The morning sessions opened with the usual USP presentation, which described its efforts domestically and globally and its goals for establishing quality metrics for products.
After USP’s presentation, Christine Simmon led a manufacturers’ roundtable called Ensuring Biosimilars Sustainability. The discussions focused on the impact of rebates and the uptake of biosimilars. The group agreed that there is too much focus on the middleman profits that can be derived from rebates and misinformation about biosimilars. They agreed that the current reimbursement system can stifle biosimilar uptake. Focus should be on the lower cost products, not just directly to patients, but also considering indirect costs like the increase in insurance premiums that are then absorbed ultimately by the consumer.
Continued education of the public and healthcare providers about the advantages of biosimilars will also be a key to improving uptake whether or not the biosimilars are approved as interchangeable. Panel members suggested that there is sufficient real-world evidence available as well as switching studies to support interchangeable use, even if the regulatory authority has not designated specific applications as such.
Continuing problems identified in the creation and improvement of the biosimilar market included the patent thicket surrounding innovator products, the incentive for use of lower cost products, and the efforts to improve incentives for biosimilar use.
Understanding Regulatory Expectations for Post-Approval Changes in ANDAs was my next stop along Day 3. The FDA presentations on labeling and chemistry manufacturing changes provided discussions of the selection of supplement types (i.e., PAS, CBE-30, CBE-0, and AR). The presentations included case studies for denial of CBE‑30 status where the supplement was changed to PAS. It was noted that, in the case of CBE supplements, very few (1.3%) are denied. This indicates that, for the most part, applicants are using FDA guidance correctly to categorize and select the correct post-approval category.
The FDA reviewers also provided tips for submission for changes, for instance:
- Identify all changes in the submission cover letter and the proposed supplement type.
- Prepare a table of the changes and justify the submission type by reference to an FDA guidance.
- Include all disciplines that may need to review the submission in the cover letter so they can be assigned and sent to appropriate reviewers.
- Ensure you perform all necessary studies and include justification to support your proposed change (e.g, include comparative dissolution studies and other testing, including COAs, when appropriate).
- Include side-by-side labeling comparisons detailing the changes.
- Update labeling to comply with RLD changes, patent and exclusivity expirations, or other revisions to labeling as required by USP changes.
- Include all facilities on the 356h form used in the application even if the change does not impact any of the facilities.
- For supplements that request priority review, be sure to note this on the cover letter and include the basis for the request.
My Day 3 journey continued to Best Practices and Strategies for Communication with FDA. Key highlights included a presentation on eCTD validation and study data issues that outlined new rejection criteria for eCTD submissions that went into effect on September 15, 2021. There are several errors that will result in rejection of eCTD submissions, one of which is the 1774 rejection, which has to do with tags for the study start date. Of the seventy‑three ANDAs submitted with study data, there were five that generated a rejection error for this element. There was a total of nine rejection notices for all four of the rejection criteria that went into effect on the above date.
There was a talk on cover letters for applications, which included information from one of the previous presentations that I’ve outlined above, with the same message: the cover letter should be a road map for your submissions.
A session discussion ensued, covering the types of meetings, mid-review cycle meetings only for complex products, post-complete response letter meetings (telcon or in-person meetings), and the requests for reconsideration. Details, including timing and how, what, and when, were outlined, all of which appear in relevant FDA guidances. and for the mid review cycle meeting, these issues also appear in the GDUFA III commitment letter. Other goal dates are outlined in the GDUFA II commitment letter.
There are four reasons for denial of post-CRL meetings:
- Non-clarifying questions
- Questions outside the scope of CRL deficiencies
- Requests for Agency pre-review (proposals)
- Incomplete Meeting Request package
Request-for-reconsideration meetings include:
- Refuse-to-receive decisions
- Tentative approval letters
- Complete response letters
- FDA determination that a Supplement-Changes Being Effected or Supplement-Changes Being Effected in thirty days is a PAS
- Classification of a major amendment to an ANDA or PAS
- Classification of standard review status of an ANDA, ANDA amendment, PAS, or PAS amendment
- Denial of a pre-ANDA meeting
- Other matters
These requests for reconsideration should not include additional information to support the request.
Additional presentations included touch points for communication during ANDA reviews, including timing and types of communication such as filing letters, information requests, discipline review letters, complete response letters, tentative approvals, or final approvals. Goal date changes can be based on how timely firms reply to various correspondences. Be sure to have a secure email channel with the FDA as most IRs, CRLs, etc. are transmitted electronically. Failure to have a designated, secure email could delay communications and impact your ability to respond.
The final clearance process was also described. Be sure that your labeling is up to date and that there are no DMF amendments outstanding that the FDA does not know about – check with your DMF holder. Check that all patents and exclusivity issues are addressed, that new patents do not need to be dealt with, and that all notifications of legal issues have been provided with your application.
Thanks for following the AAM meeting through these brief summaries. There is a lot of information that we could not cover in these blogs, so I suggest that you plan on attending the GRx-Biosims meeting next fall!