ICH M13A Doesn't Ask for a Bioequivalence Study — It Asks for a Risk Classification First

ICH M13A reached Step 4 on July 23, 2024 — the first ICH guideline built specifically around bioequivalence. Sponsors moving generic and follow-on solid oral products through development still tend to default to whatever fasting-and-fed combination their last CRO ran. M13A doesn't work that way: it opens with a risk classification, and that single call — not habit, not precedent — decides whether you run one study or two, and which bioequivalence limits apply to it.

What M13A actually harmonizes

Bioequivalence study design for oral solid products has historically run on regional variation — FDA, EMA, and other authorities each expected slightly different fasting/fed combinations and statistical approaches for the same molecule. M13A is the first ICH guideline to harmonize that directly: recommendations for conducting BE studies during both development and post-approval phases, for orally administered immediate-release solid oral dosage forms delivering their drug to systemic circulation — tablets, capsules, and granules or powders for oral suspension. The scope question comes before the risk question: a modified-release or locally acting product isn't what M13A governs, and reaching for it there is the first place sponsors misapply the guideline.

The risk classification that sets your study design

M13A's operative decision is a risk call, made before any study is designed:

• Non-high-risk products. One BE study, and a fasting study is preferred over a fed study — fasting conditions more sensitively discriminate pharmacokinetic differences between test and reference products, giving the comparison more power to detect a real difference.
• High-risk products. Two BE studies, one under fasting conditions and one under fed conditions, because a single condition isn't judged sufficient to characterize the product's behavior across both states.
• Highly variable drug products. Defined by within-subject variability of 30% or more in the BE measures. These move to a reference-scaled average bioequivalence (RSABE) approach, where the acceptance limits scale to the reference product's own variability rather than sitting fixed — and the product still has to meet a point-estimate constraint on top of the scaled limit, so a wider limit is not an easier one.

The risk classification isn't a formality before the real work starts. It is the real work — get it wrong, and you've designed a study to the wrong standard before a single subject is dosed. Why the classification comes first

M13A is not the biowaiver route

The guideline sponsors most often confuse M13A with is ICH M9, and the confusion runs in both directions. M9 decides whether a product can skip an in vivo bioequivalence study entirely, through a Biopharmaceutics Classification System-based biowaiver — and, as covered in that guideline, a clean BCS Class I result is necessary but not sufficient; dissolution and excipient-risk gates still apply. M13A picks up exactly where a biowaiver isn't available: it governs the study you actually run, and it incorporates its own BCS-based biowaiver option within that framework rather than replacing M9's. Confusing the two produces two failure modes in practice — teams that run an M13A-style study when an M9 biowaiver was available all along, and teams that assume M9 eligibility substitutes for M13A's risk classification when the biowaiver conditions were never actually met. Two further guidelines, M13B and M13C, are moving through the ICH process behind M13A to extend the framework to additional-strength biowaivers and special situations such as narrow therapeutic index drugs — treat them as still in development rather than settled until they reach Step 4.

None of this is exotic once the sequence is explicit: confirm the biowaiver isn't available, classify the risk, design to the classification, and check variability before locking the statistical approach. Sponsors who skip straight to a familiar fasting-and-fed protocol are the ones who end up re-running a study, or defending an underpowered one, after the classification surfaces late. Getting this sequence right is exactly the kind of decision our CMC regulatory strategy work and broader global regulatory strategy engagements are built to catch before a protocol is finalized, not after a CRO has already been booked.