lymphoma. The latest ADC approval was for Elahere (mirvetuximab soravysnsine-gyxn) in 2022 for treating ovarian cancer.
FDA said changes from the draft include updates to guidance terminology, new references to FDA guidances, additional considerations for ADC dosing strategies, and editorial changes to improve clarity.
For example, there is new text making reference to a July 2020 guidance on “Cancer Clinical Trial Eligibility Criteria: Patients with Organ Dysfunction or Prior or Concurrent Malignancies” in the section on key considerations for ADC dosing strategies.
There is also new language referring to a February 2022 guidance called “Population Pharmacokinetics” in the section on the dose- and exposure response in evaluating the safety and efficacy of ADCs.
There is also new text stating that the principles discussed in the guidance “might not be applicable to the development of other types of ADCs (e.g., ADCs with payloads other than cytotoxic small molecule drugs and/or for indications other than oncology).”
The Biotechnology Innovation Organization (BIO) had requested the change, and said more clarity was needed on the scope of the guidance.
The group said “it is unclear if FDA intends this guidance to apply only to ‘conventional’ ADCs that use antibodies to deliver cytotoxic, small molecule drugs selectively to target cells where the payload is internalized and released intracellularly, or whether certain aspects could be applied more broadly. BIO suggests that the guidance either be revised to account for the diversity of ADCs that exist today, or explicitly describe the products for which it would apply to.”
The finalized version also deletes a section on in vivo DDI characterization from pivotal efficacy studies. BIO had requested this elimination. The group said “it will be very challenging and not practical to evaluate ADC as a perpetrator in the pivotal efficacy study due to the diverse co-medications that may be used and complexity of different time to administer the medications. This will pose significant operational burden and cause many errors and [pharmacokinetic] PK sampling for different co-medications will be different.”
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