Biologics

Questions About ‘Plausible Mechanism’ Pathway Continue: Attorneys

David McFarland

— 1 min read
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Three Ropes & Gray attorneys say questions remain about the so-called “plausible mechanism” pathway for approving certain bespoke, personalized therapies described by FDA commissioner Marty Makary and CBER director Vinay Prasad in a recent New England Journal of Medicine article. Writing in an online post, the attorneys outline the pathway’s key aspects and list the questions the journal article raises.

The post says FDA is proposing the pathway largely in response to concerns from patient advocates and industry stakeholders that the agency’s existing product approval pathways lack sufficient flexibility for individualized therapies, where randomized trials often are not feasible or practical.

The attorneys say Makary and Prasad use a story about Baby K.J., a newborn with a rare genetic disorder treated with a personalized gene editing therapy that FDA reviewed and authorized via a single-patient expanded-access IND application, to illustrate the pathway and the criteria FDA will consider when authorizing personalized products under it.

The key elements of the proposed pathway, the attorneys say, are:

  • identification of a specific molecular or cellular abnormality;
  • targeting the underlying biological alteration;
  • use of natural history data;
  • evidence of successful target engagement or editing; and
  • demonstration of clinical improvement.

Makary and Prasad say that after a manufacturer has demonstrated success with several consecutive patients with different bespoke therapies, the agency will “move towards granting marketing authorization for the product, allowing sponsors to leverage the clinical efficacy and safety data of the platform to support marketing approval for similar personalized products in other conditions. Marketing authorization can be pursued through accelerated or traditional approval pathways, depending on the strength of the evidence in the product application, they say.

In their analysis, the attorneys note that a scientific journal article is not a formal guidance document or statement of agency policy. Given that the article is barely more than two pages, they say, significant questions remain about how FDA might operationalize and implement the proposed pathway, including:

  • alignment with existing statutory and regulatory standards;
  • submission expectations for the treatment of initial patients; and
  • chemistry, manufacturing, and control requirements.

“Makary and Prasad have promised that FDA will publish more information about the plausible mechanism pathway in the coming weeks, which will hopefully provide further guidance for developers interested in taking advantage of the pathway,” the attorneys conclude.

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