首页 > 资讯 > FDA具体产品BE指南的修订 - 企业应注意的问题

出自识林

2015-11-06 Lachman CONSULTANTS

FDA具体产品BE指南的修订对在研产品和获批产品的影响

FDA仿制药办公室（OGD）如何作出决定修订现有的生物等效性（BE）指南？当一个BE指南修订后，对于在研药品或已获批产品会如何要求？美国仿制药协会(GPhA)秋季技术会议上，OGD研究与标准办公室 (Office of Research and Standards) 主任Robert Lionberger博士和研究与标准办公室治疗效能处 (Division of Therapeutic Performance) 代理处长Larissa Lapteva医学博士解答了这些问题。

当你浏览FDA具体产品BE指南页面时，你可以看到许多新的具体产品建议，也有许多修订的建议。在最近更新的列表中（指2015年9月的更新），有42份新指南文件和18份原先发布指南文件的修订版。

根据Lapteva医学博士的报告，有许多原因可能导致指南文件被修订。在她的幻灯片中列出来的一些可能问题如下：

• 因公共健康需求驱动的修改决定
• 当变化影响仿制产品的质量、可批准性或生物等效性的有效证明时作出修订
• 修定决定有证据记录和支持
• 修订建议的发布尽可能与以下行动相协调：
• 对受控函和ANDA申请前卷宗的回复
  • 橙皮书的发布
  • ANDA批准决定

有趣的是，在问答环节，我们发现：当指南在一件申请获得批准后修订，是要求已获批申请的持有人提供更多信息还是开展新的研究？这是根据不良反应、缺乏有效性或缺乏等效性报告的增长水平来决定的。（FDA的）决定都是根据具体案例作出的，随着科学的进步，可能会存在一些例子：未决或计划申请的申请人需要满足新的要求，但之前获批的产品可能并不满足（新要求）。这都视从参照药品(RLD)得来的有关产品的新信息或上面提到的其它类型信息对公众健康的影响而定。

如果产品在研，BE指南的修订可能要求在ANDA批准前增加额外的工作或新的BE研究。给出的例子是，之前在RLD上没有发现的关于食物影响的新信息现在已经得到确认，导致FDA要求未决ANDA申请人开展食物影响研究（请见下面的幻灯片）。

OGD将评估来自RLD持有人的信息、新的科学证据、或OGD在GDUFA下开展的一些研究项目或实验的结果。

无论是处在产品研发、计划启动一项研究、拥有未决ANDA或已获批ANDA，当具体产品指南被修订时，工业界需要注意决定必须开展额外的工作还是向FDA提供额外的数据。大多数情况下，根据两位OGD官员在GPhA会议上的演讲，当需要额外的工作或数据时，OGD通常会写信给申请人提供其有关决定先前的指南可能存在潜在的安全性或有效性问题的理由，并列出OGD认为所需要的必要的信息或研究。

Lachman CONSULTANTS - Bob Pollock先生 2015-11-04
编译：识林-椒
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OGD Revision of BE Guidance – What Does it Mean for Product Development and Approved Products?
By Bob Pollock | November 4, 2015

How does the Office of Generic Drugs (OGD) make a determination to revise an existing bioequivalence (BE) guidance? What happens to the requirements for drug product under development or those products that are approved when a BE guidance is revised? These questions were addressed by Dr. Robert Lionberger and Dr. Larissa Lapteva in a session at the GPhA Fall Tech Conference.

When you look at the FDA's Product-Specific BE Guidance page (here), you can see many new product-specific recommendations, but there are also many revised recommendations. In the latest update to the list, there were 42 new Guidance documents and 18 revisions to previously issued Guidance documents.

According to Dr. Lapteva’s presentation, there are a number of reasons Guidance documents may be revised. Her slide below outlines may of the issues:

• Decisions to revise are driven by the public health needs
• Revisions are made in cases when changes affect generic product’s quality, approvability, or effective demonstration of bioequivalence
• Decisions to revise are documented and supported by evidence
• Publication of revised recommendations is coordinated as much as feasible with:
• Responses to Controlled Correspondence and pre-ANDA packages
  • Orange Book publications
  • ANDA decisions

Interesting enough, in the Q&A session, we found that, when a Guidance is revised post-approval of an application, the decision as to whether to require the sponsor of the approved application to provide additional information or perform new studies is dictated by an increased reporting level of adverse events, report of lack of effectiveness, or lack of equivalence. The decisions are made on a case-by-case basis and, as science advances, there may be instances where pending or proposed applicants may have to comply with the new requirements but previously approved products may not. Again, this would be dictated by the impact on public health associated with the new information on the product that may come from the reference listed drug (RLD) product or the other types of information identified above.

If a product is in development, it is possible that a revision in a BE guidance may require either additional work or new BE studies prior to ANDA approval. One example that was given related to where new information became available regarding a food effect previously not identified on the RLD which resulted in FDA asking sponsors of pending ANDAs to perform a food effect study (see slide below).

OGD will evaluate the information that comes from the RLD holder, new scientific evidence that becomes available to FDA, or as a result of some of the research projects or studies that OGD has commissioned under GDUFA.

Whether you are in product development, planning to start a study, have a pending ANDA, or have an approved ANDA, the industry needs to pay attention when a product-specific Guidance is revised to determine if they may have to perform additional work and or supply additional data to the Agency. In most cases, according to the two OGD presenters at the GPhA meeting, when additional work or data might be needed, OGD will typically write a letter to the applicant providing its rationale for determining that a potential safety or efficacy issue may exist with the previous Guidance and outline the necessary information or studies that they believe is required for resolution.