首页 > 资讯 > FDA参照药品撤市后仿制药标签变更指南草案

出自识林

2016-07-11 Lachman CONSULTANTS

7月8日美国FDA发布《参照药品撤市后ANDA标签更新》指南草案。描述了FDA在这种情形下预期ANDA申请人如何应对以及做出何种类型的变更。

FDA在指南中明确表示，该指南对FDA仿制药拟议标签规定不具有适用性，但表示，该指南提供了FDA对ANDA申请人在特定情况下是在FDA的指导下还是在之前已获批申请的补充申请（PAS）中变更标签的预期。在指南草案脚注11中，FDA进一步建议：“FDA已经发布拟议规定，允许ANDA持有人根据新获得的信息，独立地递交CBE0-0补充申请对标签做出某些与安全性相关的更新。见78 FR 67985（2013.11.13）。该拟议规定与收集到的评议一同仍在审查之中。如果拟议规定定稿，最终规定将决定在规定范围内实施标签更新的过程。无论是目前的监管框架还是未来拟议规定定稿的情况下，本指南中描述的过程将不会改变ANDA持有人维持最新标签的责任。”【标签拟议规定相关资讯】

FDA解释指出，往往当参照药品（RLD）因安全性或有效性之外的原因撤市一段时间后，ANDA标签可能因以下方面的原因需要更新：科学文献方面的变化、不良反应报告方面的变化，甚至是其它可能含有相同或相似活性成分的RLD产品的变化，或者是药品特定治疗类别的分类标签发生变化。指南提供了一些范例但并不详尽。

此外，FDA指出，已经从市场上停止销售但未撤销的NDA RLD仍负有保证最新标签的相同责任，即使已经不再销售该产品。

有关该指南草案中提出的行动，FDA在脚注7中指出：“本指南中提出的方法，与FDA做出某些撤市药品不是因安全性或有效性原因而撤市的决策的情况下的声明相符，包括大意为以下内容的声明“如果FDA决定应修订这些药品的标签以符合当前标准，FDA将建议ANDA申请人递交此类标签。”参见，例如80 FR 27320-27321（2015.05.13）（决定SODIUM SULAMYD（磺胺酸酰钠）滴眼液和眼膏不因安全性和有效性原因撤市）。”

在这份特殊的指南草案中，FDA指出，可以由ANDA申请人针对某些拟定变更递交PAS或在FDA的指导下递交CBE-0。如果递交PAS，FDA将审评拟定变更，如果认为可以做变更，将通知产品的所有申办人，必须对所有相同产品实施具体变更，并将根据拟定变更的重要性宣布实施变更的时间限。

FDA将利用强制安全性标签变更（SLC）法案第505(o)(4)节的授权，并将指导申办人实施FDA认为适当的SLC。

该指南草案是否提示了FDA关于最终标签规定立场的变化？如上所述，FDA没有给出关于这一问题的任何明确看法，但有趣的是FDA在该指南中的提议与GPhA和PhRMA对仿制药标签变更的替代方法相似【识林资讯 - 两大团体对FDA标签拟议的替代建议】。替代方法也是将FDA作为实施任何变更之前的最终仲裁者。

FDA指出根据该指南以下情况可能会要求标签变更：

• 为与其它具有相同活性成分或一种活性成分具有相同药理学或治疗分类的产品的标签一致，或在适当情况下，与其它批准用于相同适应症的产品的标签一致
• 为更正与先前获批的适应症相关的已过时信息；
• 为符合适用法规和目前FDA标签指南或其它指南（如根据§ 314.94(a)(8)(iv))）

FDA进一步说明：

• 根据该指南可预期的某些标签变更的具体例子
• 实施变更所使用的程序
• 该指南与现有FDA职权和程序之间的关系

由于该指南目前以草案形式发布，尚不清楚FDA希望企业何时开始执行指南中的规定。没有讨论责任、成本和对仿制药企业的影响问题，但行业和律师肯定会问及这些问题。仿制药企业需要对这一指南草案的任何新动向保持关注，因为可能会显著影响企业的下一步行动。

Lachman CONSULTANTS - Bob Pollock先生
编译：识林-椒
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Draft Guidance on Changes to ANDA Labeling Where the RLD Has Been Removed from the Market
By Bob Pollock | July 10, 2016 原文地址

FDA issued a draft Guidance titled “Updating ANDA Labeling After the Marketing Application for the Reference Listed Drug Has Been Withdrawn” (here) describing how and what type of changes FDA anticipates ANDA applicants to make in such situations.

FDA makes clear in the Guidance that it the Guidance does not have applicability to the FDA’s Proposed Labeling Rule for generic drugs, but notes that it provides guidance on FDA expectations for ANDA applicants to either a change of labeling at the direction of the FDA or in a Prior Approval Supplement (PAS) in certain circumstances. In footnote 11 in the draft, FDA further advises that: “FDA has issued a proposed rule that would allow ANDA holders to independently submit CBE-0 supplements making certain safety-related updates to their labeling, based on newly acquired information. See 78 FR 67985 (November 13, 2013). That proposed rule, along with comments received, remains under review. If the proposed rule is finalized, the final rule will govern the process for carrying out labeling updates that are within the scope of the rule. The process described in this guidance would not alter ANDA holders’ obligation to maintain up-to-date labeling, whether under the current regulatory framework or a future scenario at such time as the proposed rule is finalized. “

The Agency explains that, often when a reference listed drug (RLD) is withdrawn for other than safety or efficacy reasons, after sometime, the ANDA labeling may need to be updated due to changes in the scientific literature, changes in adverse event reporting ,even based on changes to other RLD products that may have the same or similar active ingredients, or when there are class labeling changes for a particular therapeutic category of drug product. TheGuidance provides examples but notes the list is not exhaustive.

In addition, the Agency notes that an NDA RLD that has been discontinued from marketing but not withdrawn still has the same responsibilities relative to assuring up-to-date labeling even if they are no longer marketing the product.

Relative to the actions proposed in this draft Guidance, FDA notes in footnote 7 that: “[t]he approach proposed in this guidance is consistent with FDA statements made in the context of determinations that certain drug products that have been withdrawn from sale were not withdrawn for reasons of safety or effectiveness, including statements to the effect that “[i]f FDA determines that labeling for these drug products should be revised to meet current standards, the Agency will advise ANDA applicants to submit such labeling.” See, e.g., 80 FR 27320 at 27321 (May 13, 2015) (determining that SODIUM SULAMYD (sulfacetamide sodium) Ophthalmic Solution and Ophthalmic Ointment were not withdrawn from sale for reasons of safety or effectiveness).”

In this particular draft Guidance, FDA notes that it may entertain a PAS for certain proposed changes by an ANDA applicant or a CBE-0 if by direction of the FDA. If a PAS is submitted, FDA will review the proposed change and, if it believes the change should be made, it will notify all sponsors of the product that the specific changes must be made to all of the same products and will proscribe a time frame for making the changes based on the significance of the proposed change.

FDA will utilize its authority under Section 505(o)(4) of the Act for mandated safety label changes (SLC) and will direct sponsors to make such SLCs as FDA deems appropriate.

Questions have been raised already as to whether this draft Guidance may give a hint to any changes in the FDA’s stance on its final labeling rule. As noted above, FDA does not give any clear perspective on this issue, but it is interesting that the FDA proposal in the Guidance is similar to the GPhA and PhRMA alternate approach to label changes for generic products. That approach also uses the FDA as the final arbiter prior to any change being made.

FDA states that label changes might be required under this Guidance:

• To achieve consistency with the labeling of other products that have the same active ingredient or an active ingredient in the same pharmacologic or therapeutic class, or with the labeling of other products approved for the same indication, where appropriate
• To correct outdated information related to a previously approved indication; and/or
• To achieve consistency with applicable regulations and current FDA labeling guidelines or other guidance (as already contemplated under § 314.94(a)(8)(iv)).

The FDA goes on to further describe:

• certain specific examples of labeling changes that may be contemplated under this guidance
• the process to be used to make the change and:
• The relationship of this guidance to existing FDA authority and processes.

As this Guidance document is currently issued in draft form, it is not clear if and when the FDA would expect firms to begin to implement the provisions in the Guidance. Issues of liability, costs, and impact on the generic industry were not discussed but certainly appear to be questions that the industry and lawyers will be asking. Keep your eyes peeled for any additional news on this draft Guidance because it could have significant impact on your actions. We will post additional information as we become aware of any developments.