首页 > 资讯 > FDA具体BE指南修订给企业带来的难题

出自识林

2016-05-13 Lachman CONSULTANTS

随着时间的推移，我们都看到了FDA ANDA生物等效性（BE）指南文件草案或终稿形式的多种版本。在某些情况下，FDA做出相对较小的变化，但是在另外一些情况下，FDA会要求在数据收集、指标，有时候在研究设计方面要求重大修订。例如，FDA可能要求之前没有要求的进食研究。有时，FDA修订BE指南要求完整的重复设计方法，而之前仅要求标准的双向交叉设计，就像FDA最近对环孢菌素胶囊产品的BE要求的修订。对于缓释产品，FDA经常要求添加多个部分曲线下面积（AUC）以要求BE指标，就像FDA对哌甲酯缓释产品的修订。这些变化通常是由于FDA对产品表现知识的增加，从而导致新评价的必要要求的收紧，以进一步保证仿制药产品与其参照品牌产品的表现相似。

我们都知道生物等效性科学不断发展和进步，有时需要做一些变更以进一步保证仿制药产品的治疗等效性，从而支持公众对仿制药替代的信心。

BE指南建议的变更可能发生在企业递交ANDA之前，ANDA审评期间或甚至在ANDA已经获批和上市销售一段时间（通常情况下是在获批数年之后）。那么，企业如何知道当BE指南建议修订时该做什么，尤其是因为这些指南文件代表了FDA当前的思考，对申请人不具有强制约束力，可能发现可接受的替代方法？这一事实在每份指南文件中都有指出。对于企业决策更加困难的是对于未定稿的BE草案指南的变更。

一旦做出修订，以下是企业显而易见的选择。

• 他们可以使用新修订的指南建议重复研究。
• 他们可以尝试使用在原始研究中收集的数据支持变更（这取决于变更类型，可能是可接受的）。
• 他们可以忽略变更。
• 他们可以以充足的理由提出替代方法。

显然，在ANDA递交之前的BE指南修订对企业递交会产生不利影响。他们应根据FDA原始建议开展的研究递交ANDA吗？那对于已经被FDA接收处于审评队列中的ANDA呢？企业需要等待FDA决定需要使用新建议重复研究，或者干脆直接重做研究？如果企业决定等待，那么企业将自己置于可能延迟批准的处境。对于已经上市销售的获批申请呢？怎样会触发FDA决定要求新的研究？

我们不能完全确定FDA如何做出决定修订一份BE指南文件，但我们对于FDA如何以及何时做出决定要求企业使用修订后的指南建议重复BE研究显然处于一片黑暗之中。我确定FDA将（如他们对某些产品所要求的那样）告诉企业，何时绝对必须使用新BE建议重复研究，但FDA并没有在所有情况下都做到这一点。FDA决策制定过程的标准是什么？是出于所递交的缺乏治疗等效性的报告吗？不良反应报告？缺乏效力？FDA如何决定何时不要求新的研究，批准前还是批准后？当BE指南恰好在ANDA递交之前修订，FDA如何决定接收或拒绝接收（RTR）一件ANDA？FDA何时决定这是一个审评问题或需要发布RTR函？这是企业询问我的一些问题。我想知道FDA的答案是什么？

Lachman CONSULTANTS - Bob Pollock先生
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What's a Mother to Do? By Bob Pollock | May 11, 2016

Over the course of time, we have all seen multiple revisions of FDA’s ANDA bioequivalence (BE) Guidance documents in draft or final form. In some instances, the FDA makes relatively minor changes, but, in others, they ask for significant revisions in collection of data, metrics, and sometimes study designs. For instance, FDA may ask for a fed study where none was previously required. Sometimes the FDA will revise a BE Guidance to require a fully replicate design where previously they asked for a standard 2-way crossover design, like they recently did for Cyclosporine Capsule products. For modified-release products, FDA has often required the addition of multiple partial Area Under the Curves (AUCs) to required BE metrics like they did for the methylphenidate extended-release products. These changes are typically precipitated by increased knowledge of the product performance by FDA, resulting in a tightening of requirements that are necessitated by that new evaluation, to further assure that the generic products perform like that of the brand name product upon which they rely for approval.

We all know that the science of bioequivalence continues to evolve and advance and that changes are sometimes needed to further assure therapeutic equivalence of generic products, and thus, support the public’s confidence in the substitutability of generic medications.

The changes in BE Guidance recommendations may occur prior to a firm submitting an ANDA, during the review of an ANDA, or even after an ANDA has been approved and marketed for a period of time (oftentimes, years after approval). So how does a firm know what to do when a revision in the BE Guidance recommendation changes, especially since these Guidance documents represent the Agency’s current thinking and are not binding on the applicant as an alternate approach may be found acceptable? This fact is noted in each Guidance document. What is even more difficult on a firm’s decision is when a change is made to a draft BE guidance recommendation that has not yet been finalized.

There are obvious options for a firm once a revision has been made.

• They can repeat the study using the new recommendations.
• They can try to use the data captured in the original study to try to support the change (which, depending on the type of change, may be acceptable).
• They can ignore the change.
• They can propose an alternate approach (the one they used) with justification.

Clearly, revision of a BE Guidance just prior to ANDA submission can have an adverse impact on a firm’s filing. Should they submit the ANDA with the study they performed based on FDA’s original recommendation? What about for ANDAs already received by the Agency that now sit in the review queue? Does a firm wait for FDA decide that the study needs to be repeated using the new recommendation or just go ahead and redo the study? If a firm decides to wait, then it places itself in a position of delaying its potential approval. And what about firms that have an approved application that is being marketed? What triggers FDA’s decision to ask for a new study?

We are not entirely sure how FDA makes its decisions to revise a BE Guidance document, but we are clearly in the dark as to how and when the FDA decision to require firms to repeat BE studies using the revised recommendation are made. I am sure that FDA will (as they have with certain products) tell a firm when it is absolutely necessary to repeat a study using a new BE recommendation, but FDA does not do this in all instances. What are the criteria for FDA’s decision making process? Does it stem from submitted reports of lack of therapeutic equivalence? Adverse reactions? Lack of effect? How does the Agency decide when not to ask for a new study, either pre- or post-approval? How does the FDA decide to receive or refuse-to-receive (RTR) an ANDA when a BE Guidance revises just prior to ANDA submission? When will FDA decide that it is a review issue or that there is a need to issue an RTR letter? These are some of the questions that industry has asked me. I wonder what the FDA’s answers are? If you have had experiences that you would like to share on how FDA has made such decisions based on issues you have faced, please let me know (r.pollock@lachmanconsultants.com) and I will share them (if you’d like) with our readers (blinded as to firm and drug, of course). But right now, the only question I have is: What's a mother to do?”