John Jenkins, Office of New Drugs Director, remarked on the low rate (30 percent) of firstcycle approvals for standard review applications (‘The Pink Sheet,’ Dec. 7, 2008). He attributed the low approval rate in part to the submission of applications that require amendments, often because the original submissions were incomplete or incorrect. A recent example of this problem is Roche’s Actemra.
On 8 Jan, FDA approved Roche’s novel interleukin-6 inhibitor Actemra, a
second-line therapy for rheumatoid arthritis. This approval came after a delay of more than a year following FDA’s issuance of a “complete response” letter. Among other things, the FDA required a Risk Evaluation and Mitigation Strategy (REMS), along with additional information. Whether the need for a REMS should have been anticipated is unclear. For more about REMS, see here. However, much of the additional information requested could reasonably be expected to have been included in the submission. For example, one of the requests was for an extensive safety update with data from preclinical and clinical studies regardless of indication, dosage form or dose level. The M4E Guidance clearly states that all relevant safety information (eg, data for other indications) should be included. This update also was to include case report forms and narrative summaries for patients who died during a study or who dropped out because of an adverse event, as well as narrative summaries for all serious adverse events. This statement probably refers to the clinical studies ongoing or completed after the submission because, for the studies included in the submission, all of this information should have been included in the clinical study reports (see Guideline for Industry: Structure and Content of Clinical Study Reports).
In addition, the letter requested that Roche fix some inconsistencies and formatting errors in its proposed labeling and to submit essential paperwork, such as debarment certifications and financial disclosures. A more careful review and check for completeness against the comprehensive table of contents for the submission would have been expected to catch these issues.
While a large company like Roche may be able to absorb the financial impact of a year’s delay in approval, smaller companies may not. Thus, it is important to make sure that submissions meet FDA requirements from the beginning. Companies should stay current with legal and regulatory requirements or hire a company with expertise to ensure a smooth pathway to approval. It is important for drug companies to ensure that they adhere to all relevant guidances for regulatory documents and submissions.
Camargo Researcher Lisa McChesney contributed this post.