May 2017

Regulatory Radar: 21st Century Cares Act, Promoting Innovation

The Cures Act under Subtitle B - Advancing New Drug Therapies contains provisions to promote use of drug development tools (Section 3011) and continuous manufacturing (Section 3016) brought about by scientific advances. The Cures Act aims to promote these innovations to speed up and enhance the development process of new therapeutics and reduce the failure rate by formalizing them within the regulatory framework.

To ensure the advancement of the Drug Development Tools, the Cures Act contains a timetable. Within two years of enactment (by December 13, 2018), FDA is required to:

  • Hold a public meeting to gather input on developing a process for FDA qualification of the drug development tools - biomarkers, surrogate endpoints, and clinical outcome assessments (COAs)
  • Issue a draft taxonomy for classification of biomarkers and related scientific concepts for use in drug development, followed by the final taxonomy within a year of the close of the draft comment period

Within three years (by December 13, 2019), draft guidance must be issued that establishes a process for FDA qualification of drug development tools. The document will describe requirements and timeframes for FDA review of drug development tools and provide a conceptual framework with standards and approaches to support development of biomarkers.

Section 3011 Qualification of Drug Development Tools

Section 3011 establishes a review pathway at FDA for biomarkers and other drug development tools that can be used to help shorten drug development time and reduce the failure rate in drug development.

In 2004, FDA conducted an investigation as part of their Critical Pathways Initiative (CPI) and reported a gap between scientific discoveries that have the potential to translate into disease treatments and the application of those scientific discoveries to develop disease treatments. To make use of these new tools brought about by scientific advances CDER undertook a number of initiatives to support the development of Drug Development Tools (DDTs) to benefit drug development process. Part of this effort was the creation of a formal qualification process to qualify the tools for use in the regulatory process.

A drug development tool (DDT) is the application of scientifically advanced methods, materials, or measures, including biomarkers or clinical outcome assessments, to aid in safer and more effective drug development. Qualifying it for a specific context of use allows drug developers to use the DDT in drug development without the need to reconfirm its utility to regulatory reviewers. DDTs include, but are not limited to, biomarkers, clinical outcome assessments (COAs), which the Cures Act defines as follows:

  • Drug development tool
    • a biomarker;
    • a clinical outcome assessment; and
    • any other method, material, or measure that the Secretary determines aids drug development and regulatory review.
  • Biomarkers/biological marker
    • means a characteristic (such as a physiologic, pathologic, or anatomic characteristic or measurement) that is objectively measured and evaluated as an indicator of normal biologic processes, pathologic processes, or biological responses to a therapeutic intervention; and
    • includes a surrogate endpoint

Biomarkers can be used to select patients for inclusion in a clinical trial, changes in biomarkers following treatment can be used to predict or identify safety problems, could aid in predict an eventual benefit from treatment, aide in dose selection. A notable example of use of biomarkers to predict benefit from treatment is the I-SPY 2 trial which sought to speed up the development of therapeutics for women with high-risk, rapidly growing breast cancers. In this the trial, drugs were individually targeted to the biology of each woman's tumor through us of certain biomarkers (http://www.ispytrials.org)

  • Clinical outcome assessments (COAs)
    • a measurement of a patient’s symptoms, overall mental state, or the effects of a disease or condition on how the patient functions; and
    • includes a patient-reported outcome (meaning a measurement based on a report from a patient regarding the status of the patient’s health condition without amendment or interpretation of the patient’s report by a clinician or any other person.

The Cures Act amends the Federal Food, Drug, and Cosmetic (FD&C) Act to include the Qualification of Drug Development Tools. The new section includes requirements for the Secretary of Health and Human Services (HHS) to establish a process for Qualification of DDTs, describes the process and prioritization of qualification, and outlines the transparency associated with the Qualification Process.

The process described within this regulation is structured around 3 sequential submissions to the Secretary, collectively referred to as qualification submissions: a letter of intent, a qualification plan, and a full qualification package. The requestor submits them in stages pending acceptance of the prior submission by the Secretary. If all are accepted, the Secretary will comprehensively review the package by priority of the disease targeted and will determine qualification status of the DDT and its proposed context of use based on scientific merit, which may require the engagement of external experts. Review of a full qualification package may be prioritized by factors such as (i) the severity, rarity, or prevalence of the disease or condition targeted by the drug development tool and the availability or lack of alternative treatments for such disease or condition; and (ii) the identification, by the Secretary or by biomedical research consortia and other expert stakeholders, of such a drug development tool and its proposed context of use as a public health priority.

Once qualified, a DDT and its specific context of use may be used by any person in support of NDA or BLA approval or in support of investigational use under an IND. As part of transparency, the Agency is required biannually to provide a comprehensive list of qualified DDTs and surrogate endpoints which were the basis of approval or licensure (as applicable) of a drug or biological product as well as status updates of submissions on its website. This will include information summary reviews that document conclusions and recommendations for determinations to qualify drug development tools.

For additional detail on the qualification of DDT refer to FDA Guidance for Industry entitled “Qualification Process for Drug Development Tools” (January 2014).

3016. Grants for Studying Continuous Drug Manufacturing

Section 3016 of the Act allows for the Secretary of HHS to award grants to institutions of higher education and nonprofit organizations to study and recommend improvements to the continuous manufacturing process for drugs and biologics. The number of approved drugs manufactured by continuous manufacturing remains limited. However, recent examples are Vertex’s cystic fibrosis drug Orkambi (lumacaftor/ivacaftor) which was approved in July of 2015, and Janssen Product Prezista (darunavir) for treatment of HIV infection which obtained approval in 2016 for change in their production method from “batch” to continuous manufacturing.

Find out more about provisions to encourage antibiotic drug developments under the Cures Act in the next Regulatory Radar post.

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