Regulatory Explainer: The (Updated) 21st Century Cures Act

Posted 30 April 2015 By Alexander Gaffney, RAC

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The US House Energy and Commerce (E&C) Committee has released an updated draft of a piece of legislation which proposes dramatically overhauling the way in which the US Food and Drug Administration (FDA) regulates many healthcare products.

The bill, the 21st Century Cures Act, has been under development since at least April 2014, when the E&C Committee kicked off its "21st Century Cures Initiative." The initiative is intended to speed up the pace at which FDA approves new medicines for conditions currently lacking cures, as well as a lengthy list of other proposals.

Read the text of the new legislative draft here.

The latest draft is nearly half the length of its predecessor—199 pages compared to the 393 pages of the original. The smaller size reflects efforts by legislators to cut out certain provisions of the legislation.

What follows is a section-by-section analysis of the 21st Century Cures Act's life science provisions—matters affecting the regulation of pharmaceuticals, medical devices, biotechnology products and more. It does not cover in any depth parts of the bill affecting reimbursement or funding for medical research, though they may be mentioned in brief.

Title I: Discovery

One immediate change to the newest version of the draft legislation relative to the original draft is the ordering of the legislation. The bill now jumps immediately into matters dealing with the discovery of medical products.

Importantly, the bill (Title I, Subtitle A) proposes to increase funding for the National Institutes of health, starting with $31.8 billion in 2016, and increasing to $33.3 billion and $34.8 billion in 2017 and 2018, respectively. NIH is presently funded to the tune of $30.3 billion.

In addition, the bill establishes what is to be called the "NIH Innovation Fund," which would be funded with $2,000,000 each year from 2016 through 2020. The innovation money would be used to advance several as-yet undefined programs, including ones supporting precision medicine and "young emerging scientists."

Much of the remainder of Title I is focused on NIH, its operations and programs to increase its efficacy with respect to biomedical innovation. For example:

  • Subtitle B addresses the need for strategic planning at NIH in the hopes of "preventing or eliminating the burden of a disease or condition. The section would also substantially reduce paperwork burdens on the NIH, making it easier for the institutes' staff to travel to scientific meetings and conferences.
  • Subtitle C is intended to increase supports for young or emerging scientists by reserving some of NIH's funding exclusively for those scientists. Scientists would also be eligible for student loan forgiveness if they agree to work in a research capacity for NIH.
  • Subtitle D establishes "capstone awards" to support "outstanding scientists" and their work.
  • Subtitle E promotes pediatric research by calling for the establishment of a "global pediatric clinical trial network." FDA is also encouraged in this section to work with its European counterpart, the European Medicines Agency (EMA), to encourage the participation of other regulators.
  • Subtitle F calls for data "generated through NIH-funded research"—i.e. clinical trials results—to be standardized and made available to researchers.
  • Subtitle G calls for the establishment and release of de-identified clinical trial data from "qualified clinical trials," including trials on drugs and medical devices. The section would also establish a National Neurological Diseases Surveillance System and several public-private partnerships to develop data on the natural history of diseases.
  • Subtitle H would establish a "Council for 21st Century Cures"—a nonprofit public-private corporation tasked with accelerating "the discovery, development, and delivery in the United States of innovative cures, treatments, and preventive measures for patients" by fostering collaboration. FDA and NIH would both hold a seat on the board of this corporation, as would representatives from patient groups and the life sciences industry.

Some of the changes contained within Title I might substantially affect medical research. For example, Subtitle G contains a section (13433) which directs NIH to change the way it oversees protected health information (PHI).

The bill states: "The Secretary shall revise or clarify the Rule so that research activities, including comparative research activities, related to the quality, safety, or effectiveness of a product or activity that is regulated by the Food and Drug Administration are included as public health activities for purposes of which a covered entity may disclose protected health information."

Such information could also be accessed remotely, the bill adds.

And, importantly, patients could authorize all "future research purposes" involving their health information using a single authorization form as long as the form "sufficiently describes the purposes" of the future research. An authorization could be revoked by the patient at a later date.

Title II: Patient-Focused Drug Development

Title II of the legislation seeks to build on FDA's recent launch of a Patient-Focused Drug Development (PFDD) program. That program, launched in 2012 under the Food and Drug Administration Safety and Innovation Act (FDASIA), is meant to incorporate patient preferences into FDA's regulatory decision-making. The idea behind the proposal is that different patients—even those suffering from the same disease—have varying levels of risk they are willing to accept.

For more on the Patient-Focused Drug Development Program, please see our tracker here.

As legislators explained in a white paper accompanying the last draft of the bill, "No one understands a particular condition or disease better than patients living with it." Accordingly, the bill would require FDA to establish a structured framework for the meaningful incorporation of patient experience data into the regulatory decision-making process, including the assessment of desired benefits and tolerable risks associated with new treatments.

That measure is likely to win support at FDA, which has sought to develop similar approaches in the past and has been receptive to patient feedback. Under the approach, FDA would have to, within two years, develop and implement a process to allow companies to submit "patient experience data," which could be used to develop a "structured risk-benefit assessment framework." A draft guidance document would also be due from FDA within two years.

Biomarkers

Subtitle B of Title II is slightly modified from the original draft of the legislation. It remains focused on the "qualification and use of drug development tools"—an area which has attracted significant attention from legislators in recent months. The hope is that FDA can rely on biomarkers and other surrogate endpoints to accelerate the approval of some new products for high-need populations.

"The development of biomarkers and other drug development tools can benefit the availability of new medical therapies by helping translate scientific discoveries into clinical applications," the bill explains.

The bill calls on FDA to promote the development and qualification of biomarkers by issuing new guidance documents regarding the standards for qualifying biomarkers, and to establish a process by which biomarkers can be qualified.

Curiously, FDA already maintains a program which would appear to do exactly as Congress has asked for in its bill. The agency's Drug Development Tools Qualification Program, for example, is intended to accelerate drug development by focusing on qualifying relevant biomarkers. A 2014 guidance document, Qualification Process for Drug Development Tools, describes the process by which FDA qualifies these tools. In addition, a new guidance document released to the public in March 2015 clarifies FDA's Critical Path Innovation Meetings process, at which FDA dispenses advice on the development of biomarkers, clinical outcome assessments, natural history designs and new technologies.

Accelerated Approval

Section 2022 of the draft legislation would amend federal law to facilitate accelerated approvals—approvals based on surrogate (e.g. intermediate) endpoints intended to serve as evidence that a drug would be effective in a population. FDA has long relied on surrogate endpoints to support accelerated approvals, but only for drugs intended to treat patients with life-threatening illnesses and unmet needs.

The legislation would require FDA and a sponsor to enter into an "accelerated approval development plan" (AADP) similar in concept to a special protocol assessment (SPA). The AADP would establish the minimum data parameters which, if met, would support the approval of a drug using surrogate endpoints.

Precision Medicine

The new draft bill contains an entire section on precision medicine that was not contained in the original draft. Title II, Subtitle C directs FDA to establish guidance regarding the definition of a "precision drug"—a product which is targeted to treat patients with a specific genotype of a disease. The guidance would also need to contain information "to assist sponsors in the development of such a drug, including clinical studies."

The bill also calls on FDA to release information in its guidance on how companies can identify subsets of a disease for the purposes of advancing drug development. Such subsets are often useful to drug companies, which can market a drug to that subset and obtain valuable orphan drug exclusivity (seven years) for the product during which time no generic equivalent may be brought to market.

Clinical Trials

A subsequent section, "Modern Trial Design and Evidence Development," appears to be based on legislation introduced earlier this year by Rep. Chris Collins (R-NY): The Clinical Trials Modernization Act.

The 21st Century Cures Act's legislative language proposes broader use of "innovative statistical methods in clinical protocols," including broader use of adaptive clinical trials designs and Bayesian statistical methods. FDA is again directed to release guidance.

Another section calls on FDA to develop guidance based on the clinical experience of various products outside clinical trials. Sources of data might include observational trials, product registries and therapeutic use, the bill states. Such data might be useful to support the approval of new drugs, and to support post-approval surveillance and other monitoring requirements. FDA is also directed to make better use of the data it obtains from its Sentinel system—a massive database meant to identify adverse events associated with medical products. The bill says FDA should "implement pilot demonstrations to make strategic linkages between such data captured through the Sentinel System" and other sources of public health data. (Sec. 5051)

Streamlined Data Review

Section 2063, "Streamlined Data Review Program," would establish a program through which an existing drug or biologic could be reviewed for a "new qualified indication" based on the submission of "qualified data summaries."

Drugs would be eligible for a "qualified indication" if they are already approved for use in another indication and the new indication is to treat a type of cancer. While the legislative language does not say that an indication would be entirely based on qualified data summaries, it does say such data may "support" a new qualified indication. Full data sets would still be required, the bill notes.

It's also unclear how an indication would be "qualified,"

FDA is—again—asked to release a guidance document on which data would be suitable to support a "streamlined" review. The agency is also given a blank check with which to promulgate new regulations "as may be necessary for implementation of the program."

Expediting Patient Access

As expected, the bill also contains major provisions intended to make it easier for patients to get experimental drugs on a "compassionate use" basis.

Read our background explainer on the compassionate use/expanded access process here.

As Focus has previously explained, patients are increasingly turning to social media in an attempt to pressure companies into granting so-called "expanded access"—essentially access to a drug outside of an already-approved clinical trial—to potentially life-saving drugs. In response, dozens of states have introduced new "Right-to-Try" legislation seeking to make it easier for patients to access those drugs by establishing legal liability shields for physicians.

The Cures Act seeks to partially reform the current compassionate use/expanded access system by establishing conditions for any drug hoping to obtain expedited approval.

The legislation, we should note, appears to borrow heavily from the Andrea Sloan Compassionate use Reform and Enhancement (CURE) Act, which was introduced in December 2014.

Read our explanation of the Andrea Sloan CURE Act here.

The section of the Cures Act would amend FDA's compassionate use policies to require any company whose drug is granted "breakthrough," "fast track" or "Qualified Infectious Disease Product" (QIDP) designation to make publicly available a corporate expanded access policy for compassionate use of the drug.

That policy would include, among other things, a point of contact at the company who can process requests, the procedures for making an expanded access request, the criteria for enrolling in an expanded access trial and the amount of time the company expects to take to process a request.

The policy would need to be released to the public within 60 days of a sponsor receiving a designation from FDA.

However, the draft has deleted language contained in the original legislation which would had required companies to notify patients or their representative if their request for compassionate access has been denied within 5 days of the denial, along with an explanation for why the request was denied.

FDA is also directed to finalize a draft Q&A guidance on expanded access that was released in May 2013.

Healthcare Economic Information

A brand new addition to the Cures Act draft is a section dealing with healthcare economic information. FDA was supposed to release a policy regarding how such information could be used under the 1997 Food and Drug Administration Modernization Act (FDAMA). Section 114 of FDAMA permits companies to market the economic advantages of using their products using "competent and reliable scientific evidence."

To date, FDA has not defined what it considers to be "competent" or "reliable" scientific evidence, making it difficult for companies to know whether their promotions will fall afoul of FDA advertising regulators.

For more on this issue, please read our articles here and here.

While the Cures Act does not explicitly call upon FDA to release guidance on that subject, it modifies the language to allow companies to, in addition to relying on "competent and reliable scientific evidence," include "a conspicuous and prominent statement describing any differences between the information and the indication approved [by FDA]."

Such information could only be used to market a product to a payor, formulary committee or other "similar" economic entity. The clarification could make it easier for companies to promote a product without incurring FDA’s regulatory wrath.

Antibiotics Development

Antibiotic development also features prominently in the Cures Act draft. Title II, Subtitle G—"Antibiotics Drug Development"—is closely modeled off a previous version of the Cures Act and another piece of legislation, the Promise for Antibiotics and Therapeutics for Health (PATH) Act.

As Regulatory Focus has reported, the bill calls for the creation of a "limited population pathway" for antibacterial and antifungal drugs. The pathway would allow a sponsor of a new drug to seek approval for the product intended to treat "a serious or life-threatening disease, condition or indication" that is currently not adequately served by existing therapies. The pathway could only be used if the sponsor could identify a specific population in which the medical product would be used.

Read our explanation of the PATH Act in our December 2014 article here.

Each drug product approved under this pathway would need to be labeled with the following statement: "This drug is indicated for use in a limited and specific population of patients."

The pathway also provides for the clearance of antimicrobial susceptibility testing devices, which would be used to determine if a particular microorganism is susceptible to a particular drug.

FDA is also required to set up a website to provide recommendations on which bacteria/fungi are susceptible to specific drugs.

Faster Reviews for Vaccines

Title II, Subtitle H provides for the "timely review of vaccines." As with the previous draft of the Cures Act legislation, it requires the Advisory Committee on Immunization Practices (ACIP) to review "breakthrough" (as designated by FDA) vaccine products on an "expedited basis." However, the term "timely" is not defined in the legislation.

Continuous Manufacturing

If you've listened to FDA's director of the Center for Drug Evaluation and Research (CDER), Janet Woodcock, during the last few years, you've probably heard her talk about the importance of advancing continuous manufacturing as a key component of drug quality.

Read more on continuous manufacturing and its potential benefits here.

The House E&C Committee has apparently been listening as well, as the legislation contains a provision intended to allow FDA to "award grants … for the purpose of studying and recommending improvements to the process of continuous manufacturing of drugs and biological products and similar innovative monitoring and control techniques."

Re-Importation

Another section of the legislation (Section 2126) would amend the Controlled Substances Act to make it easier to re-export a substance to another country within the European Economic Area (EEA).

Breakthrough Devices and Priority Review

Medical devices would be eligible to receive "breakthrough" designation by FDA under the new Cures Act draft. Title II, Subtitle K of the law seeks to give FDA's medical device reviewer, the Center for Devices and Radiological Health (CDRH), a toolset similar to one now used by the Center for Drug Evaluation and Research (CDER).

The Cures Act legislation seeks to build on CDRH's existing (but relatively new) priority review process for medical devices and its Expedited Access Premarket Approval (EAP) program by establishing a "program to provide priority review for devices."

The new program, closely modeled off the breakthrough therapies program for drugs, would provide priority review for devices granted the designation.

As with breakthrough drugs, breakthrough devices are those which represent "breakthrough technologies," are intended to treat conditions "for which no approved alternative exist," offer "significant advantages over existing approved or cleared alternative," and are "otherwise in the best interest of patients."

The designation would need to be specifically requested by a sponsor, and FDA would be tasked with giving the device sponsor access to "a team of staff" to "provide interactive communication with the sponsor of the device" meant to speed up its review.

Perhaps unlike the breakthrough designation for drugs, FDA is instructed to look into ways it can review a breakthrough device even more quickly. The legislation directs regulators to "take steps to ensure that the design of clinical trials is as efficient as practicable, such as through adoption of shorter or smaller clinical trials, application of surrogate endpoints and use of adaptive trial designs and Bayesian statistics." In addition, FDA is asked to help sponsors "facilitate … expedited and efficient development and review of the device through utilization of postmarket data collection."

Interestingly, the legislation notes that a device cleared through the breakthrough designation program for devices cannot be used as the basis of a 510(k) application until it has completed its required postmarketing studies.

Medical Device Regulatory Process Improvements

Title II, Subtitle L addresses a long-running gripe of the medical device industry: Getting a medical device approved can be unnecessarily slow. To help address some of these gripes, Subtitle L contains several "process improvements" meant to make the regulatory approvals process for medical devices more flexible.

For example, Section 2022 would fundamentally alter the types of evidence FDA is permitted to accept. All "valid scientific evidence," including case histories, registry data, peer-reviewed scientific data and data collected outside the US could be used to support regulatory approvals.

FDA staff would also be trained on the "least burdensome appropriate means concept," which is intended to apply the right amount of regulation—no more, no less—to a medical device during the approvals process. (Section 2203)

Another section calls on FDA to allow for the expedited recognition of outside standards, which are commonly used by Class I and II medical devices.  The legislation requires FDA to recognize standards within 60 days of the standard being published. FDA would also be responsible for determining if it does not wish to recognize a standard. The approach is meant to make it easier for device manufacturers to look to established standards to help them develop products, but the relatively short time period—just 60 days—could prove too short to allow FDA sufficient time to review applicable standards.

Another potential improvement: Section 2206 of the Cures Act would allow companies to make recommendations on the types of expertise FDA should include on an advisory committee panel. At present, highly specialized devices may be reviewed by experts without specific expertise with a particular type of device. While such differences aren't always of consequence, some companies have expressed a concern that certain advisory committees are ill-equipped to handle specific devices. The law would not, however, allow companies to recommend specific experts.

Humanitarian Device Exemption

Section 2207 of the legislation also makes a major change to humanitarian device exemptions—devices intended to treat rare diseases. At present, federal law defines a disease as "rare" for the purposes of a medical device if it affects fewer than 4,000 persons in the US. Devices intended to treat these minor populations are eligible to be approved based solely on their safety in humans—not evidence of their efficacy.

For an in-depth explanation of the HDE process, check out our explainer article here.

The Cures Act, however, would raise the bar on that threshold—from 4,000 patients to 8,000 patients in the US. That could be a major benefit for developers of humanitarian use devices, though it's unclear how many conditions fall under the 4,000-8,000 population gap.

‘Sensible Oversight’

The Cures Act continues to delve into medical technologies in Subtitle M of Title II, "Sensible Oversight for Technology Which Advances Regulatory Efficiency."

Several pieces of legislation have sought to change the way in which FDA regulates healthcare software since 2013, including the SOFTWARE Act, the MEDTECH Act and the PROTECT Act.

The Cures Act simplifies the regulation of health software into two categories: Software which FDA may regulate and software which FDA may not regulate. The bill defines the term "health software," and notes that FDA will not be permitted to regulate health software except in cases where the software "poses a significant risk to patient safety."

Such a dynamic would probably keep in place much of FDA's current regulatory framework, while also giving FDA the flexibility to go after devices which egregiously target consumers with false or misleading information.

Read how FDA regulates mobile apps here.

Read FDA's stance on regulating general wellness devices here.

Clinical Trials Changes

The law also contains several sections related to the conduct of clinical trials in the US. For example, Section 2241 would exempt some clinical trials (specifically those for vulnerable populations) from the Common Rule so long as they are subject to FDA trial protections.

Section 2242 would permit the use of non-local institutional review boards to review medical device trials, including investigational device exemptions (IDEs) and humanitarian device exemptions (HDEs)—misspelled as "human device exemptions" in the bill.

Another section, Section 2243, would permit some medical device trials posing "no more than minimal risk" to bypass the informed consent process as long as other safeguards are in place "to protect the rights, safety and welfare of the human subject." Some drug products might also fall under this section, the bill notes.

FDA Outreach

Other parts of the bill are intended to make it easier for FDA to hire highly qualified staff. For example, the bill abolishes a hard cap on the number of staff FDA is authorized to hire under its "senior service" core. Instead, FDA would be permitted to add staff to this "senior service" as long as those hired are qualified. Staff could be paid hundreds of thousands of dollars each year but could not, by law, exceed the pay of the president of the United States.

The hope, the bill notes, is that FDA will find it easier to hire and retain "qualified experts" who might otherwise seek much higher paychecks within the pharmaceutical or medical device industries.

Congress also notes in Section 2262 that all staff—highly paid or not—should be able to participate in scientific conferences and meetings.

Reagan-Udall

Outside the world of regulatory wonks, few within the health policy world have likely heard of the Reagan-Udall Foundation (RUF), a private foundation established by Congress in 2007 with the intent of helping to improve the regulatory capacity and regulatory science at FDA.

More on the history of the Reagan-Udall Foundation in Regulatory Focus, or at RUF's website.

Reforms to RUF's charter would allow FDA advisory committee members to serve on RUF's board of directors, for additional board members to join the organization, and cap the compensation of RUF's chairperson at no higher than the salary of the commissioner of FDA.

Patient Input

For most regulatory surveys, FDA must first seek approval from the Office of Management and Budget (OMB) under the Paperwork Reduction Act. That could soon change.

Under the new legislation, FDA wouldn't have to submit documents to OMB for approval if the information request is voluntary. This is intended to make it easier for FDA to collect information from patients, industry, academia and "other stakeholders," E&C explained in a press statement.

Missing in Action

What's not included in the new draft is almost as interesting as what is in the draft.

Many of the previous Cures Act iteration's most controversial sections have been excluded, including many on marketing exclusivity. Of the 10 proposals identified by Regulatory Focus as being "worth paying attention to," seven have been excluded from the new version of the draft.

For a read through of our analysis of the last draft of the legislation, please see the text below.

 

ANALYSIS OF THE OLDER VERSION OF THE LEGISLATION FOLLOWS.

 

On 27 January 2015, the US House of Representatives' Energy and Commerce Committee's Subcommittee on Health released a new bipartisan draft bill that is set to dramatically alter the ways pharmaceutical and medical device products are regulated in the US.

This Regulatory Explainer breaks down the bill's many regulatory provisions into plain English in the hopes that you, the reader, will be better able to understand them.

Last updated on 28 January 2015 at 7:45 PM EST

Background

The bill is the product of a bipartisan process known as the 21st Century Cures Initiative. Since its launch in April 2014, the initiative has held more than a dozen roundtables, eight congressional hearings and released five whitepapers—all focused on ways in which Congress might transform the way new treatments are approved and marketed in the US.

Overview

The massive, 393-page bill, known as the 21st Century Cures Act, is split up into five separate sections:

  • Title I—Putting Patients First By Incorporating Their Perspectives Into The Regulatory Process And Addressing Unmet Needs
  • Title II—Building The Foundation For 21st Century Medicine, Including Helping Young Scientists
  • Title III—Modernizing Clinical Trials
  • Title IV—Accelerating The Discovery, Development, And Delivery Cycle And Continuing 21st Century Innovation At NIH, FDA, CDC, And CMS
  • Title V—Modernizing Medical Product Regulation

Title I – A Focus on Patients

Title I of the legislation seeks to build on FDA's recent launch of a Patient-Focused Drug Development (PFDD) program. That program, launched in 2012 under the Food and Drug Administration Safety and Innovation Act (FDASIA), is meant to incorporate patient preferences into FDA's regulatory decision-making. The idea behind the proposal is that different patients—even those suffering from the same disease—have varying levels of risk they are willing to accept.

For more on the Patient-Focused Drug Development Program, please see our tracker here.

As legislators explained in an accompanying white paper on the new bill, "No one understands a particular condition or disease better than patients living with it." Accordingly, the bill would require FDA to establish a structured framework for the meaningful incorporation of patient experience data into the regulatory decision-making process, including the assessment of desired benefits and tolerable risks associated with new treatments.

That measure is likely to win support at FDA, which has sought to develop similar approaches in the past and has been receptive to patient feedback. Under the approach, FDA would have to, within two years, develop and implement a process to allow companies to submit "patient experience data," which could be used to develop a "structured risk-benefit assessment framework." A draft guidance document would also be due from FDA within two years.

Surrogate Endpoints

Title I, Subtitle B is heavily focused on the use of so-called " surrogate endpoint qualification and utilization." Those markers are used by some companies to accelerate the drug development process by allowing them to show evidence of efficacy earlier on in the process. For example, the sponsor of a cancer drug might seek FDA approval based on surrogate endpoints if the drug is shown to shrink the size of a tumor. A company could argue that shrinkage is likely to correlate with increased life expectancy.

However, as the case of the breast cancer drug Avastin illustrates, not all surrogate endpoints end up being ultimately useful.

What the 21st Century Cures Act envisions is a process by which FDA can "qualify" some of the surrogate endpoints (or biomarkers) as being useful. The agency also has similar qualification programs in place for drugs and medical devices. As with its existing program, the qualification of a surrogate would only allow its use for a specific purpose and under specific conditions. The hope, however, is that the qualification of one endpoint will spur its use by multiple companies by eliminating regulatory uncertainty.

The agency would be tasked with issuing guidance within 18 months of the passage of the bill. The agency is also encouraged, though not required, to enter into public-private partnerships to accomplish this goal.

For more on how FDA has already taken steps in this particular area, please see our article on breast cancer surrogate endpoints here.

Breakthrough Therapies

Title I, Subtitle C—"Approval of Breakthrough Therapies”—gets into familiar territory for anyone already familiar with the FDA Safety and Innovation Act of 2012. The law famously established FDA's "breakthrough therapies" designation, which allows FDA to identify potentially promising treatments early in the review process and give them additional assistance meant to expedite their approval.

For more on the breakthrough therapies designation program, please see our article here.

However, the Cures Act contains a major change to this section: FDA would be permitted to, based on "early stage clinical safety and effectiveness data that provide sufficient evidence for approval of the drug as safe and effective," approve the drug.

As part of that early approval, FDA would also be permitted to subject the drug "to a requirement that the sponsor will assess the safety and effectiveness of the drug through a postmarket assessment plan." However, as FDA explained in 2012, not all sponsors have done a good job at completing these obligations, which were established for most drugs under the 2007 FDA Amendment Act.

FDA would also be permitted to withdraw drugs from the market if they do not complete these postmarketing requirements (PMRs), but such removals have in the past proven politically difficult ( see: Avastin).

FDA would need to re-issue its guidance document on breakthrough therapies within a year, the bill states.

New Antibiotics

Title I, Subtitle D—"Antibiotic Drug Development"—appears to be closely modeled off another recently introduced piece of legislation, the Promise for Antibiotics and Therapeutics for Health (PATH) Act.

As Regulatory Focus reported last month, the bill calls for the creation of a "limited population pathway" for antibacterial and antifungal drugs. The pathway would allow a sponsor of a new drug to seek approval for the product intended to treat "a serious or life-threatening disease, condition or indication" that is currently not adequately served by existing therapies. The pathway could only be used if the sponsor could identify a specific population in which the medical product would be used.

Read our explanation of the PATH Act in our December 2014 article here.

Each drug product approved under this pathway would need to be labeled with the following statement: ”This drug is indicated for use in a limited and specific population of patients.”

FDA is also required to set up a website to provide recommendations on which bacteria/fungi are susceptible to specific drugs. (Section 1062 of the Cures Act).

Take This Antibiotic Exclusivity and Transfer It

A subsequent section (Section 1063) is also geared toward providing a new incentive for antibiotic products approved under a special designation.

Under FDASIA, legislators established a new designation for antibacterial drugs known as the Qualified Infectious Disease Product (QIDP). Products approved by FDA with QIDP status are eligible for an additional five years of marketing exclusivity in addition to whatever other exclusivity they obtain from FDA as a new drug (5 years for brand new drugs, 3 years for repurposed drugs, 12 years for new biologics, and 7 years for so-called "orphan" drug products).

Read more about the QIDP and the Generating Antibiotics Incentives Now (GAIN) Act here.

The Cures Act largely leaves this section intact, but with one major change: Companies can transfer as many as 12 months of marketing exclusivity from their five-year QIDP status to "one or more other drugs."

That could be a powerful incentive for companies to develop new antibiotic products, especially since the bill allows them to sell these exclusivity rights to other companies ("Nothing in this Act shall be construed as prohibiting the sale of any conveyed exclusivity period.")

A similar market now exists for companies to sell and re-sell priority review vouchers, which have sold for as much as $125 million. The voucher allows a company to obtain market access up to four months faster than usual.

If a similar market develops for QIDP exclusivity transfers, some drug companies might pay hundreds of millions—even billions—to keep exclusivity for their blockbuster drugs. The bill, however, seems to limit transfers of exclusivity to just 12 months per drug—but doesn't clarify if that applies to transfers from a drug or to another drug. The distinction could be important.

However, the legislation also notes that companies cannot purchase the added exclusivity if they have fewer than four years of marketing exclusivity (or parent protection) remaining on their product. That might limit the effects of the transfers, especially for companies wishing to eke out an added year of exclusivity on an expiring patent. However, for companies which have just received approval for a new drug, the ability to purchase an additional year of protections might prove valuable.

The proposal is also highly unusual in that it comes with a requirement: A company purchasing added exclusivity from another company is required to donate up to 5% of gross sales to the National Institutes of Health (NIH) to help advance antibiotic resistance research, as well as an addition 5% to patient assistance programs meant to help patients afford their drugs.

The sales calculation is made on the final year of exclusivity—not the entire term of the patent or exclusivity.

Breakthrough Devices

Subtitle E of Title I—"Priority Review for Breakthrough Devices"—seeks to give FDA's medical device reviewer, the Center for Devices and Radiological Health (CDRH), a toolset similar to one now used by the Center for Drug Evaluation and Research (CDER).

The Cures Act legislation seeks to build on CDRH's existing (but relatively new) priority review process for medical devices and its Expedited Access premarket Approval (EAP) program by establishing a "program to provide priority review for devices."

The new program, closely modeled off the breakthrough therapies program for drugs, would provide priority review for devices granted the designation.

As with breakthrough drugs, breakthrough devices are those which represent "breakthrough technologies," are intended to treat conditions "for which no approved alternative exist," offer "significant advantages over existing approved or cleared alternative," are "otherwise in the best interest of patients"  and/or have the potential to "reduce or eliminate the need for hospitalization, improve patient quality of life."

The designation would need to be specifically requested by a sponsor, and FDA would be tasked with giving the device sponsor access to "a team of staff" to "provide interactive communication with the sponsor of the device" meant to speed up its review.

Perhaps unlike the breakthrough designation for drugs, FDA is instructed to look into ways it can review a breakthrough device even more quickly. The legislation directs regulators to "take steps to ensure that the design of clinical trials is as efficient as practicable, such as through adoption of shorter or smaller clinical trials, application of surrogate endpoints and use of adaptive trial designs and Bayesian statistics." In addition, FDA is asked to help sponsor "facilitate … expedited and efficient development and review of the device through utilization of postmarket data collection."

Interestingly, the legislation notes that a device cleared through the breakthrough designation program for devices cannot be used as the basis of a 510(k) application until it has completed its required postmarketing studies.

A conceptually similar section also exists for accelerating the approval of breakthrough devices (Subtitle F/Section 1101) based on surrogate endpoints.

Reforming Parts of Expanded Access/Compassionate Use

As expected, the bill also contains major provisions intended to make it easier for patients to get experimental drugs on a " compassionate use" basis.

Read our background explainer on the compassionate use/expanded access process here.

As Focus has previously explained, patients are increasingly turning to social media in an attempt to pressure companies into granting so-called "expanded access"—essentially access to a drug outside of an already-approved clinical trial—to potentially life-saving drugs. In response, dozens of states have introduced new "Right-to-Try" legislation seeking to make it easier for patients to access those drugs by establishing legal liability shields for physicians.

The Cures Act seeks to partially reform the current compassionate use/expanded access system by establishing conditions for any drug hoping to obtain expedited approval.

The legislation, we should note, appears to borrow heavily from the Andrea Sloan Compassionate use Reform and Enhancement (CURE) Act, which was introduced in December 2014.

Read our explanation of the Andrea Sloan CURE Act here.

The section of the Cures Act would amend FDA's compassionate use policies to require any company whose drug is granted "breakthrough," "fast track" or "Qualified Infectious Disease Product" (QIDP) designation to make publicly available a corporate expanded access policy for compassionate use of the drug.

That policy would include, among other things, a point of contact at the company who can process requests, the procedures for making an expanded access request, the criteria for enrolling in an expanded access trial and the amount of time the company expects to take to process a request.

The policy would need to be released to the public within 30 days of a sponsor receiving a designation from FDA.

Companies would also be required to notify patients or their representative if their request for compassionate access has been denied within 5 days of the denial, along with an explanation for why the request was denied. The legislation does not define what constitutes a denial, however, and it remains unclear how this provision would be enforced in practice. A company might, for example, keep open a request for a lengthy amount of time instead of formally denying the request.

The legislation could prove to be difficult to implement for some small companies developing novel drugs. The establishment of a point-of-contact and fulfilling patient requests for access to a drug can be a financial strain on some companies, which sometimes only have a few dozen employees and limited funding with which to seek FDA approval.

FDA is also directed to finalize a draft Q&A guidance on expanded access that was released in May 2013.

Freeing up Drug Advertising in the Name of Free Speech

Subtitle H of the bill, "Facilitating Responsible Communication of Scientific and Medical Developments," may well wind up being one of the most-talked-about sections of the bill owing to its subject matter: advertising and social media.

The two subjects have been nothing if not touchy subjects at FDA in recent years owing to its issuance of several "social media" guidance documents covering how companies can use Twitter and Facebook to promote their drugs, notify FDA of their Internet advertisements, distribute medical information and more. FDA has even shown a keen interest in studying drug advertising, as Regulatory Focus has previously reported in depth.

Congress now apparently has a message for FDA: Your efforts in this area have fallen short. The regulator is instructed to propose "revisions" to its existing Internet/social media policies within one year.

FDA is also instructed to permit companies to "disseminate, in character-limited applications, truthful, introductory information about medical products, including the name of such products and their approved uses." That information, the legislation adds, can be available a click away through hyperlinks.

In other words, get ready for FDA to issue a social media guidance that explicitly allows companies to use social media in a way that consumers already do—and get ready to hear a lot more about the return of a "one-click" rule for tweets and other social media posts.

New Drug Indications in Less Time

Subtitle J—"Streamlined Data Review"—would, in theory, make it easier for FDA to approve for a new indication a drug which has previously been approved for a different indication.

The so-called "streamlined data review program" FDA would be required to establish would allow a drug or biologic's supplemental new drug application (sNDA) to be supported by existing data, such as data from a safety database.

The section seems geared toward just those drugs intended to treat cancer or other serious conditions FDA deems applicable.

Accelerating Cures

Subtitle K—"Cures Acceleration Network"—includes an oft-cited idea: Enhance an existing network whose focus is to accelerate the development of new cures for diseases.

The so-called "Cures Acceleration Network" was first established in 2012 by the National Center for Advancing Translational Sciences (NCATS).  ( More on NCATS here).

Read more about the Cures Acceleration Network (CAN) here.

As envisioned by NCATS, the center is meant to be a catalyst for turning outside investment into future cures—a sort of DARPA for drug discovery. The Cures Act would give new funding—as yet undetermined—to help fund CAN through 2020 in the hopes of helping it to repurpose and develop drugs for "high need" populations. The goal, the legislation explains, is to find new uses for existing drugs.

15 Years of Marketing Exclusivity?

Title I also contains provisions from a widely supported—but potentially controversial—piece of legislation known as the Modernizing Our Drug & Diagnostics Evaluation and Regulatory Network Cures (MODDERN Cures) Act of 2013. The legislation, introduced in 2014, would notably allow companies as much as 15 years of marketing exclusivity if their product is intended to treat a disease for which there is "one or more unmet need." That provision, as it turns out, applies to most new drugs approved by FDA.

For more on the MODDERN Cures Act and a similar piece of legislation, the Dormant Therapies Act, please see our prior coverage here.

The 15 years is substantially longer than the 12 years of marketing exclusivity now given to biologics—an unpopular policy President Barack Obama has sought to overturn on several occasions to little success.

As Regulatory Focus explained earlier this month, the provision could be one section that attracts significant (negative) attention from Obama. However, the bill now counts more than 100 co-sponsors in Congress.

These provisions have already resulted in criticism from the Generic Pharmaceutical Association (GPhA), which in a statement said the 15 years of exclusivity "threatens to turn back the clock more than 30 years."

More Exclusivity for Some NDAs, ANDAs

Subtitle M of Title I also contains other provisions related to extending exclusivity. The "New Therapeutic Entities" section (1241) would allow new drugs currently eligible for three years of marketing exclusivity to be eligible for up to five years of exclusivity.

Under current statute, only new drugs never before approved in any form are eligible for five years of exclusivity. Drugs which have been approved previously (such as for a different purpose or condition) are eligible for just three years of exclusivity in most cases.

Subtitle M of the Cures Act would change this by allowing a company to receive added exclusivity if their drug is shown to be able to:

  • promote greater patient adherence to an approved treatment regime relative to the previously approved formulation or design of the drug;
  • reduce the public-health risks associated with the drug relative to the previously approved formulation or design of the drug;
  • reduce the manner or extent of side effects or adverse events associated with the previously approved formulation or design of the drug;
  • provide systemic benefits to the health care system relative to the previously approved formulation or design of the drug; or
  • provide other patient benefits that are comparable to the benefits described [above]

While the language seems geared toward allowing manufacturers of abuse-resistant drugs to obtain added exclusivity, the language would also allow most follow-on drugs—provided they rely on new clinical investigations "essential to the approval of the application or supplement"—to obtain an added two years of exclusivity.

Interestingly, generic drugs submitted via the Abbreviated New Drug Application (ANDA) pathway would also be eligible for exclusivity, the bill explains.

Orphan Drugs

The next Subtitle in the Bill, Subtitle N—"Orphan Product Extensions Now"—is modeled off the Orphan products Extensions now Accelerating Cures and Treatments Act (OPEN Act) of 2014.

As explained by Regulatory Focus in November 2014, the bill is based on FDA's existing pediatric exclusivity provisions under the 1997 FDA Modernization Act which grants marketing exclusivity extensions for drugs shown to help children. That extension applies to the original drug—not just the pediatric indication.

Read our explanation of the OPEN ACT here.

The OPEN ACT provisions of the Cures Act operate on a similar concept, with some key differences.

Like the pediatric exclusivity provision, FDA would be permitted to extend a drug's exclusivity period by six months if a product—initially not approved as an orphan drug product—is later approved as such. Orphan drugs are those approved to treat rare conditions, defined as affecting fewer than 200,000 people in the US.

Unlike the pediatric provisions, 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.

Title II – Let's Talk About Science

Worried the bill would only talk about the regulation of drugs and devices? Title II is your time to take a breather. The section calls for the creation of an "Innovative Cures Consortium"—a nonprofit corporation whose intent will be to "accelerate the discovery, development and delivery … of innovative cures, treatments and preventative measures for patients."

Just as the Cures Acceleration Network is intended to catalyze discovery and development inside government, so too will the Innovative Cures Consortium (ICC) seek to catalyze that development outside government by providing grants, contracts and other assistance. However, the consortium will only be able to give grants to small businesses and nonprofits, potentially limiting its ability to collaborate with larger organizations (with the exception of academia).

A subsequent section (Subtitle B) calls for the creation of a "Medical Product Innovation Advisory Commission" to "analyze medical product innovation in the US and recommend policies to accelerate the discovery, development and delivery of new medical products."

That would make the commission one of the only—if not the only—entities in the US government solely focused on drug innovation. Among the committee's statutory duties: the review of FDA's policies "relating to the discovery, development and delivery of new medical products."

Regenerative Medicine and Rare Diseases

Subtitle C called on FDA to issue a "guidance on surrogate and intermediate endpoints for accelerated approval of regenerative medicine products."

As with Title I, Subtitle B, the section is geared toward FDA helping sponsors to accelerate approval for their products. The guidance is expected to be issued by FDA within one year of the law's passage.

The next subtitle, "Genetically Targeted Platform Technologies for Rare Diseases," amends the Federal Food, Drug and Cosmetic Act (FD&C Act) to include a new accelerated approval pathway for products whose surrogate endpoints are based on genomic information.

The accelerated approval statute would be modified to allow FDA to take into account:

(ii) evidence derived from extrapolation from adequate and well-controlled trials that have formed the basis for investigation on other products—

‘(I) that utilize the same or a very similar underlying genetically-targeted therapeutic platform technology as the product involved;

(II) for which disease genomics are known; and

(III) that possess the same or very similar drug-like characteristics as the product involved, including with respect to safety, distribution, and metabolism; or

(iii) other scientific methods or tools.

Regulating Software as a Medical Device

The bill also includes a new effort to overhaul how FDA regulates software, including mobile applications, as medical devices.

Several pieces of legislation have sought to change this dynamic since 2013, including the SOFTWARE Act, the MEDTECH Act and the PROTECT Act.

The Cures Act contains a heavily modified version of the SOFTWARE Act, which simplifies the term "medical software" into two categories: products which FDA can regulate, and those it explicitly cannot regulate.

The bill defines the term "medical software," but the draft also wonders aloud how the committee can ensure products which clearly are medical devices don't use the definition to avoid proper oversight by FDA. The other category defined by the bill is the term "health software," which is generally taken to mean products not intended to treat a specific condition or disease, but intended to assist caregivers more generally, including by managing healthcare data.

FDA would be permitted to regulate certain types of medical software, but not health software. FDA would be tasked with determining which types of regulatory software it would regulate within two years.

Read how FDA regulates mobile apps here.

Read FDA's stance on regulating general wellness devices here.

Finding Clinical Trials

Subtitle F of Title II calls for the creation of a "21st Century Data Sharing Network" to facilitate the "standardization of data" meant to make it easier for patients to find new or ongoing clinical trials.

NIH would be tasked with ensuring clinical trial results contained within a data bank are "easily used by the public" and entries are "easily compared" to one another.

NIH would also be tasked with de-identifying clinical trial data (i.e. making it impossible to determine which patients participated) to help further research.

Sharing Clinical Data

The Cures Act would also create within the Department of Health and Human Services a new commission known as the "Commission on Data Sharing for Research and Development," which would be tasked with collecting data from federal programs like Medicare, Medicaid, the Children's Health Insurance Program (CHIP) and federal exchanges established under the Patient Protection and Affordable Care Act (PPACA/"Obamacare").

The electronic data included in a to-be-established registry would be used to develop clinical practice guidelines, best practices and standards of care, the legislation states.

Combination Products

After making a brief detour into coverage determination decisions—not the expertise of Regulatory Focus, we regret to say—the Cures Act re-refocuses on the topic of healthcare product regulation, and specifically the regulation of combination products.

The subject has been the subject of much confusion at FDA over the last several years, and in 2013 the agency issued a final rule regarding how combination products—products composed of two or more components, like a drug-coated stent or a pre-filled syringe—should be manufactured correctly.

Read more about FDA's combination products rule here, or its guidance on the rule here.

The legislation seeks to clarify this area even further by directing FDA to "ensure that the agency center with primary jurisdiction for the premarket review of a combination product shall be the sole point of contact for the sponsor of the product."

The concern of legislators—and some regulatory professionals—has been that combination product reviews involving multiple centers (CDER, CBER and/or CDRH) get overly complicated when a sponsor is hearing back different things from different review groups at FDA. For example, CDER might be reviewing the drug component of a drug-device combo, while CDRH reviews the device portion of the product.

The legislation directs FDA to "coordinate communications to and from any consulting agency center involved in such premarket review." FDA would also be required to issue guidance on combination product communications within one year.

Coming Soon to a Bill Near You: Diagnostics and Interoperability

The bill—already long at 393 pages—is also slated to include even more content (Title II, Subtitles J and K) not yet contained within the bill. Those topics: the regulation of diagnostic devices and the interoperability of healthcare data.

Though the latter has little to do with FDA, the former has almost everything to do with the agency.

Earlier this year FDA announced it would soon begin to regulate lab-developed tests (LDTs) more similarly to in vitro diagnostics. LDTs have for years been regulate under the Clinical Laboratory Improvements Act (CLIA) and overseen mostly by the Centers for Medicare and Medicaid Services (CMS).

Under FDA's new plan, high-risk LDTs would be subject to a market review process.

For more about FDA's plan to regulate LDTs, please see our explanation here.

Some legislators and industry groups have strongly criticized the plan, with one going as far as to threaten litigation against FDA if it implements its decision to regulate LDTs.

For now, a plan to regulate the devices isn't in the bill, but the placeholder makes clear that the diagnostic industry should be on the lookout for new provisions related to LDTs specifically, and perhaps even diagnostic tests more broadly.

Opening up NIH Research

The Cures Act contains one provision that might be welcomed in scientific circles with open arms. Title II, Subtitle L—"NIH-Federal Data Sharing"—requires any entity receiving an award or grant from NIH to release its findings to the public and "share with the public data generated through such research."

NIH will be able to identify specific cases in which the policy shouldn't be applicable, the bill explains.

More on Data Transparency

The legislation also contains language calling for increased sharing of health data, including protected health information (PHI).

"Section 2221 would unlock the research potential of data siloed in health care facilities across the country and enable patients who want to play a more proactive role in finding better treatments or a cure for their disease to do so in a responsible manner that continues to protect their privacy," the committee explained in an accompanying statement.

Confronting Chronic Diseases

Title II, Subtitle N—"21st Century Chronic Disease Initiative Act"—proposes a "longitudinal study on outcomes of patients with a chronic disease" in the hopes of improving outcomes for those patients.

The goal, legislators said, is to "identify potential targets for preventative or therapeutic intervention."

Another section, contained in Subtitle Q, is also set aside for future language on precision medicine.

Title III – A Focus on Clinical Trials

Title III marks a pivot in the legislation toward reimagining clinical trials in the US.

Subtitle A, "Clinical Research Modernization," is focused on the protection of human subjects, and contains language indicating that HHS should "make available assistance to any Federal department or agency seeking to improve the regulation or oversight of human subject research," and in particular vulnerable populations.

HHS' Human Subject Regulations are slated to be modified under Subtitle A to "reduce regulatory duplication and unnecessary delays," to make it easier for multi-center clinical trials to take place, and for "community values" to be incorporated into research.

Importantly for device and pharmaceutical manufacturers, the section seeks to eliminate a requirement that companies use local iRBs, thereby making it easier to use a centralized IRB to oversee clinical research.

Adaptive Clinical Trial Designs

The Cures Act also seeks to increase the use of adaptive clinical trials, which are used by companies to make changes to the design of a trial based on data from pre-determined interim endpoints. While FDA has noted that adaptive trial designs could save companies time and money, it’s also expressed concern that adaptive trials could lead to error-prone results or results which are difficult to interpret.

Subtitle B of Title II calls for FDA to "establish and implement a framework through which sponsors of drugs, biological products, or devices may submit to the Secretary a proposal for the incorporation of adaptive trial designs, Bayesian methods, or other alternative statistical methods into proposed clinical protocols and marketing applications for drugs, biological products, or devices."

As part of that framework, FDA would be required to finalize its draft guidance on adaptive clinical trials from 2010.

Clinical Trial Checkups

Subtitle C of Title III goes on to require that FDA "establish a process sunder which [FDA] … shall periodically evaluate a postapproval study or clinical trial." The intent of that oversight is to determine whether a postapproval study is still "scientifically warranted" or if the design or the timeline of the trial should be renegotiated "because of changes in medical practice or the standard of care."

As we wrote earlier in this piece: Not all sponsors have done a good job at completing these postmarketing study obligations, which were established for most drugs under the 2007 FDA Amendment Act. The trials are meant to answer outstanding questions about a drug or device product, such as whether it causes rare but serious side effects that might not have manifested in smaller trials. They are required for some types of approval, such as drugs approved through FDA's accelerated approval process.

Global Pediatric Clinical Trials

The Cures Act (Section 3061) also calls for the creation of a "global pediatric clinical trial network" to be supported by FDA and other global regulatory entities, including the European Medicines Agency (EMA).

"Once a global pediatric clinical trial network is established and becomes operational, the Food and Drug Administration should continue to engage the European Medicines Agency and other foreign regulatory entities to encourage and facilitate their participation in the network with the goal of enhancing the global reach of the network," the bill states.

Title IV – Research and Vaccines

The fourth title of the Cures Act is, in comparison to the rest of the bill, fairly straightforward. At its outset it calls for additional funding for NIH research and for administrative burdens on NIH to be decreased, both of which are meant to bolster medical progress.

But it touches upon regulatory matters as well. For example, it calls for vaccines to be reviewed promptly by the CDC's Advisory Committee on Immunization Practices (ACIP) under new "standard timelines" (within 180 days).

It also establishes an "expedited review" process for reviewing vaccine products. That review process is separate from FDA's regulatory review of vaccines, which only decides whether a product is safe and effective. The ACIP, by contrast, decides when and how a vaccine should be used, and in what circumstances.

However, for products deemed by FDA to be a "breakthrough therapy" or approved for use during a public health emergency, ACIP is supposed to approve the use of the products on an "expedited basis."

And—you guessed it—legislators want HHS to issue guidance on the subject to help manufacturers navigate the expedited vaccine licensure process.

Priority Review Voucher Changes

If you thought you were done hearing about priority review vouchers for a while, you'd be wrong.

The Cures Act includes new language meant to make even more changes to the program just one month after the Adding Ebola to the FDA Priority Review Voucher Program Actwas passed into law.

For more on FDA's priority review voucher (PRV) programs and the changes made to the PRV program in the bill, please see our explanation here.

As Regulatory Focus has previously explained, FDA's tropical disease PRV program allows sponsors of drugs intended to treat a designated list of tropical diseases to receive a special, transferrable voucher that allows its holder to obtain a priority review for one of its drugs. It can also be sold.

The legislation which created the PRV program also allows FDA to add diseases to the list of diseases eligible to receive PRVs, but it's a fairly arduous process and requires FDA to issue a new regulation subject to the notice and comment provisions of federal law.

Additions to the list, however, have only been made by statute thus far. The Cures Act wants to change this by establishing a process by which FDA "designates infectious diseases" to be eligible for PRV status based on the severity of the disease and its potential to spread.

FDA would be required to update its list of tropical diseases at least once every five years, or sooner if warranted.

Changes to Biologics

Section 4046 of the bill calls for FDA to issue final guidance on making changes to approved biological products under FDA's biologics licensing application (BLA) process.

Making changes to biological products can be extremely difficult since even minor adjustments—such as to the manufacturing process used to make the product—can dramatically affect the safety, efficacy and quality of a biological product. Similar issues are now at the heart of FDA's review of so-called "biosimilar" products, which are intended to be highly similar versions of biologics manufactured by other companies.

Read about FDA's biosimilars process here, and about potential biosimilarity problems here.

The bill calls on FDA's guidance to "address changes in a licensed biological product or the labeling, production process, quality controls, equipment, facilities, or responsible personnel for such a product established in the application for the product."

On Vaccines

A short follow-on section (4047) calls for FDA to expedite the process for exporting vaccines to 10 business days—significantly shorter than the 20 calendar days for other drug products under Section 801(e)(4) of the FD&C Act.

Another section (4048) calls for NIH to "conduct or support translational science, research and research training to advance the development of vaccines for the prevention of diseases, including the advancement or vaccine development programs into clinical trials."

For now, that effort will mostly be spent planning how NIH could support these ideals—not implementing them.

Reagan-Udall Adjustments

Outside the world of regulatory wonks, few within the health policy world have likely heard of the Reagan-Udall Foundation (RUF), a private foundation established by Congress in 2007 with the intent of helping to improve the regulatory capacity and regulatory science at FDA.

More on the history of the Reagan-Udall Foundation in Regulatory Focus, or at RUF's website.

Reforms to RUF's charter would allow FDA advisory committee members to serve on RUF's board of directors, for additional board members to join the organization, and cap the compensation of RUF's chairperson at no higher than the salary of the commissioner of FDA.

Coming Soon: Reforms to FDA Hiring, Travel and Training

Section 4101 is set to include reforms to the way in which FDA hires and trains staff and allows its staff to travel—all hot-button issues for an agency that has found it hard to send staff to meetings in recent years and hire (and train) qualified staff for decades.

For example, a 2012 scandal involving the Government Services Administration (GSA) resulted in all federal agencies needing to justify travel expenses, and many agencies were forced to dramatically curtail the number of staff they could send to conferences around the world where the agency is often able to hear feedback directly from the companies it regulates. (Editor's note: RAPS, which operates Regulatory Focus, runs some of these meetings and conferences).

For some agencies, that means sending fewer employees to lavish events in Las Vegas, but for FDA that meant not being able to send its employees to attend industry conferences in person.

For more on how the GSA scandal affected FDA, read more in Focus.

What remains to be seen is whether Congress will make exemptions for FDA to better train and pay its staff, as well as travel more frequently.

Planning for New Leadership at FDA

In late 2013, a profile of CDER Director Janet Woodcock by Reuterssparked rumors that the leader of FDA's drug regulation division might soon retire. While Woodcock denied those rumors—she's still there—the article touched off a bit of soul-searching among regulatory professionals.

Read more about rumors of Janet Woodcock's retirement here.

Many of FDA's most established leaders have been working at the agency for decades, accumulating extraordinary sums of regulatory knowledge not easily replaced once they retire or leave the agency.

How, then, will FDA continue to function as an effective regulator once its most experienced staff head for the exits?

Section 4121 of the Cures Act tried to answer that question by establishing new "succession planning" procedures targeted at all of FDA's staff, and not just its figureheads.

FDA is directed to help develop staff by enhancing "the professional development of technical and scientific staff" at FDA, including ensuring that staff are able to "attend technical and scientific conferences, meetings, and working groups that provide training and education on emerging technology and science relevant to the development and regulation of products under the jurisdiction of the Administration."

FDA is also instructed to make sure it is as "efficient as practicable" for staff to request to attend meetings.

Such measures should help ensure that staff are well-trained and knowledgeable, but Section 4122 builds on this by asking FDA to work on "management succession planning."

FDA should, the bill states, "develop and implement a formal succession plan for management positions within the Food and Drug Administration at or higher than the level of a director of a center, and include in such plan staffing contingency planning, internal and external recruitment strategies, training and professional development for management candidates, and considerations regarding any need for special or direct hiring or compensation flexibility."

For example, while FDA has among the highest-paid staff in the federal government on its payroll, its pay pales in comparison to similar positions within industry. The ability to pay some employees more might allow the agency to recruit talent more easily.

Prescription Drug Plan Safety

The Cures Act has a substantial amount of text dealing with Medicare reimbursement and other topics—unfortunately not the expertise of this editor.

However, among the more interesting proposals raised by the bill is the creation of a so-called "Safe Pharmacy Access Program" (Section 4281) which would work with Medicare Prescription Drug Plans (PDPs) to identify individuals who have "obtained coverage for a covered Part D drug that is a frequently abused schedule II, III, IV or V controlled substance [Under the Controlled Substances Act]."

Those individuals would then be notified and informed that they may only obtain their Part D prescription for a controlled substance at a specific pharmacy or pharmacies. The intent is to ensure that patients aren't shopping around their prescriptions to obtain larger quantities of painkillers, and to "monitor the usage of schedule II, III, IV and V substances."

Section 4284 also required controlled substances to be prescribed using "e-prescriptions," which again would presumably decrease the number of fraudulent prescriptions for painkillers allowed to be dispensed.

Accelerating Medical Innovation

After a lengthy foray into Medicaid policy, the bill returns to the topic of medical innovation in Subtitle O, Section 4301—kind of.

The section would allow some devices to be sold to consumers prior to approval so long as a physician dispenses the device after obtaining informed consent. However, it's not clear in the bill how the Medicare provisions work within the confines of FDA's jurisdictions over the premarket review of devices—a device is misbranded under the FD&C Act if it is marketed without first obtaining FDA approval or clearance.

As a "condition of listing" on the Accelerating Innovation of Medicine (AIM) list, manufacturers would need to provide regulators with "published or publicly available data on clinical studies completed for the device" following its first three years on the AIM list.

The device would also have to be under consideration by FDA at the time it is first listed.

Sunshine Act Revisions

Buried deep within the bill is also a provision that would exempt reporting under the Sunshine Act provisions of Obamacare for continuing medical education (CME). The Sunshine Act, you may recall, more broadly requires drug manufacturers to report to the government how much they spend to promote their products to doctors.

CME groups have for years lobbied for an exemption to their status as a reportable entity under the act, saying that industry-sponsored CME shouldn't be seen as a "gift."

The Cures Act would change this by exempting peer-reviewed journals, journal reprints, journal supplements and medical textbooks from reporting requirements. Other items "intended solely for purposes of providing continuing medical education to the physician" would also be exempted.

Research Use Only Devices

Also contained toward the end of the bill is a version of the Medical Testing Availability Act, which was introduced in January 2015 by Rep. Michael Burgess.

The bill, as reported by Regulatory Focus, would make it easier for companies to distribute their products as "research-use only" products. That distinction allows products to be used by laboratories and other research facilities as long as the manufacturer does not promote their use for unapproved or uncleared purposes.

RUO products most often resemble in vitro diagnostics.

Read more about the Medical Testing Availability Act on Regulatory Focus.

Title V – Modernizing Medical Product Regulation

The fifth—and last—title of the Cures Act gets into a topic of interest to regulatory professionals: Product regulation, and how it can be modernized.

Oddly, the last section of the bill starts off by addressing the same topic as the first section—marketing exclusivity. This time, American sponsors of generic drugs and biosimilars approved under a 505(j) or 351(k) application would be designated as an "American-Manufactured" drug and granted an extension in their exclusivity periods.

To date, the legislation isn't sure about all the details, including the length of the extension, or even how to define a drug as "American made." The section was authored by Health Subcommittee Vice Chair Brett Guthrie (R-KY), according to a statement released by the E&C Committee, which touted the section as providing "incentives for manufacturing generics drugs here in the US."

That language might well be the result of major drug manufacturing problems experienced by some foreign drug makers, including those from India.

Read more about generic drug manufacturing problems from Indian companies here.

What is clear is that the intent of the language is to extend the only types of marketing exclusivity enjoyed by generic and biosimilar drug manufacturers: first-to-file exclusivity. As an incentive for generic drug companies to submit challenges to patented medicines, federal law permits FDA to grant a short period of exclusivity to the first generic manufacturer to file an application with the agency. For generic drugs, FDA is allowed to grant 180 days of marketing exclusivity.

For biologics, FDA is able to grant at least one year of exclusivity, or even longer if certain conditions are met. (42 USC 262 (k)(6)).

American drugmakers, then, might stand to benefit from Title V changes, though it's not yet clear how substantial the benefit might be.

Updating Good Manufacturing Practices (GMPs)

Among regulators, the term GMP is almost universally understood. The term refers to FDA's standards for the proper manufacture of products to ensure they are as safe and effective as they are meant to be.

Section 5021 of the law asks FDA to issue new "guidance on current good manufacturing practice requirements." Many of FDA's current GMP rules are quite old. For example, its GMP guidance on investigational new drugs was last updated in 1998. Another guidance on out-of-specification results was last updated in 2006.

That's no to say they're necessarily out of date, but with FDA placing such an increased emphasis on the quality of drug products, perhaps now wouldn't be the worst time to revisit some of those guidance documents anyway.

Read more about how FDA is changing the way it approaches drug quality here.

Medical Device Reforms

The section also includes measures meant to reform how medical devices are regulated by implementing a new "third-party quality system assessment" process. While FDA already allows some (i.e. mostly low-risk) medical device companies to be reviewed by third parties under a program known as " third party review," the Cures Act would expand this concept to cover facility inspections as well.

The intent, as evidenced by notes in the draft legislative text, is to allow accredited third parties to inspect and "Assess and certify a facility's capability to evaluate and implement" changes to their approved devices.

Not yet clear, however, is what limits will be placed on the program. The legislative notes explain there needs to be more clarity about which types of changes—technology, manufacturing, labeling and device modifications—might be able to be overseen by third parties, and which would need to be overseen by FDA.

Such changes might free up FDA resources to target higher-risk products, but at the expense of more involved oversight.

Similar systems are already used extensively in the EU, which has a "notified body" system.

The Definition of Valid Scientific Evidence

The bill also seeks to define what "valid scientific evidence" can be used by FDA to evaluate a medical device. Currently, under 21 U.S.C. 360c(a)(3)(B) FDA defines the term as evidence:

(i) which is sufficient to determine the effectiveness of a device, and

(ii) from which it can fairly and responsibly be concluded by qualified experts that the device will have the effect it purports or is represented to have under the conditions of use prescribed, recommended, or suggested in the labeling of the device

The legislation would change this to also include:

(I)Valid scientific evidence for purposes of clause (i) means evidence described in well-documented case histories, including registry data, that are collected and monitored under an acceptable protocol, and studies published in peer-reviewed journals that are internationally recognized as authoritative sources of information.

(II) The data from studies published in a journal described in subclause (I) shall be presumed valid based on the peer-review process that supports publication of the studies, and the Secretary may not require submission of the data for the Secretary’s review.

(III) Valid scientific evidence may include data collected in countries other than the United States so long as such data otherwise meets the criteria specified in subclause (I).

In theory, that would make it easier for companies to prove to FDA that their products are safe and effective. However, even if evidence can be seen as "Valid" in theory, that's no guarantee FDA will actually find the data conclusive.

Least-Burdensome Approach

If you've followed medical device regulation for any length of time in the US, you're probably familiar with the term "least burdensome approach." The term, which has made its way into dozens of FDA's documents over the years, reflects the regulator's desire to ensure its regulations are fit-for-purpose and don't ask too much of companies.

For examples of least-burdensome language, please see our articles on IVD regulation, home-use medical devices , and the expedited access premarket approval (EAP) program.

For example, while FDA could require the manufacturer of a Band-Aid to undergo a premarket approval process, it has instead decided that it's safe enough to be manufactured without any review (so long as it meets established standards).

The 21st Century Cures Act wants to take this approach even further. Section 5063 of the law calls for FDA to train its medical device regulators in the least burdensome approach if they are involved with premarket approval applications (PMAs) or 510(k) applications (also known as premarket notification).

Training is set to include "consideration of when advisory panels are appropriate and necessary to review premarket submissions under Section 515 [PMA] or 510(k)," the legislation explains. Re-training will occur on an annual basis, as well.

CDRH, FDA's device regulatory body, is also asked to publish updated guidance documents reflecting adherence to the approach.

Recognizing Outside Standards

Not all standards used by FDA are necessarily developed by the agency. Some, including hundreds used in the regulation of medical devices, are developed by outside organizations which are then recognized and incorporated by FDA.

For more about how FDA uses outside standards, please see our article here.

The Cures Act would make a change to the way in which FDA recognizes these standards. Section 5064 requires FDA to recognize those standards much more quickly—within 60 days of the standard being published. FDA would also be responsible for determining if it does not wish to recognize a standard. The approach is meant to make it easier for device manufacturers to look to established standards to help them develop products, but the relatively short time period—just 60 days—could prove too short to allow FDA sufficient time to review applicable standards.

The bill also calls for FDA employees to receive training on the use of standards upon joining the organization, and thereafter on an annual basis.

Class I Devices: 5-Day Notice

Section 5065 of the Cures Act is short, but it makes a change applicable to Class I—that is, low-risk—devices exempt from FDA's reporting requirements.

The language calls for Section 510 of the FD&C Act to be amended to allow sponsors of Class I devices to satisfy premarket notification requirements by submitting a notification to FDA that:

"the methods used in, or the facilities and controls used for, the manufacture, processing, packing, or installation of such device conforms with the requirements of section 520(f) and that is received by the Secretary not less than 5 business days before the class I device is introduced, or delivered for introduction, into interstate commerce.’’

Predicate Devices

Most medical devices are "approved"—technically "cleared"—in the US through the 510(k) pathway. That pathway requires a device to show that it is substantially similar to an already-approved predicate device.

Section 5066 of the Cures Act seeks to enact one change to that system, which has existed since 1976: FDA wouldn't be able "to refuse to an accept an indication for use (IFU) statement for a device to the extent the predicate for such device has the same indication statement," and FDA would not be allowed to "require … information or data related to an indication other than the proposed indication in the report."

Those are small changes, but could have a large impact for manufacturers looking to reference devices cleared long ago, or just hoping for a more predictable application process. However, it does hamstring FDA's ability to potentially keep unsafe or ineffective devices off the market as easily.

Humanitarian Device Exemptions

Little-known outside of the world of device regulation, the humanitarian device exemption (HDE) pathway is a way for FDA to approve devices for which there is only a small patient population—fewer than 4,000 patients per year.

For an in-depth explanation of the HDE process, check out our explainer article here.

The key thing to know about the program: While it requires manufacturers to show that a device is safe, it doesn't require it to be shown to be effective.

The program would be changed by the Cures Act to broaden its potential use. Specifically, the bill would add a section allowing the HDE pathway to be used to benefit patients in groups of patients larger than 4,000 so long as an applicant can demonstrate that:

  • the public health requires a greater availability of the device to treat or diagnose such patients; and
  • no satisfactory alternative is available for such treatment or diagnosis.

FDA would also be tasked with issuing guidance defining what it understands the term "probable benefit" to mean—terminology that is central to approvals under the HDE process. Only devices thought to provide a "probable benefit" to patients are ultimately cleared, though in the absence of rigorous efficacy data, that can be difficult to determine.

Changes to the Classification Process

Section 5068 also includes some changes to FDA's device classification panels, which are now expected to meet more quickly—60 days for most topics deemed "ready … for panel review." FDA would also need to "make available to the panel and the person whose device is subject to review by the panel … any material on the matters to be considered during [the] meeting."

Fourteen days prior to the meeting, those materials would be made public. The panels would also need to be staffed with "adequate expertise," which is further defined in the Act.

Supply Chain Security for Medical Devices

In 2013, Congress passed into law an extensive set of supply chain reforms meant to make the pharmaceutical supply chain more secure. The Drug Quality and Security Actcame in the wake of several reports of counterfeit cancer drugs entering the US supply chain and posing at legitimate products.

Read more on FDA's track and trace provisions here.

Now the 21st Century Cures Act is set to enact similar provisions, but this time aimed at medical devices.

The "Supply Chain Security for Devices" subtitle (Title V, Subtitle E)—also known as the "Device Distribution Licensing Act (DDLA) of 2015—is remarkably similar in substance to the Drug Supply Chain Security Act (DSCSA) provisions of the DQSA.

For example, the bill is aimed not just at "prescription" device manufacturers, but also wholesalers, importers, repackagers, reprocessors, retail pharmacies and third-party logistics providers.

While the provisions of the DDLA aren't yet finished, the overall intent of the act is to require device manufacturers to only trade with authorized trading partners licensed to do business under the DDLA. The bill also calls for the regulation of how those trading partners receive, store and handle medical devices, presumably to ensure their security.

In addition, FDA will be required to be notified about "any known contraband, counterfeit or misbranded nonconforming device" in the possession of a trading partner.

Trading partners will be overseen by either state or federal licensing authorities, the bill states. However, while oversight might be mixed, the standards will—as with the DSCSA—be national. Section 5087 of the act calls for a "uniform national policy" preempting any state laws from regulating device entities in the US supply chain differently.

One major difference between the DDLA and the DSCSA is that the former does not require each entity within the supply chain to transmit transactional data to each subsequent entity. The DSCSA does, primarily to ensure that falsified devices can't—or will have a much harder time—enter the supply chain. In addition, it becomes much easier to track down where a lapse in supply chain security exists under the DSCSA system.

One reason for this omission might simply be that device counterfeiting doesn't seem to be a large-scale issue. Another reason: Devices are already moving toward traceability requirements under FDA's 2013 final regulation on a Unique Device Identification System (UDI).

For more on FDA's UDI rule, please read our article here.

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Categories: Biologics and biotechnology, Drugs, Medical Devices, News, US, CBER, CDER, CDRH

Tags: Regulatory Explainer, 21st Century Cures Act, 21st Century Cures Initiative, Cures Act, House, Legislation, Congress

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