FDA issues draft guidance on mpox drug development

Regulatory NewsRegulatory News | 19 January 2023 |  By 

Mpox virus. (Source: CDC)

In a much-anticipated draft guidance issued on Thursday, the US Food and Drug Administration (FDA) said that unlike smallpox therapeutics, treatments for mpox cannot be developed under the Animal Rule, which enables the agency to approve products without human clinical trials in limited circumstances.
The agency also said that sponsors should talk to regulators early to discuss appropriate clinical trial designs and metrics to prove safety and efficacy. The guidance does not apply to the development of preventative vaccines for mpox, which “raise different and additional considerations,” FDA said.
An unprecedented outbreak of mpox was first identified in May 2022 that impacted parts of Europe, North and South America, and other parts of the world outside of Central and West Africa, where the disease is endemic. At its peak, the US was seeing upwards of 400 cases per day, though cases have fallen sharply in recent months, according to the Centers for Disease Control and Prevention (CDC).
One of the reasons cited for the decline is the availability of vaccines developed to prevent smallpox and monkeypox, such as Bavarian Nordic’s Jynneos (smallpox and monkeypox vaccine, live, nonreplicating), which is the only FDA-approved vaccine for monkeypox. There are no currently authorized or approved treatments for mpox, though two drugs – TPOXX (tecovirimat) and Tembexa (brincidofovir) – have been approved to treat smallpox under the Animal Rule. FDA notes that patients can access TPOXX through a randomized controlled clinical trial sponsored by the National Institute of Allergy and Infectious Diseases or under the CDC’s expanded access protocol; patients can access Tembexa through a single-patient emergency use investigational new drug application (IND).
Now, FDA has published a draft guidance for mpox drug developers, which explains the agency’s expectations for developing drugs to treat the disease.
The Animal Rule is meant to enable drugmakers to develop medical countermeasures (MCM) and bring them to market solely based on animal studies when it is infeasible and unethical to conduct trials involving people.
“Although FDA has approved drugs for the treatment of smallpox under regulations commonly referred to as the Animal Rule, this pathway is not applicable to drugs for mpox because researchers can design and implement clinical trials for mpox that are both ethical and feasible,” FDA said. “The Animal Rule applies to the approval of drugs for serious or life-threatening conditions caused by exposure to lethal or permanently disabling toxic biological, chemical, radiological, or nuclear substances when it is not ethical to conduct definitive human efficacy studies and not feasible to conduct field trials to study the effectiveness of a drug after an accidental or hostile exposure.”

FDA also recommends that mpox drug sponsors seeking initial drug development request a pre-IND meeting to get advice from regulators about what they need to allow the drug on the market. The agency notes such meetings can also lead to faster submission reviews and help sponsors start their clinical trials sooner.
Sponsors should also consider the pharmacology and toxicology of the drug they are developing. In particular, the agency said that sponsors should consider presenting data from good laboratory practice (GLP) compliant general toxicology studies in two species, of which at least one is nonrodent, and conduct an assessment of standard safety pharmacology parameters, which may be incorporated into general toxicology studies.
FDA said that sponsors should also present information on the virology of the disease and proposed drug. That includes information on the hypothesized or determined mechanism of action of the drug, cell culture antiviral activity data, and data addressing the impact of serum proteins on antiviral activity in cell culture among other considerations.
The draft guidance also lists a number of clinical considerations sponsors should factor in when thinking about their drug development.
“Drugs should undergo sufficient early clinical development, including clinical evaluation for safety and tolerability, before sponsors submit proposals for evaluation in phase 2 or phase 3 clinical trials,” said FDA.
“To demonstrate substantial evidence of effectiveness, development programs should include randomized controlled clinical trial data in participants with mpox,” the agency added. The primary endpoint for phase 2 or phase 3 clinical trials should be clinically meaningful and should demonstrate the clinical benefit with a favorable effect on a meaningful aspect of how a participant with mpox feels, functions, or survives.”
Stakeholders can comment on the draft guidance by 21 March on www.regulations.gov under docket no. FDA-2022-D-2395.


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