首页 > 资讯 > 受控函中有关定性定量问题的请求

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2016-05-01 Lachman CONSULTANTS

如果你认为总是可以通过受控函从仿制药办公室（OGD）获得Q1/Q2（定性（qualitatively）定量（quantitatively）相同）决定，请三思。如果问题中的产品允许非Q1/Q2处方，那么OGD将拒绝作出Q1/Q2决定。

例如，假设企业计划对某一BCS 3类药品寻求生物等效豁免。为了做到这一点，企业通常必须证明“测试产品处方与参照产品的成分组成定性相同、定量非常类似的，例如，处于速释制剂工艺放大和批准后变更（SUPAC）1级和2级中的变更。”（见指南）。此外，某些其它产品（例如局部用产品）有用于BE试验的体内或体外选择，如果是非Q1/Q2，可能会受到影响，另外对于某些其它产品，FDA要求Q1和Q2相同以避免开展体内研究。

从FDA获得这些信息谈何容易。在许多情况下，在RLD中的非活性成分无法标准测量。获得拟定产品与RLD处方定量相似的唯一方法是通过受控函请求OGD的决定。这一请求将很可能根据FDA《与仿制药研发相关的受控函指南》中的规定而被拒绝，指南中指出，“FDA不打算审评不被要求或在指南中FDA建议与RLD Q1/Q2的拟定处方”。

FDA的立场将企业置于进退两难的境地：要么赌一把，产品与RLD处方定量相似，继续走BCS生物等效性豁免途径，明知生物等效性豁免可能被拒绝或更糟糕的情况 — ANDA被拒绝接收；要么完全避免风险，开展可能会变得不必要的生物等效性研究。第一项选择采取缓兵之计通过递交后完成Q1/Q2评价。这是FDA稀缺资源的真正浪费，因为OGD将需要对重新递交的申请开展同样的审查。还将浪费企业的资源，如果FDA不同意处方Q1/Q2的性质，企业可能需要重新处方并开展新的6个月稳定性研究。第二个选择是对错误的Q1/Q2处方开展体内药代动力学（pK）或临床终点研究，如果OGD进行处方的递交前审评则可能避免这些研究。第二个选择与Hatch-Waxman法案的基本原则之一背道而驰，这一基本原则就是，避免不必要的重复人体试验，如果FDA像对其它剂型所做的那样（注射剂或眼科剂型）执行Q1/Q2递交前评价，本来可以避免这种情况。

OGD应认真考虑有关何时执行Q1/Q2决定的立场。在ANDA递交之前向企业提供必要的处方反馈，与Hatch-Waxman法案的另一基本原则一致，即帮助加快仿制药进入市场。因此，我们处在“你可以现在付款或稍后付款”的第二十二条军规当中，但最终的支付者是美国公众，在当前状况下，他们将不得不等待更长时间才能等到一个产品的仿制药版本上市。

Lachman CONSULTANTS - Terri-Lee Nataline先生
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The Price Is Right May be All Wrong
By Terri-Lee Nataline | April 28, 2016

So you think you can always get a Q1/Q2 (qualitative and quantitative sameness) determination from the Office of Generic Drugs (OGD) through a Controlled Correspondence? Well, think again. If a non-Q1/Q2 formulation is permissible for the product in question, then OGD will decline to make that Q1/Q2 determination.

For example, let’s say that the firm plans to pursue a biowaiver for a certain BCS Class 3 drug product. In order to do so, the firm must typically demonstrate that “the test product formulation is qualitatively the same and quantitatively very similar, e.g., falls within scale-up and post-approval changes (SUPAC) IR level 1 and 2 changes, in composition to the reference.” (see Guidance here). In addition, certain other products (such as topical products) that have an in vitro or in vivo option for BE testing, if not Q1/Q2, could be impacted, as well as certain other products for which the FDA requires Q1 and Q2 sameness to avoid the conduct of in vivo studies.

Well, getting this information from FDA may be easier said than done. In many instances, there are inactive ingredients present in the RLD that defy standard measurement. The only way to obtain certainty that the proposed product is quantitatively similar to the RLD formulation is by requesting OGD's determination via Controlled Correspondence. That request, however, will likely be denied on the basis set forth in FDA's Guidance on Controlled Correspondence Related to Generic Drug Development which states, “FDA does not intend to review proposed formulations that are not required or FDA-recommended in guidance to be Q1/Q2 to the RLD.”

FDA’s position places firms in a quandary: either take a gamble that the product is quantitatively similar to the RLD formulation and proceed down the BCS biowaiver pathway, knowing that the biowaiver could be rejected, or worse yet, the ANDA Refuse to Received (RTR’d), or avoid the risk altogether and conduct what could turn out to be an unnecessary bioequivalence study. The first option kicks the can down the road by having the Q1/Q2 assessment done post-filing. This is really a waste of scarce Agency resources, as OGD will need to conduct the same review upon resubmission. It would also waste firms’ resources should the FDA not concur with the Q1/Q2 nature of the formulation as firms may be required to reformulate and conduct new 6-month stability studies. The second option would be to conduct an in vivo pharmacokinetic (pK) or clinical endpoint study on the failed Q1/Q2 formulation that may have been otherwise avoided if OGD had performed a pre-submission review of the formulation. This second option runs counter to one of the basic tenets of Hatch-Waxman Act, which is to avoid unnecessary duplicative human testing and could have been avoided if FDA performed the Q1/Q2 assessment pre-submission like it does for other dosage forms (parenteral or ophthalmic).

OGD should seriously reconsider its position relative to when it will perform Q1/Q2 determinations. Providing firms with the necessary formulation feedback in advance of an ANDA submission is consistent with yet another tenet of Hatch-Waxman – namely to help speed generics to the market. So we are in a “you can pay me now or pay me later” catch 22, but the ultimate payment is made by the American public that will have to wait longer for a generic version of a product to come to market in the current state of affairs.