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In the News: February 2021 Regulatory and Development Updates

Each month, Camargo’s “In the News” series highlights important changes and advancements in the regulatory and development space and explores how those changes could impact your program.

FDA: Sponsors Seldom Disclose RTF Letters’ Existence or Contents and Often Ignore Agency Advice

The FDA revealed that pharma companies are not forthcoming when they publicly disclose the reasons behind a refuse-to-file (RTF) letter from the Agency. In fact, when they do disclose their existence, companies disclosed only 5% of the reasons for the RTF. This statistic comes from an FDA investigation and report in the Journal of the American Medical Association Internal Medicine (JAMA).

The FDA issues an RTF letter to an NDA sponsor when there are substantive issues that prevent a full review of its application or efficacy supplement. Per the FDA’s interpretation of the statues, the Agency does not reveal the existence or contents of RTF letters – it is up to the applicant whether to reveal them. Therefore, it was a bit surprising that the FDA prepared this JAMA report, though it aggregated data so as not to reveal any specific sponsors or drug products.

According to the report, the FDA came to two broad conclusions during its investigation. First, most reasons for RTF letters (84.5%) were related to the quality, safety, and efficacy of drug products. The largest portion of the 103 RTF letters evaluated were issued due to chemistry, manufacturing, and controls (CMC) considerations (19.4%), while clinical safety (15.8%) and clinical efficacy (14.6%) issues were the next most frequent reasons for refusal. Many Camargo blog posts over the last two decades have been devoted to deficiencies in CMC, which is the leading cause of ANDA and NDA approval delays.

The report also points out that 26.2% of the RTF letters were found to have pre-submission advice that the applicants apparently ignored and filed anyway. The FDA writers believe that, had those applicants followed the Agency’s advice, these RTF letters and the subsequent delays could have been avoided.

The second conclusion reached by the FDA staff was that the sponsors did not often disclose the existence of the RTF letter, and, when they did, they seldom fully publicly disclosed its contents. The FDA found that fully 84.5% of the letters studied were not publicly disclosed. Of those that were disclosed, only 5.4% of the reasons for refusal were revealed.

The writers argue that this lack of transparency may lead to less public confidence in the review process. Indeed, a 2010 report recommended that the FDA disclose both the existence and the contents of RTF letters at the time of issuance. At this time, the FDA has not implemented this recommendation, so perhaps the study was conducted and reported to reexamine greater transparency, particularly as the selection of the next FDA commissioner gets under way.

Approval of the Month: FDA Grants Sarepta Approval for DMD Drug and Rare Pediatric Disease Voucher

On February 25, the FDA approved Sarepta’s Amondys 45 (casimersen) injection for the treatment of Duchenne muscular dystrophy (DMD) in patients who have a confirmed mutation of the DMD gene that is amenable to exon 45 skipping. In addition to the product approval, the FDA granted Sarepta a rare pediatric disease voucher.

Amondys 45 follows earlier approval of Sarepta’s Exondys 51 and Vyondys 53, for exon 51 and exon 53 skipping respectively.  In each of the three drugs, the goal is to increase the levels of dystrophin, which is believed to benefit patient lives, though this conjecture remains controversial.  A confirmatory placebo-controlled outcomes study of Amondys 45, called ESSENCE, will not read out until 2024.

DMD patients remain an underserved population; in fact, the first marketed drug for DMD, Exondys 51, was not introduced until 2016. The advocacy group CureDuchenne estimates that 13% of patients are eligible for exon 51-skipping therapies, while exon 53- and 45-skipping therapies such as Amondys 45 could each treat another 8% of the population.

Sanofi and Regeneron’s Libtayo to Go Head-to-Head with Merck’s Keytruda

The FDA has added first-line treatment of patients with non-small cell lung cancer to the approved indications of Sanofi and Regeneron’s Libtayo (cemiplimab-rwlc) injection. Previous indications include metastatic basal cell carcinoma (mBCC) and metastatic cutaneous squamous cell carcinoma (CSCC). While these non-melanoma skin cancer indications are clinically important, their financial return will pale compared to the new NSCLC indication, where the product will go head-to-head with Merck’s blockbuster ($14.4B in 2020) Keytruda. Keytruda is currently the standard of care, so Regeneron has its work cut out to provide convincing data to penetrate the market.

While the review documents for this BLA approval are not available on the FDA website, presumably the approval was based on the EMPOWER-Lung 1 study. In this study, the summary of which was also reported in the sponsor’s press release, cemiplimab was compared with a former standard of care, platinum doublet chemotherapy. While the results were impressive, a similar trial comparing Keytruda to platinum doublet yielded similar outcomes. Since no head-to-head studies have been conducted and the labels are similar, it is unclear how Regeneron will position Libtayo to differentiate it from Keytruda. Marketing strategies will need to rely on teasing out patients who might respond better to monotherapy.

FDA Inspection Delays During the Pandemic, Continued

In response to the FDA’s continued manufacturing inspection delays (the recent hold-up for Mallinckrodt’s skin tissue therapy, for example) and the resulting product application approval delays, the General Accounting Office (GAO) has offered two recommendations for the FDA:

  1. It should ensure that inspection plans for future fiscal years account for the backlog of inspections and the resulting issues that could jeopardize its goal of risk-driven inspections.
  2. It should assess its alternative inspection tools and consider whether and how those and other tools could supplement regular inspection and drug oversight activities in the future.

Here is an excerpt from the GAO’s larger report:

FDA is responsible for overseeing the safety and effectiveness of all drugs marketed in the U.S., including those manufactured overseas, and typically conducts more than 1,600 inspections of foreign and domestic drug manufacturing establishments each year. In light of the COVID-19 pandemic, since March 2020, FDA has limited domestic and foreign inspections for the safety of its employees.

FDA has used alternative inspection tools to maintain some oversight of drug manufacturing quality while inspections are paused, such as reviewing foreign regulator reports. However, these tools are not equivalent to an FDA inspection in all cases. In addition, with one exception, FDA has not yet fully assessed how these tools or others can be used to supplement its regular inspection activities in the future, or as long-term substitutes for an FDA inspection.

Reportedly, the FDA was in agreement, but any potential improvement is still in the future.


Ken Phelps
President and Founder

Bill Stoltman, JD
Vice President, Regulatory Operations