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In the News: January 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.

Approval of the Month: Previously Approved Oncology Drug Cleared for Rare Pediatric Indication

Pfizer’s Xalkori (crizotinib) was approved in 2011 for the treatment of patients with locally advanced or metastatic non-small cell lung cancer that is anaplastic lymphoma kinase (ALK)-positive. PREA did not apply because of orphan drug exclusivity, so crizotinib was not studied in pediatric patients at the time. However, in January 2021, the FDA approved a new indication for pediatric patients 1 year of age and older and young adults with relapsed or refractory systemic anaplastic large cell lymphoma (ALCL) that is ALK-positive. (Pfizer did not study the drug for this indication in older adults since this alteration in ALK is much less prevalent in adult ALCL.)

This new pediatric indication approval was based on a single multi-center, single-arm, open-label study in 26 patients ages 1 to 21. Per the approved labeling, the objective response rate (ORR) in the 26 patients was 88% (95% CI: 71, 96), with a complete remission rate of 81%. Of the 23 patients who achieved a response, 39% maintained response for at least 6 months, and 22% maintained response for at least 12 months.

This new approval was celebrated by the Leukemia & Lymphoma Society, which noted, “[Crizotinib] is now an option for those whose cancer returned or worsened despite earlier treatment. This is a long-awaited treatment option for the pediatric population, as anaplastic lymphoma kinase (ALK) inhibitors have been approved for adults with metastatic non-small cell lung cancer and lymphoma for years.”

There are many drugs that have been approved for adults that may be repurposed for the pediatric population. Often, as in this case for crizotinib, the studies required for approval are small, but the difficulties associated with enrolling young patients, especially with life-threatening diseases such as cancer, can make them complex. Camargo has extensive experience in assisting clients navigate these challenges.

Report Shows that Most Drugs Fall Short of Sales Forecasts

Last month, LEK Consulting reported that more than half of the drugs rolled out since 2004 failed to live up to sales forecasts. The analysis provides a reminder of the challenges that pharmaceutical companies face in managing investors’ expectations. The reasons for underperformance are complex and multifactorial, but, importantly, the report highlights the need to develop a clear and cohesive commercial strategy early in the development process. Early commercial insights can provide sponsors and investors with an understanding of the challenges that may be encountered when launching a new product.

It is not surprising that sponsors and analysts overestimate the potential value of a product’s differentiation and underestimate how clinical tradeoffs or “real world” issues might limit the product uptake and adoption. At Camargo, we recognize the implications of mismanaged expectations and aim to help our sponsors “begin with the end in mind.” Our structured and systematic approach to decision-making incorporates market-based insights into the development program well before the designs of pivotal studies are finalized. Contact us to find out how we can support your program.

FDA Threatens to Withdraw Standard of Care Due to Post-Approval Study Failure

Makena (hydroxyprogesterone caproate) has been the standard of care for preventing recurrent preterm birth since its US approval in 2011 under the accelerated approval pathway. Since its approval, five generic equivalents have been approved. Now, the FDA is proposing withdrawing approval of these products because Makena’s required confirmatory post-approval study failed to demonstrate a clinical benefit.

This situation reflects several issues with accelerated approvals, perhaps foretelling issues with the recent Emergency Use Authorizations (EUAs) of COVID-19 vaccines. For one, meeting the FDA gold standard of a randomized, placebo-controlled trial (RCT) after product approval is very challenging; patients do not want to be given the placebo. For vaccines, the patient alone is involved in the risk assessment. In the instance of Makena, expecting mothers must also factor in their desire for a viable baby.

Since the product has been in use for such a long time, the FDA is being careful to weigh its options. It convened an Advisory Committee meeting in 2019 to evaluate PROLONG, the post-approval study. The committee was unanimous in determining that the study failed to verify Makena’s clinical benefit on neonatal outcomes. However, the committee was split on whether to withdraw the product (nine votes) or keep it on the market pending additional studies (seven votes). Complicating these decisions was the study design: The majority of the patients were from Russia and Ukraine, so reviewers said the study population was not relevant to the US.

In October 2020, the FDA gave AMAG, the current owner of Makena, an opportunity for a formal hearing on the matter. In AMAG’s submission, it proposes either a retrospective study using secondary real-world data sources; a prospective, observational study with selected sites; a blinded, retrospective, case-crossover, observational study; or a randomized, placebo-controlled trial.

Since hydroxyprogesterone caproate, the previous standard of care, was used for decades in the US before 2011, real-world evidence (RWE) could possibly be used to determine if Makena and its generic equivalents should remain on the market. While RCTs are the accepted standard for pre-approval studies, EUAs and accelerated approvals complicate the use of placebo controls. These factors have driven Camargo’s work with the FDA to use RWE both before and after approval for many products.

HHS Puts CARES Act Over-the Counter Fees on Hold

In April of 2020, this blog provided an overview of the statutory changes made to Over-the Counter (OTC) drug product law via the Coronavirus Aid, Relief and Economic Security (CARES) Act. Among the revisions was the creation of annual facility fees for manufacturing sites producing OTC products. Details, such as the amount of the fee, were to be forthcoming.

In December 2020, the FDA announced the fee structure for fiscal year 2021. The notice specified the two facility types:

  1. An OTC monograph drug facility is a foreign or domestic entity engaged in manufacturing or processing the finished dosage form of an OTC monograph drug. The Agency refers to such facility as a Monograph Drug Facility (MDF). The fee listed for MDFs was $14,060.
  2. A contract manufacturing organization (CMO) is an OTC monograph drug facility where neither the owner nor any affiliate of the owner or facility sells the OTC monograph drug produced directly to wholesalers, retailers, or consumers in the United States. The fee listed for CMOs was $9,373.

However, before most could get out their checkbook, an additional notice was published in January 2021 that withdrew the December notice, with the explanation that the FDA had lacked the delegated authority to issue it. In the January notice, the Department of Health and Human Services (HHS) announced that the FDA has been ordered to cease collection efforts related to the Over-the-Counter Drug Monograph User Fee Program (OMUFA) until HHS issues further direction on the FDA’s administration of the program that provides the public with notice and opportunity for comment.

Stay tuned until then, bearing in mind that the fees were created via a statutory change, which means that they will likely be put into place eventually.

FDA Updates Guidance on Inspections During COVID-19 Emergency

On January 29, the FDA issued an updated guidance originally issued in August of 2020, “Manufacturing, Supply Chain, and Drug and Biological Product Inspections During COVID-19 Public Health Emergency Questions and Answers.” We have previously commented on possible negative consequences of the “remote inspections” approach. Particularly, the FDA might review documents without discussing potential issues with the relevant individuals at the site. A notable addition to the revised guidance indicates progress in that quarter, of a sort:

FDA is also working directly with facilities to communicate any issues identified through a review of records or other information requested. For example, for both CDER- and CBER-regulated products, interim processes have been implemented to communicate with manufacturing facilities regarding issues identified following a review of records or other information requested in advance of or in lieu of a pre-approval or pre-license inspection. Responses from the facility regarding these issues will, as feasible, be considered before taking an action on a pending application. (Emphasis added)


Robb Lawrence
Senior Vice President, Commercial Strategy

Ken Phelps
President and Founder

Bill Stoltman, JD
Vice President, Regulatory Operations