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In the News: November 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.

Voxzogo Approved as a Growth-Improvement Therapy for Children with Dwarfism

Biomarin has obtained FDA accelerated approval for Voxzogo (vosoritide), its first-in-class drug to increase linear growth in pediatric achondroplasia patients over the age of 5 with open epiphyses (growth plates). Achondroplasia is the most common form of dwarfism, and the drug is targeted to children because growth plates close after puberty – around 18 years of age.

Biomarin conducted a single global Phase 3 study in 121 children aged 5 to 18 with achondroplasia. Patients received daily injections of the investigational drug or placebo. According to the FDA, participants who received Voxzogo grew an average 1.57 centimeters taller after one year, compared to those who received a placebo. Most (119) of the participants were enrolled in an open-label extension.

The continuation of this open-label extension study through adulthood is important for Biomarin to satisfy the requirements of the FDA’s accelerated approval pathway. Voxzogo’s approval was based on an intermediate clinical endpoint (though accelerated approvals can also come from surrogate endpoints). This means that full approval can only come from a clinical trial that assesses adult height.

Voxzogo also received a priority review voucher. While the value of these vouchers has declined in recent years, they are still worth $67-$350 million, per the most recent GAO report.

Biomarin’s stock shot up after the drug was first approved in the EU this past August, and on the day the news broke of the FDA approval, the stock improved 10.3%. The global market forecast for Voxzogo is over $850 million by 2027, with about half coming from an estimated 10,000 in the US patient population.

FDA Inspections: Numbers Exceed Expectations, but Enforcement Actions on the Rise

An often-problematic result of the COVID-19 pandemic has been the delay of FDA facility inspections, along with the subsequent backlog, and Camargo has taken note of the issue previously (for example, here, here, and here). While some facilities have likely been content with the absence of the inspections, others have experienced delays in product application approval: Until a pre-approval inspection has been completed, and any issues have been successfully resolved, an application cannot be approved. And the issues have impacted not only sponsors but also API manufacturers and CMOs; Camargo has direct experience with several such situations.

Throughout these COVID-19 delays, the FDA has been publishing information explaining its reactions to the situation and pointing to plans for mitigating the problem. In November, the Agency published “An Update to the Resiliency Roadmap for FDA Inspectional Oversight,” describing its progress from March to September 2021.

The document suggests that the FDA previously sold itself very short, exceeding its “best case scenario” for domestic inspections by 219% (best case: 2213, actual: 4849). Foreign inspections remain curtailed, with the focus largely on mission-critical inspections:

Inspections could be considered mission-critical if they are related to approval or availability of products that are used to treat a serious disease or condition for which there is no substitute, or where there is information about a serious adverse event related to a marketed product or where there is an outbreak of a foodborne illness.

So, is the situation getting better, or at least headed in the right direction? Perhaps—but an FDA official recently noted an increase in enforcement actions connected with the inspection alternatives employed by the FDA to help address the inspection logjam.

What is the answer, then, for those who need an inspection as a requirement for obtaining a drug product application approval? Be prepared for the inspection by having a robust internal audit program and conducting mock preapproval inspections so that, when the FDA does arrive, it is one and done. Camargo can assist in all phases of preparation.

FDA Publishes Guidance on Real-World Data Obtained from Registries

The FDA continued to provide direction for the use of real-world evidence in November with the draft guidance document Real-World Data: Assessing Registries to Support Regulatory Decision-Making for Drug and Biological Products.” It offers considerations for those who are either proposing to design a registry or using an existing registry to support regulatory decision-making about a drug’s effectiveness or safety.

The FDA defines real-world data (RWD) and real-world evidence (RWE) as follows:

  • RWD are data relating to patient health status and/or the delivery of health care routinely collected from a variety of sources.
  • RWE is the clinical evidence about the usage and the potential benefits or risks of a medical product derived from analysis of RWD.

Topics covered in the guidance include:

  • Considerations regarding a registry’s fitness-for-use in regulatory decision-making, focusing on attributes of a registry that support the collection of relevant and reliable data
  • Considerations when linking a registry to another data source for supplemental information, such as data from medical claims, electronic health records (EHRs), digital health technologies, or other registries
  • Considerations for supporting FDA review of submissions that include registry data

While the guidance suggests that registries may have advantages that make them a more likely source for acceptable RWD than some others, the data still must meet FDA standards:

Whether registry data are fit-for-use in regulatory decision-making depends on the attributes that support the collection of relevant and reliable data (described in this guidance) as well as additional scientific considerations related to study design and study conduct that are beyond the scope of this guidance. . . .

Before using any RWD (including registry data) for regulatory decision-making, sponsors should consider whether the data are fit-for-use by assessing the data’s relevance and reliability. For the purposes of this guidance, the term relevance includes the availability of key data elements (patient characteristics, exposures, outcomes) and a sufficient number of representative patients for the study, and the term reliability includes data accuracy, completeness, provenance, and traceability. (emphasis in the original)

The guidance spells out appropriate steps to take when using registries for regulatory decision-making in some detail, including some examples and a glossary. Consistent with similar guidance, the document recommends meeting and gaining agreement with the FDA on the proposed use of the registry data.

Real-world evidence can be extremely useful when pursuing a product approval via the 505(b)(2) regulatory pathway, which is one of Camargo’s primary areas of expertise. Contact us for assistance in successfully using the information in this guidance document.

EU’s Good Practice Document Updated to Address Human Cells Modified Without a Viral Vector

In October 2017, the European Commission (EC) and the European Medicines Agency (EMA) collaborated with the Member States’ authorities to launch a plan to reduce discrepancies across the EU in applying certain legislation to advanced therapy medicinal products (ATMPs) containing or consisting of genetically modified organisms (GMOs).

The initiative has resulted in many successful actions, such as the 2018 drafting of the “Good Practice Document.” Subsequent revisions of the document reflect the experience gained as gene therapy products of this type have been approved. Additionally, science has moved on rapidly, and genetically modified cells developed using novel technologies (such as CAR-T cells, induced pluripotent stem cells, and genome editing) are now included.

In November 2021, the fifth version, titled “Good Practice on the Assessment of GMO-Related Aspects in the Context of Clinical Trials with Human Cells Genetically Modified,” was released. It incorporates guidance on human cells genetically modified without viral vectors and addresses several key concerns for this new category. The guidance clarifies that risks to the environment, along with potential hazards to human health associated with clinical use, are considered negligible since there is no known pathology associated with non-viral vectors.

The document also provides clarity around applicable biosafety levels (BSLs): Manufacturing activities for with cells modified without a viral vector may need to be carried out under either BSL-1 or BSL-2 conditions, depending on the specific circumstances. For example, in the case of an established cell-line, BSL-1 would be considered appropriate in most cases. However, for cells for autologous treatments, if there are potential risks regarding the presence of pathogenic viruses, BSL-2 should be considered.


Bill Stoltman, JD
Vice President, Regulatory Operations

Ken Phelps
President and Founder

Federica Martini, PhD
Associate Director, Regulatory Affairs, EU
Regulatory Professionals