GMP Issues Derail a Drug Approval for the Second Time

Current good manufacturing practice (cGMP) compliance problems can result in problems for commercial manufacturing operations, but with FDA's “complete response letter (CRL),” they can also lead to rejections for new drugs. This can pose major setbacks for companies, including loss of investor confidence,  even for companies that have spent time developing promising therapies.  

It can be easy to underestimate the amount of time and resources required to optimize manufacturing, or to fix manufacturing issues during late development stages. One news item this week illustrated what can go wrong, and underscored reasons for looking closely at manufacturing issues at the earliest stages of drug development.

On July 11, FDA rejected Ocular Therapeutix’s new drug application (NDA) for Dextenza (dexamethasone insert), a drug designed to treat postoperative pain. This is the second CRL that FDA has issued the company for the drug within the past year due to cGMP issues.

In response to negative findings from a post-approval inspection in 2016, Ocular had resubmitted its NDA in February 2017, but the agency issued the company a 483 in May 2017, noting violation of current good manufacturing practices (cGMPs) that resulted in the presence of particulates in the product.

FDA reviewers found no clinical safety or efficacy problems with the drug. However, a pre-approval manufacturing plant inspection had found deficiencies in procedures and training protocols, as well as analytical testing, related to commercial manufacturing.

Ocular’s senior management notes that the company had responded immediately to the 483, and subsequently made improvements to its manufacturing processes to address the particulates issue. On July 10 2017, Ocular submitted a closeout response to the 483, and also asked that FDA consider its manufacturing changes as a major amendment to its NDA resubmission, and extend the target action date of July 19, 2017 by three months. As evidence, it submitted commercial manufacturing data generated using the modified equipment.

The response focused on the characterization of particulates, defining and recognizing their source, implementing appropriate corrective and preventive actions, and revising training protocols and documents for manufacturing technicians, according to a press release issued by Ocular. At the time, the company’s CEO, Amar Sawhney, issued the following statement. “We believe that the recent submission of our close-out response to the Form 483 and subsequent submission of the amendment to our NDA resubmission for FDA’s consideration can support an acceptable regulatory pathway for approval.”

FDA issued the CRL before reviewing the new response, and the company’s stock value plunged. FDA has noted that Ocular can include information from the data it sent on July 10, in its response to this second CRL, and the company’s CEO has restated his confidence that manufacturing issues have been addressed.  However, the story emphasizes the importance of considering manufacturing issues closely, along with clinical aspects of new drug development, and to factor the time needed to optimize them into the development timeline.

Sources: Ocular Therapeutix press releases

http://investors.ocutx.com/phoenix.zhtml?c=253650&p=irol-newsArticle&ID=2285862

http://investors.ocutx.com/phoenix.zhtml?c=253650&p=irol-newsArticle&ID=2285469

http://investors.ocutx.com/phoenix.zhtml?c=253650&p=irol-newsArticle&ID=2248172

http://investors.ocutx.com/phoenix.zhtml?c=253650&p=irol-newsArticle&ID=2238963