United States: FDA: Clarifying Drug Provisions

The 21st Century Cures Act includes portions of five previously introduced bills that were not advanced by the Senate relating to FDA regulation of drugs, biologics and combination products, including:

  • Advancing Targeted Therapies for Rare Diseases Act of 2016,
  • Patient-Focused Impact Assessment Act of 2016,
  • Promise for Antibiotics and Therapeutics for Health (PATH) Act,
  • Combination Products Regulatory Fairness Act of 2016, and

FDA and NIH Workforce Authorities Modernization Act. These provisions appear in title III of the new legislation.

Overview of the Drug Provisions in the Cures Act

The drug provisions of the Cures Act are generally friendly to sponsors and manufacturers, and largely impose additional requirements on FDA. In general, the Cures Act provisions seek to:

  • Expedite the review process for certain drugs,
  • Facilitate the recognition of drug outcome measures,
  • Encourage the consideration of data beyond that produced in randomized clinical trials to support approval,
  • Create a new priority review voucher (PRV) for material threat medical countermeasures,
  • Extend the current rare pediatric disease PRV program,
  • Clarify the scope of permissible dissemination of health care economic information (HCEI) by manufacturers, and
  • Require manufacturer publication of expanded access policies.

Why These Provisions Matter

CHANGES TO THE REVIEW AND APPROVAL PROCESS GENERALLY

The Cures Act does not modify the statutory standard for the approval of a new drug or biologic. As outlined below, however, the Cures Act included several provisions that may impact the types of evidence FDA will consider when deciding whether individual products meet the statutory standard.

The codification of FDA's current guidance-based qualification process for Drug Development Tools (DDT)—e.g., biomarkers, clinical outcome assessments, and other methods, materials or measures—may benefit drug developers and biomedical research consortia, promote drug innovation and expedite review of regulatory applications. The Cures Act requires FDA to create a process by which a sponsor, consortia or other requestor can seek to qualify a DDT for its proposed context of use. A DDT is qualified if FDA determines its proposed context of use can be relied upon to have a specific interpretation and application in drug development and regulatory review. Qualified DDTs may be used to support or obtain approval or licensure of a drug or biologic, or to support an investigational use. Companies developing drugs for conditions that lack well-established outcome measures, or for which existing measures fail to assess critical performance parameters, may benefit from an established process for the qualification of DDTs. FDA has also stated that companies can pool resources and data to develop a DDT, which may reduce the cost associated with development and recognition of such measures.

Notwithstanding objections from certain consumer advocacy groups, the statute also requires FDA to establish a program to evaluate the potential use of "real world evidence"—i.e., data regarding the usage or potential benefits or risks of a drug that is derived from sources other than randomized clinical trials—in support of applications for new indications for FDA-approved drugs and/or to support or satisfy post-approval marketing requirements. FDA must, in consultation with industry, advocacy groups and others, draft a framework for the program's implementation, and then implement the program within two years of the law's enactment.

Drug and biologics developers may also benefit from a provision that allows FDA to rely on a "qualified data summary"—a summary of clinical data that demonstrates the safety and effectiveness of a drug with respect to a qualified indication—to support the approval of applications for new uses of previously approved products. A qualified indication is an indication for a drug that FDA determines is appropriate for summary level review; the Cures Act does not, however, provide guidance on how FDA should assess whether an indication is "appropriate" for such review. A supplemental application is eligible for summary level review if (1) there is existing data available and acceptable to FDA that demonstrates the safety of the drug; and (2) data used to develop the qualified data summaries are submitted to FDA as part of the supplemental application.

CHANGES TO THE REVIEW AND APPROVAL PROCESS FOR CERTAIN DRUGS

Sponsors of drugs that FDA designates as regenerative advanced therapies (RAT)—e.g., cell therapies, therapeutic tissue engineering products, human cell and tissue products— may benefit from a provision authorizing priority review and accelerated approval. For a sponsor's drug to be designated a RAT by FDA, the drug must be intended to treat, modify, reverse or cure a serious or life-threatening disease or condition, and preliminary clinical evidence must indicate that the drug has the potential to address unmet medical needs for such disease or condition. A new drug application (NDA) or biologics license application (BLA) for a RAT may be eligible for accelerated approval through reliance on surrogate or intermediate endpoints reasonably likely to predict long term clinical benefit or data from a meaningful number of sites.

Similarly, sponsors of antibacterial and antifungal drugs intended to treat serious or life-threatening infections in a limited population of patients with unmet needs may benefit from the creation of a new "limited population" approval pathway. The new pathway is designed to expedite approval of these drugs without requiring large-scale clinical trials or testing in specific populations. The labeling and advertisements for such drugs must contain a statement that the drug's safety and effectiveness has only been demonstrated with respect to a "limited population," and the promotional materials for such drugs must be submitted to FDA prior to dissemination. FDA Commissioner Robert Califf explained that the drugs are to be "used narrowly ... while additional evidence is generated to assess safety and effectiveness for broader use."

Sponsors of genetically targeted or variant protein targeted drugs—drugs for the treatment of rare diseases or serious or life-threatening conditions which, respectively, may modulate the function of a gene or modulate the function of a product of a mutated gene—may benefit from a provision that enables FDA to permit a sponsor to rely on data previously developed and submitted by the sponsor (or another sponsor, with the appropriate right of reference) as part of an approved NDA or BLA. The law is intended to address the challenge of conducting clinical trials in small populations of patients, especially subgroups of patients with the same disease or condition but different genetic mutations. To be eligible under this provision, drugs must incorporate or use the same or similar technology as the drug in the previously approved application.

PRIORITY REVIEW VOUCHER PROGRAMS

Sponsors of material threat medical countermeasures may benefit from the law's creation of a new Priority Review Voucher (PRV) program, which entitles the holder of a PRV to expedited FDA review of a subsequent drug product application within six months, which is four months faster than the standard review process. A sponsor would receive a PRV upon approval of an application for a material threat medical countermeasure application that (1) prevents or treats harm from biological, chemical, radiological or nuclear agents that present a material threat against the US population sufficient to affect national security or (2) mitigates, prevents or treats harm from a condition that may result in adverse health consequences or death, and may be caused by administering a drug or biologic against an agent that presents a national security threat. Like other PRV programs, holders must notify FDA before using the PRV, and the program sunsets on a date certain (October 1, 2023). PRVs issued under this program are also transferable, which, given the robust market for PRVs issued under other authorities, may make the program a significant incentive toward the development of "material threat" medicines.

Sponsors of drugs for rare pediatric diseases may benefit from the extension of the corresponding PRV program through September 30, 2020.

DISSEMINATION OF HEALTH CARE ECONOMIC INFORMATION

Manufacturers and others who disseminate "health care economic information" (HCEI) related to drugs and devices may benefit from the clarification and expansion of permissible communications. HCEI will not be considered false or misleading labeling if it (1) is disseminated to persons to whom such information may be communicated; (2) relates to approved indications and is based on competent and reliable scientific evidence; and (3) includes a "conspicuous and prominent statement describing any material differences" between HCEI and FDA-approved labeling. As compared with previous interpretations of labeling, advertising and misbranding provisions in the Federal Food Drug and Cosmetic Act (FFDCA) which restricted the content and contexts in which HCEI could be disseminated, the Cures Act provides greater flexibility. The Cures Act expands the audience to whom HCEI may be communicated (to include payors and similar entities with expertise in health care economic analysis that select drugs for coverage or reimbursement), expands the types of analysis that may be shared (to include clinical data, inputs, clinical or other assumptions, methods, results, and other components underlying or comprising the analysis, as well as separate or aggregated consequences from the represented health outcomes), and liberalizes the previous requirement that HCEI "directly relate" to approved indications (now HCEI must only "relate" to such indications). The provision does not apply, however, to any analysis that relates only to unapproved indications.

SUSCEPTIBILITY TEST INTERPRETIVE CRITERIA

Holders of existing NDAs and BLAs must remove susceptibility test interpretive criteria, which characterize the susceptibility of bacteria or other microorganisms to the antimicrobial drug tested and categorize a drug's susceptibility (i.e., susceptible, intermediate, resistant), from approved drug labeling and replace the information with a reference to the newly-mandated FDA interpretive criteria website. Similarly, antimicrobial drugs approved after the website is created must reference the website in their labeling in lieu of susceptibility test interpretive criteria. The statute requires FDA to include certain disclaimers about the limits of safety and efficacy of such drugs, the clinical significance of susceptibility information and approved product labeling, on the website. Antimicrobial drug manufacturers and others may benefit from a provision permitting FDA to consider information provided by "interested third parties" when evaluating new or updated susceptibility test interpretive criteria standards.

COMBINATION PRODUCTS

In response to complaints that FDA improperly regulated certain combination products as drugs or biologics based on an overly restrictive application of the "primary mode of action" test, the Cures Act prohibits FDA from determining that a combination product's primary mode of action is that of a drug or biologic solely because the combination product has any chemical action within or on the human body. Chemical action in the body is a statutory concept that distinguishes a drug or biologic from a medical device. The Cures Act requires FDA to determine how a combination product will be regulated based on a new statutory definition of "primary mode of action," which focuses on the single mode of action expected to make the greatest contribution to the overall intended therapeutic effects of the combination product.

What Is Required by These Cures Act Provisions

STAKEHOLDER-RELATED REQUIREMENTS

Manufacturers or distributors of investigational drugs for serious diseases or conditions must make publicly available their expanded access policies on requests for such drugs within 60 days of the law's enactment or the initiation of a phase 2 or phase 3 study of an investigational drug, whichever date is later.

REQUIREMENTS IMPOSED ON FDA

FDA must issue guidance on:

  • The collection and use of patient experience data— data intended to provide information about patients' experiences with a disease or condition—in drug development (draft guidance due 18 months after enactment);
  • The process for qualification of DDTs (draft guidance due three years after enactment);
  • The circumstances under which drug sponsors and FDA may rely on real world evidence (draft guidance due five years after enactment);
  • Pre-submission interactions with sponsors developing combination products and submissions of information with meeting requests (final guidance due four years after enactment); and
  • The criteria, processes and considerations for demonstrating safety and effectiveness of limited population antibacterial and antifungal drugs (draft guidance due 18 months after enactment).

The agency may also issue updated guidance and regulations within one year of developing standards to support the development, evaluation and review of regenerative medicine therapies and RATs.

FDA must issue the following reports assessing:

  • The use of patient experience data in regulatory decision-making (by June 1 of 2021, 2025 and 2031);
  • The qualification process for DDTs (five years after enactment);
  • Approval of RATs, as well as the number of applications for which FDA granted accelerated approval or priority review (by March 1 of each year);
  • Approvals of antibacterial or antifungal drugs under the limited population pathway (every two years); and
  • The implementation of the new statute on the susceptibility test interpretive criteria (two years after enactment).

The Cures Act also requires FDA to take other actions:

  • Issue a draft framework for implementation of a program to evaluate real world evidence;
  • Post information on the review of supplemental applications that rely on qualified data summaries;
  • Develop standards and consensus definitions related to the development, evaluation and review of regenerative medicine therapies and RATs;
  • Provide advice to sponsors of limited population drugs on data needed for approval;
  • Identify, list and update susceptibility test interpretive criteria and susceptibility test interpretive criteria standards on the new FDA interpretive criteria website; and
  • Post guidelines of best practices for drug safety surveillance using the FDA Adverse Event Reporting System and criteria for public posting of adverse event signals.

ACTION STEPS FOR DRUG MANUFACTURERS AND OTHER STAKEHOLDERS

Manufacturers should re-evaluate the extent to which they hold promising data but set aside certain FDA submissions due to an inability to run the randomized controlled trials that would likely have been required. Insofar as one or more of the additional sources of evidence recognized in the Cures Act could support an application, sponsors should consider citing the Cures Act in negotiations with the agency regarding the amount and type of evidence required to support a successful application.

Manufacturers should also evaluate the extent to which new drugs or new indications for old drugs may be candidates for an expedited review pathway or a PRV, and evaluate the extent to which they have the data to support such applications or can generate the required information. Sponsors of genetically targeted drugs and variant protein targeted drugs should consider what previously submitted data may be used in support of subsequent NDAs and BLAs.

With regard to marketing and labeling, manufacturers should re-evaluate whether the relaxed restrictions on HCEI might make it more feasible to proactively address payor and other reimbursement issues that they previously declined to discuss due to regulatory concerns.

Finally, insofar as many of the above provisions require FDA to take steps to implement the changes envisioned by Congress, stakeholders such as manufacturers, clinical trial sponsors, academic institutions, clinicians, industry organizations and standard setting organizations should consider participating in public meetings or other outreach efforts by FDA to develop or revise applicable standards, guidance documents and regulations.

FDA: Clarifying Drug Provisions

The content of this article is intended to provide a general guide to the subject matter. Specialist advice should be sought about your specific circumstances.

To print this article, all you need is to be registered on Mondaq.com.

Click to Login as an existing user or Register so you can print this article.

Authors
 
In association with
Related Video
Up-coming Events Search
Tools
Print
Font Size:
Translation
Channels
Mondaq on Twitter
 
Register for Access and our Free Biweekly Alert for
This service is completely free. Access 250,000 archived articles from 100+ countries and get a personalised email twice a week covering developments (and yes, our lawyers like to think you’ve read our Disclaimer).
 
Email Address
Company Name
Password
Confirm Password
Position
Mondaq Topics -- Select your Interests
 Accounting
 Anti-trust
 Commercial
 Compliance
 Consumer
 Criminal
 Employment
 Energy
 Environment
 Family
 Finance
 Government
 Healthcare
 Immigration
 Insolvency
 Insurance
 International
 IP
 Law Performance
 Law Practice
 Litigation
 Media & IT
 Privacy
 Real Estate
 Strategy
 Tax
 Technology
 Transport
 Wealth Mgt
Regions
Africa
Asia
Asia Pacific
Australasia
Canada
Caribbean
Europe
European Union
Latin America
Middle East
U.K.
United States
Worldwide Updates
Check to state you have read and
agree to our Terms and Conditions

Terms & Conditions and Privacy Statement

Mondaq.com (the Website) is owned and managed by Mondaq Ltd and as a user you are granted a non-exclusive, revocable license to access the Website under its terms and conditions of use. Your use of the Website constitutes your agreement to the following terms and conditions of use. Mondaq Ltd may terminate your use of the Website if you are in breach of these terms and conditions or if Mondaq Ltd decides to terminate your license of use for whatever reason.

Use of www.mondaq.com

You may use the Website but are required to register as a user if you wish to read the full text of the content and articles available (the Content). You may not modify, publish, transmit, transfer or sell, reproduce, create derivative works from, distribute, perform, link, display, or in any way exploit any of the Content, in whole or in part, except as expressly permitted in these terms & conditions or with the prior written consent of Mondaq Ltd. You may not use electronic or other means to extract details or information about Mondaq.com’s content, users or contributors in order to offer them any services or products which compete directly or indirectly with Mondaq Ltd’s services and products.

Disclaimer

Mondaq Ltd and/or its respective suppliers make no representations about the suitability of the information contained in the documents and related graphics published on this server for any purpose. All such documents and related graphics are provided "as is" without warranty of any kind. Mondaq Ltd and/or its respective suppliers hereby disclaim all warranties and conditions with regard to this information, including all implied warranties and conditions of merchantability, fitness for a particular purpose, title and non-infringement. In no event shall Mondaq Ltd and/or its respective suppliers be liable for any special, indirect or consequential damages or any damages whatsoever resulting from loss of use, data or profits, whether in an action of contract, negligence or other tortious action, arising out of or in connection with the use or performance of information available from this server.

The documents and related graphics published on this server could include technical inaccuracies or typographical errors. Changes are periodically added to the information herein. Mondaq Ltd and/or its respective suppliers may make improvements and/or changes in the product(s) and/or the program(s) described herein at any time.

Registration

Mondaq Ltd requires you to register and provide information that personally identifies you, including what sort of information you are interested in, for three primary purposes:

  • To allow you to personalize the Mondaq websites you are visiting.
  • To enable features such as password reminder, newsletter alerts, email a colleague, and linking from Mondaq (and its affiliate sites) to your website.
  • To produce demographic feedback for our information providers who provide information free for your use.

Mondaq (and its affiliate sites) do not sell or provide your details to third parties other than information providers. The reason we provide our information providers with this information is so that they can measure the response their articles are receiving and provide you with information about their products and services.

If you do not want us to provide your name and email address you may opt out by clicking here .

If you do not wish to receive any future announcements of products and services offered by Mondaq by clicking here .

Information Collection and Use

We require site users to register with Mondaq (and its affiliate sites) to view the free information on the site. We also collect information from our users at several different points on the websites: this is so that we can customise the sites according to individual usage, provide 'session-aware' functionality, and ensure that content is acquired and developed appropriately. This gives us an overall picture of our user profiles, which in turn shows to our Editorial Contributors the type of person they are reaching by posting articles on Mondaq (and its affiliate sites) – meaning more free content for registered users.

We are only able to provide the material on the Mondaq (and its affiliate sites) site free to site visitors because we can pass on information about the pages that users are viewing and the personal information users provide to us (e.g. email addresses) to reputable contributing firms such as law firms who author those pages. We do not sell or rent information to anyone else other than the authors of those pages, who may change from time to time. Should you wish us not to disclose your details to any of these parties, please tick the box above or tick the box marked "Opt out of Registration Information Disclosure" on the Your Profile page. We and our author organisations may only contact you via email or other means if you allow us to do so. Users can opt out of contact when they register on the site, or send an email to unsubscribe@mondaq.com with “no disclosure” in the subject heading

Mondaq News Alerts

In order to receive Mondaq News Alerts, users have to complete a separate registration form. This is a personalised service where users choose regions and topics of interest and we send it only to those users who have requested it. Users can stop receiving these Alerts by going to the Mondaq News Alerts page and deselecting all interest areas. In the same way users can amend their personal preferences to add or remove subject areas.

Cookies

A cookie is a small text file written to a user’s hard drive that contains an identifying user number. The cookies do not contain any personal information about users. We use the cookie so users do not have to log in every time they use the service and the cookie will automatically expire if you do not visit the Mondaq website (or its affiliate sites) for 12 months. We also use the cookie to personalise a user's experience of the site (for example to show information specific to a user's region). As the Mondaq sites are fully personalised and cookies are essential to its core technology the site will function unpredictably with browsers that do not support cookies - or where cookies are disabled (in these circumstances we advise you to attempt to locate the information you require elsewhere on the web). However if you are concerned about the presence of a Mondaq cookie on your machine you can also choose to expire the cookie immediately (remove it) by selecting the 'Log Off' menu option as the last thing you do when you use the site.

Some of our business partners may use cookies on our site (for example, advertisers). However, we have no access to or control over these cookies and we are not aware of any at present that do so.

Log Files

We use IP addresses to analyse trends, administer the site, track movement, and gather broad demographic information for aggregate use. IP addresses are not linked to personally identifiable information.

Links

This web site contains links to other sites. Please be aware that Mondaq (or its affiliate sites) are not responsible for the privacy practices of such other sites. We encourage our users to be aware when they leave our site and to read the privacy statements of these third party sites. This privacy statement applies solely to information collected by this Web site.

Surveys & Contests

From time-to-time our site requests information from users via surveys or contests. Participation in these surveys or contests is completely voluntary and the user therefore has a choice whether or not to disclose any information requested. Information requested may include contact information (such as name and delivery address), and demographic information (such as postcode, age level). Contact information will be used to notify the winners and award prizes. Survey information will be used for purposes of monitoring or improving the functionality of the site.

Mail-A-Friend

If a user elects to use our referral service for informing a friend about our site, we ask them for the friend’s name and email address. Mondaq stores this information and may contact the friend to invite them to register with Mondaq, but they will not be contacted more than once. The friend may contact Mondaq to request the removal of this information from our database.

Security

This website takes every reasonable precaution to protect our users’ information. When users submit sensitive information via the website, your information is protected using firewalls and other security technology. If you have any questions about the security at our website, you can send an email to webmaster@mondaq.com.

Correcting/Updating Personal Information

If a user’s personally identifiable information changes (such as postcode), or if a user no longer desires our service, we will endeavour to provide a way to correct, update or remove that user’s personal data provided to us. This can usually be done at the “Your Profile” page or by sending an email to EditorialAdvisor@mondaq.com.

Notification of Changes

If we decide to change our Terms & Conditions or Privacy Policy, we will post those changes on our site so our users are always aware of what information we collect, how we use it, and under what circumstances, if any, we disclose it. If at any point we decide to use personally identifiable information in a manner different from that stated at the time it was collected, we will notify users by way of an email. Users will have a choice as to whether or not we use their information in this different manner. We will use information in accordance with the privacy policy under which the information was collected.

How to contact Mondaq

You can contact us with comments or queries at enquiries@mondaq.com.

If for some reason you believe Mondaq Ltd. has not adhered to these principles, please notify us by e-mail at problems@mondaq.com and we will use commercially reasonable efforts to determine and correct the problem promptly.