Bioequivalence and Bioavailability Forum

Hi Praful,

with a few exceptions the local comparator has to be used in bioequivalence. That’s a legal requirement in most countries.

• Reference Listed Drug (RLD) is a term of the U.S. FDA. It means that it was approved via the NDA-pathway. Note there might be more than one RLD. Consult the current edition of the “Orange Book”.
  
• In the European Economic Area (= EU + Norway, Iceland, Liechtenstein) any comparator product, which was approved based on a complete dossier (in accordance with Articles 8(3), 10a, 10b, or 10c of Directive 2001/83/EC), can be used.
  Say, you purchased the comparator in Member State X and want to apply in numerous other member states (even if not in Mem­ber State X), this is still acceptable in a Mutual Recognition Procedure (MRP, where one country acts as the Reference Member State – RMP and others as Concerned Member States – CMSs). Only if you apply directly at the EMA and are successful, the product will automatically be approved in all members states of the EEA.

ICH M13A ‘Bioequivalence for Immediate-Release Oral Dosage Forms’ was adopted by the EMA in July 2024 and is effective with 25 January 2025 – superseding applicable parts of the 2010 guideline related to design considerations and data ana­ly­sis for non-re­pli­cate studies. IMHO, relevant is the second paragraph of Section 3.2.3:

For new intended label use/instructions, e.g., oral suspensions as an extension to another orally administered IR drug product, BE studies may be conducted to determine whether the oral suspension is BE to the comparator product. In this scenario, the oral suspension product should be administered according to its intended labelling and compared with the comparator product administered as per its labelling.

I guess (‼) the suitable European comparator would be Bristol Myers Squibb’s Hydrea 500 mg Hard Capsules. Since your product is a different pharmaceutical form, it is not a generic in the strict sense. You may apply for approval as a hybrid medicinal product, which may require – additional to comparative BA – clinical studies. However, the use of hydroxyurea is well established for decades and thus, clinical studies might be waived. I strongly recommend seeking scientific advice to be sure.