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FDA/CDER considerations on NAMsfor pharmaceutical developmentPaul C. Brown, CDER/FDAApril 17, 2020

This presentation reflects the views of theauthor and should not be construed torepresent FDA’s views or policies.www.fda.gov2

Highlights Regulations allow alternativesGuidance allows alternativesUseful assays are those that meet a data needData are needed to show an assay does what isclaimed Multiple ways to talk to FDA3

Regulations allow submission ofalternative methodsIND regulations21 CFR 312.23 (a)(8) Pharmacology and ToxicologyInformation“Adequate information about pharmacological andtoxicological studies of the drug involving laboratoryanimals or in vitro, on the basis of which the sponsorhas concluded that it is reasonably safe to conductthe proposed clinical investigations.”4

Regulations allow submission ofalternative methodsNDA regulations21 CFR 314.50 (d)(2) Nonclinical Pharmacologyand Toxicology Section“A section describing, with the aid of graphs andtables, animal and in vitro studies with drug, ”5

Guidances allow submission ofalternative methodsExample FDA guidance wording:“FDA supports the principles of the 3Rs(replace/reduce/refine) for animal use in testing whenfeasible. FDA encourages sponsors to consult with reviewdivisions when considering a nonanimal testing methodbelieved to be suitable, adequate, and feasible. FDA willconsider whether the alternative method is adequate to meetthe nonclinical regulatory need.”Draft Nonclinical Safety Evaluation of theImmunotoxic Potential of Drugs and Biologics6

Guidances allow submission ofalternative methodsExample ICH guidance wording:“ consideration should be given to use of new invitro alternative methods for safety evaluation.These methods, if validated and accepted by allICH regulatory authorities, can be used to replacecurrent standard methods.”ICH M3(R2)7

Some guidances explicitly describealternative approaches ICH S3 Q&A - microsampling ICH S5(R3) - in vitro, ex vivo and nonmammalianembryofetal toxicity ICH S10 - in chemico and in vitro phototoxicity Draft Nonclinical Immunotoxicity guidance– insilico, in chemico and in vitro skin sensitizationmethods8

Other alternatives routinely accepted Ocular irritation - OECD Guidelines 437, 438,460, 491, 492, 494 Skin irritation – OECD Guideline 4399

FDA has a Predictive Toxicology Roadmap FDA’s Predictive logy-roadmap10

What is the roadmap? What isn’t the roadmap? Is a high level document – think highways not neighborhood streets– Not a check list of things to do to get an assay accepted– While many scientific issues are shared across FDA centers, Centers havedifferent regulatory mandates and authorities– Because of different Contexts of Use, it is likely that there will be multiplepathways for adoption of new approach methodologies.11

Moving toward regulatory use Does an assay provide data that can be used to answer fundamental drugdevelopment questions?Is the assay mature enough? What endpoints are being measured? Has scientific validity been shown?– Stable platform, cells– Are they predictive of in vivo effects?– Translatable to human?– Is it reproducible?– What test compounds have been assessed? Need compounds with in vivo dataPositives and negatives Applicability domain Criteria for success– Define compounds the assay can assess and not assess– What are sensitivity and specificity?12

“Pre-regulatory” Opportunities No FDA “acceptance” is required in drugdiscovery Increased understanding of disease processesand identifying promising interventions Early screening and derisking for toxicity Early use of such models can contribute to the3Rs by reducing iterative cycles of drugcandidate selection13

Context of use What question needs to be answered and for whatpurpose? How much “validation/qualification” is needed for aparticular assay will depend on the particular context of use.Discovery/ScreeningReplacement of pivotalnonclinical safety study Helps define acceptable applicability domain and limitations Context could be expanded over time14

Submitting drug developmentdata to the FDA There are no preset requirements forsubmitting in vitro data to a drug application. A method does not have to be formallyvalidated before it is submitted. When assessing in vitro data submitted tothe agency, reviewers consider howscientifically valid the information is for theparticular purpose based on supportinginformation.15

Alternative Methods Working Group (AMWG) Under Office of Chief Scientist, Office of Commissioner– Chaired by Drs. Fitzpatrick (CFSAN) and Mendrick (NCTR),includes members from each Center and OCS Discuss alternative activities across FDA Interact with U.S. federal partners and global partnersto facilitate discussion, development, and acceptanceof regulatory performance criteria for such assays16

AMWG Goals Key goal is to strengthen FDA’s long commitment to promotingthe development and use of new technologies to better predicthuman and animal responses to a wide range of substancesrelevant to FDA’s regulatory mission.Discuss new and emerging methods and methodologies acrossFDA, including research, training, and communication to ensurecommunication within and between all parts of FDA.Interact with U.S. Federal partners and other global stakeholdersto facilitate discussion and development of performance criteriafor such assays.Establish a dialogue and develop partnerships with FDAstakeholders to explore regulatory science applications for suchtechnologies.17

Webinar Series on Emerging PredictiveMethods Opportunity for developers/users to present new methods andmethodologies to FDA Webinars will be advertised to all FDA scientists exclusively If selected as a webinar:– participation in FDA’s webinar series would not constitute the agency’sendorsement of a new method or methodology– it would not mean that FDA would assist the developer in qualifyinghis/her new method for regulatory use18

Coming Soon FDA will have an Alternative Method WorkGroup Activities page on the FDA External Siteon www.fda.gov Comments can be sent [email protected]

Sponsors are encouraged to discuss withFDA the potential use of NAMs– AMWG webinars– Pre-IND meetings/written responses– Critical Path Innovation Meetings – outside ofa regulatory application– CDER is exploring other possible pathways(stay tuned)[email protected]