Mercy,
I just lived through this scenario for a product that was a change in formulation from an RLD. In the end, we decided to abandon the 505(b)(2) approach because the work needed to "bridge" the differences in drug substance and drug product from the RLD was significant and challenging. In the end we had to do pivotal clinical studies to support safety and efficacy and could not rely on the RLD for all or even part of the required information for approval. As you know, the 505(b)(2) approach is to support modification of an RLD so as indicated a PK/PD study or studies is more likely than a BA/BE used for generic equivalence. Typically for a 505(b)(2) as indicated, every change from the RLD has to be demonstrated to be comparable to the RLD. If your drug substance profile is not the same (impurities) you will need a head to head toxicology study in an appropriate species or studies with both products. Then you have to link these results to the product; if the DS differences translates to drug product difference, you'll need a head to head comparability study CMC and then bridge the difference is a head to head clinical study (PK/PD and pivotal) in order to use the RLD information, if at all. Then you need to look at your label and the RLD label and modify the information as appropriate from all the information you generated. You may be better off as a stand-alone program or find a way to use the nonclinical data (if Drug substance is the same and same profile) for which you are still a 505(b)(2) and conduct a stand alone clinical program relying on your own data for S&E.
I would discuss the 505(b)(2) pathway with your review division as early as possible as identifying the data required to use the RLD data vs. not is important. Key is to identify which data you plan to rely on how. FDA will help you identify the types of studies and provide feedback on the pathway. Luckily we received FDA feedback early in our development plan before we initiated our Phase 3 pivotal studies.
We had to conduct our own PK/PD and pivotal studies along with key toxicology studies. As you already know the CMC section will be different and not part of the 505(b)(2) approach.
Hope this is helpful along with the other comments, Good luck@!
Dar
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Darlene Rosario RAC
Principal Consultant RA, Quality and Compliance
Velocity Consulting
Ventura CA
United States
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Original Message:
Sent: 01-28-2015 12:41
From: Jim Bonner
Subject: 505(b)(2) pathway with a different dosage strength from RLD
The below should be helpful.
http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2010/01/WC500070039.pdf
Non-oral immediate release dosage forms with systemic action This section applies to e.g. rectal formulations. In general, bioequivalence studies are required. A
biowaiver can be considered in the case of a solution which contains an active substance in the same
concentration as an approved solution and with the same qualitative and similar quantitative
composition in excipients (conditions under oral solutions may apply in this case).
Parenteral solutions
Bioequivalence studies are generally not required if the test product is to be administered as an
aqueous intravenous solution containing the same active substance as the currently approved product.
However, if any excipients interact with the drug substance (e.g. complex formation), or otherwise
affect the disposition of the drug substance, a bioequivalence study is required unless both products
contain the same excipients in very similar quantity and it can be adequately justified that any
difference in quantity does not affect the pharmacokinetics of the active substance.
In the case of other parenteral routes, e.g. intramuscular or subcutaneous, and when the test product is
of the same type of solution (aqueous or oily), contains the same concentration of the same active
substance and the same excipients in similar amounts as the medicinal product currently approved,
bioequivalence studies are not required. Moreover, a bioequivalence study is not required for an
aqueous parenteral solution with comparable excipients in similar amounts, if it can be demonstrated
that the excipients have no impact on the viscosity.
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Jim Bonner PHD
The One When
Collegeville PA
United States
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Original Message:
Sent: 01-28-2015 09:05
From: Robert Meyer
Subject: 505(b)(2) pathway with a different dosage strength from RLD
A 505(b)(2) requires a pharmacokinetic comparison, but not necessarily BE. However, you must support the differences in your product from the RLD. In this case, that would include things like preclinical support on local toxicities and, depending on how much you "match" the PK of the RLD, you indeed may need some clinical support of differences (that would include not just Cmax, Cmin and AUC, but might also include pattern of exposure, depending on the drug in question).
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Robert Meyer
Director, Virginia Center for Translational and Regulatory Sciences
University of Virginia, School of Medicine
Charlottesville VA
United States
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Original Message:
Sent: 01-27-2015 11:09
From: Mercy James
Subject: 505(b)(2) pathway with a different dosage strength from RLD
I have question regarding product development for mucosal delivery where the comparator (RLD) is an injectable. The intended regulatory pathway is 505(b)(2). Since the comparator is an injectable dosage form, the new dosage strength will be different from the comparator. The plan is to develop appropriate dosage strength to match the PK of the comparator. Is the FDA BE criteria applicable for 505(b)(2) NDA approval when the molar strength of the new dosage form is different from the RLD? Does it require efficacy studies for 505(b)(2) NDA approval of the new film dosage strength?
Thanks so much for your response to my question.
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Mercy James PHD, RAC, SCD
Warren NJ
United States
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