By Kurt R. Karst –
This blogger’s oldest child started middle school this past week. Naturally, I was excited to get his impressions of the first day of school. “Good” was his initial comment – a now all to familiar one-word tween response. So I pressed further: “Tell me more.” “It’s all so different from elementary school,” he said. “I got 8 pages of homework on the first day!” While I expressed surprise, what I was really thinking was: “If only life could be that simple again.” That thought is similar to this blogger’s first reaction after reviewing FDA’s latest draft guidance document issued in preparation for the October 1, 2014 implementation of the review and performance goals agreed to under the Generic Drug User Fee Amendments of 2012 (“GDUFA”): “Controlled Correspondence Related to Generic Drug Development.” When did every little aspect of generic drug development – even simple correspondence to FDA – become so complicated? Of course, we know the answer to that question: when GDUFA was enacted. But just as we get used to new responsibilities as we move through the education process, the generic drug industry will step up to the task of evolving with GDUFA no matter how complicated things get.
So-called “controlled correspondence” has been a mainstay of the generic drug development and approval process for many years now. It’s how many companies have been able to get answers from FDA’s Office of Generic Drugs (“OGD”) to questions like “What are the bioequivalence requirements for drug X?” and “How close is my formulation to that of the brand-name reference listed drug?” OGD gets a ton of controlled correspondence each year. Although the volume of controlled correspondence was reduced with OGD’s decision – after some internal FDA legal wranglings – to publish product-specific bioequivalence recommendations (see our previous post here), OGD continues to receive hundreds (if not thousands) of controlled correspondence requests each year. Not surprisingly, there’s been a backlog of controlled correspondence awaiting a response from OGD.
For a long time there was no guidance (informal or formal) on how to submit controlled correspondence to FDA – or even what controlled correspondence encompassed. Eventually, FDA posted some recommendations on the Agency’s website. And then GDUFA came along . . . .
Early on in GDUFA negotiations it was suggested that timeframes be established for controlled correspondence between FDA and industry to support application review targets. Those suggestions were ultimately captured in the GDUFA review and performance goals letter where controlled correspondence was described (below) and where FDA agreed to response metrics. The following is from the review and performance goals letter:
Controlled correspondence – FDA’s Office of Generic Drugs provides assistance to pharmaceutical firms and related industry regarding a variety of questions posed as “controlled documents.” . . . Controlled correspondence does not include citizen petitions, petitions for reconsideration or requests for stay.
Controlled Correspondence Metrics
- Controlled Correspondence
- FDA will respond to 70 percent of controlled correspondence in 4 months from date of submission in FY 2015.
- FDA will respond to 70 percent of controlled correspondence in 2 months from date of submission in FY 2016.
- FDA will respond 90 percent of controlled correspondence in 2 months from date of submission in FY 2017.
- If the controlled correspondence requires input from the clinical division, one additional month will be added to the goals outlined above.
- In the case of controlled correspondence which raises an issue or question that is the same as or related to the issue or question that is the subject of one or more pending citizen petitions, or petitions for stay or reconsideration, the above goals will apply from the date FDA issues responses to the pending petitions.
FDA’s draft controlled correspondence guidance, which is announced in an August 27, 2014 Federal Register notice and is the topic of a pre-recorded webinar, puts some meat on the bones of the review and performance goals letter. We knew the draft guidance would be issued soon. After all, FDA identified the guidance as a topic for discussion at a public hearing on GDUFA implementation scheduled for September 17, 2014 (see our previous post here).
The draft controlled correspondence guidance provides, for the first time, a definition of “controlled correspondence” (at least for the purposes of GDUFA): “A correspondence submitted to the Agency, by or on behalf of a generic drug manufacturer or related industry, requesting information on a specific element of generic drug product development.” It also limits controlled correspondence to inquiries and requests from generic drug manufacturers and related industry. “Inquiries related to generic drugs submitted by other parties (for example, private citizens, financial firms, or public advocacy groups that are not directly involved in developing generic drug products) should be directed to CDER’s Division of Drug Information,” says FDA in the draft guidance. From there, FDA puts some controls on what types of controlled correspondence are subject to the GDUFA metrics and when responses may be issued. For example, FDA says that the goal dates for responding to controlled correspondence concerning issues raised in a pending citizen petition (including a petition for reconsideration or a request for stay) depend on when a petition response is issued:
If a controlled correspondence is submitted that raises an issue that is the same as or related to an issue or question that is the subject of one or more pending citizen petitions, petitions for reconsideration, or requests for a stay, the goal dates set forth in the GDUFA Commitment Letter for controlled correspondence will apply from the date FDA issues responses to the pending petitions. Likewise, if a citizen petition, petition for reconsideration, or request for stay is submitted that raises an issue that is the same as or related to an issue or question in a pending controlled correspondence, the goal date for that controlled correspondence will apply from the date FDA issues a response to the related citizen petition, petition for reconsideration, or stay request. For example, if a controlled correspondence is submitted in FY 2015 that relates to an issue in a pending petition, and the Agency responds in FY 2016 to that petition, the 4-month goal date for FY 2015, the year in which the controlled correspondence was submitted, will apply to the controlled correspondence from the 2016 date that the petition is answered.
For controlled correspondence related to matters still under consideration by FDA (e.g., requests for specific approval requirements for an ANDA for a complex drug product for which FDA is still considering the scientific standards for approval), parties may get a non-response response that will close the matter. According to FDA:
For such questions that call for developing a new policy, FDA will respond to the controlled correspondence to notify the requestor that such a policy is under development, but that the Agency cannot provide information at that time because the matter is still under consideration. The Agency will consider this response to close the controlled correspondence, and it will not provide additional direct communications to an inquirer on the matter.
Although FDA’s draft guidance does provide some specific examples of what inquiries and topics are appropriate for controlled correspondence (e.g., requests related to inactive ingredients, formulation assessments, and labeling standards for certain container/closure systems), along with general guidance that controlled correspondence should involve “inquiries on a specific element of generic drug development, and not general questions related to product planning,” FDA spends quite a bit of time explaining what topics fall outside the scope of controlled correspondence, as well as what controlled correspondence is excepted from GDUFA goals. “First, the Agency considers any question related to a pending ANDA a review issue,” says FDA. “Such inquiries will not be treated as controlled correspondence and should be submitted only to the ANDA so they can be included as part of the full administrative record for that application.” “Second, inquiries that are submitted to FDA that are not directly related to generic drug development will not be considered controlled correspondence for the purposes of GDUFA.” Finally, “general, open-ended, or insufficiently detailed questions related to product development are not the appropriate subject of [controlled correspondence].”
Excepted from the GDUFA goals are three types of inquiries that fall within the definition of controlled correspondence, but that FDA has historically treated differently than other inquiries on generic drug development: (1) requests for bioequivalence study recommendations for a specific drug produc; (2) requests for review of bioequivalence clinical protocols; and (3) requests for pre-ANDA meetings to discuss generic drug development. “FDA will continue to respond to these inquiries consistent with its current practices, and to exclude these inquiries from the goal dates in the GDUFA Commitment Letter,” writes FDA.
Finally, the draft guidance provides detailed information on how generic drug manufacturers or related industry should go about submitting controlled correspondence, the specific components FDA expects to see in controlled correspondence, and what OGD disciplines might review and respond to controlled correspondence.
The draft guidance is a lot to digest, but it’s also welcomed detail of an information request process that is intended to result in quicker ANDA approval. Nevertheless, some questions still remain. For example, how will FDA’s focus on addressing controlled correspondence submitted in Fiscal Years 2015-2017 affect controlled correspondence submitted during the first two years of GDUFA (and before)? Will those pending requests be put on a backburner?