FDA approves reference listed drugs and generic drugs that meet safety and efficacy standards for marketing in the United States. Generic drug companies must show that their drug is (1) the same as the reference listed drug with respect to the active ingredient(s), conditions of use, route of administration, dosage form, strength, and labeling (with certain permissible differences, as approved by FDA); and (2) bioequivalent to the reference listed drug, meaning it generally delivers the same amount of active ingredient(s) in the same amount of time as the reference listed drug. When the reference listed drug is available, it is also designated as the reference standard drug, which is the product generic drug companies must use to conduct bioequivalence testing. When the reference listed drug is not available, FDA will select an approved generic of the reference listed drug to serve as the reference standard drug. All drugs pose some level of safety risk to patients. According to FDA, for most drugs, routine, risk-minimization measures, such as FDA-approved professional labeling, are sufficient to protect the public from the drug’s risks. However, in some cases, FDA may require a drug company to take additional actions to ensure that the benefits of the drug outweigh its risks and to help mitigate or prevent serious risks of adverse side effects. Specifically, FDA may require the drug company to establish a REMS that includes one or more risk-mitigation strategies beyond the drug’s professional labeling. According to FDA, most REMS are designed to reinforce patients’ and health care providers’ behaviors and actions that support the safe use of the particular drug they cover. For example, FDA may require drug companies to give patients and health care providers additional information to reinforce certain safe use conditions or specific risks described in the approved labeling of a certain drug. FDA may require a REMS either before a drug is approved or after approval if FDA becomes aware of new safety information. When determining whether a REMS is necessary, FDA considers several factors, including, for example, the estimated size of the population likely to use the drug and the seriousness of the disease or condition being treated. FDA may require a REMS to include one or more components. For example, FDA may require drug companies to provide patients with certain information in the form of medication guides. Generally, medication guides include information on serious side effects, including those that might require emergency medical care or involve life- threatening conditions. Similarly, FDA may require drug companies to develop communication plans for how the drug company will disseminate information to health care providers. Communication plans can include, for example, information on any serious risks of the drug and any safety protocols to ensure its safe use. Thus, for one REMS, FDA could require a drug company to provide a medication guide. For a second REMS, FDA could require a drug company to provide both a medication guide and a communication plan. Table 1 below includes a list of selected REMS components. Additionally, if a reference listed drug is subject to a REMS, an approved generic drug is also subject to some of the same REMS requirements. FDA can also require drug companies to implement another REMS component, called “elements to assure safe use” (ETASU), if a drug has been shown to be effective, but is associated with a specific serious risk. Depending on the risk, FDA may require any or all of the following ETASU measures: Prescribers have specific training or special certifications; Pharmacies or health care settings where the drug is dispensed have Drugs are dispensed only in certain health care settings, such as hospitals; Drugs are dispensed with evidence of safe-use by the patient, such as requiring a patient’s acknowledgement that she has been counseled on a drug’s risks and understands and accepts these risks; Patients are monitored, for example, while taking the drug for specific adverse events or outcomes; or Patients are enrolled in a registry for collection of certain information, such as patient outcomes and adverse reactions associated with the drug. According to FDA, these measures are for drugs that can be marketed only if there are requirements in place to mitigate a specific serious risk listed in the drug’s labeling. If FDA requires certain ETASU measures, it may also require a drug company to develop an implementation system to enable the drug company to monitor and evaluate implementation of the ETASU measures by health care providers, pharmacists, and other responsible parties. Also, if a reference listed drug is subject to a REMS with ETASU and a generic version is being developed, the reference drug company and the generic drug company are required to develop a shared system—a system that is used by participating companies to coordinate their REMS activities and information about a drug’s risks. Under a required shared system, the generic drug company and the reference drug company use the same REMS documentation and other materials on the drug’s risks and generally share in the implementation and maintenance of any database and infrastructure (e.g., call center). According to FDA, shared systems can be beneficial in reducing the burden for patients and health care providers, such as prescribers and pharmacies, when accessing REMS informational materials or completing administrative requirements, including any required training or certifications for providers. Generic drug companies must submit REMS documentation and materials as part of their generic drug application. Generally, before FDA can approve generic drugs that are subject to REMS with ETASU, reference drug companies and generic companies must reach agreement on a required shared system. According to FDA, generic drug companies that are developing a required shared system should submit their proposed REMS materials to FDA by the midpoint of the application review process or another time as specified by the agency. Any delays in the development of a required shared system can affect FDA’s ability to approve a generic drug application. A generic company may request a waiver from FDA, which if granted, would allow the generic company to develop a separate system that includes the same ETASU measures required for the reference listed drug. For example, if the reference listed drug’s ETASU measures require prescriber certification and the dispensing of the drug in certain health care settings, then the generic drug company’s separate system must also include the same ETASU measures. In recent years, FDA and FTC have identified two practices that can hinder competition by preventing or delaying the development and marketing of generic drugs. The first practice the agencies identified involves limiting access to samples of reference standard drugs, which generic companies generally need to conduct bioequivalence testing. This practice can apply both to reference standard drugs subject to REMS, specifically those subject to certain ETASU measures, and those not subject to REMS. For example, some drug companies might limit access to samples of reference standard drugs subject to REMS, citing ETASU measures that limit distribution, such as the measure that limits distribution of drugs subject to REMS to only certain health care settings. Additionally, drug companies may limit access to samples of reference standard drugs that are not subject to REMS. Typically, generic companies obtain samples through normal distribution channels such as wholesale distributors. However, drug companies could, for example, limit the sale of their reference standard drugs to certain pharmacies, such as specialty pharmacies. FDA and FTC have testified before Congress that these distribution limits—for reference standard drugs with and without ETASU-related distribution measures—can hinder generic companies’ ability to develop generic drugs and to submit a generic drug application to FDA for review. The second practice involves circumstances when a reference drug company delays its negotiations with generic drug companies on a required shared system. The negotiations to develop a required shared system can be complex because all parties must agree on the implementation of the REMS as well as issues related to cost-sharing, confidentiality, and product liability concerns. As part of their generic drug application, generic companies must include an adequate REMS program in order to be approved. Therefore, delays in the development of a required shared system can affect FDA’s ability to approve a generic drug application. Our analysis of FDA data shows that as of March 18, 2019, there were 74 approved active REMS that apply to 523 drugs. These drugs pose a variety of risks to users, treat a variety of conditions, and some are generics. A REMS can apply to one drug, more than one drug, or to a large number of drugs. Specifically, the approved REMS apply to: 136 drugs because they pose a high risk of serious medical side effects, 384 drugs because they pose a high risk of serious medical side effects from misuse and abuse, and Three drugs because they have the risk of medical side effects from both the use of the drug and from misuse and abuse. These drugs also treat at least 15 different types of medical conditions such as cancer, cardiovascular, and respiratory conditions. Twenty-two are orphan drugs, which are drugs intended to treat rare diseases. One hundred forty-three of these drugs are reference standard drugs, and 64 of these reference standard drugs have one or more approved generics that are also subject to REMS. (See Table 2) For example, FDA approved a generic of the drug Clozaril, which is used to treat mental and mood disorders. Both Clozaril and its generic, Clozapine, are subject to a REMS to prevent adverse medical side effects. Medicare and Medicaid paid at least $11.8 billion in 2017 for reference standard drugs subject to REMS. Specifically, in 2017 Medicare paid at least $8.5 billion for 83 of 139 reference standard drugs subject to REMS. This amount accounted for at least 8 percent of all Medicare drug spending in 2017. In the same year, Medicaid paid at least $3.3 billion—or at least 15 percent of all Medicaid drug spending—for 83 of the 139 reference standard drugs subject to REMS. Appendix I provides information from available data on Medicare and Medicaid spending on reference standard drugs subject to REMS. Of the 74 active REMS in our analysis, 51 have at least one required ETASU measure, and 35 specifically limit how drugs are distributed. Thirty-one of the 74 active REMS also require medication guides explaining the risks of the drug to be given to patients, and 12 require a communication plan for how the company will disseminate information to health care providers. Similar to how the 74 active REMS can have more than one REMS component, the 51 active REMS with ETASU measures can have more than one required measure. For example, 19 active REMS have an ETASU measure requiring patients to be enrolled in a registry and an ETASU measure requiring drug companies to provide training to prescribers of the drugs. Over half of the 51 active REMS with ETASU include measures that may limit how drugs are distributed. Specifically, 35 active REMS with ETASU measures include a requirement for drug companies to ensure drug dispensing settings are specially certified before they distribute the drugs. The certification process may require dispensing pharmacies to enroll in education programs provided by the drug companies. For example, to mitigate the risk of accidental overdoses from the misuse and abuse of fentanyl products, dispensing pharmacies are required to complete an education program that addresses—among other things— the risks of fentanyl products, patient selection, drug dosage, and patient counseling. In addition, for 10 of the 74 active REMS, companies have entered into a shared system. In three of the 10 shared systems, generic companies received a waiver from the shared system requirement after they were not successful in negotiating a shared system with the reference drug companies. In these three cases, the generic drug companies entered into shared systems that are separate from the reference drug company systems. For example, after developing generics of Lotronex, which is subject to REMS with ETASU and intended to treat gastrointestinal conditions, the generic companies were required to enter into a shared system with the reference drug company. When these companies were not successful in negotiating a required shared system, FDA determined the burden of developing a required shared system with the reference drug company outweighed the benefits of having one and waived the requirement. Once FDA granted the waiver, multiple generic companies were allowed to share REMS materials and administrative requirements with heath care providers via one shared system that is separate from Lotronex’s REMS system. FDA and FTC have taken four actions to address circumstances when generic drug companies cannot access samples of reference standard drugs or experience delays in negotiating required shared systems. According to FDA and FTC, both circumstances can hinder generic drug companies’ ability to develop and market generic drugs. Three of the actions focus on making samples of reference standard drugs accessible and the fourth focuses on facilitating the development of a required shared system. While all four of the actions pertain to drugs subject to REMS, only two of the actions pertain to drugs both subject to REMS and not subject to REMS. According to FDA officials, the agency is even more limited in what actions it can take when drugs not subject to REMS are involved. Drug Companies’ Perspectives on Limited Access to Samples of Reference Standard Drugs with Elements to Assure Safe Use (ETASU) that Limit Distribution Officials from all four of the generic drug companies we interviewed told us that their inability to access samples of reference standard drugs with ETASU measures that limit distribution either delayed or discouraged them from developing generic drugs. Officials from two of the five reference drug companies we interviewed told us they were unaware of specific instances when generic companies had difficulty obtaining samples or that generic companies had requested samples of reference standard drugs with ETASU measures that limit distribution. Also, officials from two reference drug companies cited safety concerns as the reason for limiting the distribution of their drug. FDA issued draft guidance on how to obtain a safety determination letter. One of FDA’s actions focused on facilitating generic drug companies’ access to reference standard drugs with ETASU-related limited distribution measures. (See sidebar for drug companies’ perspectives on this practice.) In 2014, FDA issued draft guidance describing how a generic drug company could ask the agency to send what is known as a safety determination letter to the reference drug company on the generic drug company’s behalf. The draft guidance explains how FDA could send a letter stating that the agency had reviewed the generic company’s plans for its bioequivalence testing and determined that these plans included safety measures that were comparable to those in the ETASU measures for the reference standard drug. For example, if the reference standard drug’s ETASU required protections to prevent fetal exposure to the drug, the generic company’s plans should include the same protections. The safety letter would also note that FDA would not consider it a REMS violation to provide reference standard drug samples to the generic company requesting the safety determination letter. According to FDA, some reference drug companies were concerned that providing samples to the generic drug company would violate REMS requirements. From 2016 to 2018, FDA issued 12 safety determination letters to reference drug companies on behalf of generic companies, according to agency data. However, FDA did not issue a safety determination letter for all of the requests it received. According to FDA officials, there are various reasons why they might not issue a safety determination letter to the reference drug company. For example, a generic company must sign a disclosure form in order for FDA to send the letter to the reference drug company, but the generic company does not always choose to do this. Additionally, the generic company might have withdrawn its request for a safety determination letter, or FDA might be waiting for additional information from the generic company in order to complete its review. According to FDA officials, there is no need for a safety determination letter (which assures the reference drug company that providing samples to the generic drug company will not be considered a violation of their REMS) when there is no REMS for the product in the first place. Drug Companies’ Perspectives on Limited Access to Samples of Reference Standard Drugs Not Subject to Risk Evaluation and Mitigation Strategies (REMS) Officials from three of the four generic companies in our review told us they had experience with drug companies’ imposed distribution limits on reference standard drugs not subject to REMS. Of the four generic companies in our review, officials from one company said they were not able to obtain the samples they needed and chose not to pursue developing a particular drug. Officials from one of the five reference drug companies said they have limited distribution for reference standard drugs not subject to REMS. They said their companies do so to ensure that their products are efficiently distributed, in part by using certain pharmacies. FDA published a web page with information about inquiries that included drugs both subject to and not subject REMS. In February 2019, FDA published a web page with information on inquiries made to FDA by generic companies seeking to obtain samples of reference standard drugs in order to develop generic drugs. (See sidebar for drug companies’ perspectives on this practice.) FDA officials said they published this list to increase transparency about continuing issues related to accessing samples and to raise awareness about the potential effect these issues might have on reducing competition in the drug market. This list included drugs subject to and not subject to REMS, the names of reference drug companies, and the number of inquiries made. According to the web page as of February 2019, inquiries were made for 54 reference standard drugs, including 25 drugs with ETASU-related limited distribution measures and 29 drugs without such measures. According to FDA data, the number of inquiries had been generally decreasing in the years prior to when the list was published. FTC officials reviewed inquiries the agency received from FDA and generic companies and filed two briefs. FTC told us it reviewed inquiries the agency had received from generic companies and FDA, including those related to information on FDA’s published web page. However, FTC officials said, to date, they have not brought a case charging a reference drug company with violating federal antitrust law for refusing to provide samples to a generic drug company. In order to take enforcement action, FTC needs to find sufficient evidence of activity that violates the Federal Trade Commission Act or the Sherman Act. For example, FTC would need to find that a reference drug company’s practice constituted monopolization in violation of the Sherman Act. According to FTC officials, they have not brought any antitrust cases to the courts, but have filed two amicus briefs related to cases involving drugs subject to REMS. In both of these briefs, FTC noted that the generic companies’ respective allegations, if true, established an antitrust violation and that the generic companies’ lawsuits should be allowed to continue. Drug Companies’ Perspectives on Negotiating Required Shared Systems Officials from one generic company said that the respective reference drug companies would not meet with them to negotiate the development of a required shared system REMS. Officials from another generic company said the negotiation process with the reference drug company lasted almost 2 years. Officials from four of the five reference drug companies we interviewed had experience negotiating required shared systems. Officials from three of these four companies told us that developing a shared system is a difficult, challenging, and complex process. Officials from one reference drug company said that the level of complexity can increase based on the number of companies and the different people involved. FDA issued waivers that allowed generic drug companies to develop a separate system from the REMS of the reference listed drug and issued draft guidance on how to obtain such a waiver. According to FDA, since 2007, the agency has received 13 requests for a waiver from the shared system requirement, and at the time of our data collection and analysis, FDA had approved three, the first in 2013. (See sidebar for drug companies’ perspective on required shared systems.) These waivers allowed the generic drug company to develop a separate system that includes the same ETASU measures required for the reference listed drug. According to officials, FDA was unable to grant the remaining waivers for different reasons. For example, the agency may still be reviewing the generic drug application submitted by the company that requested a waiver. Officials explained that the waiver request is part of the overall generic drug application and the agency cannot approve a waiver without approving the application as well. To further facilitate the process, in 2018, FDA issued draft guidance describing what factors the agency considers when granting waivers. The statute authorizes FDA to grant a waiver (1) if the burden of creating a required shared system outweighs the benefit of having it, taking into account the impact on the health care providers, patients, and drug companies involved or (2) if an aspect of the ETASU is covered by an unexpired patent or entitled to trade secret protection, and the generic company was unsuccessful in obtaining a license for use. FDA’s guidance describes examples of the potential benefits of having a shared system and the burdens of forming a shared system on health care providers, patients and drug companies that FDA will consider. For example, having a shared system could benefit drug companies by making a REMS for multiple products more efficient. In contrast, the drug companies negotiating a required shared system could be market competitors and involved in patent litigation related to the drug product. In general, the four generic drug companies and five reference drug companies we interviewed disagreed on the usefulness of FDA’s and FTC’s efforts to address the practices that may affect the development of generic drugs. FDA’s safety determination letters. Officials from three of the generic companies in our review said that the safety determination letters were not useful because they were not enforceable and did not require a reference drug company to provide a generic company with samples of a reference standard drug. In its comments on FDA’s draft guidance on obtaining a safety determination letter, one stakeholder representing generic companies expressed concern that reference drug companies now use safety determination letters as another requirement to obtain samples. In contrast, officials from three reference drug companies we interviewed told us that FDA’s safety determination letters addressed their safety concerns regarding sharing samples of reference standard drugs with generic companies. Further, officials from two of these three reference drug companies said they request these letters from generic companies that request samples of reference standard drugs. Officials from the remaining two reference drug companies we interviewed said they were not aware of FDA’s safety determination letters or did not have concerns or a position on the issue. FDA’s publication of its web page. Officials from one of the four generic companies we interviewed told us they thought the inquiries web page published by FDA was helpful. However, this same company said it had not noticed a significant effect in being able to access samples of reference standard drugs because of the web page. Officials from another generic company said it was too early to tell about the usefulness of FDA’s web page. Of the remaining two generic companies, officials from one company were unaware of the web page and officials from the second company noted that they were uncertain why a generic company would be included in the list of companies on FDA’s web page. Officials from two of the five reference drug companies we interviewed, and whose companies appeared on the web page, said they were unaware of any inquiries made to their companies requesting samples of reference standard drugs. Additionally, officials from one company told us they did not know why they were on FDA’s published web page because the company had sold the reference standard drug to another company and had informed FDA that this had occurred. According to FDA, the web page reflects the owner of the reference standard drug at the time the agency received an inquiry, regardless of whether the drug was later sold. Additionally, some generic companies might contact FDA directly without contacting the reference drug company because they anticipate having difficulties accessing samples of the reference standard drug. FDA notes on its web page that the agency did not independently investigate or confirm the access limitations described in the inquiries it received. FTC’s filing of amicus briefs. Officials from two of the generic companies in our review said FTC’s filing of amicus briefs was generally a positive step. Officials from two companies said the amicus briefs helped negotiations with reference drug companies. A third generic company said the amicus briefs helped raise awareness about issues generic companies are having. Officials from a fourth generic company said FTC’s actions could impact the company’s efforts to develop generic versions of reference listed drugs in the future. Officials from the five reference drug companies we interviewed did not have any comments on FTC’s specific amicus briefs. Waivers for a required shared system. Officials from three of the four generic companies we spoke with had experience with waivers. Officials from one of these three companies said the waiver guidance was helpful. However, officials from this generic company and a second company said it took FDA almost a year to grant their waivers. According to officials from a third company, they obtained their waiver within a month, in part, because negotiations had been ongoing for more than a year. According to FDA officials, the review of a waiver request is part of the generic drug company’s drug application. FDA will not grant a waiver unless the generic drug company meets the waiver requirements and its generic drug application is approved. Reference drug companies and other stakeholders expressed concerns about these waivers. Officials from three of the five reference drug companies we spoke with said the burden on health care providers or patients should be considered when granting waivers. Officials from one company specifically expressed concerns that as FDA grants additional waivers, it could place an additional burden on the health care system. For example, health care providers could be required to use multiple systems to access REMS information on the drug’s risks or to complete administrative requirements, such as required certification. The remaining reference drug companies did not have comments on the topic. In comments we reviewed on FDA’s draft guidance on these waivers, stakeholders noted concerns similar to those raised by the reference drug companies. For example, two groups representing pharmacists and pharmacies said that if FDA grants additional waivers, it could place a burden on the health care system. Historically, FDA has attempted to limit the number of required shared systems created under waivers. If a generic drug company is granted a waiver, it is allowed to create a separate system that includes the same ETASU measures required of the reference listed drug. However, to date, FDA has only granted waivers to generic drug companies that agree to share their systems with other drug companies that concurrently or subsequently develop generic or brand versions of the same reference listed drugs. We provided a draft of this product to FDA and FTC for their review and comment. Both agencies provided technical comments, which we incorporated as appropriate. As agreed with your office, unless you publicly announce the contents of this report earlier, we plan no further distribution until 30 days from the report date. At that time, we will send copies to the appropriate congressional committees, the Secretary of HHS, and other interested parties. In addition, the report is available at no charge on the GAO website at http://www.gao.gov. If you or your staff have any questions about this report, please contact me at (202) 512-7114 or dickenj@gao.gov. Contact points for our Offices of Congressional Relations and Public Affairs may be found on the last page of this report. GAO staff who made key contributions to this report are listed in appendix II. In order to estimate Medicare and Medicaid spending on reference standard drugs subject to risk evaluation and mitigation strategies (REMS), we compared data from the Food and Drug Administration (FDA) on drugs subject to REMS as of March 18, 2019, to publicly available 2017 data on the Medicare Part D Drug Spending Dashboard and the Medicaid Drug Spending Dashboard, maintained by the Centers for Medicare & Medicaid Services (CMS). These data covered drug spending and utilization for both of these programs for calendar year 2017, the most current data available. However, not all spending and utilization data for reference standard drugs subject to REMS were available. Since we analyzed data as of March 18, 2019, we were able to identify 139 reference standard drugs subject to REMS with corresponding cost data. To assess the reliability of these data, we interviewed knowledgeable agency officials. We determined that the data were sufficiently reliable for the purposes of our report. Medicare and Medicaid paid at least $11.8 billion in 2017 for reference standard drugs subject to REMS, according to cost data available from the CMS’s drug pricing dashboard. Specifically, Medicare Part D paid at least $8.5 billion for reference standard drugs subject to REMS. This amount—which includes Medicare Part D plan sponsors and beneficiaries Part D payments such as copays, but not price concessions, such as manufacturers’ rebates—accounted for at least 8 percent of all Medicare drug spending in 2017. Similarly, Medicaid paid at least $3.3 billion for reference standard drugs subject to REMS, or at least 15 percent of all Medicaid drug spending in 2017. Of the 139 reference standard drugs in our analysis, the greatest share of these programs’ spending, across medical conditions, was on reference standard drugs subject to REMS for cancer, based on our analysis of available data. Specifically, Medicare and Medicaid spent at least $4.6 billion on 8 reference standard drugs that treat cancer. See table 3 below for Medicare and Medicaid spending for reference standard drugs subject to REMS by medical condition treated. Further, our analysis of available data showed that Medicare and Medicaid spent the most on Revlimid, a drug used to treat cancer, totaling $3.6 billion with Medicare accounting for $3.3 billion of this total. More than 37,000 Medicare beneficiaries used this drug, at an average cost per dosage unit of $626.94. (See table 4.) In contrast, Medicaid spent the most on Suboxone, a drug used to treat opioid dependence, totaling $0.7 billion, based on available data. More than 3 million Medicaid claims were filed for this drug in 2017, at an average cost per dosage unit of $7.89. Vivitrol was the third most utilized drug under Medicaid. (See table 5.) Based on our analysis of available data, the selected examples of reference standard drugs subject to REMS had higher average cost per dosage unit compared to the generic. For example, Medicare spent an average cost per unit of $12.20 for Clozaril, a drug used to treat mental health conditions, compared to $0.99 for clozapine, a generic version of Clozaril. Table 6 below shows selected examples comparing Medicare spending for reference standard drugs to Medicare spending for a generic version, based on our analysis of available data. Our analysis of available Medicaid data showed similar results to our analysis of Medicare data. For example, Medicaid spent an average cost of $11.71 for Clozaril, a drug used to treat mental health conditions, compared to $0.97 for clozapine, a generic version Clozaril. Table 7 below shows selected examples comparing Medicaid spending for reference standard drugs to Medicaid spending for a generic version, based on our analysis of available data. In addition to the contact named above, Geri Redican-Bigott and Tom Conahan, Assistant Directors; Carolyn Garvey, Analyst-in-Charge; Zhi Boon, Gay Hee Lee, and McKenna Storey made key contributions to this report. Also contributing were Sam Amrhein, Kaitlin Farquharson, Cathy Hamann, and Diona Martyn.