Comment from The Arab Expert's Office at Arab Union of the Manufacturers of Pharmaceuticals and Medical Appliances (AUPAM)

The Arab Union of Pharmaceutical Manufacturers (AUPAM), through the Arab Expert's Office, respectfully submits the attached 19-page letter on the FDA Draft Guidance "General Considerations for the Use of New Approach Methodologies (NAMs) in Drug Development" (Docket FDA-2025-D-6131; 91 FR 13313; published 19 March 2026). AUPAM is the regional federation of pharmaceutical manufacturers across the Arab world. The Arab Expert's Office is its technical-scientific arm, convening regulators, manufacturers and academic specialists across the Middle East and North Africa. This submission represents the collective view of the Office's Regulatory Science and Drug Development Working Group, with members active across generic and innovator pharmaceuticals, biosimilars and biological medicines, vaccines and ATMPs, APIs and finished dosage forms, OTC and herbal medicines, and medical devices. OVERALL POSITION: Partial support, with twelve constructive proposed edits. The four-pillar validation framework in Section III (Context of Use, Human Biological Relevance, Technical Characterization, Fit-for-Purpose) is structurally correct, scientifically grounded, and aligned with the ICCVAM Validation Workgroup Report (February 2024) and OECD GIVIMP (December 2018). The flexibility at lines 34-40 - that a fit-for-purpose NAM need not be formally validated where the weight of evidence supports its use - is welcome. The Working Group offers twelve proposed edits, each accompanied in the attached letter by ready-to-insert draft text, a stated Agency benefit, an honest implementation-burden estimate, and citations to the Agency's own existing framework. Eight of the twelve are editorial; the remaining four require minor drafting. None requires rulemaking, new statutory authority, or new resource commitments. SUMMARY OF THE TWELVE PROPOSED EDITS (full text in the attached PDF): 1. Sec.II line 76 - Define "scientifically validated nonanimal method" (OECD TG / ICCVAM / EURL-ECVAM pathways). 2. Sec.II cross-cutting - Clarify applicability to ANDAs, 505(b)(2) applications and biowaivers (consistent with ICH M9, M7, M13A). 3. Sec.III.A and lines 34-40 - Add a tiered weight-of-evidence rubric for fit-for-purpose acceptance, modelled on the FDA Biomarker Qualification Program. 4. Sec.III.B - Extend worked examples to cardiotoxicity (CiPA / ICH S7B(R1)), nephrotoxicity (proximal-tubule-on-chip) and immunotoxicity. 5. Sec.III.C - Disaggregate technical-characterisation guidance for in silico (PBPK, QSP, QSAR), in chemico, and in vitro/organ-chip platforms. 6. Sec.III.C - Introduce inter-laboratory reproducibility as a discrete validation parameter (per OECD GD 34 and ICCVAM). 7. Sec.III.C new sub-section - Cross-reference existing FDA Data Integrity and Compliance with Drug CGMP doctrine for NAM-derived electronic data. 8. Sec.III new sub-section III.F - Integrate IATA and Defined Approaches explicitly (OECD GD 260, TG 497). 9. Sec.III new sub-section III.E - Add considerations for AI/ML-derived NAMs, modelled on the FDA December 2024 Predetermined Change Control Plan guidance. 10. Cross-cutting - Acknowledge the existing FDA-EMA cluster on alternative methods and bilateral reliance arrangements. 11. Cross-cutting - Clarify that the existing Type C pre-IND meeting and ISTAND pilot pathways serve NAM pre-acceptance dialogue. 12. Cross-cutting - Note the Agency may wish to extend existing case-study and decision-summary publication practice to NAM submissions. ALIGNMENT WITH AGENCY MANDATES: Each edit maps to a specific FDA statutory or policy anchor - FDORA section 3209, FD&C Act sections 505(z) and 505G(r)(2)(B), the FDA Modernization Act 2.0, the April 2025 FDA Roadmap to Reducing Animal Testing, the FDA Biomarker Qualification Program, the ISTAND pilot programme, and the December 2024 PCCP guidance. The attached letter Section 2 details these anchors. The attached letter also includes Annex C "Anticipated questions and AUPAM responses", pre-empting five questions the Agency may have. The Working Group offers, on a pro bono basis, to co-host a joint scientific workshop on NAM implementation for MENA regulators and manufacturers, and to support the dissemination of the final guidance across the Arab region. The Arab Expert's Office at AUPAM commends the Center for Drug Evaluation and Research on a substantively important draft and thanks the Agency for the opportunity to contribute. Submitted by: Associate Prof. Dr. Rer.Nat. Osama Abd Elrahman Chairman, Arab Expert's Office - AUPAM Email: prof.dr.osama@gmail.com On behalf of the Regulatory Science and Drug Development Working Group of the Arab Expert's Office at the Arab Union of Pharmaceutical Manufacturers.