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21st Century Cures Act – Provisions Impacting Pharmaceutical Regulation

On July 2, 2015 the House passed the 21st Century Cures Act . The focus is on expediting research and development on debilitating diseases, and smoothing the process to get important therapeutic options to patients who need them quickly. The Senate has not yet approved this Act and it may get revised, but our readers should keep up with the various provisions under discussion because of the impact it would have on 505(b)(2) drug development.

Some of the Acts major provisions include:

Subtitle A – Patient-Focused Drug Development

  • FDA implementation of a structured framework to facilitate the incorporation of patient experiences in the assessment of a drug’s benefits and risks.
  • In the context of the new drug review process, this section would require the FDA to implement a structured framework to facilitate the incorporation of patient experiences in the consideration of a drug’s benefits and risks. FDA would be required to develop and implement a process to allow companies to submit data on patient experiences allowing for a structured risk-benefit assessment framework to be developed. This process would be captured in a draft guidance issued by the FDA within 2 years.

A recent example of the FDA initiative in this area entails a notice of public meeting (80 FR 42503 – 17Jul2015; Docket No. FDA-2012-N-0967) intended to allow FDA to obtain patient perspectives on the impact of Huntington’s disease and Parkinson’s disease on daily life and patient views on treatment approaches. This meeting will be held on September 22, 2015

Subtitle B – Qualification and Use of Drug Development Tools

Section 2021 – Qualification of Drug Development Tools

  • Establishing a structured framework at FDA for the submission, review, and qualification of drug development tools such as biomarkers, for use in specific contexts that, if qualified, can subsequently be employed and relied on by ‘any person’ for such purposes, including 505(b)(2) NDAs.
  • Such tools could accelerate the approval of some new products for populations with unmet medical needs, because waiting for long-term clinical trials with objective endpoints, such as mortality or morbidity, often slows down the regulatory process, thus delaying bringing a potentially useful drug to patients.
  • Interestingly, the FDA recently presented guidance documents focusing on the qualification of relevant biomarkers as well as the process that FDA employs to qualify these tools. Further, another recent guidance Critical Path Innovation Meetings, provides insight into how Sponsors can obtain FDA’s perspective on the development of biomarkers, clinical outcome assessments, natural history study designs and implementation, emerging technologies and innovative conceptual approaches to clinical trial design and analysis.

Section 2022 – Accelerated Approval Development Plan

  • This section amends section 506 of the FDCA to add section 506(g). Section 506(g) allows sponsors of drugs eligible for accelerated approval to request, after the submission of an investigational new drug application (IND), including the use of a surrogate endpoint as a primary basis of a claim that the drug is effective, that FDA agree to an accelerated approval development plan.
  • Entailing amending federal law to facilitate accelerated approvals – based on surrogate endpoints intended to serve as evidence that a drug would be effective in a population. The use of surrogate endpoints to support accelerated approval has existed in the past but has been limited to drugs intended to treat patients with ‘life-threatening illnesses and unmet needs’.
  • As part of this new legislation, the FDA and a sponsor could enter into an “accelerated approval development plan” similar to a special protocol assessment (SPA). This plan would establish the minimum data parameters which, if met, would support the approval of a drug using surrogate endpoints.

Subtitle C – FDA Advancement of Precision Medicine

Section 2041 – General Agency Guidance on Precision Medicine

  • This section would add sections 591 and 592 to the FDCA.
  • Section 591 requires FDA establishment of a guidance defining a “precision drug” – a product that is targeted to treat patients with a specific genotype of a disease as well as evidence needed to support the use of biomarkers. Focus will be on the development of biomarkers that inform prescribing decisions, and when such information may be included in the approved prescription labeling.
  • Section 592 provides that in the case of a precision drug or biological product that is the subject of an application submitted under section 505(b)(1), for the treatment of a serious or life-threatening disease or condition and has been designated under section 526 as a drug for a rare disease or condition, the Secretary may—
    • (1) consistent with applicable standards for approval, rely upon data or information previously submitted by the sponsor of the precision drug or biological product, or another sponsor, provided that the sponsor of the precision drug or biological product has obtained a contractual right of reference to such other sponsor’s data and information, in an application approved under section 505(c) or licensed under section 351(a) of the Public Health Service Act, as applicable—(emphasis added)
  • (A) for a different drug or biological product; or
  • (B) for a different indication for such precision drug or biological product, in order to expedite clinical development for a precision drug or biological product that is using the same or similar approach as that used to support approval of the prior approved application or license, as appropriate; and
  • (2) as appropriate, consider the application for approval of such precision drug or biological product to be eligible for expedited review and approval programs, including accelerated approval.

Here the statute places special emphasis on accelerating approval of precision drugs for serious, life threatening as well as rare diseases, i.e., both conditions apply. The point being that given the right circumstances, the length and cost of bringing the product to market could be significantly reduced.

Subtitle D – Modern Trial Design and Evidence Development

Section 2061 – Broader Application of Bayesian Statistics and Adaptive Design

  • FDA is required to provide assistance to sponsors in incorporating adaptive designs (used by companies to make changes to the design of a trial based on pre-determined interim endpoints) and Bayesian Statistical modeling into proposed clinical protocols.
  • Previously, FDA has expressed concern that adaptive trial designs could lead to error-prone results or results that are difficult to interpret (Draft Guidance: Adaptive Design Clinical Trials for Drugs and Biologics; Feb 2010; Section IV (A) page 11). The statute seeks to mandate further progress in the use of Bayesian statistics and Adaptive Designs

Section 2062 – Utilizing Evidence from Clinical Experience

  • Requires FDA establishment of a program to evaluate the potential use of evidence from clinical experience to help support the approval of a new indication for a previously approved drug under Section 505(b) and to help support or satisfy post-approval study requirements. Sources of such data would come from other than randomized clinical trials, such as observational studies, product registries and therapeutic use. This would likely take some time (see below) but suggests that the requirements for obtaining approval for additional indications (read: off label uses) might be reduced or modified at some point.
  • In parallel, FDA would identify and execute pilot demonstrations to extend existing use of the Sentinel System (a massive database used to monitor the safety of FDA-regulated medical products; launched in 2008) to support these efforts. This system enables FDA to actively query diverse automated healthcare data holders—like electronic health record systems, administrative and insurance claims databases, and registries—to evaluate possible medical product safety issues quickly and securely. A “Mini-Sentinel” safety pilot program was initiated in 2011.
  • To promote this undertaking – “no later dates” would be specified: Program Framework – not later than 18 months after the date of enactment, the Secretary shall establish a draft framework for implementation of the program; Program Implementation – not later than 24 months after the date of enactment; Guidance for Industry – not later than 36 months after the date of enactment.

Section 2063 – Streamlined Data Review Program

  • FDA must establish a program (including releasing a guidance document) through which an existing drug (under Section 505(b)(1)) or biologic (under section 351(a) of the PHSA) could be reviewed for a new qualified indication based on the submission of qualified data summaries. A qualified data summary is a summary of clinical data intended to demonstrate the safety and effectiveness of the qualified indication.
  • The drug would have to be originally approved for one or more indications, and such approval or licensure remains in effect; the new indication would be a “qualified indication” (an indication for the treatment of cancer other types of indications deemed acceptable); have an acceptable existing database; the supplemental application incorporates or supplements the available data submitted in the original application and the full data sets used to develop the qualified data summaries (summary of clinical data intended to demonstrate safety and effectiveness with respect to a qualified indication) are submitted.

Subtitle I – Orphan Product Extensions Now; Incentives for a New Indication for a Rare Disease or Condition

Section 2151 – Extension of Exclusivity Periods for a Drug Approved for a New Indication for a Rare Disease or Condition

  • This section would incentivize the repurposing of major market drugs for rare diseases – advancing safe and effective treatments and cures to patients facing these rare diseases.
  • A one-time, six-month extension of certain exclusivity periods and patent protection for an already-approved drug if the drug’s sponsor obtains approval of a new indication for the drug for a rare disease or condition would be provided. The approval would have to be for an entirely new indication, and not just show the product works in a rare subset of the existing population.

Section 2152 – Reauthorization of Rare Pediatric Disease Priority Review Voucher Incentive Program

  • In a previous blog, we indicated that the rare pediatric disease PRV pilot program was set to expire one year after the third pediatric voucher is awarded, which occurred recently (17 March 2015). This section would reauthorize the rare pediatric disease priority review voucher (PRV) program through December 31, 2018. In addition, it would broaden the definition of a rare pediatric disease to ensure that pediatric oncology drugs and treatments for sickle cell disease are eligible for designation.

Although this initial Bipartisan Victory was based on common ground, it is clear from the flurry of internet activity that this common ground is a little unstable for the non-political arena. Many acknowledge the potential benefit, as the cost and challenges of bringing novel treatments for debilitating diseases to market is daunting. The Act’s regulatory changes would help companies bring beneficial drugs addressing unmet medical conditions to market sooner. Fred Upton (R-MI), the House Energy and Commerce Committee Chairman, stated during remarks in support of the bill – “This bill is about making sure our laws, regulations, and resources keep pace with scientific advances…. It is time for Congress to do something positive to boost research and innovation and deliver some hope for more cures by expediting the approval of drugs and devices…. It’s about hope – hope that the burden for patients and caregivers is less tomorrow than it was yesterday.” However, some, have suggested that the “bill would erode the quality of evidence the FDA uses to evaluate new drugs and devices, making it easier for companies to bring substandard or ineffective medicines and devices to market”. The editor (Rita Redberg) of the journal JAMA Internal Medicine, wrote in a recent comment (Faster Drug Approvals Are Not Always Better and Can Be Worse) – “In our rush to find new effective treatments, we should not harm our patients with ineffective toxic ones.”

Keep in mind that the House passage does not ensure that the Act will inevitably become law as the Senate will have to act. Further, the Senate could pass a different version, in which case the differences would have to resolved and then passed by both houses. However, if it does, its impact will also be felt across the 505(b)(2) regulatory arena.


Stacey Ayres, PhD
Director of Scientific Research Services