Senate Medical Innovation Bills: Overview and Comparison with the 21st Century Cures Act (H.R. 6)

Senate Medical Innovation Bills

Senate Medical Innovation Bills:

Overview and Comparison with the 21st

Century Cures Act (H.R. 6)

C. Stephen Redhead, Coordinator

Specialist in Health Policy

Amanda K. Sarata, Coordinator

Specialist in Health Policy

Judith A. Johnson

Specialist in Biomedical Policy

Agata Dabrowska

Analyst in Health Policy

Frank Gottron

Specialist in Science and Technology Policy

Sarah A. Lister

Specialist in Public Health and Epidemiology

Elayne J. Heisler

Specialist in Health Services

May 17, 2016

Congressional Research Service

7-....

www.crs.gov

R44502

Senate Medical Innovation Bills

Summary

Both the House and the Senate are considering legislation to support medical innovation,

primarily through reforms to the National Institutes of Health (NIH) and changes to the drug,

biologic, and device approval pathways at the Food and Drug Administration (FDA). On

February 3, 2015 Senators Lamar Alexander and Patty Murray, chairman and ranking Member of

the Committee on Health, Education, Labor and Pensions, announced the start of a bipartisan

initiative to “examine the process for getting safe treatments, devices and cures to patients and the

roles of the [FDA] and the [NIH] in that process.” This initiative culminated in a package of 19

bipartisan bills that were reported out of the Senate Health, Labor, Education, and Pensions

(HELP) Committee in a series of three executive sessions held on February 9, 2016; March 9,

2016; and April 6, 2016.

The Senate’s medical innovation package is that chamber’s companion effort to the House’s 21st

Century Cures initiative, which culminated in the House passage of H.R. 6, the 21st Century

Cures Act, on July 10, 2015, on a vote of 344 to 77. H.R. 6 is the result of a series of hearings and

roundtable meetings hosted by the House Energy and Commerce Committee dating back to

spring 2014. While consisting of many different provisions, H.R. 6 is primarily focused on efforts

to increase strategic investments in medical research at NIH and change some aspects of how the

FDA executes its regulatory oversight mission with regard to the review and approval of new

drugs, biologics, and medical devices.

This report provides for each of the bills in the Senate medical innovation package (1)

background on the issue, or issues, addressed by the bill, including a summary of relevant current

law; (2) a summary of the bill’s provisions; and (3) where applicable, identification of

comparable provisions in H.R. 6 that address the same topic. For a summary of all the provisions

in H.R. 6, as passed by the House, including an explanation of how the bill would change current

law, see CRS Report R44071, H.R. 6: The 21st Century Cures Act.

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Contents

Introduction ..................................................................................................................................... 1

Report Roadmap........................................................................................................................ 2

The FDA Device Accountability Act of 2015 (S. 1622) .................................................................. 2

Use of Nonlocal Institutional Review Boards for Review of Investigational Device

Exemptions and [Humanitarian] Device Exemptions (§2) .................................................... 2

Issue Background ................................................................................................................ 2

Senate Legislation ............................................................................................................... 3

Comparable Provisions in the 21st Century Cures Act (H.R. 6) .......................................... 3

CLIA Waiver Study Design Guidance for In Vitro Diagnostics (§3) ........................................ 3

Issue Background ................................................................................................................ 3

Senate Legislation ............................................................................................................... 4

Comparable Provisions in the 21st Century Cures Act ........................................................ 4

Ensuring Least Burdensome Means of Evaluating Devices (§4) .............................................. 4

Issue Background ................................................................................................................ 4

Senate Legislation ............................................................................................................... 6

Comparable Provisions in the 21st Century Cures Act (H.R. 6) .......................................... 6

Preventing Superbugs and Protecting Patients Act (S. 2503) .......................................................... 7

Issue Background ................................................................................................................ 7

Senate Legislation ............................................................................................................... 8

Comparable Provisions in the 21st Century Cures Act ........................................................ 8

The Advancing Breakthrough Medical Devices for Patients Act of 2016 (S. 1077) ....................... 8

Issue Background ................................................................................................................ 8

Senate Legislation ............................................................................................................. 10

Comparable Provisions in the 21st Century Cures Act (H.R. 6) .........................................11

Advancing Hope Act of 2016 (S. 1878) .........................................................................................11

Issue Background ...............................................................................................................11

Senate Legislation ..............................................................................................................11

Comparable Provisions in the 21st Century Cures Act ...................................................... 12

Advancing Targeted Therapies for Rare Diseases Act of 2016 (S. 2030) ..................................... 13

Issue Background .............................................................................................................. 13

Senate Legislation ............................................................................................................. 13

Comparable Provisions in the 21st Century Cures Act ...................................................... 14

Patient-Focused Impact Assessment Act of 2016 (S. 1597) .......................................................... 14

Issue Background .............................................................................................................. 14

Senate Legislation ............................................................................................................. 14

Comparable Provisions in the 21st Century Cures Act ...................................................... 15

Promise for Antibiotics and Therapeutics for Health Act (S. 185) ................................................ 15

Issue Background .................................................................................................................... 15

Antibacterial Resistance Monitoring (§2) ............................................................................... 16

Senate Legislation ............................................................................................................. 16

Comparable Provisions in the 21st Century Cures Act ...................................................... 16

Limited Population Pathway for Antibacterial Drugs & Prescribing Authority (§§3-4)......... 16

Senate Legislation ............................................................................................................. 16

Comparable Provisions in the 21st Century Cures Act ...................................................... 17

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Advancing Precision Medicine Act of 2016 (S. 2713) .................................................................. 18

Issue Background .............................................................................................................. 18

Senate Legislation ............................................................................................................. 20

Comparable Provisions in the 21st Century Cures Act ...................................................... 20

The Combination Products Innovation Act of 2016 (S. 1767) ...................................................... 21

Issue Background .............................................................................................................. 21

Senate Bill ......................................................................................................................... 21

Comparable Provisions in the 21st Century Cures Act ...................................................... 23

Health Software: The Medical Electronic Data Technology Enhancement for Consumers’

Health Act (S. 1101) ................................................................................................................... 23

Issue Background .............................................................................................................. 23

Senate Legislation ............................................................................................................. 24

Comparable Provisions in the 21st Century Cures Act ...................................................... 25

Interoperability: Improving Health Information Technology Act (S. 2511) .................................. 25

Issue Background .............................................................................................................. 25

Senate Legislation ............................................................................................................. 28

Comparable Provisions in the 21st Century Cures Act ...................................................... 29

The Medical Countermeasures Innovation Act of 2015 (S. 2055) ................................................ 30

Medical Countermeasures (§§2-6) .......................................................................................... 30

Issue Background .............................................................................................................. 30

Senate Legislation ............................................................................................................. 30

Comparable Provisions in the 21st Century Cures Act ...................................................... 32

Priority Review to Encourage Treatments for Agents that Present National Security

Threats (§§7-8)..................................................................................................................... 32

Issue Background .............................................................................................................. 32

Senate Legislation ............................................................................................................. 32

Comparable Provisions in the 21st Century Cures Act ...................................................... 32

Next Generation Researchers Act (S. 2014) .................................................................................. 33

Issue Background .............................................................................................................. 33

Senate Legislation ............................................................................................................. 33

Comparable Provisions in the 21st Century Cures Act ...................................................... 34

Advancing NIH Strategic Planning and Representation in Medical Research Act (S.

2745) .......................................................................................................................................... 35

NIH Strategic Plan (§2) ........................................................................................................... 35

Issue Background .............................................................................................................. 35

Senate Legislation ............................................................................................................. 36

Comparable Provisions in the 21st Century Cures Act (H.R. 6) ........................................ 36

Inclusion of Women and Minorities in Research (§§3-9) ....................................................... 36

Issue Background .............................................................................................................. 36

Senate Legislation ............................................................................................................. 37

Comparable Provisions in the 21st Century Cures Act (H.R. 6) ........................................ 38

Promoting Biomedical Research and Public Health for Patients Act (S. 2742) ............................ 38

Reducing and Streamlining Administrative Burden at NIH (§2, 3, 5, and 10) ....................... 38

Issue Background .............................................................................................................. 39

Senate Legislation ............................................................................................................. 39

Comparable Provisions in the 21st Century Cures Act (H.R. 6) ........................................ 41

Reimbursement for Research Substances and Living Organisms (§4) ................................... 41

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Issue Background .............................................................................................................. 41

Senate Legislation ............................................................................................................. 41

Comparable Provisions in the 21st Century Cures Act (H.R. 6) ........................................ 41

National Vaccine Injury Compensation Program (§6) ............................................................ 42

Issue Background .............................................................................................................. 42

Senate Legislation ............................................................................................................. 42

Comparable Provisions in the 21st Century Cures Act (H.R. 6) ........................................ 42

Vaccine Meetings; Report on Vaccine Innovation (§7) ........................................................... 42

Issue Background .............................................................................................................. 42

Senate Legislation ............................................................................................................. 43

Comparable Provisions in the 21st Century Cures Act (H.R. 6) ........................................ 43

Clinical Trials Database (§§8-9) ............................................................................................. 43

Issue Background .............................................................................................................. 43

Senate Legislation ............................................................................................................. 44

Comparable Provisions in the 21st Century Cures Act (H.R. 6) ........................................ 44

National Center for Advancing Translational Sciences (§11) ................................................. 45

Issue Background .............................................................................................................. 45

Senate Legislation ............................................................................................................. 45

Comparable Provisions in the 21st Century Cures Act (H.R. 6) ........................................ 46

Enhancing the Stature and Visibility of Medical Rehabilitation Research at the NIH Act

(S. 800) ....................................................................................................................................... 46

Issue Background .............................................................................................................. 46

Senate Legislation ............................................................................................................. 46

Comparable Provisions in the 21st Century Cures Act ...................................................... 47

Advancing Research for Neurological Diseases Act of 2016 (S. 849) .......................................... 47

Issue Background .............................................................................................................. 47

Senate Legislation ............................................................................................................. 47

Comparable Provisions in the 21st Century Cures Act ...................................................... 47

FDA and NIH Workforce Authorities Modernization Act (S. 2700) ............................................. 48

Silvio O. Conte Senior Biomedical Research Service (§2) ..................................................... 48

Issue Background .............................................................................................................. 48

Senate Legislation ............................................................................................................. 48

Comparable Provisions in the 21st Century Cures Act ...................................................... 48

Hiring Authority for Scientific, Technical, and Professional Personnel (§3) .......................... 49

Issue Background .............................................................................................................. 49

Senate Legislation ............................................................................................................. 49

Comparable Provisions in the 21st Century Cures Act ...................................................... 49

Establishment of Food and Drug Administration Intercenter Institutes (§4) .......................... 50

Issue Background .............................................................................................................. 50

Senate Legislation ............................................................................................................. 50

Comparable Provisions in the 21st Century Cures Act ...................................................... 51

Scientific Meetings (§5) .......................................................................................................... 51

Issue Background .............................................................................................................. 51

Senate Legislation ............................................................................................................. 51

Comparable Provisions in the 21st Century Cures Act (H.R. 6) ........................................ 51

Reagan-Udall Foundation for the Food and Drug Administration (§6) .................................. 52

Issue Background .............................................................................................................. 52

Senate Legislation ............................................................................................................. 52

Comparable Provisions in the 21st Century Cures Act ...................................................... 52

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NIH Research Information Collection Exempted from Paperwork Reduction Act (§7) ......... 53

Issue Background .............................................................................................................. 53

Senate Legislation ............................................................................................................. 53

Comparable Provisions in the 21st Century Cures Act (H.R. 6) ........................................ 53

Studies (§8) ............................................................................................................................. 53

Issue Background .............................................................................................................. 53

Senate Legislation ............................................................................................................. 54

Comparable Provisions in the 21st Century Cures Act ...................................................... 54

Summary Level Review (§9) .................................................................................................. 54

Issue Background .............................................................................................................. 54

Senate Legislation ............................................................................................................. 55

Comparable Provisions in the 21st Century Cures Act ...................................................... 55

Drug Surveillance (§10) .......................................................................................................... 56

Issue Background .............................................................................................................. 56

Senate Legislation ............................................................................................................. 56

Comparable Provisions in the 21st Century Cures Act ...................................................... 57

Biological Product Innovation (§11) ....................................................................................... 57

Issue Background .............................................................................................................. 57

Senate Legislation ............................................................................................................. 57

Comparable Provisions in 21st Century Cures Act (H.R. 6) ............................................. 57

Expanded Access Policy (§12) ................................................................................................ 57

Issue Background .............................................................................................................. 57

Senate Legislation ............................................................................................................. 58

Comparable Provisions in the 21st Century Cures Act ...................................................... 58

Finalizing Draft Guidance on Expanded Access (§13) ........................................................... 58

Issue Background .............................................................................................................. 58

Senate Legislation ............................................................................................................. 59

Comparable Provisions in the 21st Century Cures Act ...................................................... 59

Amendments to the Orphan Drug Act (§14) ........................................................................... 59

Issue Background .............................................................................................................. 59

Senate Legislation ............................................................................................................. 60

Comparable Provisions in the 21st Century Cures Act ...................................................... 60

Standards for Regenerative Medicine and Advanced Therapies (§15) ................................... 60

Issue Background .............................................................................................................. 60

Senate Legislation ............................................................................................................. 60

Comparable Provisions in 21st Century Cures Act (H.R. 6) ............................................. 61

Good Guidance Practices (§16)............................................................................................... 61

Issue Background .............................................................................................................. 61

Senate Legislation ............................................................................................................. 61

Comparable Provisions in the 21st Century Cures Act ...................................................... 62

Paperwork Reduction Act Waiver during a Public Health Emergency (§17) ......................... 62

Issue Background .............................................................................................................. 62

Senate Legislation ............................................................................................................. 63

Comparable Provisions in the 21st Century Cures Act ...................................................... 63

Contacts

Author Contact Information .......................................................................................................... 63

Congressional Research Service

Senate Medical Innovation Bills

Introduction

Both the House and the Senate are considering legislation to support medical innovation,

primarily through reforms to the National Institutes of Health (NIH) and changes to the drug,

biologic and device approval pathways at the Food and Drug Administration (FDA). Both NIH

and FDA are agencies within the Department of Health and Human Services (HHS). On February

3, 2015 Senators Lamar Alexander and Patty Murray, chairman and ranking Member of the

Committee on Health, Education, Labor and Pensions, announced the start of a bipartisan

initiative to “examine the process for getting safe treatments, devices and cures to patients and the

roles of the [FDA] and the [NIH] in that process.”1 This initiative culminated in a package of 19

bipartisan bills that were reported out of the Senate Health, Labor, Education, and Pensions

(HELP) Committee in a series of three executive sessions held on February 9, 2016; March 9,

2016; and April 6, 2016.

One of these 19 bills, The Adding Zika Virus to the FDA Priority Review Voucher Program Act

(S. 2512), subsequently was passed by both chambers and signed into law on April 19, 2016 (P.L.

114-146). The remaining 18 bills that comprise the Senate’s medical innovation legislative effort

include the following:

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S. 1878, The Advancing Hope Act of 2015;

S. 1622, The FDA Device Accountability Act of 2015;

S. 2503, Preventing Superbugs and Protecting Patients Act;

S. 2030, The Advancing Targeted Therapies for Rare Diseases Act of 2015;

S. 2014, Next Generation Researchers Act;

S. 800, The Enhancing the Stature and Visibility of Medical Rehabilitation

Research at NIH Act;

S. 849, Advancing Research for Neurological Diseases Act of 2015;

S. 2511, Improving Health Information Technology Act;

S. 1077, The Advancing Breakthrough Medical Devices for Patients Act of 2015;

S. 1101, The Medical Electronic Data Technology Enhancement for Consumers

Health Act;

S. 2055, The Medical Countermeasures Innovation Act of 2015;

S. 1767, The Combination Products Innovation Act of 2015;

S. 1597, Patient Focused Impact Assessment Act of 2015;

S. 185, Promise for Antibiotics and Therapeutics for Health Act;

S. 2713, Advancing Precision Medicine Act of 2016;

S. 2745, Advancing NIH Strategic Planning and Representation in Medical

Research Act;

S. 2742, Promoting Biomedical Research and Public Health for Patients Act; and

S. 2700, FDA and NIH Workforce Authorities Modernization Act.

1 Senate Health, Education, Labor, and Pensions Committee, February 3, 2015, at http://www.help.senate.gov/chair/

newsroom/press/alexander-murray-announce-initiative-to-examine-drug-device-development-and-review-process.

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The Senate’s medical innovation package is that chamber’s companion effort to the House’s 21st

Century Cures initiative, which culminated in the House passage of H.R. 6, the 21st Century

Cures Act, on July 10, 2015, on a vote of 344 to 77. H.R. 6 is the result of a series of hearings and

roundtable meetings hosted by the House Energy and Commerce Committee dating back to

spring 2014. The hearings and roundtables focused on a broad range of topics, including

modernizing clinical trials, incorporating patient perspectives into medical research and

regulatory processes, precision/personalized medicine, digital health care, and more.

While consisting of many different provisions, H.R. 6 is primarily focused on efforts to increase

strategic investments in medical research at NIH and change some aspects of how the FDA

executes its regulatory oversight mission with regard to the review and approval of new drugs,

biologics, and medical devices.

Report Roadmap

This report provides for each of the 18 bills in the Senate medical innovation package: (1)

background on the issue, or issues, addressed by the bill including a summary of relevant current

law; (2) a summary of the bill’s provisions; and (3) where applicable, identification of

comparable provisions in H.R. 6 that address the same topic. In some cases, the House and Senate

legislation address the same topic in an entirely different way. In other cases, the House and

Senate legislation address the topic in a similar way but with key substantive differences. In a few

instances, the language in the House and Senate bills is substantively identical.

For a summary of all the provisions in H.R. 6, as passed by the House, including an explanation

of how the bill would change current law, see CRS Report R44071, H.R. 6: The 21st Century

Cures Act.

The FDA Device Accountability Act of 2015 (S. 1622)

Use of Nonlocal Institutional Review Boards for Review of

Investigational Device Exemptions and [Humanitarian]2 Device

Exemptions (§2)

Issue Background

The HHS Human Subject Regulations are a core set of federal standards for protecting human

subjects in HHS-sponsored research.3 These regulations are commonly referred to as the

Common Rule because the same requirements have been adopted by many other federal

departments and agencies, which apply the regulations to the research they fund. Under the

Common Rule, research protocols must be approved by an Institutional Review Board (IRB) to

ensure that the rights and welfare of research subjects are protected.4

2 Senate provision uses the word “Human.”

3 45 C.F.R. Part 46, Subpart A.

4 45 C.F.R. §46.109.

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FDA has issued its own set of Human Subject Regulations, which are similar, but not identical, to

the Common Rule.5 FDA applies these regulations to all the research it regulates, including

clinical trials of new drugs and medical devices, regardless of the source of funding for the

research. All clinical evaluations of investigational devices (unless exempt) must have an

investigational device exemption (IDE) before the clinical study is initiated.6 An IDE allows an

unapproved device (most commonly an invasive or life-sustaining device) to be used in a clinical

study to collect the data required to support a premarket approval (PMA) submission.7 The IDE

permits a device to be shipped lawfully for investigation of the device without requiring that the

manufacturer comply with other requirements of the Federal Food, Drug, and Cosmetic Act

(FFDCA), such as registration and listing. Devices approved by FDA via the humanitarian device

exemption (HDE) are for diagnosing or treating diseases or conditions that affect fewer than

4,000 individuals in the United States each year. An HDE application is similar to a PMA, but it

is exempt from the effectiveness requirements. Such devices may be used in a facility only after a

local IRB has approved their use in that facility, except in certain emergency situations.8

Senate Legislation

The provision would amend Section 520(g) of the FFDCA, regarding IDEs, and Section 520(m)

of the FFDCA, regarding HDEs, by removing the word “local” in all references to local IRBs,

including in the stipulation that an approved humanitarian use device may be used in a facility

only after a local IRB has approved such use, except in certain emergency situations.

Comparable Provisions in the 21st Century Cures Act (H.R. 6)

The use of non-local IRBs for review of IDEs and HDEs provision in H.R. 6 (i.e., Title II,

Subtitle O, Section 2262) is comparable to S. 1622. The House provision would also require the

Secretary, within 12 months of enactment, to revise or issue regulations or guidance, as necessary,

to carry out these amendments.

CLIA Waiver Study Design Guidance for In Vitro Diagnostics (§3)

Issue Background

The Clinical Laboratory Improvement Amendments (CLIA) of 1988 provide the Centers for

Medicare & Medicaid Services (CMS) with authority to regulate clinical laboratories to ensure

the accuracy of test results, given that these results drive clinical decisionmaking.9 CLIA requires

laboratories to receive certification before they are allowed to carry out clinical laboratory testing

on a human sample. CLIA certification is based on the level of complexity of testing that a

laboratory is performing, graded as low, moderate, or high. FDA is responsible for categorizing

clinical laboratory tests according to their level of complexity.10 Laboratories that perform only

5 21 C.F.R. Parts 50, 56, 312, and 812.

6 See 21 C.F.R. §812. Devices are exempt from IDE requirements when testing is noninvasive, does not require

invasive sampling, does not introduce energy into a subject, and is not stand-alone (i.e., is not used for diagnosis

without confirmation by other methods or medically established procedures). See 21 C.F.R. §812.2(c)(3).

7 FDA, Device Advice: Investigational Device Exemption (IDE), July 9, 2009, http://www.fda.gov/MedicalDevices/

DeviceRegulationandGuidance/HowtoMarketYourDevice/InvestigationalDeviceExemptionIDE/default.htm.

8 FFDCA §520(m)(4).

9 PHSA §353; 42 U.S.C. §263a.

10 See FDA, “CLIA Categorizations,” http://www.fda.gov/medicaldevices/deviceregulationandguidance/

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low-complexity tests (called waived tests) receive a certificate of waiver (COW) from CMS.

Conversely, only laboratories certified to do so may perform moderate- and high-complexity

tests.

FDA determines whether a test is waived (i.e., low-complexity) or not based on information

submitted about the test by the manufacturer, and FDA has issued guidance to support the

manufacturer’s submission of this information.11 Under current law, waived tests are those “that

have been approved by FDA for home use or that, as determined by the Secretary, are simple

laboratory examinations and procedures that have an insignificant risk of an erroneous result.”12

The guidance recommends ways to demonstrate that a test is both “simple” and has “an

insignificant risk of an erroneous result.” Demonstrating the latter includes showing that a test’s

accuracy is comparable to a method whose accuracy has already been established and

documented. (Section V of the guidance document addresses approaches to demonstrating

accuracy.)

Senate Legislation

S. 1622 Section 3 would require the Secretary, not later than one year after enactment, to publish

draft guidance that revises Section V of the current guidance, including providing clarification on

the appropriate use of comparable performance between a waived and moderately complex

laboratory user to demonstrate accuracy. Not later than one year after the comment period for the

draft guidance closes, the Secretary would be required to publish final revised guidance.

Comparable Provisions in the 21st Century Cures Act

Section 2228 of H.R. 6 (Title I, Subtitle M) is substantively identical to the Senate legislation.

Ensuring Least Burdensome Means of Evaluating Devices (§4)

Issue Background

Section 205 of the Food and Drug Administration Modernization Act of 1997 (FDAMA, P.L.

105-115) amended Section 513 of the Federal Food, Drug, and Cosmetic Act (FFDCA), adding

two provisions commonly referred to as the “Least Burdensome Provisions.” The two provisions

stipulate that FDA consider the “least burdensome” data or information “necessary” to

demonstrate a reasonable assurance of device effectiveness in a premarket approval (PMA)

application or substantial equivalence to predicate devices with differing technological

characteristics in certain 510(k) notifications. The two provisions are as follows:

Section 513(a)(3)(D)(ii) Any clinical data, including one or more well-controlled

investigations, specified in writing by the Secretary for demonstrating a reasonable

assurance of device effectiveness shall be specified as a result of a determination by the

Secretary that such data are necessary to establish device effectiveness. The Secretary shall

consider, in consultation with the applicant, the least burdensome appropriate means of

ivdregulatoryassistance/ucm393229.htm.

11 FDA, “Guidance for Industry and FDA Staff: Recommendations for Clinical Laboratory Improvement Amendments

of 1988 (CLIA) Waiver Applications for Manufacturers of In Vitro Diagnostic Devices,” Center for Devices and

Radiological Health, January 30, 2008, http://www.fda.gov/downloads/MedicalDevices/

DeviceRegulationandGuidance/GuidanceDocuments/ucm070890.pdf.

12 PHSA §353(d)(3), “Requirements for Certificate of Waiver”; 42 U.S.C. §263a(d)(3).

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evaluating device effectiveness that would have a reasonable likelihood of resulting in

approval.

Section 513(i)(1)(D) Whenever the Secretary requests information to demonstrate that

devices with differing technological characteristics are substantially equivalent, the

Secretary shall only request information that is necessary to making substantial equivalence

determinations. In making such requests, the Secretary shall consider the least burdensome

means of demonstrating substantial equivalence and request information accordingly.

FDA published final guidance on the least burdensome provisions on October 4, 2002.13 Under

the guidance, FDA may allow the use of non-clinical data—such as laboratory and/or animal

testing—in place of clinical data for the approval of PMA devices in certain circumstances, such

as “devices or modifications of approved devices for which scientifically valid information is

available in the public domain.”14 When clinical data are needed, FDA allows manufacturers to

consider study designs to shorten the length of the study. Such study designs include the use of

“surrogate endpoints and statistical methods, such as Bayesian analyses,” and study designs other

than the gold standard—the randomized controlled trial.15 Although FDA allows for substitution

of laboratory data in certain circumstances, the absence of problems in laboratory testing may not

always predict what happens to a device over time in the human body, where forces that cannot

be replicated in laboratory testing act upon the device. For example, “the malfunction of

[Medtronic and St. Jude Medical] implantable cardioverter-defibrillator leads, which resulted in a

widespread recall, and the hazards posed by particles shed from [DePuy] metal-on-metal hip

replacements were not predictable based on engineering insights or in vitro studies.”16

The 2002 FDA guidance states, “[r]eliance on postmarket controls (e.g., ... postmarket

surveillance, and the Medical Device Reporting requirements) should be considered as a

mechanism to reduce the premarket burden for 510(k)s and PMAs, while still ensuring the safety

13 FDA, The Least Burdensome Provisions of the FDA Modernization Act of 1997: Concept and Principles; Final

Guidance for FDA and Industry, October 4, 2002, http://www.fda.gov/RegulatoryInformation/Guidances/

ucm085994.htm.

14 Ibid.

15 Ibid. In a randomized controlled trial (RCT), participants are randomly assigned to two or more groups. One group

receives the intervention (the new treatment), while the control group receives current therapy or a placebo.

Randomization ensures that any patient characteristics that might affect the outcome will be roughly equal across each

group in the study. Any difference in outcomes between the groups is then likely due to the intervention. The RCT is

often called the gold standard of evidence for a clinical trial. A surrogate end point may not be a reliable predictor of

actual patient benefit. It is a laboratory measurement, such as blood pressure or cholesterol level, used as a substitute

for a clinically meaningful end point that measures directly how a patient feels, functions, or survives. The use of

Bayesian analyses allows studies to be combined in order to reduce the sample size needed for the experimental and/or

control device.

16 Steven N. Goodman and Rita F. Redberg, “Opening the FDA Black Box,” JAMA, vol. 311, no. 4 (January 22, 2014),

pp. 361-363. The Medtronic Sprint Fidelis and the St. Jude Medical Riata leads are specific models of cardiac

electrodes (thin wires) that connect an implantable cardioverter-defibrillator (ICD) directly to the heart. An ICD

monitors heart rhythms and can deliver an electrical shock to restore normal rhythm if life-threatening, irregular

heartbeats are detected. The ICD keeps the heart from beating too fast and is surgically implanted in patients who may

be at risk of sudden cardiac arrest. Both the Medtronic Sprint Fidelis and the St Jude Medical Riata were recalled

because of the potential for wire fracture, causing the ICD to deliver an unnecessary shock or to not operate at all.

Deaths and serious injuries were reported in which a fractured Sprint Fidelis or Riata lead may have been a possible or

likely contributing factor. As of October 4, 2007, about 268,000 Sprint Fidelis leads had been implanted worldwide,

including 172,000 Sprint Fidelis leads implanted in the United States. More than 227,000 Riata leads had been

distributed worldwide, and as of 2011, about 79,000 Riata leads remained implanted in U.S. patients. See FDA website

at http://www.fda.gov/ForConsumers/ConsumerUpdates/ucm103022.htm and

http://www.fda.gov/MedicalDevices/Safety/AlertsandNotices/ucm314930.htm.

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and effectiveness of the device.”17 However, the FDA’s authority to require postmarket studies of

medical devices is limited. A September 2015 GAO study found that of the 392 postmarket

surveillance studies ordered by FDA between May 1, 2008, and February 24, 2015, 88% were

inactive, 10% were ongoing, and 2% were complete.18 Activities related to implementing the least

burdensome provision, including training for staff and advisory panels, are posted on FDA’s

website.19

Senate Legislation

S. 1622, Section 4, would amend FFDCA Section 513 by adding a new subsection (j), “Training

and Oversight of Least Burdensome Requirements.” The Secretary would be required to ensure

that each FDA employee involved in the review of premarket submissions, including supervisors,

receives training on the “meaning and implementation of the least burdensome requirements” and

to periodically assess the implementation of such requirements, including employee training.

Under the Senate bill, 18 months after enactment, the FDA ombudsman responsible for device

premarket review would be required to conduct an audit of the least burdensome training,

including the effectiveness of the training. The audit would be required to include “interviews of

persons who are representatives of the industry regarding their experience in the device premarket

review process” and a list of the measurement tools used to assess the implementation of the least

burdensome requirement. A summary of the audit findings would be required to be submitted to

the Senate HELP Committee and the House Energy and Commerce Committee and posted on the

FDA website.

Regarding PMA applications, S. 1622 would amend FFDCA Section 515(c), adding a new

paragraph that would require the Secretary to “consider the least burdensome appropriate means

necessary to demonstrate device safety and effectiveness.” It would define the term necessary to

mean “the minimum required information that would support a determination by the Secretary

that an application provides a reasonable assurance of the safety and effectiveness of the device”

and would state that the role of postmarket information must be considered in determining the

least burdensome means of demonstrating a reasonable assurance of device safety and

effectiveness.

In addition, the provision would amend FFDCA Section 517A(a), adding that each substantive

summary of the scientific and regulatory rationale for any decision made by FDA’s Center for

Devices and Radiological Health (CDRH) regarding the submission or review of a PMA, a

510(k), or an IDE must also include a brief statement on how the least burdensome requirements

were considered and applied.

Comparable Provisions in the 21st Century Cures Act (H.R. 6)

The provision regarding training and oversight in least burdensome appropriate means in H.R. 6

(Title II, Subtitle M, Section 2223) is comparable to S. 1622. Under the House provision, the

Secretary would be required to issue draft guidance, no later than 12 months after enactment, that

17 FDA, The Least Burdensome Provisions of the FDA Modernization Act of 1997: Concept and Principles; Final

Guidance for FDA and Industry, October 4, 2002, http://www.fda.gov/RegulatoryInformation/Guidances/

ucm085994.htm.

18 GAO, Medical Devices: FDA Ordered Postmarket Studies to Better Understand Safety Issues, and Many Studies Are

Ongoing, GAO-15-815, September 2015.

19 FDA, Medical Devices, The Least Burdensome Provisions - Activities Related to Implementation,

http://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/Overview/

MedicalDeviceProvisionsofFDAModernizationAct/ucm136685.htm#7.

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would update the October 4, 2002, final guidance on the least burdensome provisions. In

developing the draft guidance, the Secretary would be required to hold a meeting of stakeholders

“to ensure a full record to support the publication of such document.”

The House provision amending FFDCA Section 515(c) would not require that postmarket

information be considered in determining the least burdensome means of demonstrating a

reasonable assurance of device safety and effectiveness.

The House provision does not amend FFDCA Section 517A(a) regarding the substantive

summary of any decision made by CDRH on the least burdensome requirements.

Preventing Superbugs and Protecting Patients Act

(S. 2503)

Issue Background

FFDCA Section 510(k) requires medical device manufacturers to register with the Secretary and,

at least 90 days prior to introducing a device intended for human use into interstate commerce, to

report to the Secretary (1) the class in which the device is classified and (2) actions taken to

comply with applicable device regulatory requirements under FFDCA Sections 514 and 515. This

notification requirement is part of the 510(k) premarket approval pathway, a process that is

unique to medical devices and if successful results in FDA clearance. Under the 510(k) pathway,

the manufacturer must demonstrate that a new device is substantially equivalent to a device

already on the market (a predicate device). Substantial equivalence is determined by comparing

the performance characteristics of a new device with those of a predicate device; clinical data

demonstrating safety and effectiveness are usually not required.

Reusable medical devices are those devices that may be reprocessed and used on multiple

patients. In March of 2015, FDA released final guidance on the reprocessing of reusable medical

devices: Reprocessing Medical Devices in Health Care Settings: Validation Methods and

Labeling. This guidance states that, among other things, “(m)anufacturers seeking to bring to

market certain reusable devices, such as duodenoscopes, bronchoscopes and endoscopes, should

submit to the FDA for review their data validating the effectiveness of their reprocessing methods

and instructions.”20

Under Section 604 of the Food and Drug Administration Safety and Innovation Act (FDASIA),

the Secretary was required to withdraw draft guidance, issued by FDA in July 2011, entitled

“Guidance for Industry and FDA Staff—510(k) Device Modifications: Deciding When to Submit

a 510(k) for a Change to an Existing Device,” and leave the prior guidance issued in 1997 in

effect. Although patient and consumer groups have generally supported a more rigorous 510(k)

notification system, industry had voiced concerns that the 2011 guidance would slow the device

regulatory process.21 Section 604 of FDASIA also required a report to House and Senate

committees on when a 510(k) notification should be submitted for a modification or change to a

legally marketed device. Any new draft guidance (or proposed regulation) on 510(k) device

20 FDA, “Reprocessing Medical Devices in Health Care Settings: Validation Methods and Labeling,” March 15, 2015,

http://www.fda.gov/downloads/MedicalDevices/DeviceRegulationandGuidance/GuidanceDocuments/

UCM253010.pdf.

21 Alexander Gafney, “In a Major Victory for Industry, FDA says Existing 510(k) Guidance to Remain ‘Mostly

Unchanged,’” RAPS Regulatory Focus, February 26, 2014, at http://www.raps.org/regulatoryDetail.aspx?id=9982.

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modification could not be issued before the committees received the report. Final guidance (or

regulation) could not be issued until one year after the committees had received the report. This

report was completed by FDA in January 2014.22

Senate Legislation

S. 2503 would amend FFDCA Section 510 by adding a new subsection (q), “Reusable Medical

Devices,” which would require the Secretary, not later than six months after enactment, to

identify and publish a list of reusable device types for which reports under Section 510(k) must

include (1) instructions for use and (2) validation data regarding cleaning, disinfection, and

sterilization. Reports issued after the publication of this list would be required to include

instructions for use and validation data, as specified by the Secretary.

S. 2503 also would require the Secretary, acting through the FDA Commissioner and not later

than one year after the date on which the comment period closes for the draft guidance, to issue

final guidance regarding when a notification under 510(k) would have to be submitted for a

modification or change to a legally marketed device.

Comparable Provisions in the 21st Century Cures Act

There are no comparable provisions in H.R. 6.

The Advancing Breakthrough Medical Devices for

Patients Act of 2016 (S. 1077)

Issue Background

Under FFDCA Section 515(d)(5), in order to provide for more effective treatment or diagnosis of

life-threatening or irreversibly debilitating human diseases or conditions, the Secretary shall

provide review priority for devices that represent breakthrough technologies for which no

approved alternatives exist, that offer significant advantages over existing approved alternatives,

or whose availability is in the best interest of the patients.

On April 23, 2014, FDA issued the following draft guidance: Expedited Access for Premarket

Approval Medical Devices Intended for Unmet Medical Need for Life Threatening or Irreversibly

Debilitating Diseases or Conditions - Draft Guidance for Industry and Food and Drug

Administration Staff. As indicated in the title, the FDA draft guidance covered only premarket

approval (PMA) medical devices. FDA issued final guidance on April 13, 2015.23

The guidance focuses on balancing risks versus benefits for patients, drafting a Data

Development Plan by the medical device sponsor, and collecting postmarket data on a medical

device that has received a priority review designation. As described in the FDA guidance, the

22 FDA, Report to Congress, Report on FDA’s Policy to be Proposed Regarding Premarket Notification Requirements

for Modifications to Legally Marketed Devices, January 7, 2014, at http://www.fda.gov/downloads/AboutFDA/

CentersOffices/OfficeofMedicalProductsandTobacco/CDRH/CDRHReports/UCM387121.pdf.

23 See http://www.fda.gov/downloads/MedicalDevices/DeviceRegulationandGuidance/GuidanceDocuments/

UCM393978.pdf. Note that the final FDA Guidance added de novo 510(k) devices. A de novo 510(k), a modified type

of 510(k) review pathway, though requiring more data than a traditional 510(k), often requires less information than a

PMA application. According to the final guidance, de novo devices “are not eligible for the full scope of the EAP

program.” For a definition of EAP, see page 9.

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expedited review process for a medical device that has received a priority review designation in

exchange for lower requirements in the premarket review process, such as less information in the

PMA application, relies on the use of surrogate endpoints24 and the collection of postmarket data.

According to FDA, the “Expedited Access PMA” (EAP) program features “earlier and more

interactive engagement with FDA staff—including the involvement of senior management and a

collaboratively developed plan for collecting the scientific and clinical data to support approval—

features that, taken together, should provide these patients with earlier access to safe and effective

medical devices.”25

FDA intends to withdraw approval for a device if the sponsor fails to adhere to the postmarket

requirements, such as data collection, or if the postmarket data prove the device is not safe and

effective:

As part of the EAP program, FDA intends to impose postmarket requirements, including

requiring post-approval studies as a condition of approval for devices subject to a PMA

when applicable.26 The extent to which FDA will accept certain data to be collected for an

EAP Device in the postmarket setting, rather than premarket, is affected by the Agency’s

current authority to mandate completion of post-approval studies and to withdraw PMA

approval for marketed devices for which FDA later determines that there is a lack of a

showing of reasonable assurance that the device is safe or effective under the conditions of

use prescribed, as well as by the current capabilities of FDA’s medical device surveillance

system.27

Comments on the April 2014 FDA draft guidance questioned FDA’s ability to enforce postmarket

study requirements and urged the agency and Congress “to evaluate whether FDA has sufficient

authorities to promptly withdraw product approval if the necessary data are not promptly

collected or suggest that the product benefits do not outweigh risks.”28 One media source stated

that, regarding the EAP program, FDA “estimates that, at least in the early stages, on average,

about six devices a year may qualify for the program, and the [agency] believes it has the

resources available to handle that volume.”29 The estimated six devices would represent about

24 The FDA guidance on pages 23-24 describes a surrogate endpoint as follows: “a surrogate endpoint is not itself a

measure of clinical benefit, but is used in trials as a substitute which is reasonably likely to predict clinical benefit,

based on epidemiologic, therapeutic, pathophysiologic or other scientific evidence. The types of measurements which

may be used as a surrogate endpoint are in vitro laboratory or medical imaging measurements, or physical signs (e.g.,

blood pressure measurements in trials of antihypertensive therapeutics, as a surrogate for clinical endpoints such as

stroke, myocardial infarction, or mortality).”

25 See http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm394294.htm.

26 21 C.F.R. 814.82 states: “FDA may impose post-approval requirements in a PMA approval order or by regulation at

the time of approval of the PMA or by regulation subsequent to approval.” In addition, under §522 of the FD&C Act

and FDA’s implementing regulations at 21 C.F.R. Part 822, FDA may order postmarket surveillance for certain Class

III devices.

27 FDA, Expedited Access for Premarket Approval and De Novo Medical Devices Intended for Unmet Medical Need

for Life Threatening or Irreversibly Debilitating Diseases or Conditions, Guidance for Industry and Food and Drug

Administration Staff, April 13, 2015, pp. 8-9, http://www.fda.gov/downloads/MedicalDevices/

DeviceRegulationandGuidance/GuidanceDocuments/UCM393978.pdf.

Regarding de novo 510(k) devices, the final FDA Guidance on page 9 also stated the following: “FDA would not offer

a greater ability to collect postmarket benefit-risk data otherwise typically collected premarket for a de novo request (as

we may for a PMA device) because once a de novo request is granted, the product can serve as a predicate for a device

that need only demonstrate substantial equivalence for a 510(k) clearance. This would be problematic if we granted a

de novo for a device that subsequently was shown not to be safe or effective based on required postmarket data

collection.”

28 See http://www.pewtrusts.org/en/about/news-room/news/2014/07/22/pew-comments-to-fda.

29 David Filmore, “Leap ahead with EAP? FDA proposes new expedited PMA pathway,” The Gray Sheet, vol. 40, no.

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15% of FDA’s total PMA applications in one year. Other comments on the FDA draft guidance

questioned whether FDA has sufficient resources to dedicate to the EAP program.30

Senate Legislation

S. 1077 would add a new Section 515B, “Priority Review for Breakthrough Devices,” to Chapter

V of the FFDCA. The new section would require the Secretary to establish a program to provide

priority review for devices that (1) provide more effective diagnosis or treatment of a lifethreatening or irreversibly debilitating condition; and (2) represent breakthrough technologies for

which no approved alternatives exist, offer significant advantages over existing alternatives, or

the availability of which is in the best interest of patients. The section would allow requests for

priority review from device sponsors of PMA medical devices and one other type of regulatory

decision involving a medical device.31

The section would require the Secretary in 60 days to determine whether the request for priority

review would be granted. Such requests would be evaluated by a team of experienced FDA staff

and senior managers. All determinations—either approval or denial of priority review—would

require a “substantive summary of the scientific and regulatory rationale” for the determination,

pursuant to FFDCA Section 517A.

If the Secretary approves a priority review designation for a device, the Secretary would not be

able to withdraw the designation because another “breakthrough” device was subsequently

cleared or approved, thereby resulting in the specified criteria (i.e., no approved alternatives exist,

offer significant advantages over existing approved or cleared alternatives, or the availability of

which is in the best interest of patients) no longer being met.

Each priority review device would be assigned a team of staff, “including a team leader with

appropriate subject matter expertise and experience.” Senior FDA personnel would oversee each

team to facilitate the efficient development and review of the device. Among other things, the

Secretary would be required to “provide for interactive communication with the device sponsor

during the review process,” and expedite “the Secretary’s review of manufacturing and quality

systems compliance.” The Secretary would be required to “disclose to the sponsor, not less than 5

business days in advance the topics of any consultation concerning the sponsor’s device that the

Secretary intends to undertake with external experts or an advisory committee and provide the

sponsor an opportunity to recommend such external experts.”

The Secretary would be allowed to, as appropriate, “coordinate with the sponsor regarding early

agreement on a data development plan.” The Secretary would also be able to ensure that clinical

trial design is as efficient as practicable and would be able to facilitate “expedited and efficient

development and review of the device through utilization of timely postmarket data collection”

with regard to PMA applications. Agreements on clinical protocols would be considered binding,

but may be subject to change under certain circumstances. The provision specifies that both the

agreement and subsequent changes to the clinical protocol must be agreed to in writing.

The Secretary would be required to issue, not later than one year after enactment, guidance on the

implementation of the new Section 515B of the FFDCA. In addition, the Secretary would be

required to issue a report, on January 1, 2017, to the Senate Health, Education, Labor and

Pensions Committee and the House Energy and Commerce Committee describing the program

17 (April 28, 2014), pp. 1, 5-6.

30 See http://center4research.org/public-policy/testimony-briefings-statements/comments-on-expedited-access-forpremarket-approval-medical-devices/.

31 A petition for classification under FFDCA §513(f)(2).

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added under new FFDCA Section 515B, including recommendations to strengthen the program

and better meet patient needs in a timely manner.

Comparable Provisions in the 21st Century Cures Act (H.R. 6)

The provision in H.R. 6 regarding priority review for breakthrough devices (Title II, Subtitle L,

Sections 2201) is comparable to S. 1077. Importantly, the House provision would allow priority

review requests from device sponsors of both 510(k) devices and PMA medical devices, and one

other type of regulatory decision involving a medical device.32 The House provision would allow

denied priority review requests to be reconsidered if reconsideration is requested within 30 days

of the denial and other specified criteria are met.

The House provision does not specify the number of business days in which FDA would

“disclose to the sponsor, in advance the topics of any consultation concerning the sponsor’s

device that [FDA] intends to undertake with external experts or an advisory committee and

provide the sponsor an opportunity to recommend such external experts.” The House provision

adds specific details regarding efficient clinical trial design, such as “the adoption of shorter or

smaller clinical trials, application of surrogate endpoints, and use of adaptive trial designs and

Bayesian statistics.” The House provision does not specify that the agreement on clinical

protocols and any subsequent changes must be agreed to in writing. The House provision does not

specify a deadline on the requirement for FDA guidance on Section 515B of the FFDCA, nor

does it require a report by FDA on the program added under FFDCA Section 515B.

Advancing Hope Act of 2016 (S. 1878)

Issue Background

FDASIA (P.L. 112-144) added a new FFDCA Section 529, creating the pediatric priority review

voucher program. This voucher program, funded by user fees, provides a transferable voucher,

under specified conditions, to a sponsor of an approved new drug or biological product for a rare

pediatric disease to be used for the priority review of another application. The term “rare pediatric

disease” refers to a disease that affects (1) individuals aged from birth to 18 years, and (2) fewer

than 200,000 persons in the United States, or affects more than 200,000 persons in the United

States and for which there is no reasonable expectation that the cost of developing and making the

drug available in the United States will be recovered from U.S. sales.

FDASIA terminated the authority to award such vouchers one year after the Secretary awards the

third-priority voucher and required the GAO, beginning on the date of the third voucher award, to

study and then report on the effectiveness of the voucher program in the development of products

that prevent or treat rare pediatric diseases. FDA awarded the third voucher in March 2015,

triggering the March 2016 sunset of this authority. This authority was extended until September

30, 2016, by the Consolidated Appropriations Act of 2016 (P.L. 114-113).

Senate Legislation

S. 1878 would amend the definition of “rare pediatric disease” in FFDCA Section 529(a) by

adding the following words in italics: “The disease is a serious or life-threatening disease in

which the serious or life-threatening manifestations primarily affect individuals aged from birth

to 18 years, including age groups often called neonates, infants, children, and adolescents.” This

32 A petition for classification under FFDCA §513(f)(2).

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legislation also would amend the definition of a “rare pediatric disease product application” to

mean a human drug application, as specified, that is approved after the enactment of S. 1878.

S. 1878 would amend FFDCA Section 529(b)(4) by adding the requirement that the sponsor of a

rare pediatric disease product application that intends to request a voucher for a rare pediatric

disease product notify the Secretary of such intent upon submission of the rare pediatric disease

product application. It would also extend eligibility for a rare pediatric disease priority review

voucher, to a sponsor of a rare pediatric disease product application, unapproved as of the date of

enactment of S. 1878, that submitted the application at least 90 days after the enactment of the

Prescription Drug User Fee Amendments of 2012 and on or before the date of enactment of S.

1878.

The bill would extend the authority to award such priority review vouchers until September 30,

2022. A new drug application or a biologics license application submitted to FDA after the

enactment of S. 1878 and before September 30, 2022, would remain eligible to receive a priority

review voucher even if approval comes after September 30, 2022, provided the application is

approved before September 30, 2027, and is designated as a drug for a rare pediatric disease. This

section also would prohibit a sponsor of a rare pediatric disease product application from

receiving more than one priority review voucher issued under S. 1878 for the same product

application.

S. 1878 also would require that GAO study the voucher program and report to the Senate

Committee on Health, Education, Labor, and Pensions and the House Committee on Energy and

Commerce, by January 31, 2022, on the program’s effectiveness as an incentive for developing

drugs that treat or prevent rare pediatric diseases and that would not otherwise have been

developed.

Comparable Provisions in the 21st Century Cures Act

H.R. 6 contains a comparable provision (Section 2152, Reauthorization of Rare Pediatric Disease

Priority Review Voucher Incentive Program), which would extend the authority to award rare

pediatric disease priority review vouchers until December 31, 2018. A new drug application or a

biologics license application submitted to FDA after the enactment of H.R. 6 and before

December 31, 2018, would remain eligible to receive a priority review voucher even if approval

comes after December 31, 2018. Similar to S. 1878, the House provision also would amend the

definition of “rare pediatric disease” by adding the following words in italics: “The disease is a

serious or life-threatening disease in which the serious or life-threatening manifestations

primarily affect individuals aged from birth to 18 years, including age groups often called

neonates, infants, children, and adolescents.” Unlike the Senate bill, the House provision would

add to the list of characteristics of a pediatric rare disease product application that the product not

have received a tropical disease priority review voucher.33 Like S. 1878, the House provision also

would require that GAO study the voucher program and report to the House Committee on

Energy and Commerce and the Senate Committee on Health, Education, Labor, and Pensions, by

December 31, 2017, on the program’s effectiveness as an incentive for developing drugs that treat

or prevent rare pediatric diseases and that would not otherwise have been developed.

33 FFDCA §524. Priority review to encourage treatments for tropical diseases.

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Advancing Targeted Therapies for Rare Diseases Act

of 2016 (S. 2030)

Issue Background

Precision medicine is a relatively new term for what has traditionally been called personalized

medicine (or targeted medicine), the idea of providing health care to individuals based on specific

patient characteristics. This approach relies on companion diagnostics to target drugs and

biological products to specific subsets of patients. Rare diseases often have genetic origins, and

advances in medicine have resulted in the development of new treatments that work by targeting

genetic mutations that cause the disease. It is inherently difficult to develop drugs for rare

diseases because of the small patient population available to conduct clinical trials, so targeted

therapies are generally first developed for patients with the most frequent disease-causing

mutations. However, to provide therapies for the full spectrum of certain genetic rare diseases,

additional targeted therapies would need to be developed.

Targeted therapies, because they may be treating small subsets of patients, sometimes qualify as

“orphan drugs.” Such drugs are called orphan drugs because firms may lack the financial

incentives to sponsor products to treat small patient populations. Orphan drugs receive their

designation pursuant to FFDCA Section 526(a),34 a designation that was created by the Orphan

Drug Act (P.L. 97-414) to encourage firms to develop pharmaceuticals to treat rare diseases and

conditions by providing an extended period of market exclusivity. Section 526(a) defines “rare

disease or condition” as any disease or condition that affects fewer than 200,000 persons in the

United States or affects more than 200,000 persons in the United States and for which there is no

reasonable expectation that the cost of developing and making the drug available in the United

States will be recovered from U.S. sales.

Senate Legislation

S. 2030, the Advancing Targeted Therapies for Rare Diseases Act of 2015, would add a new

Section 529A “Targeted Drugs for Rare Diseases” to Subchapter B of chapter V of the FFDCA,

with the purpose of facilitating the “development, review, and approval of genetically targeted

drugs and variant protein targeted drugs to address an unmet medical need in one or more patient

subgroups, including subgroups of patients with different mutations of a gene, with respect to rare

diseases or conditions that are serious or life-threatening.”

This legislation would authorize the Secretary to allow the sponsor of a new drug application for

a genetically targeted drug or a variant protein-targeted drug to rely on data and information that

has been previously developed and submitted, either by the same or a different sponsor (with

permission), for a drug that incorporates or utilizes the same or similar genetically targeted

technology or for a variant protein-targeted drug.35 S. 2030 would define genetically targeted

drugs, genetically targeted technology, and variant protein-targeted drugs. New Section 529A

should not be construed to limit the Secretary’s product approval authorities, or to entitle

34 FFDCA §526, “Designation of Drugs for Rare Diseases or Conditions”; 21 U.S.C. §360bb.

35 An example of a variant protein-targeted drug is Gleevec (imatinib), which is used to treat leukemia and other kinds

of cancer. It targets at least one variant form of a tyrosine kinase enzyme (an enzyme is a protein) called BCR-Abl

tyrosine kinase (chromosol translocation); see http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1907317/.

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sponsors to obtain information in another sponsor’s application without permission of the other

sponsor.

Comparable Provisions in the 21st Century Cures Act

The comparable provision in the House bill (H.R. 6, Title II, Subtitle C, Section 2041, “Precision

Medicine Guidance and Other Programs of Food and Drug Administration”) would add a new

Subchapter J, Precision Medicine, to Chapter V of the FFDCA; this subchapter would include a

new Section 592, “Precision medicine regarding orphan-drug and expedited-approval programs.”

For a precision drug or biological product application where the product is for the treatment of a

serious or life-threatening disease or condition and has been designated as an orphan drug under

FFDCA Section 526 as a drug for a rare disease or condition, the new FFDCA Section 592 would

allow the Secretary to do two things. First, as with the Senate bill, the Secretary would be allowed

to rely on information about a drug or biological product that has been previously submitted,

either by the same or a different sponsor (with permission), in approval of an application. This

may be for either a new product, or for a different indication for an existing product. Second, in

contrast to the Senate bill, it would allow the Secretary to consider the application for expedited

review programs, including accelerated approval. Similar to S. 2030, new Section 592 should not

be construed to limit the Secretary’s product approval authorities, or to entitle sponsors to obtain

information in another sponsor’s application without permission of the other sponsor.

Patient-Focused Impact Assessment Act of 2016 (S.

1597)

Issue Background

FDASIA (P.L. 112-144) expanded FDA’s authorities and strengthened the agency’s ability to

safeguard and advance public health. 36 FDASIA added a new FFDCA Section 569C “Patient

Participation in Medical Product Discussion,” facilitating increased involvement of patients

earlier in the regulatory process for medical product review. Section 569C directs the Secretary to

develop and implement strategies to solicit the views of patients during the medical product

development process and consider the perspectives of patients during regulatory

discussions by (1) fostering participation of a patient representative who may serve as a

special government employee in appropriate agency meetings with medical product

sponsors and investigators; and (2) exploring means to provide for identification of patient

representatives who do not have any, or have minimal, financial interests in the medical

products industry.

Senate Legislation

S. 1597 would amend FFDCA Section 569C by adding a new subsection (b), “Statement of

Patient Experience,” which would require the Secretary, upon approval of a new drug application,

to make public any patient experience data and related information submitted and reviewed as

part of the application. “Data and information” refers to patient experience data, information on

36 FDA, The Food and Drug Administration Safety and Innovation Act (FDASIA) Section 1137: Patient Participation

in Medical Product Discussions Report on Stakeholder Views, February 19, 2016, see

http://www.fda.gov/downloads/ForPatients/About/UCM486859.pdf.

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patient-focused drug development tools, and other relevant information, as determined by the

Secretary.

In addition, S. 1597 would require the Secretary, acting through the FDA Commissioner, to

develop a plan to issue draft and final guidance, over a period of five years, regarding the

collection of patient experience data and the use of such data in drug development. This section

describes the content of those required guidance documents and defines, for the purposes of this

section, “patient experience data” as

data that are collected by any persons (including patients, family members and caregivers

of patients, patient advocacy organizations, disease research foundations, researchers, and

drug manufacturers); and are intended to provide information about patients’ experiences

with a disease or condition, including the impact of such disease or condition, or a related

therapy, on patients’ lives; and patient preferences with respect to treatment of such disease

or condition.

Finally, S. 1597 would require the Secretary, acting through the FDA Commissioner, to publish,

no later than June 1, 2021, 2026, and 2031, on the FDA website, a report “assessing the trends of

the Food and Drug Administration with respect to the review of patient experience data and

information on patient-focused drug development tools as part of approved applications.”

Comparable Provisions in the 21st Century Cures Act

H.R. 6 also contains a provision related to patient experience data (Title II, Subtitle A, Section

2001, “Development and Use of Patient Experience Data to Enhance Structured Risk-Benefit

Assessment Framework”). However, the House provision is quite different from the Senate bill.

H.R. 6 would amend FFDCA Section 505 by deleting a clause from Section 505(d) and adding

new subsections (x) and (y). The new 505(x) would restate the deleted 505(d) requirement for the

Secretary to “implement a structured risk-benefit assessment framework in the new drug approval

process.” The new 505(y) would require the Secretary to “establish and implement processes

under which” entities “seeking to develop patient experience data” could submit ideas and data to

the Secretary and the Secretary could request materials from those entities, which could include

the manufacturer and nonmanufacturer groups. This provision would define “patient experience

data” as

data collected by patients, parents, caregivers, patient advocacy organizations, disease

research foundations, medical researchers, research sponsors, or other parties determined

appropriate by the Secretary that is intended to facilitate or enhance the Secretary’s riskbenefit assessments, including information about the impact of a disease or a therapy on

patients’ lives.

The new subsection would also require the Secretary to issue implementation guidance after

holding several methodological workshops and a public meeting.

Promise for Antibiotics and Therapeutics for Health

Act (S. 185)

Issue Background

According to the Centers for Disease Control and Prevention (CDC), each year in the United

States, at least 2 million people become infected with bacteria that are resistant to antibiotics, and

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at least 23,000 of them die from these infections.37 Antibiotics are intended for short-term use,

making the development of new ones potentially less attractive to drug developers. Addressing

barriers to antibiotic drug approval may help counter this problem. One such proposal is the socalled Limited Population Antibacterial Drug (LPAD) approval pathway for new antibacterial

drugs.38 Such a pathway would involve smaller clinical trials in a limited population of patients

that have serious or life-threatening infections and unmet medical needs due to the lack of an

effective approved antibiotic. This streamlined approach would result in more uncertainty about

potential risks posed by the product, and therefore a greater need for post-market scrutiny.39

Antibacterial Resistance Monitoring (§2)

Senate Legislation

Section 2 would amend PHSA Section 319E to require the HHS Secretary to (1) encourage and

assist in reporting of antibacterial drug use, drug resistance, and antibiotic stewardship programs 40

in health care facilities of the Indian Health Service, Department of Veterans Affairs (VA), and

Department of Defense (DOD); (2) report annually on antibacterial drug resistance trends,

stewardship programs, and other matters; (3) provide guidance and other informational materials

about antibiotic stewardship for residential and ambulatory health care facilities; (4) assist states

with their antibacterial resistance prevention activities; and (5) establish a mechanism for

facilities to report antibiotic stewardship activities and drug resistance, including for drugs

approved under the LPAD pathway established in the Act.

Comparable Provisions in the 21st Century Cures Act

Section 2121, subsection (g) would add a new subsection 317U to the PHSA requiring the HHS

Secretary to establish a monitoring system for the use of antibacterial and antifungal drugs,

including products approved under the LPAD pathway, as well as changes in bacterial and fungal

resistance to drugs. The Secretary would be required to make summaries of data from this system

publicly available.

Limited Population Pathway for Antibacterial Drugs & Prescribing

Authority (§§3-4)

Senate Legislation

Section 3 would create new FFDCA Section 506(g), “Limited population pathway for

antibacterial drugs.” This review pathway would allow the Secretary to approve an antibacterial

37 Centers for Disease Control and Prevention (CDC), “Antibiotic Resistance Threats in the United States, 2013,”

http://www.cdc.gov/drugresistance/threat-report-2013/.

38 Note that this is a proposed pathway and that FDA does not currently have the authority to review and approve new

antibacterial drugs using the LPAD pathway. See for example Allan Coukell, “To Fight Antimicrobial Resistance,

Allow FDA to Approve New Drugs for Limited Populations,” Health Affairs Blog, April 5, 2016,

http://healthaffairs.org/blog/.

39 Ibid. See also President’s Council of Advisors on Science and Technology (PCAST), Report to the President on

Combating Antibiotic Resistance, “Goal 4.2. Drug approval based on clinical trials in limited patient populations,”

September 2014, pp. 32 ff., https://www.whitehouse.gov/administration/eop/ostp/pcast.

40 Antibiotic stewardship refers to policies and programs of antibiotic use intended to optimize health benefits while

minimizing the risk of development of drug resistance. For more information see CDC, “Core Elements of Hospital

Antibiotic Stewardship Programs,” http://www.cdc.gov/getsmart/healthcare/implementation/core-elements.html.

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drug as an LPAD drug if certain conditions are met: (1) if the drug is intended to treat a serious or

life-threatening infection in a limited population of patients with unmet needs; (2) the standards

for new drug application approval are met; and (3) the Secretary receives a written request from

the sponsor to approve the drug as an LPAD drug. This review pathway would include the

following elements:









It would require that the Secretary’s determination of the safety and efficacy of a

limited population antibacterial drug “reflect[s] the benefit-risk profile of the

drug in the intended limited population.”

Products approved using this pathway must carry prominent labeling noting the

intended use for a limited and specific population of patients.

Sponsors must submit promotional materials to FDA for review 30 days prior to

dissemination.

Sponsors may pursue this pathway concurrently with other specified streamlined

approval pathways, as applicable.

Section 3 would require the Secretary to issue within 18 months of enactment guidance

“describing criteria, processes, and other general considerations for demonstrating the safety and

effectiveness of limited population antibacterial drugs.” It would also require the Secretary to

provide advice to the sponsor regarding the approval of an LPAD drug. If an LPAD drug obtains

approval for a broader indication, this legislation would allow the Secretary to remove any postmarketing conditions (e.g., labeling requirements).

Section 3 would require the Secretary to report to Congress at least every two years on the

number of requests for approval and the number of approvals of LPAD drugs. It also would

require GAO to report on the coordination of monitoring activities required by S. 185, and the

extent to which this limited pathway has streamlined premarket approval for such antibacterial

drugs for limited populations, among other things.

Section 4 states that S. 185 should not be construed to alter current prescribing or other medical

practices.

Comparable Provisions in the 21st Century Cures Act

The House bill contains a comparable provision (Title II, Subtitle G, Section 2121, “Approval of

Certain Drugs for Use in a Limited Population of Patients”). The House provision would add a

new FFDCA subsection 505(z), “Approval of certain antimicrobial and antifungal drugs for use in

a limited population of patients.” This would be an expedited review pathway for certain

antibacterial and antifungal drugs (including biologics) intended for use in limited, defined

populations of patients that have severe, life-threatening infections for which current treatment

options may be limited or absent, and for which the benefits of a product could outweigh harms

that would not be acceptable in broader population use.

Some elements of the review pathway proposed in the House bill are comparable to those in the

Senate bill, for example:





The Secretary could consider limited data sets and non-clinical data as substantial

evidence of safety and effectiveness, recognizing the smaller populations

available for study of an LPAD drug, and the different balance of benefit versus

harm in these populations.

Products approved using this pathway must carry prominent labeling noting the

intended use for a limited and specific population of patients.

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







Sponsors must submit promotional materials to FDA for review 30 days prior to

dissemination.

Sponsors may pursue this pathway concurrently with other specified streamlined

approval pathways, as applicable.

FDA would be required to issue draft implementation guidance within 18 months

of enactment.

This provision should not be construed to alter current prescribing or other

medical practices (such as off-label prescribing).

Other elements of the review pathway were found only in the House provision, for example:





Upon a sponsor’s request, FDA may enter into written agreement with the

sponsor to define the process and data needed to review the limited population

use application. The process could not proceed without such written agreement.

The process must adhere to existing goals and procedures agreed upon by

sponsors and FDA in the Prescription Drug User Fee Amendments of 2012 (P.L.

112-144, Title I).

In addition, the House provision would require the Secretary to conduct and publish an

assessment of the program within 48 months of enactment, and to seek public input. It also would

allow the Secretary to expand the limited population use pathway if deemed beneficial by the

assessment above.

Advancing Precision Medicine Act of 2016 (S. 2713)

Issue Background

Precision medicine is a relatively new term for what has traditionally been called personalized

medicine, the idea of providing health care to individuals based on specific patient characteristics.

Currently, medical care is generally provided in a “trial and error” manner, with treatment

adjusted based on real-time patient response. Precision medicine would tailor medical treatment

to individual patients, thus aiming to improve health outcomes and save health care costs.

On February 25, 2016, the White House hosted a Precision Medicine Initiative (PMI) Summit to

mark the one year anniversary of the initiative’s launch, first announced in the 2015 State of the

Union address. The mission of the PMI is “(t)o enable a new era of medicine through research,

technology, and policies that empower patients, researchers, and providers to work together

toward development of individualized care.”41 In the first year, the PMI’s three key agencies—

National Institutes of Health (NIH), Food and Drug Administration (FDA), and the Office of the

National Coordinator for Health Information Technology (ONC)—began work in this area. The

FY2017 President’s budget requests a total of $309 million for the PMI: $4 million to FDA, $5

million to ONC, and the remaining $300 million to NIH.

For More Information

CRS Insight IN10227, The Precision Medicine Initiative, by

Amanda K. Sarata and Judith A. Johnson.

41 Executive Office of the President, “The Precision Medicine Initiative,” https://www.whitehouse.gov/precision-

medicine.

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Precision medicine research efforts rely on the

CRS Report R44026, Genomic Data and Privacy:

collection of large amounts of health data;

Background and Relevant Law, coordinated by Amanda

K. Sarata.

therefore, access to this data may be a concern

in the context of this type of research. The

sharing of genetic and genomic data among private individuals, researchers, and the federal

government has, at times, prompted concerns that the information, if collected or retained by a

federal executive branch agency, could be subject to public release pursuant to the Freedom of

Information Act (FOIA). FOIA, however, specifies nine categories of information that may be

exempted from the rule of disclosure, allowing agencies to withhold applicable records.

Exemption 3 allows agencies to withhold applicable records if the data are specifically exempted

from disclosure by a statute other than FOIA, if that statute meets criteria laid out in FOIA. These

types of Exemption 3 statutes are often referred to as b(3) exemptions because they are authorized

in 5 U.S.C. §552(b)(3).

As a mechanism for addressing compelled disclosure of research data, NIH currently issues

Certificates of Confidentiality pursuant to §301(d) of the Public Health Service Act (42 U.S.C.

§241(d)) at the request of an investigator. A Certificate of Confidentiality protects investigators

from being compelled to disclose information that would identify research subjects in any civil,

criminal, administrative, legislative, or other proceeding. This requirement can help promote

participation in research by adding an additional layer of privacy protection.

In contrast to compelled disclosure of research data by FOIA request, sharing of genomic data

generated by NIH-funded research is a priority of NIH. The agency has established a

comprehensive policy for the sharing of genomic data that “applies to all NIH-funded research

that generates large-scale human or non-human genomic data as well as the use of these data for

subsequent research.”42 This policy requires investigators to outline their data-sharing plans as

part of their funding applications; if investigators fail to submit the required data, NIH may

withhold funding.

Precision medicine research will often be considered to be highly innovative, risky, and

potentially high-reward, and will also often require close partnerships with private industry. The

NIH Common Fund, within the Office of the NIH Director, supports the High-Risk, High-Reward

Research Program. This program has “four unique funding opportunities for exceptionally

creative scientists who propose highly innovative approaches to major challenges in biomedical

research.”43 These awards are intended “to encourage creative, outside-the-box thinkers to pursue

exciting and innovative ideas about biomedical research.”

Other transaction (OT) authority is a special vehicle used by certain federal agencies for obtaining

or advancing research and development (R&D). An OT is not a contract, grant, or cooperative

agreement, and there is no statutory or regulatory definition of “other transaction.” Only those

agencies that have been provided OT authority may engage in other transactions. Generally, OT

authority is created because the government needs to obtain leading-edge R&D from commercial

sources, but some companies (and other entities) are unwilling or unable to comply with the

government’s procurement regulations.

42 National Institutes of Health, “National Institutes of Health Genomic Data Sharing Policy,”

http://gds.nih.gov/PDF/NIH_GDS_Policy.pdf, p. 1.

43 NIH, Office of Strategic Coordination, The Common Fund, High-Risk Research, at

https://commonfund.nih.gov/highrisk/index.

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Senate Legislation

S. 2713, the Advancing Precision Medicine Act of 2016, has five provisions that together would

support precision medicine by (1) codifying the PMI; (2) requiring issuance of Certificates of

Confidentiality to investigators of federally funded research; (3) protecting identifiable, sensitive

information from release under FOIA; (4) requiring the sharing of NIH-supported research data in

certain circumstances; and (5) supporting high-risk, high-reward research. Specifically, the

provisions would support precision medicine in the following ways:











Codify the President’s Precision Medicine Initiative (PMI) by encouraging the

Secretary to establish and carry out the PMI, and by allowing specified

components and authorities in the carrying out of the PMI as well as identifying

requirements of the initiative (§2).

Amend PHSA Section 301(d) to require the Secretary to issue a Certificate of

Confidentiality to research investigators of federally funded research in which

sensitive, identifiable information is collected to protect the privacy of research

participants. The provision would prohibit the individual with the certificate from

disclosing sensitive information about the research participants, with certain

exceptions, as specified, and would make this type of information immune from

the legal process (§3).

Amend PHSA Section 301 to allow the Secretary to exempt from disclosure

under FOIA exemption (b)(3) specified biomedical information that identifies an

individual or that has an associated risk that the information may be reidentified.

The Secretary would be required to make each such exemption available in

writing and to the public, upon request (§4).

Amend PHSA Section 402(b) to allow the Secretary to require recipients of NIH

grants or agreements to share data generated from such NIH grants or agreements

in a manner consistent with all applicable federal law (§5).

Add a new PHSA Section 402(m) to allow the NIH Director to approve requests

by institute and center directors to engage in transactions other than a contract,

grant, or agreement with respect to projects for high-impact, cutting-edge

research, as specified. This provision would require the Secretary to submit a

report to Congress evaluating the activities under this new subsection by

September 30, 2020 (§6).

Comparable Provisions in the 21st Century Cures Act

Title II, Subtitle C, Section 2041, of H.R. 6 addresses precision medicine but is not comparable to

S. 2713 in its approach. This section would require the Secretary, not later than 18 months after

enactment, to issue and periodically update guidance to help sponsors develop a precision drug or

biological product. It would also, for a precision drug or biological product application where the

product is for the treatment of a serious or life-threatening disease or condition and has been

designated as an orphan drug, allow the Secretary to consider the application for expedited review

programs and to rely on previously submitted information about the drug or biological product

(for more information, see S. 2030, the Advancing Targeted Therapies for Rare Diseases Act of

2015).

In addition, Section 1028 of H.R. 6 (Title I, Subtitle B) addresses high-risk, high-reward research,

and has a similar focus as the Senate bill provision; however, it would not establish OT authority,

nor would it require a report to Congress. This section would require the NIH institute directors to

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establish programs to conduct or support projects that pursue innovative approaches to major

contemporary challenges in biomedical research and to set aside a specific percentage of funding

for such projects. The Senate bill would not require the allocation of a certain percentage of

funding for this research.

The Combination Products Innovation Act of 2016

(S. 1767)

Issue Background

FDA regulatory authority over medical product safety and effectiveness covers drugs, biological

products, and medical devices. The agency generally divides responsibilities for the review of

marketing applications in its product-centered offices. The Center for Drug Evaluation and

Research (CDER) reviews new drug applications for approval, the Center for Biologics

Evaluation and Research reviews biologics license applications for licensure, and the Center for

Devices and Radiological Health (CDRH) reviews premarket approval applications for approval

and 510(k) notifications for clearance.

In 2002, Congress directed FDA to establish an Office of Combination Products (OCP) to

facilitate the timely review and regulation of drug-device, drug-biologic, and device-biologic

combination products, pursuant to the requirements in FFDCA Section 503. Both drugs and

devices are defined in the FFDCA as products intended to diagnose, prevent, or treat disease, or

otherwise affect the structure or any function of the body. Unlike a drug, however, a device “does

not achieve its primary intended purposes through chemical action within or on the body ... and is

not dependent upon being metabolized for the achievement of its primary intended purposes.”

OCP is required to determine the primary mode of action of a combination product and regulate it

based on that determination. Generally, OCP treats a drug-device combination product as a drug

unless the manufacturer can prove that it satisfies the device exclusionary clause; i.e., the product

does not rely on chemical action to achieve its primary intended purpose.

A manufacturer whose product is assigned to CDER will have a higher standard of evidence, a

potentially higher requirement for supporting data, a higher user fee, and probably a longer

premarket review time period than a manufacturer whose product is assigned to CDRH.

Senate Bill

S. 1767 would amend Section 503(g) of the FFDCA to require the Secretary to assign a primary

center for the regulation of combination products and to conduct premarket review of these

products under a single application whenever appropriate, among other things. The bill would

require the Secretary to determine the primary mode of action for a combination product—

defined as the single mode of action expected to make the greatest contribution to the overall

intended therapeutic effects of the product—in order to determine how best to review the product.

The Secretary would not be permitted to determine that the primary mode of action is that of a

drug or biologic solely because the combination product has any chemical action within or on the

body.

If the sponsor of a combination product disagreed with the Secretary’s determination and

requested an explanation, the Secretary would be required to provide a substantive scientific

rationale for the determination. In addition, the sponsor would be able to propose and, subject to

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an agreement with the Secretary, conduct additional studies to establish the relevance of any

chemical action in the product’s primary mode of action.

At any time following the Secretary’s determination of the product’s primary mode of action, the

sponsor would be permitted to submit a proposed combination product review plan, as specified.

The Secretary would be required to provide a written response to the sponsor indicating whether

the plan was accepted, accepted in part, or denied. The bill would allow the sponsor, if the plan

were to be denied, to request a meeting with the Secretary to discuss the information and

requirements necessary to make the plan acceptable. A denied plan would be allowed to be

resubmitted.

With respect to an accepted plan, in whole or part, the Secretary would be required to accept the

plan if the Secretary determines the data to be collected are appropriate for premarket approval; in

addition, a plan, in whole or in part, that has been accepted would be required to remain in effect

except with written agreement of the Secretary and the sponsor or pursuant to a decision by the

reviewing primary agency center director that a relevant scientific issue had been identified since

acceptance of the plan. If such a decision were to be issued, the Secretary would be required to

provide written notice to the sponsor as well as an opportunity for a meeting.

For premarket review of a combination product that includes an approved constituent component

(e.g., a drug or device), the Secretary would be allowed to require that a sponsor submit only that

information that is necessary to determine the safety of the combination product, including any

incremental risks or benefits posed by the product, taking into account any prior findings for the

approved constituent parts.

For premarket review of a combination product that contains an approved drug constituent, the

applicant would be permitted to rely upon investigational studies not conducted by the applicant

and for which the applicant has not obtained a right of reference.44 In relying upon these studies,

the applicant would be required to certify any patents that claim the approved drug or claim use

of the approved drug.45 The applicant would also be required to give notice to the holder of the

approved application and patent owner that the patent is invalid or will not be infringed upon. The

approval of an application containing such certification would be required to be made effective as

specified in FFDCA Section 503(c)(3), among other requirements. Notwithstanding any other

provision of Section 503(g)(5), an application for a combination product that contains an

approved drug constituent would be considered a 505(b)(2) application.46 The bill would not

prohibit a sponsor from submitting separate applications for the constituent parts of a

combination product, unless the Secretary determines that a single application is necessary.

The bill would further require OCP to help coordinate timely review of combination products

across relevant agency centers and to ensure that persons are designated in each primary agency

center as points of contact for the sponsors of combination products. The bill would specify

additional duties for OCP related to communication; facilitating meetings between the agency and

the sponsors; and dispute resolution. The bill would require the Secretary, not later than four years

after enactment, to issue final guidance on the combination product review process, as specified,

44 Right of reference means “the authority to rely upon, and otherwise use, an investigation for the purpose of obtaining

approval of an application, including the ability to make available the underlying raw data from the investigation for

FDA audit, if necessary.” 21 C.F.R. 314.3.

45 Such patent information is generally published in the Orange Book when the application is approved.

46 A 505(b)(2) application is one for which one or more of the investigations relied upon by the applicant for approval

"were not conducted by or for the applicant and for which the applicant has not obtained a right of reference or use

from the person by or for whom the investigations were conducted.” FFDCA §505(b)(2)).

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and would add reporting requirements to the annual report to Congress on the activities of OCP as

specified.

The bill would amend FFDCA Section 520(h)(4) to prohibit the use of information contained in

an application for premarket approval of a class III device from being used in an application for

premarket approval of a combination product that contains an approved drug constituent, unless

the applicant provides a patent certification and notifies the holder of the approved application

and patent owner that the patent is invalid or will not be infringed upon.

The bill would also require the Secretary to identify, not later than 18 months after enactment,

types of combination products that the Secretary proposes may adopt different good

manufacturing practices. This list would be required to be published in the Federal Register and

updated as needed.

Comparable Provisions in the 21st Century Cures Act

Section 2181 of H.R. 6 addresses the issue of combination products, but would take a different

approach than the Senate legislation. The H.R. 6 section would amend FFDCA Section

503(g)(4)(C) to require that the Secretary “issue final guidance that describes the responsibilities

of each agency center regarding its review of combination products.”

Health Software: The Medical Electronic Data

Technology Enhancement for Consumers’ Health

Act (S. 1101)

Issue Background

Increasingly, health care facilities are using computer systems for routine administrative and

financial transactions (e.g., patient scheduling, claims processing) and for capturing and

exchanging clinical information (e.g., electronic health records). One area that is undergoing

especially rapid growth and innovation is mobile health. This term refers to the use of portable

devices, such as smartphones and tablets, for medical purposes. Users interface with mobile

devices through the use of software applications (“apps”).

The number of health-related mobile apps being developed, downloaded, and used is increasing

at an almost exponential rate. Some apps simply access stored medical information, while others

capture and input patient data into an electronic health record (EHR). Many apps now provide

clinical decision support (CDS) using algorithms that use clinical information to generate

customized (i.e., patient-specific) diagnosis and treatment recommendations.

Regulators are particularly interested in mobile apps that could pose a risk to patients if they

malfunction. These include apps used to display and transfer data from a patient monitor; apps

that control an existing device; and apps that transform a mobile platform into a medical device

(e.g., an app that allows patients to use their smartphone to record electrocardiograms using a lead

that connects to the phone).

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Under the FFDCA, the FDA has regulatory authority over software that meets the statutory

definition of a medical device and is “intended for use in the diagnosis of disease or other

conditions, or in the cure, mitigation, treatment, or prevention of disease.”47

FDA released a nonbinding guidance document on mobile medical apps in September 2013, in

which it stated its intention to focus on the functionality of the mobile health product, not the

mobile platform itself.48 Thus, the agency does not plan to regulate smartphone or tablet

manufacturers. FDA further stated its intention to adopt a risk-based approach by applying its

regulatory oversight to “only those mobile apps that are medical devices and whose functionality

could pose a risk to patient safety if the mobile app were to not function as intended.”

In February 2015, FDA released updated guidance on its risk-based approach to regulating mobile

medical apps.49 The agency provided examples of mobile apps that do not meet the statutory

definition of a medical device and so are not subject to its regulatory authority. They include apps

used to automate general office operations in health care settings. The agency then gave examples

of mobile apps that may meet the definition of a medical device but for which the agency intends

to exercise enforcement discretion—meaning that it does not intend to apply regulatory

oversight—because the apps pose minimal risk to the public. This category includes mobile apps

that help asthmatics track inhaler usage and asthma episodes; apps that give patients a portal into

their own EHR; and apps intended for individuals to log, track, or make decisions related to

general wellness (e.g., Fitbit).

Finally, FDA provided examples of mobile apps that are the focus of the agency’s regulatory

oversight. These apps meet the definition of a medical device, and they pose a significant risk to

patient safety if they do not function as intended. Examples include apps that connect to an

existing device for the purpose of controlling its operation, function, or energy source; apps that

are used in active patient monitoring or analyzing patient-specific medical device data from a

connected device; and apps that transform a mobile platform into a regulated medical device.

The updated guidance did not address regulation of CDS software. That topic remains under

consideration.

Senate Legislation

S. 1101, the Medical Electronic Data Technology Enhancement for Consumers’ Health

(MEDTECH) Act, would exclude certain types of health software from the FFDCA definition of

medical device, including products that provide a variety of administrative and health

management functions; electronic health record technology that creates, stores, transfers, and

displays patient information; and software that interprets and analyzes patient data to help make

clinical diagnosis or treatment decisions (including CDS tools). In general, this would preclude

FDA from regulating these products as medical devices.

However, S. 1101 creates an exception allowing FDA to exercise regulatory authority if the

agency determines that the use of the software “would be reasonably likely to have serious

adverse health consequences” based on four specified criteria. One of the criteria is the likelihood

and severity of patient harm if the software were not to perform as intended. The exception would

47 FFDCA §201(h), 21 U.S.C. §321(h).

48 Food and Drug Administration, Mobile Medical Applications: Guidance for Industry and Food and Drug

Administration Staff, September 25, 2013.

49 Food and Drug Administration, Mobile Medical Applications: Guidance for Industry and Food and Drug

Administration Staff, February 9, 2015, http://www.fda.gov/downloads/MedicalDevices/UCM263366.pdf.

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apply to EHR systems (and other software that simply creates, stores, transfers, and displays

data), as well as CDS and other analytic tools.

This risk-based approach broadly reflects the agency’s current guidance on regulating mobile

medical apps.

Comparable Provisions in the 21st Century Cures Act

The health software provisions in H.R. 6, Sections 2241-2243, are similar to those in S. 1101.

Like the Senate bill, H.R. 6 would exclude various types of software applications from FDA’s

regulatory oversight. Excluded applications include products that provide administrative and

health management functions; software that creates, stores, transfers, and displays patient

information; and analytic tools that provide both general health information and patient-specific

information (i.e., CDS). The House bill also would establish a risk-based exception allowing FDA

to exert regulatory authority. However, H.R. 6 would create a narrower exception for CDS

software that the agency determines “poses a significant risk to patient safety” based on the same

four criteria specified in S. 1101.

Interoperability: Improving Health Information

Technology Act (S. 2511)

Issue Background

The Health Information Technology for Economic and Clinical Health (HITECH) Act of 2009

authorized Medicare and Medicaid incentive payments to acute-care hospitals and physicians

who attest to being meaningful users of certified electronic health record (EHR) technology.50 The

law instructed the Secretary to make the measures of meaningful use more stringent over time,

which CMS has done in stages.

Stage 1 of meaningful use requires eligible hospitals and physicians to use EHR technology to

meet a series of meaningful use objectives that generally involve capturing and storing structured

patient data (e.g., vital signs, medications, lab test results). Providers must use EHR technology

that has been tested and certified as having the capability to perform these functions. Testing and

certification entities are authorized by the HHS Office of the National Coordinator for Health

Information Technology (ONC).

Stage 2 of meaningful use requires eligible hospitals and physicians to use their EHR technology

to perform more advanced functions, such as giving patients access to their electronic health

information and exchanging patient data during transitions of care (e.g., a hospital discharge to a

rehabilitation facility, or a physician referral).

Beginning in 2015, hospitals and physicians that are not meaningful EHR users are subject to a

Medicare payment adjustment (i.e., penalty) unless they qualify for a hardship exception.

CMS published a final rule in October 2015 modifying the meaningful use Stage 2 objectives and

establishing the objectives for Stage 3, which hospitals and physicians must meet by 2018.51 The

agency made significant changes to the meaningful use program in response to the concerns of

50 P.L. 111-5, Division B, Title IV; 123 Stat. 467.

51 Centers for Medicare & Medicaid Services, “Medicare and Medicaid Programs; Electronic Health Record Incentive

Program - Stage 3 and Modifications to Meaningful Use in 2015 Through 2017; Final Rule,” 80 Federal Register

62761, October 16, 2015.

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health care providers about the challenges and burdens they face in making EHR technology

work. For example, CMS eliminated several clinical documentation objectives, and instead

focused on a few objectives that capture more advanced uses of the technology (e.g., CDS, health

information exchange).

CMS also published an accompanying final rule (the 2015 Edition final rule) that expands the

certification program.52 In addition to certifying the next generation of EHR technology that

hospitals and physicians need to achieve meaningful use Stage 3, the program will be able to

certify health information technology (HIT) products with a different combination of capabilities

and functionalities that meet the needs of other types of health care providers and settings that are

not eligible to participate in the EHR incentive program.

The 2015 Edition final rule for the certification program established new transparency

requirements for HIT developers. It also seeks to improve interoperability, for example, by

requiring certified HIT products to adopt new and updated vocabulary and content standards for

structured health information, including a common clinical data set composed of standardized

data elements, and by improving the testing of the ability of HIT systems to transmit, receive, and

use standardized clinical documents.

ONC released a national interoperability roadmap in October 2015—developed over an 18-month

period with input from numerous stakeholders—to coordinate efforts around achieving HIT

interoperability.53 ONC expects the roadmap to evolve in partnership with the public and private

sectors as technology and policy dictate. The roadmap establishes interoperability goals for the

next 10 years, with 2017 set as the deadline for individuals and health care providers along the

care continuum to be able to send, receive, find, and use core clinical data.

The roadmap discusses the payment and regulatory drivers for promoting interoperability, as well

as the central policy and technical components of a fully interoperable nationwide health

information infrastructure. A key challenge is overcoming legal and governance barriers to trusted

information exchange by getting stakeholders to agree to and follow a common set of standards,

services, policies, and practices that facilitate exchange and use of electronic health information

without limiting competition.

Medicare Access and CHIP Reauthorization Act of 2015 (MACRA)54

MACRA declared it a national objective to achieve widespread interoperability of certified EHR

technology by the end of 2018. The law defines interoperability as the ability of health

information systems to not only exchange clinical information but to also use the information

based on common standards in order to improve care and patient outcomes.

In addition, MACRA instructed the Secretary, within one year of enactment, to submit a report to

Congress on ways to help health care providers compare and select certified EHR technology,

such as through surveying EHR users and vendors and making such information publicly

available.

52 Office of the National Coordinator for Health Information Technology, “2015 Edition Health Information

Technology (Health IT) Certification Criteria, 2015 Edition Base Electronic Health Record (EHR) Definition, and

ONC Health IT Certification Program Modifications; Final Rule,” 80 Federal Register 62601, October 16, 2015.

53 Office of the National Coordinator for Health Information Technology, Connecting Health and Care for the Nation:

A Shared Nationwide Interoperability Roadmap, Final Version 1.0, October 2015, https://www.healthit.gov/sites/

default/files/hie-interoperability/nationwide-interoperability-roadmap-final-version-1.0.pdf.

54 P.L. 114-10, §106(b), 129 Stat. 138.

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Finally, MACRA required the Secretary, in consultation with stakeholders, to establish

interoperability metrics to measure progress toward achieving the national objective of

widespread interoperability of certified EHR technology by July 1, 2016. If that objective is not

met by December 31, 2018, the Secretary will have until December 31, 2019, to submit a report

to Congress identifying the barriers to widespread interoperability and providing

recommendations for achieving it.

Information Blocking

ONC released a report to Congress on health information blocking in April 2015.55 The report

defined information blocking as knowingly and unreasonably interfering with the exchange or use

of electronic health information, and examined the nature and extent of the practice based on

available evidence. It also detailed the actions that ONC is taking, in coordination with other

federal agencies, to address information blocking. Finally, the report identified gaps in authority

that limit the ability of ONC and other federal agencies to effectively target, deter, and remedy

such conduct.

MACRA requires eligible hospitals and physicians, beginning April 2016, to indicate through

meaningful use attestation (or some other process specified by the Secretary) that they have not

knowingly and willfully taken any action to limit or restrict the interoperability of their certified

EHR technology.

Patient Access

The Health Insurance Portability and Accountability Act (HIPAA) Privacy Rule gives individuals

the right of access to inspect, obtain a copy of, and transmit to a third party a copy of their health

information.56

One of the meaningful use objectives that must be met by hospitals and physicians using certified

EHR technology is to provide individuals with the ability to view, download, and transmit (VDT)

their electronic health information. As part of meeting that objective, the 2015 Edition final rule

for the certification program requires EHR developers to publish programming instructions to

enable other software application developers to produce apps giving individuals access to their

clinical data.

Patient Matching

ONC released a report on patient identification and matching (i.e., linking patient records with the

correct individual) in February 2014. It recommended standardizing patient attributes for the

purpose of information exchange, coordinating activities among organizations, and introducing

EHR certification criteria for capturing patient identification standards.

Patient matching was addressed in the 2015 Edition final rule for the HIT certification program.

Certified EHR systems must be able to create a summary-of-care document that includes the

following standardized patient data: first name; last name; previous name; middle name

(including middle initial); suffix; date of birth (year, month, and day are required fields; hours and

minutes are optional); address; phone numbers (home, business, cell); and sex.

55 Office of the National Coordinator for Health Information Technology, Report on Information Blocking, Report to

Congress, April 2015, https://www.healthit.gov/sites/default/files/reports/info_blocking_040915.pdf.

56 45 C.F.R. §164.524.

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Senate Legislation

The Improving Health Information Technology Act (S. 2511) includes multiple provisions to

promote HIT interoperability, penalize information blocking, reduce the administrative and other

burdens of using EHR technology, and increase patient access to electronic health information. In

broad terms:













S. 2511 would require ONC to reduce the regulatory and administrative burdens

of using EHR technology and relieve physicians of EHR documentation

requirements specified in HHS regulations. ONC also would be required to

encourage the certification of HIT for use in medical specialties and sites of

service, and to adopt certification criteria for HIT used by pediatricians. (§2)

S. 2511 would establish a program and methodology for calculating and

awarding a star rating to each certified HIT product—based on criteria such as

the product’s security, user-centered design, interoperability, and conformance to

certification testing—to help health care providers choose HIT products. HIT

developers would be required to report on these criteria for each of their certified

products. The rating program’s methodology and criteria would be posted online,

as would each HIT product’s star rating (the rating system must use at least three

stars). Each developer of an HIT product that received a one-star rating would

have to develop and implement a plan to improve the rating, or risk having the

product decertified. Hospitals and physicians would be exempted from the

Medicare EHR payment adjustment if their EHR technology was decertified.

(§3)

S. 2511 would give the HHS Office of Inspector General the authority to

investigate and penalize information-blocking practices by HIT developers,

health information exchanges and networks, and health care providers.

Developers, exchanges, and networks found to have engaged in information

blocking would be subject to civil monetary penalties. Health care providers

found to have engaged in information blocking would be subject to incentives

and disincentives to change their behavior. ONC would be authorized to refer

instances of information blocking to the Office for Civil Rights if a HIPAA

privacy consultation would resolve the matter. (§4)

S. 2511 would require ONC to convene stakeholders to develop a trusted

exchange framework and a common agreement among existing networks to

exchange electronic health information (i.e., a “network of networks”). The

Secretary would be required to establish a digital contact directory for health care

professionals, practices, and facilities. (§5)

S. 2511 would require certified HIT to be capable of transmitting data to, and

receiving data from, clinician-led (and other) registries. And it would extend

federal privilege and confidentiality protections to HIT developers who report

and analyze patient safety information related to HIT use. (§6)

S. 2511 would facilitate patients’ access to their electronic health information by

requiring ONC to (1) encourage partnerships between health information

networks, health care providers, and other stakeholders to offer access through

secure, user-friendly software; (2) educate providers on using exchanges to

provide patient access; and (3) issue guidance to exchanges on providing patient

access. ONC and OCR would be required to develop policies that support

dynamic technology solutions for promoting patient access, and would have to

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

help educate individuals and providers on patients’ rights under HIPAA. Finally,

ONC would have to ensure that HIT standards and certification support patients’

access to their electronic health information. (§7)

S. 2511 would require GAO to conduct a review of the methods used for secure

patient matching and report its findings to Congress within two years. (§8)

Comparable Provisions in the 21st Century Cures Act

Section 3001 of the 21st Century Cures Act (“Ensuring Interoperability of Health Information

Technology”) includes a series of HIT interoperability provisions. While a few of these provisions

are comparable—though by no means identical—to the language in S. 2511, other provisions in

H.R. 6 have no counterpart in the Senate bill. Similarly, several of the topics addressed in S. 2511

are not covered in the House bill.

Like S. 2511, the House bill would give the HHS Office of Inspector General new enforcement

authority to investigate claims of HIT developers engaged in information blocking. However, in

place of the Senate bill’s star rating program for certified HIT products, which H.R. 6 does not

include, the House bill would require HIT developers to attest to a series of requirements as a

condition of product certification. They include not taking any action (including business,

technical, or organizations practices) that constitutes information blocking.

In other areas of comparability between the two bills, H.R. 6 also would extend federal privilege

and confidentiality protections to HIT developers who report and analyze patient safety

information related to HIT use. And it would require ONC to publish guidance on the HIPAA

privacy rule and its relationship to information blocking.

H.R. 6 addresses a number of areas not covered by the Senate bill. For example, the House bill

includes extensive language on the development of new interoperability standards. It would

eliminate the HIT Standards Committee and require the Secretary to contract directly with

standards development organizations. In addition, beginning in 2020, hospitals and physicians

demonstrating EHR meaningful use would have to attest that they are not engaged in information

blocking. Importantly, H.R. 6 would repeal the interoperability provisions in MACRA.

Unlike the Senate bill, H.R. 6 would not establish a star rating program for certified HIT

products, nor would it address patient access to electronic health information, patient record

matching, the regulatory and administrative burdens of using EHR technology, or the

development of trusted relationships between existing HIT networks.57

57 For a detailed comparison of the interoperability provisions in H.R. 6 and S. 2511, see CRS congressional

distribution memorandum, “Side-by-Side Comparison of the HIT Interoperability provisions in H.R. 6 (21st Century

Cures Act), as Passed by the House, and S. 2511 (Improving Health Information Technology Act), Reported by the

Senate HELP Committee,” February 12, 2016. The memorandum is available upon request to congressional staff.

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The Medical Countermeasures Innovation Act of

2015 (S. 2055)

Medical Countermeasures (§§2-6)

Issue Background

Following the terrorist attacks of 2001, the federal government determined that it needed

additional medical countermeasures (such as diagnostic tests, drugs, vaccines, and other

treatments) to respond to an attack using chemical, biological, radiological, or nuclear (CBRN)

agents. The Project BioShield Act (P.L. 108-276), the Pandemic and All-Hazards Preparedness

Act (PAHPA, P.L. 109-417), and Pandemic and All-Hazards Preparedness Reauthorization Act of

2013 (PAHPRA, P.L. 113-5) established new authorities and programs in the Department of

Health and Human Services (HHS) to support the development and procurement of new CBRN

medical countermeasures.

Implementation of the federal countermeasure strategy requires coordinated activities by several

separate agencies. An interagency working group, the Public Health and Emergency Medical

Countermeasure Enterprise (PHEMCE), is responsible for coordinating these activities to ensure

federal countermeasure needs are addressed efficiently. The PHEMCE is headed by the HHS

Assistant Secretary for Preparedness and Response (ASPR) and includes representatives from the

Food and Drug Administration, Centers for Disease Control and Prevention, National Institutes of

Health, Department of Defense, Department of Homeland Security, Department of Agriculture,

and Department of Veterans Affairs. In addition, the Pandemic and All-Hazards Preparedness

Reauthorization Act of 2013 (P.L. 113-5) requires the ASPR to develop an annual “coordinated 5year budget plan” for countermeasure basic and advanced research, development, and

procurement activities.

The Pandemic and All-Hazards Preparedness Act (P.L. 109-417) established the Biomedical

Advanced Research and Development Authority (BARDA) to develop and procure medical

countermeasures against CBRN agents, pandemic influenza, and emerging infectious diseases.

BARDA contracts with companies to develop and commercialize potential countermeasures.

These contracts specify development activities for the company to perform and may extend

multiple years. The Project BioShield Act (P.L. 108-276) established a special process and

funding mechanism through which the HHS Secretary may obligate funds to procure

countermeasures that still need up to 10 more years of development. Up to half of the total

amount of the Project BioShield contract may be paid out for the company meeting specified

developmental milestones. The remaining amount of the contract is payable on delivery of the

countermeasure to the Strategic National Stockpile. Thus, HHS has two separate mechanisms to

support CBRN countermeasure advanced development and commercialization: (1)

countermeasure advanced development contracts and (2) Project BioShield acquisition contracts

with developmental milestone payments.

Senate Legislation

S. 2055, The Medical Countermeasures Innovation Act of 2016, as reported, has several

provisions that would change the manner in which the federal government supports the

development and procurement of medical countermeasures against CBRN agents.

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Section 2 of S. 2055 would require the HHS Secretary to provide “timely and accurate

recommended” guidelines for using the medical countermeasures in the Strategic National

Stockpile. Under current law, the HHS Secretary must report to “appropriate committees of

Congress” within “30 days” when the amount available for Project BioShield procurements (the

“special reserve fund”) falls below $1.5 billion. This bill would change that requirement to

specify the recipients of the report as the Senate Committee on Health, Education, Labor, and

Pensions, the Senate Committee on Appropriations, the House Committee on Energy and

Commerce, and the House Committee on Appropriations. This report would be required by

“March 1 of each year in which” the amount available drops below $1.5 billion.

Section 3 would move contracting authority for Project BioShield and BARDA advanced

development from ASPR to BARDA. Such a move was recommended by the Blue Ribbon Panel

on Biodefense to “reduce unnecessary bureaucratic delays, improve efficiency and decision

making, and enhance BARDA program effectiveness and accountability.”58

Section 4 would require ASPR to provide additional information in its “coordinated 5-year budget

plan” and require that it be made publically available in “a manner that does not compromise

national security.” The budget plan would also need to consider the development of

countermeasures and products for emerging infectious diseases that may present “a threat to the

nation.”

Section 5 would allow the HHS Secretary to partner with “an independent, non-profit entity” to

“foster and accelerate the development of medical countermeasures; ... promote the development

of new and promising [countermeasure] technologies; ... [and] address unmet public health needs

... such as novel antimicrobials for multidrug resistant organisms and multiuse platform

technologies for diagnostics, prophylaxis, vaccines, and therapeutics.” This partner could provide

business advice and use venture capital practices to invest in companies developing medical

countermeasures. The U.S. intelligence community has successfully used a similar strategic

investor model to address its unmet technology needs through In-Q-Tel.59 This bill would

establish certain criteria for the partner, including prior experience in technology innovation and

successful partnering with the federal government. The HHS Secretary acting through the

BARDA Director would provide the entity with the government needs and requirements and a

description of the work to be done under the agreement. The entity would be required to provide

regular reports on the spending of funds provided by HHS and on progress meeting the identified

needs. The bill would require the Government Accountability Office to evaluate this partnership

four years after enactment. This authority would sunset on September 30, 2022.

Section 6 would remove the current need for the President to approve use of the Project BioShield

special reserve fund.60 The Blue Ribbon Study Panel on Biodefense recommended this change to

streamline the Project BioShield contracting process.61 This section would also specify the

congressional committees that HHS must notify of a decision to use Project BioShield funds as

the Senate Committee on Health, Education, Labor, and Pensions, the House Committee on

Energy and Commerce, and the appropriation committees in each chamber.

58 Blue Ribbon Study Panel on Biodefense, A National Blueprint for Biodefense: Leadership and Major Reform

Needed to Optimize Efforts, Washington, DC, October 2015, p. 57, http://www.biodefensestudy.org/.

59 See https://www.iqt.org.

60 The President delegated this authority to the Office of Management and Budget.

61 Blue Ribbon Study Panel on Biodefense, A National Blueprint for Biodefense: Leadership and Major Reform

Needed to Optimize Efforts, Washington, DC, October 2015, p. 57.

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Comparable Provisions in the 21st Century Cures Act

Other than the provisions relating to Food and Drug Administration priority review (discussed

elsewhere in this report), the 21st Century Cures Act contains no comparable provisions to S.

2055 as reported.

Priority Review to Encourage Treatments for Agents that Present

National Security Threats (§§7-8)

Issue Background

Under the Prescription Drug User Fee Act of 1992 (PDUFA), FDA agreed to specific goals for

improving the drug review time and created a two-tiered system of review times: Standard

Review and Priority Review. Compared with the amount of time standard review generally takes

(approximately 10 months), a Priority Review designation means FDA’s goal is to take action on

an application within 6 months.62 Currently, FDA has two authorized priority review voucher

programs (the rare pediatric disease priority review program, and the tropical disease priority

review program), funded by user fees, which provide a transferable voucher, under specified

conditions, to a sponsor of an approved new drug or biological product to be used for the priority

review of another application. The purpose of the priority review drug voucher programs is to

incentivize development of new treatment for diseases that may otherwise not attract

development interest from companies due to either cost or lack of market opportunities.

Senate Legislation

Section 7 of this bill would add a new FFDCA section 565A, “Priority Review to Encourage

Treatments for Agents that Present National Security Threats.” This section would establish a new

priority review voucher program, funded by user fees, to provide a transferable voucher, under

specified conditions, to a sponsor of an approved new human drug product application for a

material threat medical countermeasure to be used for the priority review of another application.

This section defines a “material threat medical countermeasure application” as, among other

things, a human drug application “to prevent or treat harm from a biological, chemical,

radiological, or nuclear agent identified as a material threat” under the Public Health Service

Act,63 or “to mitigate, prevent, or treat harm from a condition that may result in adverse health

consequences or death and may be caused by administering a drug, or biological product against

such agent.”

Section 8 of this bill would require GAO to report on the effectiveness of the priority review

voucher program.

Comparable Provisions in the 21st Century Cures Act

There is no comparable provision in the House bill.

62 FDA, Priority Review, http://www.fda.gov/ForPatients/Approvals/Fast/ucm405405.htm.

63 PHSA §319F-2(c)(2)(A)(ii)

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Next Generation Researchers Act (S. 2014)

Issue Background

Congress has had a long-standing interest in developing the future biomedical research

workforce. Recent concerns have focused on ways to reduce the time between when young

investigators complete their training and when they receive their first independent NIH research

grant (i.e., achieve research independence). The NIH has created a number of initiatives that

strive to shorten this time, in part, to attempt to better retain young investigators in biomedical

research.64 The Departments of Labor, Health and Human Services, and Education, and Related

Agencies Appropriations Act, 2016 (P.L. 114-113, Division H), instructed the NIH Director to

enter into a contract with the National Academy of Sciences (NAS) to conduct a comprehensive

study of the policies affecting the next generation of researchers in the United States.

NIH funds seven loan repayment programs for researchers.65 Three of these are intramural

programs that provide educational loan repayment benefits to researchers in exchange for

undertaking research while employed by NIH. Intramural loan repayment programs support

researchers from disadvantaged backgrounds, those who are investigating AIDS, and those

undertaking general research (including general research by physicians during their fellowship

training). NIH also funds four programs to assist in the repayment of extramural researchers’

educational loans. These funds are awarded competitively to researchers who are employed by a

qualifying educational institution. Specific programs are available to extramural researchers

investigating health disparities, undertaking contraception and infertility research, engaging in

clinical research, and examining pediatric-related topics. Researchers may receive up to $35,000

per year in loan repayment benefits under each of these programs. The regulations that govern the

National Health Service Corps Loan Repayment program regarding participant eligibility,

application procedures, selection criteria, loan repayment contract terms, tax liability for

payments received, service obligation, and penalties for breach of contract apply to the NIH loan

repayment programs (where not inconsistent with the specific program).66 Under current law,

appropriations for loan repayments remain available until the end of the second fiscal year after

they are appropriated.

Senate Legislation

S. 2014, the Next Generation of Researchers Act, includes two provisions that would create

programs designed to develop and retain the biomedical workforce funded or employed by the

NIH.

Section 2 of S. 2014 would amend Part A of Title IV of the PHSA by adding a new Section 404M

to establish within the office of the NIH Director the Next Generation of Researchers Initiative

(the Initiative). Through the Initiative, the NIH Director would be required to coordinate all NIH

policies and programs focused on promoting and providing opportunities for new researchers.

64 See discussion in “NIH Initiatives to Assist Young Investigator” in CRS Report R41705, The National Institutes of

Health (NIH): Background and Congressional Issues.

65 For description of these programs, see Appendix A of CRS Report R43571, Federal Student Loan Forgiveness and

Loan Repayment Programs.

66 For program description, see CRS Report R43920, National Health Service Corps: Background and Trends in

Funding and Recruitment. For program guidance, see U.S. Department of Health and Human Services, Health

Resources and Services Administration, “National Health Service Corps: Loan Repayment Program,” available at

http://nhsc.hrsa.gov/loanrepayment/lrpapplicationguidance.pdf.

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Among other things, the NIH Director would have to coordinate with relevant agencies,

professional associations, and academic institutions to improve and update information on the

biomedical workforce in order to inform training, recruitment, and retention programs of

biomedical researchers. In establishing the Initiative, the NIH Director would have to take into

consideration recommendations made by NAS in its study on the next generation of researchers.

Not later than two years after completion of the NAS study, the NIH Director would be required

to submit a report to specified congressional committees regarding any actions taken by NIH with

respect to the NAS recommendations.

(Note that S. 2745 Section 5(a) also would add a new PHSA Section 404M, “Research Related to

Sexual and Gender Minority Populations.”)

Section 3 of S. 2014 would amend PHSA Section 487A to consolidate existing NIH intramural

and extramural loan repayment programs. Regarding intramural loan repayment programs,

Section 3 would (1) transfer the authority to administer these program from the HHS Secretary to

the NIH Director; (2) increase annual loan repayment amounts from a maximum of $35,000 to a

maximum of $50,000; and (3) provide loan repayment benefits for individuals who conduct

research in areas of emerging scientific or workforce needs, in addition to individuals who

conduct research on AIDS, and clinical researchers from disadvantaged backgrounds. Under the

provision, the NIH Director would be authorized to amend the categories eligible for intramural

loan repayment as scientific and workforce priorities change. Finally, the provision would

prohibit the NIH Director from entering into a loan repayment contract with individuals unless

they have substantial amounts of educational loans relative to income as determined by the NIH

Director and would permit amounts appropriated for new loan repayment contracts to remain

available until the end of the second fiscal year after they are appropriated.

Section 3 of S. 2014 would similarly amend the NIH’s extramural loan repayment program.

Specifically, it would increase loan repayment amounts to a maximum of $50,000 per year,

prohibit the NIH Director from entering into a loan repayment contract with individuals unless

they have substantial amounts of educational loans relative to income as determined by the NIH

Director, and allow amounts appropriated for new loan repayment contracts to remain available

until the end of the second fiscal year after they are appropriated. The provision would also retain

authorization for current topics eligible for extramural loan repayment (contraception and

infertility, pediatric research, minority health disparities, clinical research, and clinical research

conducted by individuals from disadvantaged backgrounds), and make eligible for loan

repayment benefits extramural researchers who are conducting research in an area of emerging

scientific or workforce need, and authorize the NIH Director to amend the categories eligible for

extramural loan repayment as scientific and workforce priorities change.

Finally, this provision would repeal existing authorizations for NIH loan repayment programs in

PHSA Sections 464z, 487C, 487E, and 487F and would require a GAO report, not later than 18

months after enactment, that would (1) report on NIH efforts to attract, retain, and develop

emerging scientists, including underrepresented individuals in the sciences; (2) report on the

research areas where individuals are receiving increased loan repayment amounts; and (3) analyze

the impact of changes included in this act on addressing workforce shortages.

Comparable Provisions in the 21st Century Cures Act

Subtitle C of H.R. 6 titled “Supporting Young Emerging Scientists” included two provisions that

are similar, but less comprehensive, than those included in S. 2014. The first, Section 1042 of

H.R. 6, would require the NIH Director to submit to Congress a report, not later than 18 months

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following enactment, on NIH efforts “to attract, retain and develop emerging scientists, including

underrepresented individuals in the sciences, such as women and other minorities.”67

The second provision in H.R. 6, Section 1041, focuses on NIH’s loan repayment programs;

however, rather than consolidating programs like the Senate bill would do, it would authorize a

new extramural NIH loan repayment program that would provide not more than $50,000 of loan

repayment benefits annually to extramural researchers investigating areas identified as NIH

scientific or workforce needs, which is similar to the new category of intramural and extramural

loan repayment that the Senate bill would create. H.R. 6 would also increase the amounts that

could be repaid under existing loan repayment programs from $35,000 to $50,000 and would,

unlike the Senate bill, authorize the HHS Secretary to adjust these amounts annually for inflation

beginning in FY2017.

Advancing NIH Strategic Planning and

Representation in Medical Research Act (S. 2745)

NIH Strategic Plan (§2)

Issue Background

Section 402(b)(5) of the PHSA specifies that the NIH Director “shall ensure that scientifically

based strategic planning is implemented in support of research priorities as determined by the

agencies of the National Institutes of Health.” NIH provides access to many of its strategic plans

on the agency’s website.68

The focus of NIH research, and to some extent its organizational structure, have been criticized

by some in the academic literature.69 A point often made is that the United States spends more on

health care than any of the other 30 countries that make up the Organization for Economic

Cooperation and Development (OECD)—in fact, U.S. health care spending is more than 2.5

times the OECD average—and yet, the health of the U.S. populace, as measured by life

expectancy, is ranked 24th of the 30 countries.70 “Despite its name, NIH’s mission has not

generally been current health, per se, but rather research for tomorrow’s health.... An agency

devoted to current health would do well to focus on tobacco control, exercise, nutrition,

sanitation, and more cost-effective delivery of health care—prevention and efficiency, rather than

research on diseases currently not treatable.”71 Questioning or making changes to the focus of

NIH research (whether basic, clinical, prevention, health care delivery, or patient-centered

outcomes research) is perhaps “especially pertinent in light of the nation’s continually mediocre

public health outcomes, and their stark contrast to the sophistication and productivity of the

biomedical research enterprise.”72

67 Amendment 4 (Castro), agreed to by voice vote during floor debate on H.R. 6, added the language ensuring that

underrepresented individuals in the sciences (women and minorities) would be included as a focus topic in the NIH

report to Congress.

68 See for example http://report.nih.gov/strategicplans/#tab2.

69 See for example Michael M. Crow, “Time to rethink NIH,” Nature, vol. 471 (March 31, 2011), pp. 569-571; and

Robert Cook-Deegan, “Has NIH lost its halo?” Issues in Science and Technology, Winter 2015, pp. 37-47.

70 Michael M. Crow, “Time to rethink NIH,” Nature, vol. 471 (March 31, 2011), p. 570.

71 Robert Cook-Deegan, “Has NIH lost its halo?” Issues in Science and Technology, Winter 2015, p. 43.

72 Ibid.

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Senate Legislation

The Senate bill would amend Section 402 of the PHS Act by adding a new subsection (m), which

describes a strategic plan for NIH. Within two years of enactment, and once every six years

thereafter, the NIH Director, in consultation with the Institute and Center (IC) Directors, would

develop and submit to the appropriate committees of Congress, and post on the NIH website, a

six-year NIH Strategic Plan. The NIH Strategic Plan would provide direction to the biomedical

research investments made by NIH, facilitate IC collaboration, leverage scientific opportunity,

and advance biomedicine.

The NIH Strategic Plan would identify research priorities, such as advancement of treatment, cure

and prevention of health conditions, emerging scientific opportunities, and rising public health

challenges. The research strategy would address the disease burden in the United States,

including rare diseases, and the many factors that contribute to health disparities. Other elements

to be included in the NIH Strategic Plan would be coordination of research among the ICs,

priorities for funding research through the Common Fund, training the biomedical workforce, and

collaboration with other agencies and departments. The individual IC strategic plans would be

required to be prepared regularly and informed by the NIH Strategic Plan.

Comparable Provisions in the 21st Century Cures Act (H.R. 6)

The NIH Research Strategic Plan provision in H.R. 6 Section 1021 is comparable to S. 2745.

The House provision would add a new subsection (m) to Section 402 of the PHSA, which

describes a Research Strategic Plan for NIH. Every five years, beginning in 2016, the NIH

Director, along with the IC Directors, researchers, patient advocacy groups, and industry leaders,

would be required to develop a biomedical research strategic plan. The strategic plan would be

used to identify research opportunities and develop individual strategic plans for each IC’s

research activities. The IC plans would have a common template and identify strategic focus

areas. The IC plans would consider and identify the return on investment to the U.S. public of

such biomedical research and identify contributions to improving U.S. public health through

biomedical research. Mission Priority Focus Areas would be identified that best serve the goals of

preventing or eliminating the burden of a disease and scientifically merit focused research over

the next five years. Rare and pediatric diseases would remain a priority. In developing the

strategic plan, the NIH Director would be required to ensure that maintaining the biomedical

workforce, including the participation of scientists from traditionally underrepresented groups,

would remain a priority. The initial strategic plan would be completed not later than 270 days

after enactment. The NIH Director, in consultation with the IC Directors, would be required to

conduct annual progress reviews for each strategic focus area in the IC plans. The plans would be

reviewed and updated every five years.

Inclusion of Women and Minorities in Research (§§3-9)

Issue Background

Minorities traditionally have been underrepresented in clinical trials. For example, according to a

2011 report from an FDA-sponsored conference, “African Americans represent 12% of the U.S.

population but only 5% of clinical trial participants and Hispanics make up 16% of the population

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but only 1% of clinical trial participants.”73 There can be biological differences in how people

process or respond to medical products, based on, for example, genetic differences. This could

make a treatment less effective or perhaps more toxic for individuals with specific genotypes.

Therefore, it is important to study in clinical trials the safety and effectiveness of medical

products in a broadly representative sample of people who will likely use the products following

FDA approval.

Section 492B of the PHSA requires the Director of NIH to include women and minorities in NIHfunded clinical research and to conduct or support outreach to recruit minorities and women into

clinical research. Section 492B(d) requires the Director of NIH, in consultation with the Director

of the Office of Research on Women’s Health and the Director of the Office of Research on

Minority Health, to develop guidelines regarding the requirements under Section 492B.

Senate Legislation

Sections 3 through 9 of S. 2745 address aspects of NIH research related to inclusion of women

and minority populations in clinical research.

Section 3 would amend Section 402(b) of the PHSA. The NIH Director, in assessing research

priorities, would be required to assemble accurate data on study populations in clinical research

that specifies the inclusion of women, members of minority groups, relevant age categories, and

other demographic variables. The data would have to be disaggregated by research area,

condition, and disease categories and made publically available on the NIH website. The NIH

Director also would be required to foster collaboration between the ICs that conduct research on

human subjects, allow for an increase in the number of subjects studied, and utilize a diverse

study population with special consideration of the determinants that contribute to health

disparities.

Section 4 would amend Section 492B of the PHSA, adding that the IC Directors must consult at

least once annually with the Director of the National Institute on Minority Health and Health

Disparities and the Director of the Office of Research on Women’s Health regarding IC objectives

to ensure that the objectives take into account women and minorities and focus on reducing health

disparities. The IC strategic plans would have to include details of such objectives. The NIH

Director would be required to consider whether applicable grant award recipients have complied

with the reporting requirements of ClinicalTrials.gov when awarding any future grants to such an

entity. Reporting requirements for IC advisory councils under Section 492B of the PHS Act

would change from biennial to triennial. Each such triennial report would have to include

specified data on the number of women and members of minority groups included in clinical

research projects conducted during the reporting period.

Section 5 would amend Part A of Title IV of the PHSA, adding a new Section 404M, “Research

Related to Sexual and Gender Minority Populations.” It would require the NIH Director to

encourage efforts to improve research related to the health of sexual and gender minority

populations through the increased participation of such groups in clinical research. The Secretary,

in collaboration with the NIH Director and taking into account the recommendations of the

National Academy of Sciences, would have to continue to support research for the development

of appropriate measures related to reporting health information of sexual and gender minority

populations. Within two years of enactment, the Secretary would have to disseminate and make

public such measures.

73 FDA, For Consumers, Clinical Trials Shed Light on Minority Health, at http://www.fda.gov/ForConsumers/

ConsumerUpdates/ucm349063.htm.

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Section 6 would amend Section 464z-3 of the PHSA, adding that the Director of the National

Institute on Minority Health and Health Disparities may foster partnerships between the ICs and

may encourage the funding of collaborative research to achieve the goals of the NIH related to

minority health and health disparities.

Section 7 would require the Secretary, acting through the Director of NIH, to convene a working

group to make recommendations for a formal policy to enhance the rigor and reproducibility of

scientific research funded by the NIH. It would require the working group to consider various

specified factors, including, for example, preclinical and clinical experiment design, and methods

of statistical analysis. It also would require the Director of NIH, not later than 18 months after

enactment, to consider the recommendations and develop or update policies as appropriate.

Finally, the section would require the Director of NIH to issue a report to the Secretary and

Congress, not later than two years after enactment, regarding the recommendations and any

subsequent policy changes.

Section 8 would require the Secretary, not later than 90 days after enactment, to establish a Task

Force on Research Specific to Pregnant and Lactating Women. It specifies the duties,

membership, meeting schedule, and reporting requirements of the task force, which would be

terminated two years after its establishment, with an option for a two-year extension. The section

would require the Secretary, not later than two years after enactment, to update regulations and

guidance, as appropriate, regarding the inclusion of pregnant women and lactating women in

research.

Section 9 would require the Director of NIH, within two years of enactment and taking into

consideration the findings of the working group established under Section 7 of this bill, to

develop policies for basic research to assess relevant biological variables, including sex, and how

differences between male and female cells, tissues, or animals may be studied. It also would

require the Director of NIH to consult with outside groups and conduct outreach in developing

(and updating) the policies, among other requirements. With respect to clinical research involving

women and minorities, the section would require the Director of NIH to update the guidelines

established under PHSA Section 492B(d) to reflect the science regarding sex differences and

improve adherence to the requirements of Section 492B of the PHSA, among other things.

Comparable Provisions in the 21st Century Cures Act (H.R. 6)

Section 1029 of H.R. 6, “The Sense of Congress on Increased Inclusion of Underrepresented

Communities in Clinical Trials,” is broadly comparable to Sections 3 through 6 of S. 2745. The

House provision would express the sense of Congress that the NIH National Institute on Minority

Health and Health Disparities “should include within its strategic plan ways to increase

representation of underrepresented communities in clinical trials.”

Promoting Biomedical Research and Public Health

for Patients Act (S. 2742)

Reducing and Streamlining Administrative Burden at NIH (§2, 3, 5,

and 10)

S. 2742 contains several provisions aimed at streamlining and improving administrative matters

at NIH. These include Sections 2, 3, 5, and 10.

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Issue Background

Title IV of the PHSA establishes numerous reporting requirements for the NIH Director related to

the ac

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