Hypersonic Weapons: Background and Issues for Congress

Summary: The United States has actively pursued the development of hypersonic weaponsâmaneuvering weapons that fly at speeds of at least Mach 5âas a part of its conventional prompt global strike program since the early 2000s. In recent years, the United States has focused such efforts on developing hypersonic glide vehicles, which are launched from a rocket before gliding to a target, and hypersonic cruise missiles, which are powered by high-speed, air-breathing engines during flight. As Vice Chairman of the Joint Chiefs of Staff and former Commander of U.S. Strategic Command General John Hyten has stated, these weapons could enable "responsive, long-range, strike options against distant, defended, and/or time-critical threats [such as road-mobile missiles] when other forces are unavailable, denied access, or not preferred." Critics, on the other hand, contend that hypersonic weapons lack defined mission requirements, contribute little to U.S. military capability, and are unnecessary for deterrence.

Summary: Funding for hypersonic weapons has been relatively restrained in the past; however, both the Pentagon and Congress have shown a growing interest in pursuing the development and near-term deployment of hypersonic systems. This is due, in part, to the growing interest in these technologies in Russia and China, both of which have a number of hypersonic weapons programs and are expected to field an operational hypersonic glide vehicleâpotentially armed with nuclear warheadsâas early as 2020. The United States, in contrast to Russia and China, is not currently considering or developing hypersonic weapons for use with a nuclear warhead. As a result, U.S. hypersonic weapons will likely require greater accuracy and will be more technically challenging to develop than nuclear-armed Chinese and Russian systems.

Summary: The Pentagon's FY2021 budget request for all hypersonic-related research is $3.2 billionâup from $2.6 billion in the FY2020 requestâincluding $206.8 million for hypersonic defense programs. At present, the Department of Defense (DOD) has not established any programs of record for hypersonic weapons, suggesting that it may not have approved either requirements for the systems or long-term funding plans. Indeed, as Assistant Director for Hypersonics (Office of the Under Secretary of Defense for Research and Engineering) Mike White has stated, DOD has not yet made a decision to acquire hypersonic weapons and is instead developing prototypes to assist in the evaluation of potential weapon system concepts and mission sets.

Summary: As Congress reviews the Pentagon's plans for U.S. hypersonic weapons programs, it might consider questions about the rationale for hypersonic weapons, their expected costs, and their implications for strategic stability and arms control. Potential questions include the following:

Summary: What mission(s) will hypersonic weapons be used for? Are hypersonic weapons the most cost-effective means of executing these potential missions? How will they be incorporated into joint operational doctrine and concepts? Given the lack of defined mission requirements for hypersonic weapons, how should Congress evaluate funding requests for hypersonic weapons programs or the balance of funding requests for hypersonic weapons programs, enabling technologies, and supporting test infrastructure? Is an acceleration of research on hypersonic weapons, enabling technologies, or hypersonic missile defense options both necessary and technologically feasible? How, if at all, will the fielding of hypersonic weapons affect strategic stability? Is there a need for risk-mitigation measures, such as expanding New START, negotiating new multilateral arms control agreements, or undertaking transparency and confidence-building activities?

The United States has actively pursued the development of hypersonic weapons as a part of its conventional prompt global strike (CPGS) program since the early 2000s. In recent years, it has focused such efforts on hypersonic glide vehicles and hypersonic cruise missiles with shorter and intermediate ranges for use in regional conflicts. Although funding for these programs has been relatively restrained in the past, both the Pentagon and Congress have shown a growing interest in pursuing the development and near-term deployment of hypersonic systems. This is due, in part, to the growing interest in these technologies in Russia and China, leading to a heightened focus in the United States on the strategic threat posed by hypersonic flight. Open-source reporting indicates that both China and Russia have conducted numerous successful tests of hypersonic glide vehicles, and both are expected to field an operational capability as early as 2020 .

Experts disagree on the potential impact of competitor hypersonic weapons on both strategic stability and the U.S. military's competitive advantage. Nevertheless, current Under Secretary of Defense for Research and Engineering (USD R&E) Michael Griffin has testified to Congress that the United States does not "have systems which can hold [China and Russia] at risk in a corresponding manner, and we don't have defenses against [their] systems." Although the John S. McCain National Defense Authorization Act for Fiscal Year 2019 (FY2019 NDAA, P.L. 115-232 ) accelerated the development of hypersonic weapons, which USD R&E identifies as a priority research and development area, the United States is unlikely to field an operational system before 2023. However, the United States, in contrast to Russia and China, is not currently considering or developing hypersonic weapons for use with a nuclear warhead. As a result, U.S. hypersonic weapons will likely require greater accuracy and will be more technically challenging to develop than nuclear-armed Chinese and Russian systems.

In addition to accelerating development of hypersonic weapons, Section 247 of the FY2019 NDAA required that the Secretary of Defense, in coordination with the Director of the Defense Intelligence Agency, produce a classified assessment of U.S. and adversary hypersonic weapons programs, to include the following elements:

(1) An evaluation of spending by the United States and adversaries on such technology.

(2) An evaluation of the quantity and quality of research on such technology.

(3) An evaluation of the test infrastructure and workforce supporting such technology.

(4) An assessment of the technological progress of the United States and adversaries on such technology.

(5) Descriptions of timelines for operational deployment of such technology.

(6) An assessment of the intent or willingness of adversaries to use such technology.

This report was delivered to Congress in July 2019. Similarly, Section 1689 of the FY2019 NDAA requires the Director of the Missile Defense Agency to produce a report on "how hypersonic missile defense can be accelerated to meet emerging hypersonic threats." The findings of these reports could hold implications for congressional authorizations, appropriations, and oversight.

The following report reviews the hypersonic weapons programs in the United States, Russia, and China, providing information on the programs and infrastructure in each nation, based on unclassified sources. It also provides a brief summary of the state of global hypersonic weapons research development. It concludes with a discussion of the issues that Congress might address as it considers DOD's funding requests for U.S. hypersonic technology programs.

Several countries are developing hypersonic weapons, which fly at speeds of at least Mach 5 (five times the speed of sound), but none have yet introduced them into their operational military forces. There are two primary categories of hypersonic weapons

Hypersonic glide vehicles (HGV) are launched from a rocket before gliding to a target. Hypersonic cruise missiles are powered by high-speed, air-breathing engines, or "scramjets," after acquiring their target.

Unlike ballistic missiles, hypersonic weapons do not follow a ballistic trajectory and can maneuver en route to their destination. As Vice Chairman of the Joint Chiefs of Staff and former Commander of U.S. Strategic Command General John Hyten has stated, hypersonic weapons could enable "responsive, long-range, strike options against distant, defended, and/or time-critical threats [such as road-mobile missiles] when other forces are unavailable, denied access, or not preferred." Conventional hypersonic weapons use only kinetic energyâenergy derived from motionâto destroy unhardened targets or, potentially, underground facilities.

Hypersonic weapons could challenge detection and defense due to their speed, maneuverability, and low altitude of flight. For example, terrestrial-based radar cannot detect hypersonic weapons until late in the weapon's flight. Figure 1 depicts the differences in terrestrial-based radar detection timelines for ballistic missiles versus hypersonic glide vehicles.

This delayed detection compresses the timeline for decision-makers assessing their response options and for a defensive system to intercept the attacking weaponâpotentially permitting only a single intercept attempt.

Furthermore, U.S. defense officials have stated that both terrestrial- and current space-based sensor architectures are insufficient to detect and track hypersonic weapons, with USD R&E Griffin noting that "hypersonic targets are 10 to 20 times dimmer than what the U.S. normally tracks by satellites in geostationary orbit." Some analysts have suggested that space-based sensor layersâintegrated with tracking and fire-control systems to direct high-performance interceptors or directed energy weaponsâcould theoretically present viable options for defending against hypersonic weapons in the future. Indeed, the 2019 Missile Defense Review notes that "such sensors take advantage of the large area viewable from space for improved tracking and potentially targeting of advanced threats, including HGVs and hypersonic cruise missiles."

Other analysts have questioned the affordability, technological feasibility, and/or utility of wide-area hypersonic weapons defense. As physicist and nuclear expert James Acton explains, "point-defense systems, and particularly [Terminal High-Altitude Area Defense (THAAD)], could very plausibly be adapted to deal with hypersonic missiles. The disadvantage of those systems is that they can only defend small areas. To defend the whole of the continental United States, you would need an unaffordable number of THAAD batteries." In addition, some analysts have argued that the United States' current command and control architecture would be incapable of "processing data quickly enough to respond to and neutralize an incoming hypersonic threat." (A broader discussion of hypersonic weapons defense is outside the scope of this report.)

The Department of Defense (DOD) is currently developing hypersonic weapons under the Navy's Conventional Prompt Strike program, which is intended to provide the U.S. military with the ability to strike hardened or time-sensitive targets with conventional warheads, as well as through several Air Force, Army, and DARPA programs. Those who support these development efforts argue that hypersonic weapons could enhance deterrence, as well as provide the U.S. military with an ability to defeat capabilities such as advanced air and missile defense systems that form the foundation of U.S. competitors' anti-access/area denial strategies. In recognition of this, the 2018 National Defense Strategy identifies hypersonic weapons as one of the key technologies "[ensuring the United States] will be able to fight and win the wars of the future."

Unlike China and Russia, the United States is not currently developing hypersonic weapons for use with a nuclear warhead. As a result, U.S. hypersonic weapons will likely require greater accuracy and will be more technically challenging to develop than nuclear-armed Chinese and Russian systems. Indeed, according to one expert, "a nuclear-armed glider would be effective if it were 10 or even 100 times less accurate [than a conventionally-armed glider]" due to nuclear blast effects.

According to open-source reporting, the United States has a number of major offensive hypersonic weapons and hypersonic technology programs in development, including the following (see Table 1 ):

U.S. NavyâConventional Prompt Strike (CPS); U.S. ArmyâLong-Range Hypersonic Weapon (LRHW); U.S. Air ForceâAGM-183 Air-Launched Rapid Response Weapon (ARRW, pronounced "arrow"); DARPAâTactical Boost Glide (TBG); DARPAâOperational Fires (OpFires); and DARPAâHypersonic Air-breathing Weapon Concept (HAWC, pronounced "hawk").

These programs are intended to produce operational prototypes, as there are currently no programs of record for hypersonic weapons. Accordingly, funding for U.S. hypersonic weapons programs is found in the Research, Development, Test, and Evaluation accounts, rather than in Procurement.

In a June 2018 memorandum, DOD announced that the Navy would lead the development of a common glide vehicle for use across the services. The common glide vehicle is being adapted from a Mach 6 Army prototype warhead, the Alternate Re-Entry System, which was successfully tested in 2011 and 2017. Once development is complete, "Sandia National Laboratories, the designer of the original concept, then will build the common glide vehiclesâ¦. Booster systems are being developed separately."

The Navy's Conventional Prompt Strike (CPS) is expected to pair the common glide vehicle with a submarine-launched booster system, achieving initial operational capability (IOC) on a Virginia-class submarine with Virginia Payload Module in FY2028. The Navy is requesting $1 billion for CPS in FY2021âan increase of $415 million over the FY2020 request and $496 million over the FY2020 appropriationâand $5.3 billion across the five-year Future Years Defense Program (FYDP).

The Army's Long-Range Hypersonic Weapon program is expected to pair the common glide vehicle with the Navy's booster system. The system is intended to have a range of 1,400 miles and "provide the Army with a prototype strategic attack weapon system to defeat A2/AD capabilities, suppress adversary Long Range Fires, and engage other high payoff/time sensitive targets." The Army is requesting $801 million for the program in FY2021â$573 million over the FY2020 request and $397 million over the FY2020 appropriationâand $3.3 billion across the FYDP. It plans to conduct flight tests for LRHW from FY2021 to FY2023, field combat rounds in FY2023, and transition to a program of record in the fourth quarter of FY2024.

T he AGM-183 Air- L aunched Rapid Response Weapon is expected to leverage DARPA's Tactical Boost Glide technology to develop an air-launched hypersonic glide vehicle prototype capable of travelling at speeds up to Mach 20 at a range of approximately 575 miles. Despite testing delays due to technical challenges, ARRW completed a successful flight test in June 2019 and is expected to complete flight tests in FY2022. The Air Force has requested $382 million for ARRW in FY2021âup from $286 million in the FY2020 request and appropriationâand $581 million across the FYDP, with no funds requested beyond FY2022. ARRW is a project under the Air Force's Hypersonics Prototyping Program Element, which is intended to demonstrate concepts "to [enable] leadership to make informed strategy and resource decisions â¦ for future programs."

In February 2020, the Air Force announced that it had cancelled its second hypersonic weapon program, the Hypersonic Conventional Strike Weapon (HCSW), which had been expected to use the common glide vehicle, due to budget pressures that forced it to choose between ARRW and HCSW. Air Force acquisition chief Will Roper explained that ARRW was selected because it was more advanced and gave the Air Force additional options. "[ARRW] is smaller; we can carry twice as many on the B-52, and it's possible it could be on the F-15," he explained. The Air Force will continue its technical review of HCSW through March 2020.

DARPA, in partnership with the Air Force, continues to test Tactical Boost Glide, a wedge-shaped hypersonic glide vehicle capable of Mach 7+ flight that "aims to develop and demonstrate technologies to enable future air-launched, tactical-range hypersonic boost glide systems." TBG will "also consider traceability, compatibility, and integration with the Navy Vertical Launch System" and is planned to transition to both the Air Force and the Navy. DARPA has requested $117 millionâdown from the $162 million FY2020 request and the $152 million FY2020 appropriationâfor TBG in FY2021.

DARPA's Operational Fires reportedly seeks to leverage TBG technologies to develop a ground-launched system that will enable "advanced tactical weapons to penetrate modern enemy air defenses and rapidly and precisely engage critical time sensitive targets." DARPA has requested $40 million for OpFires in FY2021âdown from the $50 million FY2020 request and appropriationâand intends to transition the program to the Army.

In the longer term, DARPA, with Air Force support, is continuing work on the Hypersonic Air-breathing Weapon Concept, which "seeks to develop and demonstrate critical technologies to enable an effective and affordable air-launched hypersonic cruise missile." Assistance Director for Hypersonics Mike White has stated that such a missile would be smaller than DOD's hypersonic glide vehicles and could therefore launch from a wider range of platforms. Director White has additionally noted that HAWC and other hypersonic cruise missiles could integrate seekers more easily than hypersonic glide vehicles. DARPA requested $7 million to develop HAWC in FY2021âdown from the $10 million FY2020 request and $20 million FY2020 appropriation.

DOD is also investing in counter-hypersonic weapons capabilities, although USD R&E Michael Griffin has stated that the United States will not have a defensive capability against hypersonic weapons until the mid-2020s, at the earliest. In September 2018, the Missile Defense Agency (MDA)âwhich in 2017 established a Hypersonic Defense Program pursuant to Section 1687 of the FY2017 NDAA ( P.L. 114-840 )âcommissioned 21 white papers to explore hypersonic missile defense options, including interceptor missiles, hypervelocity projectiles, laser guns, and electronic attack systems. In January 2020, MDA issued a draft request for prototype proposals for a Hypersonic Defense Regional Glide Phase Weapons System interceptor. This effort is intended to "reduce interceptor key technology and integration risks, anchor modeling and simulation in areas of large uncertainty, and to increase the interceptor technology readiness levels (TRL) to level 5." MDA has also awarded four companiesâNorthrop Grumman, Raytheon, Leidos, and L3Harrisâwith $20 million contracts to design prototype space-based (low-Earth orbit) sensors by October 31, 2020. Such sensors could theoretically extend the range at which incoming missiles could be detected and trackedâa critical requirement for hypersonic missile defense, according to USD Griffin. MDA requested $206.8 million for hypersonic defense in FY2021âup from its $157.4 million FY2020 requestâand $659 million across the FYDP. In addition, DARPA is working on a program called Glide Breaker, which "will develop critical component technology to support a lightweight vehicle designed for precise engagement of hypersonic threats at very long range." DARPA requested $3 million for Glide Breaker in FY2021âdown from $10 million in FY2020.

According to a study mandated by the FY2013 National Defense Authorization Act ( P.L. 112-239 ) and conducted by the Institute for Defense Analyses (IDA) , the United States had 48 critical hypersonic test facilities and mobile assets in 2014 needed for the maturation of hypersonic technologies for defense systems development through 2030 . These specialized facilities, which simulate the unique conditions experienced in hypersonic flight (e.g., speed, pressure, heating), included 10 DOD hypersonic ground test facilities, 11 DOD open-air ranges, 11 DOD mobile assets, 9 NASA facilities, 2 Department of Energy facilities, and 5 industry or academic facilities. In its 2014 evaluation ofÂ  U.S. hypersonic test and evaluation infrastructure, IDAÂ noted thatÂ  " no current U.S. facility can provide full-scale, time-dependent, coupled aerodynamic and thermal-loading environments for flight durations necessary to evaluate theseÂ characteristics aboveÂ Mach 8. " Â Since the 2014Â study report was published,Â the University of Notre Dame has opened a Mach 6 hypersonic wind t unnel and at least one hypersonic testing facility has been inactivated. D evelopment of Mach 8 and Mach 10 wind tunnels at Purdue University and the University of Notre Dame , respectively, is ongoing. In addition, t he University of Arizona plans to modify one of its wind tunnels to enable Mach 5 testing by early 2021 , while Texas A&M Universityâ in partnership with Army Futures Commandâplans to complete construction of a kilometer-long Mach 10 wind tunnel by 2021 . ( For a list of U.S. hypersonic test assets and their capabilities, see the Appendix .)

The United States also uses the Royal Australian Air Force Woomera Test Range in Australia and the AndÃ¸ya Rocket Range in Norway for flight testing. In January 2019, the Navy announced plans to reactivate its Launch Test Complex at China Lake, CA, to improve air launch and underwater testing capabilities for the conventional prompt strike program.

In addition, in March 2020, DOD announced that it had established a "hypersonic war room" to assess the U.S. industrial base for hypersonic weapons and identify "critical nodes" in the supply chain. Initial findings are to be released in mid-2020.

Although Russia has conducted research on hypersonic weapons technology since the 1980s, it accelerated its efforts in response to U.S. missile defense deployments in both the United States and Europe, and in response to the U.S. withdrawal from the Anti-Ballistic Missile Treaty in 2001. Detailing Russia's concerns, President Putin stated that "the US is permitting constant, uncontrolled growth of the number of anti-ballistic missiles, improving their quality, and creating new missile launching areas. If we do not do something, eventually this will result in the complete devaluation of Russia's nuclear potential. Meaning that all of our missiles could simply be intercepted." Russia thus seeks hypersonic weapons, which can maneuver as they approach their targets, as an assured means of penetrating U.S. missile defenses and restoring its sense of strategic stability.

Russia is pursuing two hypersonic weapons programsâthe Avangard and the 3M22 Tsirkon (or Zircon)âand has reportedly fielded the Kinzhal ("Dagger"), a maneuvering air-launched ballistic missile.

Avangard ( Figure 2 ) is a hypersonic glide vehicle launched from an intercontinental ballistic missile (ICBM), giving it "effectively 'unlimited' range." Reports indicate that Avangard is currently deployed on the SS-19 Stiletto ICBM, though Russia plans to eventually launch the vehicle from the Sarmat ICBM. Sarmat is still in development, although it may be deployed by 2021. Avangard features onboard countermeasures and will reportedly carry a nuclear warhead. It was successfully tested twice in 2016 and once in December 2018, reportedly reaching speeds of Mach 20; however, an October 2017 test resulted in failure. Russian news sources claim that Avangard entered into combat duty in December 2019.

In addition to Avangard, Russia is developing Tsirkon, a ship-launched hypersonic cruise missile capable of traveling at speeds of between Mach 6 and Mach 8. Tsirkon is reportedly capable of striking both ground and naval targets. According to Russian news sources, Tsirkon has a range of between approximately 250 and 600 miles and can be fired from the vertical launch systems mounted on cruisers Admiral Nakhimov and Pyotr Veliky , Project 20380 corvettes, Project 22350 frigates, and Project 885 Yasen-class submarines, among other platforms. These sources assert that Tsirkon was successfully launched from a Project 22350 frigate in January 2020. U.S. intelligence reports indicate that the missile will become operational in 2023.

In addition, Russia has reportedly fielded Kinzhal, a maneuvering air-launched ballistic missile modified from the Iskander missile. According to U.S. intelligence reports, Kinzhal was successfully test fired from a modified MiG-31 fighter (NATO code name: Foxhound) as recently as July 2018âstriking a target at a distance of approximately 500 milesâand is expected by U.S. intelligence sources to become ready for combat by 2020. Russia plans to deploy the missile on both the MiG-31 and the Su-34 long-range strike fighter. Russia is working to mount the missile on the Tu-22M3 strategic bomber (NATO code name: Backfire), although the slower-moving bomber may face challenges in "accelerating the weapon into the correct launch parameters."

Russian media has reported Kinzhal's top speed as Mach 10, with a range of up to 1,200 miles when launched from the MiG-31. The Kinzhal is reportedly capable of maneuverable flight, as well as of striking both ground and naval targets, and could eventually be fitted with a nuclear warhead. However, such claims regarding Kinzhal's performance characteristics have not been publicly verified by U.S. intelligence agencies, and have been met with skepticism by a number of analysts.

Russia reportedly conducts hypersonic wind tunnel testing at the Central Aero-Hydrodynamic Institute in Zhukovsky and the Khristianovich Institute of Theoretical and Applied Mechanics in Novosibirsk, and has tested hypersonic weapons at Dombarovskiy Air Base, the Baykonur Cosmodrome, and the Kura Range.

According to Tong Zhao, a fellow at the Carnegie-Tsinghua Center for Global Policy, "most experts argue that the most important reason to prioritize hypersonic technology development [in China] is the necessity to counter specific security threats from increasingly sophisticated U.S. military technology, including [hypersonic weapons]." In particular, China's pursuit of hypersonic weapons, like Russia's, reflects a concern that U.S. hypersonic weapons could enable the United States to conduct a preemptive, decapitating strike on China's nuclear arsenal and supporting infrastructure. U.S. missile defense deployments could then limit China's ability to conduct a retaliatory strike against the United States.

China has demonstrated a growing interest in Russian advances in hypersonic weapons technology, conducting flight tests of a hypersonic-glide vehicle (HGV) only days after Russia tested its own system. Furthermore, a January 2017 report found that over half of open-source Chinese papers on hypersonic weapons include references to Russian weapons programs. This could indicate that China is increasingly considering hypersonic weapons within a regional context. Indeed, some analysts believe that China may be planning to mate conventionally armed HGVs with the DF-21 and DF-26 ballistic missiles in support of an anti-access/area denial strategy. China has reportedly not made a final determination as to whether its hypersonic weapons will be nuclear- or conventionally-armedâor dual-capable.

China has conducted a number of successful tests of the DF-17, a medium-range ballistic missile specifically designed to launch HGVs. U.S. intelligence analysts assess that the missile has a range of approximately 1,000 to 1,500 miles and could be deployed in 2020. China has also tested the DF-41 intercontinental ballistic missile, which could be modified to carry a conventional or nuclear HGV, according to a report by a U.S. Congressional commission. The development of the DF-41 thus "significantly increases the [Chinese] rocket force's nuclear threat to the U.S. mainland," the report states.

China has tested the DF-ZF HGV (previously referred to as the WU-14) at least nine times since 2014. U.S. defense officials have reportedly identified the range of the DF-ZF as approximately 1,200 miles and have stated that the missile may be capable of performing "extreme maneuvers" during flight. Although unconfirmed by intelligence agencies, some analysts believe the DF-ZF will be operational as early as 2020.

According to U.S. defense officials, China also successfully tested Starry Sky-2 (or Xing Kong-2), a nuclear-capable hypersonic vehicle prototype, in August 2018. China claims the vehicle reached top speeds of Mach 6 and executed a series of in-flight maneuvers before landing. Unlike the DF-ZF, Starry Sky-2 is a "waverider" that uses powered flight after launch and derives lift from its own shockwaves. Some reports indicate that the Starry Sky-2 could be operational by 2025. U.S. officials have declined to comment on the program.

China has a robust research and development infrastructure devoted to hypersonic weapons. USD (R&E) Michael Griffin stated in March 2018 that China has conducted 20 times as many hypersonic tests as the United States. China tested three hypersonic vehicle models (D18-1S, D18-2S, and D18-3S)âeach with different aerodynamic propertiesâin September 2018. Analysts believe that these tests could be designed to help China develop weapons that fly at variable speeds, including hypersonic speeds. Similarly, China has used the Lingyun Mach 6+ high-speed engine, or "scramjet," test bed ( Figure 3 ) to research thermal resistant components and hypersonic cruise missile technologies.

According to Jane's Defence Weekly , "China is also investing heavily in hypersonic ground testing facilities." CAAA operates the FD-02, FD-03, and FD-07 hypersonic wind tunnels, which are capable of reaching speeds of Mach 8, Mach 10, and Mach 12, respectively. China also operates the JF-12 hypersonic wind tunnel, which reaches speeds of between Mach 5 and Mach 9, and the FD-21 hypersonic wind tunnel, which reaches speeds of between Mach 10 and Mach 15. China is expected to have an operational wind tunnel capable of reaching speeds of Mach 25 by 2020. China is known to have tested hypersonic weapons at the Jiuquan Satellite Launch Center and the Taiyuan Satellite Launch Center.

As Congress reviews the Pentagon's plans for U.S. hypersonic weapons programs during the annual authorization and appropriations process, it might consider a number of questions about the rationale for hypersonic weapons, their expected costs, and their implications for strategic stability and arms control. This section provides an overview of some of these questions.

Although the Department of Defense is funding a number of hypersonic weapons programs, it has not established any programs of record, suggesting that it may not have approved requirements for hypersonic weapons or long-term funding plans. Indeed, as Assistant Director for Hypersonics (USD R&E) Mike White has stated, DOD has not yet made a decision to acquire hypersonic weapons and is instead developing prototypes to "[identify] the most viable overarching weapon system concepts to choose from and then make a decision based on success and challenges." As Congress conducts oversight of U.S. hypersonic weapons programs, it may seek to obtain information about DOD's evaluation of potential mission sets for hypersonic weapons, a cost analysis of alternative means of executing these mission sets, and an assessment of the enabling technologiesâsuch as space-based sensors or autonomous command and control systemsâthat may be required to employ or defend against hypersonic weapons.

Assistant Director for Hypersonics (USD R&E) Mike White has noted that DOD is prioritizing offensive programs while it determines "the path forward to get a robust defensive strategy." This approach is reflected in DOD's FY2021 request, which allocates $206.8 million for hypersonic defense programsâof a total $3.2 billion request for all hypersonic-related research. Similarly, in FY2020, DOD requested $157.4 million for hypersonic defense programsâof a total $2.6 billion for all hypersonic-related research.

Although the Defense Subcommittees of the Appropriations Committees increased FY2020 appropriations for both hypersonic offense and defense above the FY2020 request, they expressed concerns, noting in their joint explanatory statement of H.R. 1158 "that the rapid growth in hypersonic research has the potential to result in stove-piped, proprietary systems that duplicate capabilities and increase costs." To mitigate this concern, they appropriated $100 million for DOD to establish a Joint Hypersonic Transition Office to "develop and implement an integrated science and technology roadmap for hypersonics" and "establish a university consortium for hypersonic research and workforce development" in support of DOD efforts. Given the lack of defined mission requirements for hypersonic weapons, it may be challenging for Congress to evaluate the balance of funding for hypersonic weapons programs, enabling technologies, supporting test infrastructure, and hypersonic missile defense.

Analysts disagree about the strategic implications of hypersonic weapons. Some have identified two factors that could hold significant implications for strategic stability: the weapon's short time-of-flightâwhich, in turn, compresses the timeline for responseâ and its unpredictable flight pathâwhich could generate uncertainty about the weapon's intended target and therefore heighten the risk of miscalculation or unintended escalation in the event of a conflict. This risk could be further compounded in countries that co-locate nuclear and conventional capabilities or facilities .

Some analysts argue that unintended escalation could occur as a result of warhead ambiguity, or from the inability to distinguish between a conventionally armed hypersonic weapon and a nuclear-armed one. However, as a United Nations report notes, "even if a State did know that an HGV launched toward it was conventionally armed, it may still view such a weapon as strategic in nature, regardless of how it was perceived by the State firing the weapon, and decide that a strategic response was warranted." Differences in threat perception and escalation ladders could thus result in unintended escalation. Such concerns have previously led Congress to restrict funding for conventional prompt strike programs.

Other analysts have argued that the strategic implications of hypersonic weapons are minimal. Pavel Podvig, a senior research fellow at the United Nations Institute for Disarmament Research, has noted that the weapons "don't â¦ change much in terms of strategic balance and military capability." This, some analysts argue, is because U.S. competitors such as China and Russia already possess the ability to strike the United States with intercontinental ballistic missiles, which, when launched in salvos, could overwhelm U.S. missile defenses. Furthermore, these analysts note that in the case of hypersonic weapons, traditional principles of deterrence hold: "it is really a stretch to try to imagine any regime in the world that would be so suicidal that it would even think threating to useânot to mention to actually useâhypersonic weapons against the United States ... would end well."

Some analysts who believe that hypersonic weapons could present a threat to strategic stability or inspire an arms race have argued that the United States should take measures to mitigate risks or limit the weapons' proliferation. Proposed measures include expanding New START, negotiating new multilateral arms control agreements, and undertaking transparency and confidence-building measures.

The New START Treaty, a strategic offensive arms treaty between the United States and Russia, does not currently cover weapons that fly on a ballistic trajectory for less than 50% of their flight, as do hypersonic glide vehicles and hypersonic cruise missiles. However, Article V of the treaty states that "when a Party believes that a new kind of strategic offensive arm is emerging, that Party shall have the right to raise the question of such a strategic offensive arm for consideration in the Bilateral Consultative Commission (BCC)." Accordingly, some legal experts hold that the United States could raise the issue in the BCC of negotiating to include hypersonic weapons in the New START limits. However, because New START is due to expire in 2021, unless extended through 2026, this solution is likely to be temporary.

As an alternative, some analysts have proposed negotiating a new international arms control agreement that would institute a moratorium or ban on hypersonic weapon testing. These analysts argue that a test ban would be a "highly verifiable" and "highly effective" means of preventing a potential arms race and preserving strategic stability. Other analysts have countered that a test ban would be infeasible, as "no clear technical distinction can be made between hypersonic missiles and other conventional capabilities that are less prompt, have shorter ranges, and also have the potential to undermine nuclear deterrence." These analysts have instead proposed international transparency and confidence-building measures, such as exchanging weapons data; conducting joint technical studies; "providing advance notices of tests; choosing separate, distinctive launch locations for tests of hypersonic missiles; and placing restraints on sea-based tests."

Appendix. U.S. Hypersonic Testing Infrastructure114


Off-Label Use of Prescription Drugs

Summary: When the Food and Drug Administration (FDA) approves a drug for sale in the United States, the approval includes a section entitled "Indications for Use." This section lists the one or more diseases, conditions, or symptoms for which the drug's sponsor (usually the manufacturer) has provided, to FDA's satisfaction, evidence in support of the drug's safety and effectiveness. FDA approval is also based on its review of the drug's dosage, packaging, manufacturing plan, and labeling. Before changing any of those elements, the sponsor must inform, and usually receive permission from, FDA.

Summary: In essence, FDA regulates all approval and post-approval aspects of a drug product. But FDA traditionally has not regulated the practice of medicine. Physicians, therefore, may prescribe an FDA-approved drug for indications that FDA has not reviewed for safety and effectiveness. Those uses, furthermore, are not addressed in the labeling information regarding, among other things, dosing, warnings about interactions with other drugs, and possible adverse events.

Summary: How Are Off-Label Prescription Drugs Used?

Summary: Prescribing for so-called off-label uses can be accepted medical practice, often reflecting cutting-edge clinical expertise. For example, this is the case with oncology drug use, more than half of which is off-label. Off-label prescribing can be a reasonable choice when labeling overlooks certain populationsâfor example, when a drug tested in adults is prescribed to children. A drug may be used off-label when it was tested for the treatment of one disease and prescribed in an attempt to prevent or treat another, when it was tested at one dose and used at higher or lower doses, or when it was tested in an eight-week trial and prescribed for long-term use. Estimates for how common off-label prescriptions are in the United States are hardly precise. Credible researchers have estimated they make up as little as 12% and as much as 38% of doctor-office prescriptions.

Summary: What Are the Risks of Off-Label Prescriptions?

Summary: Prescriptions for off-label uses of FDA-approved drugs are made without the benefit of an FDA-reviewed analysis of safety and effectiveness data. Physicians may resort to such prescribing to take advantage of new ideas and treatment approaches when available information to support them is inadequate. However, despite the potential risks associated with off-label uses, efforts to prohibit such uses might hurt the public. Some off-label prescribing may result because manufacturers have chosen not to invest the resources needed to have FDA add indications to the drug's approval and labeling.

Summary: A worst-case scenario for the nation's health would be the widespread acceptance of a drug for an off-label use that sufficient research would have revealed to be ineffective, unsafe, or both. Aside from the drug's direct harm, the time spent waiting to see whether it worked would have been time not spent exploring other treatment options.

Summary: Unchecked off-label prescribing may also threaten the FDA gold standard of drug approval. If clinicians had already accepted a new use into practice through off-label prescribing, a manufacturer may choose to not invest resources to go through clinical trials and the FDA process to win approval.

Summary: Although manufacturers do share information on off-label uses, courts have sometimes found they had overstepped allowable bounds. Congress has given permission for limited sharing. Are there other ways to share clinical information that do not put the public's health or FDA's authority at risk?

Summary: What Role Can Congress Play in the Use of Off-Label Prescriptions?

Summary: How might Congress, in its legislative or oversight roles, consider the use of off-label drugs to protect the public's health? Legislators and health analysts have suggested both restrictive and permissive actions regarding off-label use. Ideasâsome of which conflict with othersâinclude

Summary: disclosure to patients; data collection, availability, and analysis; dissemination of clinical data; linking reimbursement and coverage to evidence of safety and effectiveness; clinical research and research transparency; clinical guidance; congressional oversight through the Government Accountability Office, the Federal Trade Commission, and the Department of Health and Human Services; and consideration of other countries' approaches to off-label use.

Summary: Some actions would require federal legislation. Other proposals would involve actions by other entities, such as state authorities and professional organizations, which Congress could urge.

Both legislators and regulators have expressed concern about the safety and effectiveness of prescription drugs prescribed for "off-label uses"âpurposes other than those for which the Food and Drug Administration (FDA) has approved their sale. Two recent incidents illustrate the bases for those concerns.

The first involves a drug already on the market. Safety experts raised concerns about ketamine, a drug available as an injectable anesthetic. They noted that physicians have created outpatient clinics to administer intravenous ketamine in an off-label use to treat depression and migraines. FDA has not reviewed clinical data that could support the clinics' promotional claims of safety and effectiveness.

In August 2018, a second incident occurred in a Texas courtroom. Astra Zeneca settled a case concerning its alleged promotion of Seroquel for uses other than those for which it had sought and obtained FDA approval for sale in the United States. The core of the complaint by the state of Texas was that the company promoted the drug's use in children, although the FDA-approved labeling of the drug was for adult use. It was one of a number of settlements since 2000 resulting in payments by drug companies for the promotion of off-label uses.

To help understand the issues involving off-label use, and how these issues might concern Congress, this report addresses five questions:

What is drug labeling? What is off-label use? How are off-label prescriptions used in medicine today? What are the risks and benefits associated with off-label prescriptions? What concerns, if any, does Congress have about such prescriptions? If Congress wanted to do something about off-label prescriptions, what would be some of the options?

To market a prescription drug in the United States, a manufacturer needs FDA approval. To obtain that approval, the manufacturer must demonstrate the drug's safety and effectiveness according to criteria specified in law and agency regulations. It must also ensure that its manufacturing plant passes FDA inspection.

Finally, it must obtain FDA approval for the drug's labelingâa term that covers all written material about the drug, including, for example, packaging, prescribing information for physicians, and patient brochures. FDA, thus, approves the drug and its labeling for a specific use. That use specifies the disease or condition, the population, and the way the drug is packaged and administered.

When a physician prescribes a drug for reasons other than those specified in the FDA approval and labeling, the medical profession considers this to be off-label use .

FDA regulates the drug and the manufacturer. Each state regulates clinicians and pharmacies. A licensed physician mayâexcept in highly restricted circumstances âprescribe the approved drug without limitation. A prescription to an individual whose demographic or medical characteristics differ from those indicated in a drug's FDA-approved labeling is accepted medical practice.

In a 2006 study of drug prescribing by office-based physicians, 21% of prescriptions were written for off-label uses. Of those off-label prescriptions, the study's authors found that 27% were backed by strong scientific support. A 2016 Canadian study of primary care clinics found an overall rate of 12% of prescriptions for off-label uses. The percentage varied, however, by therapeutic class, ranging from 5% for ear, nose, and throat medications to 25% for central nervous system medications. An econometric model from the National Ambulatory Medical Care Survey estimated a 38% rate of off-label use.

Research has shown that more than half of oncology drug use is off-label. A 2018 study examined 43 FDA-approved cancer drugs and compared their 99 labeled uses with the acceptable uses published by a national compendium Medicare relies on to make coverage decisions. Of the 451 compendium-accepted uses, 56% were off-label. Of the off-label uses, the authors deemed 91% as "well-accepted off-label use."

Labeling: History, Requirements, and Value

History. Drug labeling has been central to FDA's role as a protector of the public's health since 1906. That year, Congress (1) required that sellers state on a drug's label the "quantity or proportion of any alcohol [or] opium" contained, and (2) considered as "misbranded" any drug whose label was "false or misleading." Requirements that drugs be safe were not established until 1938. Congress did not require they be effective until 1962.

Requirements. Today, a drug's labeling is more than the sticker the pharmacy places on the amber vial it dispenses to a customer. The Federal Food, Drug, and Cosmetics Act (FFDCA) and associated FDA regulations require and describe a product's labeling as "a compilation of information about the product, approved by FDA, based on the agency's thorough analysis of the new drug application (NDA) or biologics license application (BLA) submitted by the applicant. This labeling contains information necessary for safe and effective use."

FDA requires that labeling begin with a highlights section that includes, if appropriate, black-box warnings, so called because their black borders signify importance. The regulations list the required elements of labeling:

Value. Labeling plays a major role in the presentation of safety and effectiveness information. For clinicians, it is a primary source of prescribing information. The manufacturer submits the approved labeling for publication in the widely used Physician's Desk Reference . That labeling also serves as the basis for several patient-focused information sheets that manufacturers, pharmacy vendors, and many web-based drug information sites produce.

Off-label prescribing can reflect cutting-edge clinical expertise. It can also be a response to price: a physician may choose to prescribe a lower-priced drug instead of a specifically labeled higher-priced one. Or a physician may prescribe off-label in an attempt to try a different treatment approach when other options have failed.

Sometimes an off-label use becomes so widespread that it becomes accepted practice. However, without the backing of carefully designed clinical trials and expert analysis, it remains unknown whether the drug is, in fact, safe and effective for the off-label use. Also unknown are dosing details and systematically evaluated associated adverse events.

a drug tested for the treatment of one disease prescribed in an attempt to prevent or treat another; a drug tested at one dose used at higher or lower doses; a drug tested in adults prescribed to children; and a drug tested in an eight-week trial prescribed for long-term use.

Table 1 lists several examples of FDA-approved drugs widely prescribed for off-label uses.

Although FDA materials do not list off-label uses, several drug compendia include both labeled and off-label uses. For Medicare coverage, for example, the Social Security Act defines "medically accepted indication" as those, in addition to uses approved by FDA, that have been evaluated and supported and listed in one of several compendia, or for which there is "supportive clinical evidence in peer reviewed medical literature."

Why has Congress given FDA the authority to regulate whether a drug may be on the U.S. market? Two key reasons: to protect patients and to encourage research in a competitive pharmaceutical industry.

By statute and regulation, FDA now approves a drug for a specific use once its sponsor (usually the manufacturer) has provided sufficient evidence that the drug is safe and effective for that use. FDA has developed procedures for the review of that evidence. The FDA-approved labeling, which informs the clinician about dosing and likely and unlikely adverse events, helps protect the individuals for whom the drug is prescribed.

Labeling also helps protect the interests of the manufacturers who invest in the clinical trials that demonstrate safety and effectiveness. For new drugs and new uses of already approved drugs, the sponsor receives a period of market protection, in the form of regulatory exclusivity for the sale of the drug for those uses. Payorsâsuch as private health insurers or Medicareâbenefit from FDA-approved labeling in their evaluation of whether to pay for a drug's use.

But use of a drug evolves as clinicians (and the manufacturer) share their experiences regarding off-label uses, which, by definition, were not part of the premarket clinical studies used to obtain FDA approval. Off-label use can benefit patients. In some instances, such as in the treatment of rare diseases, clinical practice may use drugs approved for other indications. A manufacturer may choose not to invest in trials for such a small patient group. A patient whose physician is already prescribing the drug off-label may not want to enroll in a clinical trial where there is a chance he or she may be assigned to the placebo group. Once drugs are well-established in off-label uses, manufacturers rarely design studies to determine or verify the safety and effectiveness of such uses. Individuals and groups wanting to conduct such studies may find it hard to obtain funding.

Examples of adverse events (AEs) associated with the use of drugs for specific off-label uses include heart valve damage from the use of fenfluramine and phentermine (fen-phen) for weight loss, and seizures from the use of tiagabine hydrochloride for depression. Using a Canadian primary care database that captured all prescriptions, the reason for each prescription, and adverse events, researchers looked at the rate of AEs for on-label use, off-label use associated with "strong scientific evidence," and off-label use without such evidence. They found more AEs for off-label prescriptions than for on-label prescriptions. However, off-label use associated with strong scientific evidence had similar rates of AEs as did on-label uses. The increased risk of AEs for off-label use was concentrated in those uses without strong scientific evidence.

Manufacturers benefit from sales for off-label uses. However, they risk losing that market should a competitor complete studies to obtain FDA approval and labeling for those uses. Researchers who are not supported by the manufacturer who try to assess the safety and effectiveness of off-label uses are hampered by the inexact nature of secondary data sources: the standard clinical trial data collection in preparation for an FDA application is not available for off-label uses. What may begin as hopeful and intermittent off-label use may gain momentum and offer opportunities for planned studies.

Drug and device companies argue that current regulations prevent them from distributing important information to physicians and payors about unapproved, off-label uses of their products. In November 2016, FDA held a two-day public meeting to hear from various groups regarding off-label uses of approved or cleared medical products. In June 2018, FDA issued final guidances explaining the agency's policy about medical product communications that include data and information not contained in FDA-approved labeling.

One FDA guidance document, in particular, described the types of information that a manufacturer could provide payors and formulary committees about unapproved uses of approved products. FDA made two points especially relevant to off-label uses.

First, FDA differentiates among its audiences in its presentation of information. The material it allows in product labeling is directed to a clinical audience. FDA staff have reviewed the information and require that it be presented in a way that is understandable by individual clinicians, who often do not have the statistical sophistication or data analysis skills or resources to fully evaluate the claims of manufacturers. This guidance notes, though, that payors and formulary committees do have such expertise and resources. FDA also acknowledges that it is useful for payors to have information in their decisions on coverage, but it wants to ensure that the information manufacturers provide is not misleading.

Second, the FDA guidance describes what harm could come from allowing more sharing of information about off-label use.

Some firm communications regarding unapproved products or unapproved uses of approved/cleared/licensed medical products may potentially undermine substantial government interests related to health and safety. These interests include motivating the development of robust scientific data on safety and efficacy; maintaining the premarket review process for safety and efficacy of each intended use in order to prevent harm, to protect against fraud, misrepresentation, and bias, and to develop appropriate instructions for use for medical products; protecting the integrity and reliability of promotional information regarding medical product uses; and preventing the diversion of health care resources toward ineffective treatments.

The concerns FDA raised in the June 2018 final guidance documents might explain why Congress may be interested in exploring the issue of off-label use further.

History of Congressional Interest and Action

Congress has developed a system to protect the public by ensuring that drugs sold in the United States have met clinical and manufacturing standards of safety and effectiveness. Labeling is the mechanism that bridges the regulated drug and the use of that drug in clinical practice. The labeling establishes the uses for which the manufacturer has demonstrated safety and effectiveness to FDA's satisfaction. Congress and the FDA have tried several approaches, using labeling as a tool, to reduce the risk to patients. Table A-1 includes examples of congressional and FDA actions to expand the information provided in a drug's labeling. The actions have addressed topics such as

content labeling, directions for use, permissible and prohibited advertising, research incentives to support labeling specific to population subgroups (e.g., children), criteria for Medicare coverage, required and permissible labeling changes, and balance of benefit and risk information in labeling and advertising.

Manufacturers, meanwhile, want to be able to provide information to insurers and other entities (such as the Centers for Medicare and Medicaid Services [CMS] and hospital pharmacy and therapeutics committees) that decide whether to cover a drug in a policy and whether to limit reimbursement for specific uses. Congress has provided some leeway relative to its earlier prohibition on promotional activities. For example, in 2016, it broadened the types of health care economic information drug and device manufacturers could provide to payors (e.g., insurance companies). Although the underlying FFDCA section continues to exclude information related only to an off-label use, it now requires "a conspicuous and prominent statement describing any material differences between the health care economic information and the labeling approved for the drug." Several bills concerning off-label use have been introduced that would have expanded the information that manufacturers could provide about off-label uses. For example, the Subcommittee on Health of the House Committee on Energy and Commerce marked up H.R. 2026 (115 th Congress), the Pharmaceutical Information Exchange Act, in January 2018, which would have allowed the provision of scientific information to payors, in addition to health care economic information. Then-Subcommittee Chair Michael Burgess, in commenting on the bill's effort to clarify how manufacturers can share "if it is based on competent and reliable evidence," expressed strong support for the bill. He noted "the importance of cutting edge information in medicine and science to optimize patient care and outcomes â¦ and [how the bill] could have the potential to save patients' lives."

Then-Ranking Member (now, Chair) Frank Pallone, Jr., though, argued that the ability to communicate about off-label use "had great potential to undermine" FDA's approval process and to "hamstring" its enforcement efforts. H.R. 2026 passed the subcommittee, although it did not reach the floor in the 115 th Congress.

Possible Avenues of Future Congressional Interest

Off-label use presents both opportunities and risks to clinicians, patients, manufacturers, and researchers. At times, those interests clash. Academics, public health organizations, and journals have suggested what actions Congress might take based on their particular concerns regarding off-label prescriptions. These actions include both direct legislation and oversight activities to encourage action by other entities. The 116 th Congress might consider some of these varied approaches, summarized in the issues described below.

Disclosure to patients. Most individuals, unaware of the nuances of FDA regulation, may not know that physicians may prescribe drugs for uses that FDA has not reviewed for safety and effectiveness. Several potential opportunities for providing this information exist. Congress could require or work with the states to require that

the prescriber inform the patient about the off-label use and describe the meaning of off-label use; the prescriber note in the prescription why the drug is being prescribed; or the pharmacist inform the patient that the use is off-label.

Data collection and availability. FDA, under federal law, determines whether a drug requires a prescription. The states, under their individual laws, determine what information the prescription order contains. Because clinicians do not need to note on the prescription order why they are prescribing a drug (e.g., simvastatin for high cholesterol or citalopram for depression), the information in pharmacy, administrative, and clinical databases often cannot directly identify off-label uses. Therefore, as Congress and other public policy groups consider whether and how to address off-label drug prescribing, they do not have adequate information on the scope and details of the practice. Congress could require or work with the states to encourage

clinicians to note on prescriptions the reason for medication use (e.g., the specific condition, disease, or symptom), thereby allowing that information to appear in pharmacy databases, which would enable focused analysis of off-label uses; the establishment of confidential registries of off-label prescribing and follow-up information that FDA (or other designated scientifically appropriate agencies) could use in its electronic surveillance systems to identify associated adverse events and other drug use problems; or FDA to increase its surveillance of available data sources, such as registries and administrative and clinical databases, to identify patterns of off-label use and evidence suggesting effectiveness and associated adverse events.

Dissemination. Because some information may be valuable to clinicians and entities that influence prescribing decisions (such as insurers and pharmacy and therapeutics committees), Congress could allow manufacturers to disseminate information about off-label uses that they have developed or of which they are aware, perhaps subject to certain limitations or accompanying reporting requirements. Possibilities include

broader sharing of clinical analyses of off-label use with coverage deciders (e.g., CMS, insurers, pharmacy and therapeutics committees) to support requests that they cover a particular use of the drug; and dissemination of clinical analyses of off-label use at clinical and pharmaceutical conferences.

Oversight. With an estimated 12% to 38% of all prescriptions' (and 56% of oncology prescriptions') being written for uses not listed on FDA-approved labeling, valid information on the extent of off-label use and the effect of such use on manufacturer, insurer, and clinician behavior could potentially better inform debate on how to best protect the public's health. Congress could direct

the Government Accountability Office (GAO) to study the extent of off-label use in government-provided care (e.g., Department of Veterans Affairs, Bureau of Prisons, and Indian Health Service) and in government-funded care (e.g., Medicare and Medicaid); the Secretary of Health and Human Services (HHS) to contract with the National Academy of Medicine or a similar organization to assemble management or industrial policy experts to study the costs and rewards to industry of off-label prescriptions; or FDA and the Federal Trade Commission to investigate drugs whose off-label prescriptions account for a particularly high percentage of all prescriptions or that generate a particularly high percentage or high dollar value of sales.

Pricing. The decision to use a drug off-label based solely or primarily on price introduces a new element to study. For example, the pricing difference between Avastin and Lucentis, both made by the same manufacturer with the same active ingredient, is so large that many ophthalmologists use the lower priced Avastin in their treatment of macular degeneration, despite its being an off-label use. The manufacturer included the treatment of macular degeneration in its application to FDA for Lucentis. To explore the ramifications of a traditionally nonclinical element in prescribing decisions, Congress could require

the HHS Secretary to study the relationship among pricing, access, and prescribing and its effect on patient safety.

Reimbursement. Although FDA approval of a drugânot for each use of a drugâis a requirement for sale in the United States, the decision to reimburse a physician or patient for a drug is made by entities such as the CMS and private insurers. Such decisions, therefore, influence what drugs are prescribed and, in part, for what uses drugs are prescribed. Congress could direct

the HHS Secretary to study such coverage decisions or to contract with the National Academy of Medicine or a similarly equipped entity to do so; or HHS to form a task force to include CMS and FDA, along with private insurers and others involved in coverage decisions, and patient and clinician groups representing those affected by coverage decisions, to identify areas in need of action and to recommend steps in those directions.

payors to require safety and effectiveness evidence before covering off-label uses.

Research. The traditional path toward adding an indication (reason for use) to the labeling of a drug already approved for other uses has been for the sponsor of the drug to conduct clinical trials and submit a supplemental new drug application (NDA) to FDA. The widespread extent of off-label use suggests that relying on that model is not helping prescribers get better information. Congress could consider

assigning responsibility (and funding) to the National Institutes of Health and the Patient-Centered Outcomes Research Institute for safety and effectiveness evaluations of off-label uses; or requiring, for a drug that has substantial (to be defined) off-label sales, that the manufacturer fund studies, such as clinical trials, to assess the safety and effectiveness of the drug for the off-label use and submit evidence to the HHS Secretary. Depending on the Secretary's assessment of the evidence, the Secretary could request that the manufacturer amend the drug's labeling either to add the off-label use to the label as an approved use or to add a statement that clinical evidence does not support the safety and effectiveness of the drug for the off-label use.

Research transparency. FDA regulations describe standards for the design and analysis of clinical trials that a sponsor uses in an NDA. Studies done by or for the manufacturer or by other groups or individuals are not always made public, in which case their findings cannot be reviewed and evaluated. Because the results of such studies may be used in support of off-label uses, by providing positive and negative incentives, Congress could consider requiring or encouraging

prospective posting of the designs and statistical plans of studies of off-label uses; or public reporting of studies of off-label use.

Clinical guidance. Professional societies and other clinical groups often supplement the information available to prescribers from FDA-approved labeling, medical journals, and information from manufacturers. They can issue guidelines and recommend best practices. Congress could engage such groups and encourage

professional societies to develop evidence-based clinical guidelines and training regarding off-label use.

Precedents from other countries. The United States is not alone in facing the health care and economic implications of off-label use. For example, the member countries of the European Union have addressed measures involving reimbursement, guidance for prescribers, professional standards, and informed consent. Congress could require

HHS to contract with the National Academy of Medicine or a similarly equipped entity to review measures taken by the European Union and other regulatory bodies and recommend legislative or administrative actions as appropriate.

Concerns over off-label use overlap with questions raised by some legislators and regulators in other contexts. In addition to clearly related issues such as what is allowable information in direct-to-consumer advertising, promotion to clinicians, and material shared with payors and insurers, off-label use also affects the entire basis of FDA regulation of drugs through its authority to approve drugs. That means it directly or indirectly affects research, clinical innovation, transparency, patents and exclusivities, pricing, and access.

Changes in law or regulation in any one area may have benefits in some areas and drawbacks in others. For example, FDA's initiative to encourage research in drugs used traditionally but never reviewed and approved by FDAâso-called legacy drugsâstems from its desire for evidence of safety and effectiveness. Such evidence helps protect patients from possible use of ineffective, unsafe, or misdosed drugs. That initiative, in turn, helps enable sponsors to conduct the clinical trials, submit new drug applications, obtain regulatory exclusivity with the new drug approvalâand then raise the price of the new branded product while expecting FDA to honor the exclusivity and block the sale of the drug by others. For example, clinicians had been prescribing a compounded version of progestin for use in preventing preterm delivery. Such use had never been adequately tested in clinical trials. One company conducted those trials, and FDA approved its new drug application. The initial price for the new drug, Makena, was $30,000 for a 20-week course; patients had been paying pharmacists $200-$400 for the same course. Unanticipated price increases can also arise from the apparent following of FDA procedures. For example, a new owner of the FDA-approval of an old antiparasitic generic drug raised the price from $14 per tablet to $750, Daraprim's initial price. Such sudden and large price increases become a barrier to patient access and, therefore, a potential threat to health.

In the case of off-label prescribing, actions in any directionâwhether by Congress, FDA, or the courtsâcould have both intended and unanticipated effects. Actions to limit off-label prescribing could have the intended effects of reducing safety risks and the economic cost of using drugs ineffective for their prescribed purposes. Such limits, however, could also stifle informed clinical exploration. Similarly, incentives to mount clinical trials needed to add an indication to the label could help identify and disseminate information on dosing and contradictions. Such incentives, however, could also hurt. For example, a brand drug that added a new indication to its labeling could prevent, through exclusivities, generics from similarly modifying their labeling. Patients could need to pay more.

The recent debates over the right-to-try movement regarding use of investigational drugs by terminally ill patients may preview discussion about any proposed restrictions on off-label use. The Goldwater Institute, considered a key impetus to development and passage of the 2018 enactment of a right-to-try act, looks to diminish government's role in an individual's choice and has supported dissemination of off-label information.

Congress has built a process in which a robust FDA can regulate drugs to protect the public's health. Is there cause for concern that perhaps a third of prescriptions are for off-label uses and that, in at least one study, three-quarters of those had minimal or no accepted scientific evidence to support their use?

Policy tension exists over the line between wanting to ensure individuals' freedom to take drugs for off-label uses and wanting to protect the public from the risk of unsafe or ineffective drugs. Where to draw that lineâand how to know when it may be time to move the lineâis of continuing interest to regulators and legislators.

Appendix. Selected Actions to Expand Information in Drug Labeling