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The
Summary
The Federal Food, Drug, and Cosmetic Act (FFDCA) authorizes the Food and Drug Administration (FDA) regulatesto regulate the safety and effectiveness of drug products sold in the United States. The statutory standard for FDA approval is that a drug is safe and effective for its intended use. FDA's determination that a drug is safe does not signify an absence of risk but rather that the drug's clinical benefits outweigh its known and potential risks.
For most drugs, FDA has generally considered routine risk minimization measures to be sufficient; for example, updated labeling based on new information from postmarket surveillance. In certain cases, however, the agency has recommended or required additional measures to minimize drug risk. Early risk management programs at FDA, voluntarily instituted by manufacturers, included elements such as education for patients and providers, and restrictions on distribution. In 2007, the FDA Amendments Act (FDAAA) expanded the risk management authority of FDA, authorizing the agency to require for certain drugs, under specified conditions, risk evaluation and mitigation strategies (REMS). REMS is a required risk management plan that uses risk mitigation strategies beyond FDA-approved professional labeling. As part of a REMS, a drug manufacturer may be required to provide certain information to patients (e.g., a medication guide) and health care providers (e.g., a communication plan) or to impose restriction on a drug's sale and distributiondistribution or use via one or more "Elements to Assure Safe Use" (ETASU).
A REMS-restricted distribution program controls the chain of supply so that the drugs are provided only to patients with prescriptions from authorized physicians or pharmacies under specified conditions. Although the law prohibits the holder of an approved new drug or biologics license application (i.e.,drug application (generally the brand company) from using ETASU "to block or delay approval of ana generic drug application," FDA, the Federal Trade Commission, generic drug manufacturers, and some Members of Congress have expressed concern that brand companies are using REMS to prevent or delay generic drugs from entering the market. A 2014 study sponsored by the Generic Pharmaceutical Association (GPhA; recently renamed as the Association for Affordable Medicines [AAM]) estimated that misuse of REMS and other restricted distribution programs costs the United States $5.4 billion annually, with the federal government bearing a third of this burden. REMS have come up in the context of user fee reauthorization, with the Director of the Center for Drug Evaluation and Research at FDA testifying that some brand drug manufacturers have used REMS and distribution restrictions to delay or refuse to sell quantities of a brand-name drug to generic product developers, potentially delaying consumer access to less expensive generic drugs. Without the brand-name drug against which to test bioequivalence of the generic product, the generic product developer cannot complete the required application to FDA. Others argue that REMS are rare, and that FDA only requires REMS with restricted distribution for drugs that would otherwise not be allowed on the market due to safety risks.
In the 114th Congress, two bills were introduced to keep brand companies from using REMS to prevent or delay generic drugs from entering the market: the Fair Access for Safe and Timely Generics Act of 2015 (or the FAST Generics Act of 2015 [H.R. 2841]) and the Creating and Restoring Equal Access to Equivalent Samples Act of 2016 (or the CREATES Act of 2016 [S. 3056]). As of the date of this report, neither of these two bills has been reintroduced in the 115th Congress. However, in the 115th Congress, two bills have been introduced that address generic drug development: the Lower Drug Costs through Competition Act (H.R. 749) and the Increasing Competition in Pharmaceuticals Act (S. 297). Both bills contain a provision titled "Study on REMS," which would require GAO to conduct a study on REMS and its implementation; the study would examine, among other things, the "burden associated with REMS," including on generic drug manufacturers."
A 2014 study sponsored by the Generic Pharmaceutical Association (GPhA; now called the Association for Affordable Medicines [AAM]) estimated that misuse of REMS and other restricted distribution programs costs the United States $5.4 billion annually, with the federal government bearing a third of this burden. In the 115th Congress, legislation to keep brand companies from using REMS to prevent or delay generic drugs from entering the market has been introduced: the Fair Access for Safe and Timely Generics Act of 2017 (or the FAST Generics Act of 2017 [H.R. 2051]) and the Creating and Restoring Equal Access to Equivalent Samples Act of 2017 (or the CREATES Act of 2017 [S. 974, H.R. 2212]). Legislation aimed at reforming REMS has been discussed as a means of reducing healthcare spending, although CRS is not aware of any formal cost estimates from the Congressional Budget Office (CBO) or other entities.The Food and Drug Administration (FDA) regulatesThe Director of the Center for Drug Evaluation and Research (CDER) at FDA, for example, has testified that some brand pharmaceutical companies have used REMS and distribution restrictions to impede competition by (1) withholding or refusing to sell samples of the brand drug to the generic company for purposes of bioequivalence testing and (2) prolonging negotiations related to developing a single, shared system of REMS. Effectively, withholding samples prevents the generic company from obtaining data necessary to support an application for approval, while prolonging negotiations of a single, shared system REMS delays approval of the generic application. Others argue that REMS are rare, and that FDA requires REMS with restricted distribution only for drugs that would otherwise not be allowed on the market due to safety risks.
Introduction
The Federal Food, Drug, and Cosmetic Act (FFDCA) authorizes the Food and Drug Administration (FDA) to regulate the safety and effectiveness of drug products sold in the United States. Prior to marketing a drug, a manufacturer must submit to FDA a new drug application (NDA) demonstrating that the drug is safe and effective for its intended use. FDA reviews each NDA with three major concerns: (1) safety and effectiveness in the drug's proposed use; (2) appropriateness of the proposed labeling; and (3) adequacy of manufacturing methods to ensure the drug's identity, strength, quality, and purity.1 FDA's determination that a drug is safe does not signify an absence of risk but rather that the drug has an appropriate benefit-risk balance for its intended use and population. For most drugs, FDA has generally considered routine risk minimization measures to be sufficient; for example, FDA-approved labeling and postmarket studies. In certain cases, however, FDA has recommended or required additional measures to minimize risk.
This report provides a brief history of FDA drug regulation, describes FDA's early risk management programs, and focuses on the agency's current risk management authorities, specifically risk evaluation and mitigation strategies (REMS). The report also discusses issues that have arisen as a result of REMS, particularly the impact on generic drug competition. It does not discussWhile this report generally focuses on REMS in the context of generic drug development, the issues discussed are also relevant to biological and biosimilar product development.2 This report does not address antitrust issues raised by restricted distribution systems.
The regulation of drugs by the federal government began with the Pure Food and Drug Act of 1906, which prohibited the interstate commerce of adulterated and misbranded drugs.23 The law did not require drug manufacturers to demonstrate safety or effectiveness prior to marketing.
In 1937, a safety incident surrounding the drug Elixir Sulfanilamide generated public support for increased government regulation over drug safety.34 The following year, the Federal Food, Drug, and Cosmetic Act (FFDCA)FFDCA was signed into law, requiring a manufacturer to demonstrate, prior to marketing, that a drug was safe.45 In 1951, the FFDCA was amended to include a prescription-only category of drugs; drugs in this category require health practitioner supervision (due to drug toxicity, potential harmful effects, and/or method of use), compared with over-the-counter drugs, which may be used without a prescriber's authorization, provided that they have an acceptable safety margin, among meeting other conditions.56 In 1962, the FFDCA was amended again to require a manufacturer to demonstrate that a drug is effective, in addition to safe, for its intended use. This standard became the basis for the current NDA process.6
In 1992, in response to concerns about the timeliness of drug review, FDA and Congress worked together to develop a new revenue source for the agency (user fees) in exchange for performance goals related to drug review times. The resulting legislation, the Prescription Drug User Fee Act (PDUFA, later called PDUFA I), authorized FDA to collect fees from the pharmaceutical industry and use the revenue to support "the process for the review of human drug applications."7 PDUFA has been reauthorized on four subsequent occasions; with each reauthorization, Congress has expanded the scope of activities covered by user fees.8 For example, PDUFA III authorized the use of FDA user fees for drug safety and risk management activities; PDUFA IV authorized the agency to require for certain drugs, under specified conditions, a REMS (defined as a required risk management plan that uses risk mitigation strategies beyond FDA-approved professional labeling); and PDUFA V amended the requirements and procedures concerning assessments of approved REMS and their modification. Congressional authorization for PDUFA, as well as the three other FDA medical product user fee programs—medical device, generic drug, and biosimilar—are scheduled to expire at the end of FY2017.9 Due to the importance of user fees to FDA's budget (43% of FDA's enacted FY2016 total program level), reauthorization of the programs is often considered "must pass" legislation. As Congress generally uses the reauthorization bill to address related FDA regulatory concerns, it will likely serve as an important driver for the ongoing modification of overall agency regulatory policy.
The Drug Price Competition and Patent Term Restoration Act of 1984 ("Hatch-Waxman Act," P.L. 98-417) amended the FFDCA to establish an expedited pathway for generic drugs, allowing a generic drug manufacturer to submit an abbreviated new drug application (ANDA) to FDA for premarket review. Rather than replicate and submit data from animal, clinical, and bioavailability studies, the generic sponsor must show that the generic product is the same as the brand drug (i.e., the reference listed drug [RLD]).8 Specifically, the generic product must have the same active ingredient(s), strength, dosage form, and route of administration and must be bioequivalent9 to the RLD, along with meeting other requirements (e.g., reviews of chemistry, manufacturing, controls, labeling, and testing).10 In 2007, the Food and Drug Administration Amendments Act (FDAAA; P.L. 110-85) gave FDA the authority to require for certain drugs, under specified conditions, risk evaluation and mitigation strategies (REMS). REMS is defined as a required risk management plan that uses risk mitigation strategies beyond FDA-approved professional labeling. While REMS has allowed FDA to approve certain drugs that otherwise may have been kept off the market due to safety risks, the implementation of REMS, particularly REMS with restricted distribution, has raised some concerns. One such concern is that certain brand pharmaceutical companies have used REMS to delay competition by refusing generic product developers access to samples needed to conduct the necessary bioequivalence testing to support an ANDA. In 2012, in response to concerns surrounding misuse of REMS, legislation was introduced that would have generally prohibited the use of REMS to restrict availability of a drug for purposes of bioequivalence testing by a generic product developer; it was not enacted.11 With growing concern over high drug prices, REMS reform came to the forefront again during the 2017 user fee reauthorization, proposed as a way to increase generic product competition and reduce drug prices.12 One issue that has been raised in the context of user fee reauthorization is FDA REMS. Specifically, in a March 2017 hearing on generic drug user fee reauthorization7
1013 The Director haddirector had previously raised this same issue in a January 2016 hearing on generic drugs.1114 The Federal Trade Commission (FTC), the generic drug industry, and some Members of Congress have expressed similar concerns regarding the misuse of REMS, and in the 114th Congress, two bills addressing the REMS issue were introduced.12and 115th Congresses, legislation addressing REMS in the context of generic drug development was introduced.15 During the House Energy and Commerce full committee markup of H.R. 2430, which was later enacted as the FDA Reauthorization Act of 2017 (FDARA, P.L. 115-52), language targeting misuse of REMS was offered as an amendment to the bill.16 However, it was withdrawn and ultimately not included in the bill reported out of committee.17
As aforementioned, prior to marketing a drug in the United States, a manufacturer is required to obtain approval from FDA. The statutory standard for FDA approval is that the drug is safe and effective for its intended use. FDA's determination that a drug is safe does not signify an absence of risk but rather that the product has an appropriate benefit-risk balance for its intended use and population.1318
Beginning in the 1980s, the first risk management programs for drugs were instituteddeveloped at FDA.19 These programs included elements such as education for patients and providers and restrictions on distribution.14 One example of an early formalized risk management program was the Accutane (isotretinoin) Pregnancy Prevention Program (PPP). In 1982, FDA approved Accutane for the treatment of severe acne. Due to the potential for teratogenicity,1520 warnings against use of the product during pregnancy were included in three sections of the package insert—"warnings," "precautions," and "contraindications—as well as in the patient information brochure.1621 Accutane materials provided to physicians contained warnings about the potential teratogenicity of the drug, and education programs about adverse events related to Accutane. In the summer of 1983, reports emerged of human malformation associated with Accutane exposure. In response to these reports, the Accutane package insert was revised to highlight warnings, and health communication letters (Dear Doctor and Dear Pharmacist letters) were sent to 500,000 prescribers and 60,000 pharmacists to reiterate the information from the "contraindications" section on the package insert.1722
The Accutane PPP was implemented following a May 1988 Dermatologic Advisory Committee Meeting, and it was the first risk management program introduced by a pharmaceutical company. Elements of the program included a boxed warning; informed consent for female patients; a PPP kit for physicians containing patient information brochures and pregnancy counseling materials for the prescriber; a prescriber tracking survey; and annual and quarterly meetings with FDA.1823 Prior to FDAAA (i.e., 2007), 16 drugs were approved with restrictive risk management programs, including Clozapine (the "No Blood, No Drug" program) and Thalidomide (the "System for Thalidomide Education and Prescribing Safety," program, or S.T.E.P.S.).1924
In 2002, the Public Health Security and Bioterrorism Preparedness and Response Act (P.L. 107-188) was signed into law. Title V of the law (PDUFA III) reauthorized prescription drug user fees through FY2007, and in exchange for industry user fees, FDA committed to several performance goals, including those related to the agency's risk management activities such as:20
26Pursuant to the PDUFA III agreement, FDA issued three risk management guidance documents, including RiskMAPs contained elements similar to REMS (described in the next section), and while FDA could recommend that a sponsor implement such a safety program, FDAAA gave FDA the explicit authority to require REMS if necessary to ensure the benefits of a drug outweigh the risks.29 Some drug applications approved prior to the effective date of FDAAA contained elements to assure safe use, which typically appeared in approved RiskMAPs. In March 2008, FDA identified and published in the Federal Register a list of drug and biological products that were deemed to have an approved REMS and directed application holders to submit a proposed REMS, as specified.30 a guidance on the development, implementation, and evaluation of risk minimization action plans (RiskMAPs) for prescription drugs products (and biologics).2227 A RiskMAP is defined as a safety program designed to meet specific goals (i.e., a desired end result such as a health outcome) and objectives (i.e., an intermediate step to achieving goal) in minimizing the known risks of a drug while preserving its benefits (see Table 1). A RiskMAP targets one or more safety goals and uses certain tools (e.g., targeted education and outreach) to achieve those goals.2328
|
Drug |
Goal |
Objective |
|
Clozapine |
No agranulocytosis |
White blood cell monitoring |
|
Thalidomide |
No fetal exposure |
Pregnancy prevention and monitoring for pregnancy |
|
Lindane |
Minimize CNS toxicity and death |
No misuse (overdose or extended use) |
|
Dofetilide |
Minimize arrhythmia (torsade de pointes) |
Dose adjustment in renal impaired, hospitalize patients while initiating therapy |
Source: FDA Office of Surveillance and Epidemiology, Presentation, "Practical Experience with Risk Management Plans in the US," 2006, see http://www.fda.gov/downloads/AboutFDA/CentersOffices/CDER/ucm119346.pdf.
While RiskMAPs contained elements similar to REMS (described in the next section), FDA could recommend but not require a sponsor to implement such a safety program.
In 2007, FDAAA expanded the risk management authority of FDA, authorizing the agency to require REMS for certain drugs, under specified conditions, a REMS. Although FDA practice had long included most of the elements that a REMS may contain, FDAAA gave FDA, through the REMS process, the authority for structured follow-through, dispute resolution, and enforcement.24
REMS is a required risk management plan that uses risk mitigation strategies beyond FDA-approved professional labeling. FDA may determine that a REMS is required upon the manufacturer's submission of an NDA, after or BLA, as part of the initial approval or licensing, when a manufacturer presents a new indication or other change, or when the agency becomes aware of certain new information. As part of a REMS, a drug manufacturer may be required to provide certain information to patients (e.g., a medication guide) and health care providers (e.g., a communication plan) or to impose restriction on a drug's sale and distributionrestrictions on distribution or use of the drug via one or more "Elements to Assure Safe Use" (ETASU). In determining whether a REMS is necessary, the law requires the consideration of the following factors:
An approved REMS must include a timetable of when the manufacturer will provide reports to FDA to assess the effectiveness of the REMS components; this includes an assessment, at minimum, by 18 months, three years, and in the seventh year after the REMS is approved, or as otherwise specified.2633 The assessment requirement may be removed after three years if FDA determines that the risks of the drug have been adequately identified, assessed, and managed.
In addition to the required timetable of assessments, a REMS may include the following elements:
Patient Information: The REMS may require the manufacturer to develop materials for distribution to each patient when the drug is dispensed. This could be a Medication Guide, as provided for under FDA regulations,2734 or a patient package insert. In 2011 guidance, FDA determined that it was no longer necessary to consider every Medication Guide to be an element of a REMS.2835 The updated FDA policy allowed manufacturers with REMS that included only a Medication Guide and a timetable for assessment (and no ETASU) to request a modification to eliminate the REMS; however, a Medication Guide could still be required under FDA regulations.2936
Communication Plan: The REMS may require the manufacturer to create a communication plan, which could include sending letters to health care providers; disseminating information to providers about REMS elements to encourage implementation or explaining safety protocols; or disseminating information through professional societies about any serious risks of the drug and any protocol to assure safe use.
ETASU: An ETASU is a restriction on distribution or use that is intended to (1) allow access to those who could benefit from a drug while minimizing the risk of adverse events, and (2) block access to those for whom the risks would outweigh the potential benefits. For example, an ETASU could require that pharmacies, practitioners, or health care settings that dispense the drug be specially certified, or that the patient using the drug be subject to monitoring (e.g., regular pregnancy testing for a drug associated with birth defects). By including such restrictions, FDA is able to approve a drug that it otherwise would have to keep off the market due to safety issues.
Implementation System: The REMS may include an implementation system related to ETASU through which the manufacturer may be required to take reasonable steps to monitor and evaluate those in the health care system (e.g., doctors, pharmacists) responsible for implementing the ETASU.3037
As of March 2, 2017, there were 77According to FDA's website, as of January 2018, there are 72 active, approved REMS, of which 45 include ETASU, 10 include only a communication plan, and 17 include only the medication guide.38 The number of REMS has changed over time, and FDA's website provides information on both the number of active and released REMS (i.e., products whose REMS are no longer in effect).39 active, approved REMS (see Table 2 for a breakdown by risk management element).31 The number of approved REMS has fluctuated over time. A REMS data file available via FDA's website provides information on all of the drugs that have ever been part of a REMS program, including products that are no longer marketed and/or no longer subject to a REMS; the file lists a total of 253 approved REMS, 176 of which were inactive as of March 2, 2017.32 As aforementioned, in 2011, FDA determined that it was no longer necessary to consider every Medication Guide to be an elementpart of a REMS and subsequently released from REMS, under certain circumstances, drugs that had a only Medication Guide and timetable for submission of assessments.40
Examples of Approved REMS of a REMS and subsequently released from REMS drugs that had a Medication Guide as the only risk management element.33
|
Medication Guide |
Communication Plan |
ETASU |
Implementation System |
Total |
|
37 |
24 |
44 |
37 |
77 |
Source: Created by CRS using the FDA approved REMS Database https://www.accessdata.fda.gov/scripts/cder/rems/. These numbers are current as of March 2, 2017.
Note: The columns do not add to a total of 77 because several of the REMS systems include more than one element.
REMS can be required for an individual drug or a class of drugs. One example of a REMS for an individual drug is the REMS for Mifeprex (mifepristone), used together in a regimen with the drug misoprostol, to terminate a pregnancy through 70 days gestation.3541 The REMS was initially approved in June 2011 and has been updated on subsequent occasions.3642 It includes an ETASU requiring health care providers who prescribe Mifeprex to be specially certified, as specified; an implementation system requiring distributors of Mifeprex to follow specified processes and procedures; and a timetable for submission of assessments.37 (See Table A-1 for a list of materials included in the REMS.) 43 The REMS specifies that Mifeprex must be dispensed to patients only in certain health care settings—specifically clinics, medical offices, and hospitals—by or under the supervision of a certified prescriber. Mifeprex may not be distributed to or dispensed through retail pharmacies or other settings not described above.3844
An example of a REMS that affects an entire class of drugs is the REMS for Extended-Release and Long-Acting (ER/LA) Opioid Analgesics, which covers brand-name and generic products formulated with the active ingredients fentanyl, hydrocodone, hydromorphone, methadone, morphine, oxycodone, and oxymorphone.39pain-reducing medications that bind to opioid receptors in the body.45 While opioid drugs are a necessary component of pain management for certain patients and have therapeutic benefits when used properly, they also present serious risks.4046 Past efforts to prevent the misuse, abuse, and overdose of these drugs, such as additional warnings on the label, risk management plans, and inter-agency collaborations, were found to be insufficient. InThus, in February 2009, FDA sent letters to manufacturers of extended-release, long-acting (ER/LA)ER/LA opioids indicating that a REMS would be required to ensure that the benefits of these drugs continue to outweigh the risks.4147 The REMS for ER/LA opioids was initially approved on July 9, 2012, and has been updated on subsequent occasions. It includes a medication guide, an ETASU providing training to health care providers who prescribe ER/LA opioids, and a timetable for submission of assessments.42 (See Table A-2 for a list of materials included in the ER/LA REMS.)
Some drug applications approved prior to the effective date of FDAAA contained ETASUs that were agreed upon by the applicant and FDA; these elements typically appeared in approved RiskMAPs. In March 2008, FDA published in the Federal Register a list of products that were deemed to have an approved REMS and directed application holders to submit a proposed REMS by September 21, 2008.43 Drugs that had RiskMAPs prior to FDAAA that have transitioned to a REMS include Thalomid (thalidomide), Accutane (isotretinoin), Mifeprex (mifepristone), and Clozaril (clozapine).44
The Hatch-Waxman Act created an abbreviated pathway for generic drugs, allowing a generic drug manufacturer to submit to FDA an ANDA, rather than a full NDA, demonstrating that the generic product is the same as the brand drug (i.e., the reference listed drug [RLD]).50 To prove sameness, the generic product must have the same active ingredient(s), strength, dosage form, and route of administration as the RLD; be bioequivalent to the RLD; and meet other requirements (e.g., reviews of chemistry, manufacturing, controls, labeling, and testing).51 The Drug Price Competition and Patent Term Restoration Act of 1984 ("Hatch-Waxman Act," P.L. 98-417) amended the FFDCA to establish an expedited pathway for generic drugs, allowing a generic drug manufacturer to submit an abbreviated NDA (ANDA) to FDA for premarket review. Rather than replicate and submit data from animal, clinical, and bioavailability studies, the generic sponsor must show that the generic product is pharmaceutically equivalent (e.g., has the same active ingredient(s), strength, dosage form, route of administration) and bioequivalent45 to the brand-name product, among meeting other requirements (e.g., reviews of chemistry, manufacturing, controls, labeling, and testing).46In 2017, for example, FDA announced that immediate-release (IR) opioids would be subject to the same REMS requirements as ER/LA opioids.48 The REMS includes a medication guide, an ETASU that requires covered manufacturers to provide training to health care providers, and a timetable for submission of assessments.49
Impact of REMS on Generic Drug Development
A REMS-restricted distribution program controls the chain of supply so that the drugs are provided only to patients with prescriptions from authorized physicians or pharmacies under specified conditions. Although theThe law prohibits the holder of an approved NDA or BLAapplication (i.e., the brand company, which is the reference listed drug [RLD] holder)47RLD holder) from using ETASU "to block or delay approval of an application,"48 FDA, the Federal Trade Commission (FTC), generic drug manufacturers, and several physician, pharmacist, hospital and consumer groups have raised concern that some brand companies may be using REMS to delay generic drugs from entering the market by withholding samples needed for bioequivalence testing and by delaying negotiation of a single shared system of ETASU.49 under [FFDCA] section 505(b)(2) or (j)."56 However, FDA, FTC, the Association for Accessible Medicines (AAM), and others have alleged that some brand companies may be using REMS to delay competition by refusing to sell samples of the brand drug to generic product developers and delaying negotiation of a single, shared system REMS (see the section "Developing a Single, Shared System REMS").57 By withholding samples, the RLD holder is generally able to prevent or delay the generic product developer from conducting the required testing and submitting an application for review; by delaying negotiation of a single shared system REMS, the RLD holder is effectively able to stay FDA approval of the ANDA. Brand companies have typically justified their refusal to sell samples by citing safety concerns, particularly that generic firmsproduct developers may not ensure the safe use of these drugs, and that the brand company could be held liable.50 Some have maintained that negotiations over a single, shared system are complicated and take time.5158
To obtain approval of the generic version of a brand-name drugan RLD, the generic product developer must demonstrate to FDA that, among other things, the generic drug is pharmaceutically equivalent and bioequivalent to the brand drugthe same as the RLD. To conduct the required bioequivalence (BE) testing, the generic drug developer must obtain a sufficient quantity of samples of the brand-name drugRLD. Although the generic product developer generally needs samples to conduct BEbioequivalence testing, the law does not require brand manufacturersthe RLD holder to provide samples to generic product developers. By restricting distribution of the drug product, the license holder can delay or prevent the generic developer from obtaining samples for testing.
Typically, generic drug companies have obtained necessary samples of brand products from wholesale distributorsdistribution channels. However, when a drug is subject to REMS with ETASU and distribution restrictions are in place, the generic product developer is not an authorized entity and, thus, the wholesale distributor of the brand drug wouldRLD may be in violation of the terms of the REMS if theyit were to sell the samples to an unauthorized party.5259
Generic companies have looked to FDA to intervene when a brand companythe RLD holder has refused to sell a drug to an eligible drugproduct developer for testing purposes, citing the REMS with ETASU as justification. In December 2014, FDA issued draft guidance, How to Obtain a Letter from FDA Stating that Bioequivalence Study Protocols Contain Safety Protections Comparable to Applicable REMS for RLD. This guidance outlines the steps that a generic drug developer outlining the steps that an ANDA sponsor should take to obtain a letter from FDA to the brand companyRLD holder, indicating the generic drug applicantANDA sponsor's proposed bioequivalence testing protocol is comparably as safe as the applicable REMS ETASU, and that it would not be a violation of the REMS to provide the product samples for BEsuch testing.60 The FDA letter cannot compel the brand companyRLD holder to sell the samples to the generic product developer, but rather states that the agency finds the safety protections proposed in the bioequivalence protocol to be comparable to the brand company's REMS program.61
Per the guidance, when requesting FDA to send such a letter to the RLD holder, the generic drug developer should complete a disclosure authorization form, which authorizes the agency to disclose to the RLD holder the name of the generic drug developer and the active ingredient of the proposed generic drug product, in addition to other potentially confidential commercial or financial information or trade secrets. By signing this letter, the generic drug developer is agreeing to hold FDA harmless for any injury caused by sharing such information with the RLD holder. In electing to involve FDA, the generic product developer authorizes FDA to disclose potentially confidential information to the RLD holder in hopes of acquiring samples for testing, yet the letter from FDA is not legally binding, sobut the RLD holder may still choose to withhold the samples.53
In a June 2016 testimony before the Senate Judiciary Subcommittee on Antitrust, Competition, Policy, and Consumer Rights, a representative from the generic pharmaceutical manufacturer Amneal testified that in December 2013, the company requested samples of a brand product subject to REMS for purposes of bioequivalence testing. The testimony reports that it took nearly three years to sign a supply agreement, yet four months later, at the time of the hearing, the company had still not received the samples.5463 Brand companies have cited safety and liability concerns as justification for refusing to sell samples. During that same June 2016 hearing, a representative of brand drug companies testified that various safety concerns could arise as a result of certain legislative attempts to make it easier for generic companies to obtain samples (see "The CREATES Act, (114th Congress)").55.64 The representative added in his testimony that
Congress and FDA have long recognized the risks associated with drugs requiring REMS—and particularly the products whose REMS must also include ETASU in order to receive or maintain FDA approval. Examples of such serious safety issues associated with currently approved drugs with ETASU include risks of shortened overall survival, increased risk of tumor progression or recurrence, increased risks of first trimester pregnancy loss and congenital malformations, and central nervous system depression.5665
Current law requires that if a brand drugthe RLD is subject to REMS, the ANDA (generic drug application) referencing that product is subject to two of the REMS components: (1) the medication guide or package insert and (2) the ETASU, specifically that the ANDAgeneric and RLD must enter into a single, shared system of ETASU with the brand drug.57.66 The Secretary may waive this requirement for the generic drug if (1) the burden of creating a single, shared system outweighs the benefit, taking into consideration the impact on health care providers, patients, the generic applicant, and the RLD holder, or (2) an aspect of the ETASU for the brand drugRLD is claimed by an unexpired patent or is a method entitled to protection, and the generic applicant "certifies that it has sought a license for use of an aspect of the [ETASU] for the applicable listed drug and that it was unable to obtain a license."58
As described in an FDA presentation,59FDA presentations, the process of developing a single, shared system of ETASUREMS begins with the Office of Generic Drugs (OGD), which first notifies the ANDA sponsor of the requirement for a single, shared system via a REMS notification letter.68 This letter directs the ANDA sponsor to contact the RLD holder. The ANDA sponsor initiates discussions with the RLD holder regarding the shared system., and FDA then hosts a kick-off meeting to convey expectations and facilitate development of the single, shared system. The generic and brand companiesdeveloper and RLD holder may form an industry working group (IWG) to develop a proposal for the single, shared system REMS, providing biweekly updates to the agency. FDA forms a REMS review team comprising members from various offices within CDER; this review team is responsible for tasks such as communicating to the IWG expected timeframes for milestones and for scheduling periodic teleconferences with the IWG. Once the single, shared systemREMS proposal is developed, the brand and generic companiesRLD holder and ANDA sponsor submit it to FDA for review. If either the brand or generic company indicates to FDA that the other company in the IWG is not receptive or responsive to developing the single,a shared systemREMS, the agency may serve as facilitator to aid in reaching a resolution.
The purpose of a single, shared system is to reduce burden for stakeholders by providing a single portal to access REMS materials and other documentation. Doing so would enable prescribers, pharmacies, and health care settings to complete certification and other administrative requirements once rather than separately for the brand and generic drug. However, generic drug companies have reported difficulty in trying to develop a single, shared system with brand companies.60 Negotiationsnegotiations surrounding shared REMS often include issues such as cost-sharing, confidentiality, product liability concerns, antitrust concerns, and access to a license for elements protected by a patent.61
As of March 2, 2017, FDA's database listed 77 approved REMS, 8 of which are shared systems REMS. For example, the Clozapine shared system REMS and the Buprenorphine Transmucosal Products for Opioid Dependence (BTOD) REMS include multiple NDAs and ANDAs.,69 and generic drug companies have reported difficulty in trying to develop a single, shared system with brand companies.70
While the law does provide for a waiver if a single, shared system REMS is not feasible, the agency considers the waiver as an "option of last resort."62 71 To date, the agency has issued three such waivers. During the course of negotiations, if FDA or the sponsors believe that a waiver may be necessary, the agency would determine whether the statutory criteria for a waiver have been met; if so, the agency may permit the ANDA sponsor to use a "different, comparable aspect" of the ETASU (e.g., contains the same elements, must achieve the same level of safety).63
In November 2017, as part of FDA's Drug Competition Action Plan, the agency issued draft guidance to facilitate the submission and review process for shared system REMS.73 The guidance addresses how companies with products in shared system REMS programs can use a single Drug Master File to submit one collective set of files to the agency. According to FDA, the process "eliminates duplicative paperwork for sponsors, and will decrease the volume of forms the FDA's reviewers must assess."74 CDER plans to publish two guidance documents, Development of a Shared System REMS and Waivers of the Single, Shared System REMS Requirement, during calendar year 2018.75
In a June 2016 testimony before the Senate Judiciary Subcommittee on Antitrust, Competition, Policy, and Consumer Rights, a representative of brand drug companies testified that "negotiations over a single, shared REMS are complicated—in large part because they deal with important safety issues and a complex healthcare system," and that it takes time for parties to reach agreement on "the range of concerns that must be addressed (e.g., REMS design, adverse event reporting protocols, collective standard operating procedures, cost sharing, decision-making authority about REMS administration, assessments, and modification, and associated legal issues such as intellectual property and product liability)."64
While FDA may require a REMS with ETASU for certain drugs or biologics with known or potential serious safety risks, some brand companies have implemented restricted distribution programs not mandated by FDA. For example, Turing Pharmaceuticals employed a non-REMS restricted distribution system whereby prescriptions could be obtained only from a single source—a specialty pharmacy—and the company could refuse sale to competitors (e.g., generic product developers).6577 Such restricted distribution programs are self-imposed by the company rather than mandated by FDA and have raised antitrust concerns that go beyond the scope of this report.6678
Stakeholders generally agree that ensuring access to safe and effective drugs is important. While REMS has allowed FDA to approve certain drugs that otherwise may have been kept off the market due to safety risks, the implementation of REMS, particularly REMS with restricted distribution, has raised some issues.
The first issue concerns access to samples and whether brand companies are withholding samples for BEbioequivalence testing due to safety reasons or to delay competition. Generic drug companies have reported that brand companies are inappropriately using REMS-restricted distribution systems to prevent product developers from obtaining samples for BE testing and thus delaying market entry of lower cost drugs. In a March 2017 hearing on restricted distribution systems, CDER Director Dr. Janet Woodcock stated that FDA has received about 150 "inquiries" from generic product developers regarding difficulty accessing samples for BEbioequivalence testing.6779 Brand companies have justified their refusal to sell samples by citing safety concerns (e.g., that the generic company may not ensure safe use of the drug), particularly for REMS-restricted distribution drugs that could have serious side effects or are prone to abuse.6880 Brand companies have also expressed concern that they could be held liable for any injuries caused by the generic product, which could result in FDA requiring additional REMS elements or taking further regulatory action against the brand drug.69RLD.81 In addition, adverse events associated with the generic could impact the brand companyRLD holder's reputation.7082 As aforementioned, FDA can review the generic product developer's BEbioequivalence protocol and send a letter to the brand companyRLD holder stating that providing samples for BEsuch testing would not be a violation of the REMS; however, FDA does not have the authority to compel the brand company to provide the samples. The RLD holder to provide the samples. The Pharmaceutical Research and Manufacturers of America (PhRMA) trade group has provided feedback to FDA on the guidance, writing that "final guidance should provide meaningful detail on how FDA plans to ensure that a [bioequivalence] study contains adequate safety measures to protect research participants." The FTC has also weighed in on the issue, stating that although the law allows brand-name drug manufacturers to use restricted drug distribution programs in ways that impede generic competition, the Hatch-Waxman Act cannot function as intended if generic drug companies are unable to access samples of brand-name productsthe RLD for the necessary testing.71
The second issue concerns entry into a single, shared system of ETASUREMS, and whether delays are a result of complex and time-consuming negotiations or attempts to delay competition. Current law requires that unless waived by the Secretary, the brandRLD and generic products must enter into a single, shared system of ETASUREMS. The purpose of this requirement is to reduce the burden for stakeholders (e.g., health care providers and patients) by providing a single portal to access REMS materials and other documentation. The FDA and generic drug manufacturersindustry have expressed concern that brand companies may be using this requirement to prevent or delay generic drugs from entering the market by impeding development of a single, shared system. In a January 2016 hearing, CDER Director Dr. Janet Woodcock stated that the requirement of a shared REMS system has posed some challenges:
The statutory requirement that REMS programs that include elements to assure safe use (ETASU) be implemented through a "single shared system" relies on brand and generic companies to agree on such a system before generic drugs may come to market. This is challenging to implement and frequently results in blocking generic competition.72
This concern was reiterated at a March 2017 hearing during which Dr. Woodcock identified inappropriate use of REMS as one factor that can delay consumer access to less expensive generic drugs.7384 Brand companies, however, have said that "negotiations over a single, shared REMS are complicated—in large part because they deal with important safety issues and a complex healthcare system" and that it takes time for both parties to reach agreement on issues such as REMS design, adverse event reporting protocols, collective standard operating procedures, cost sharing, decision-making authority about REMS administration, assessments, and modification, and associated legal issues such as intellectual property and product liability.7485 This is consistent with an FDA presentation stating that negotiations surrounding shared REMS often include issues such as cost-sharing, confidentiality, product liability concerns, antitrust concerns, and access to a license for elements protected by a patent.75
Some Members of Congress have expressed concern regarding "tactics that appeared to frustrate the intent of the Hatch-Waxman Act—a law enacted to streamline and expedite the approval process for generic drugs."7687 In the 112th Congress, in response to concerns surrounding misuse of REMS, an early draftversion of the FDASIAFood and Drug Administration Safety and Innovation Act (FDASIA; P.L. 112-144) legislation (S. 2516) contained a provision—Section 1131 "Drug Development and Bioequivalence Testing"—that would have generally prohibited the use of ETASU to restrict availability of a covered drug for BE testing by an eligible product developer, as specified. In addition, the provision would have allowed the developer to seek authorization from the Secretary to obtain a covered drug; it would not have addressed the issue of developing a single, shared system of ETASU.77among other things.88 Section 1131 was ultimately not included in the final version of the bill signed into law as FDASIA.
In the 114115th Congress, two bills to keep brand companies from using REMS to prevent or delay generic drugs from entering the market were introduced: the Fair Access for Safe and Timely Generics Act of 20152017, or the FAST Generics Act of 20152017 (H.R. 2841),2051) and the Creating and Restoring Equal Access to Equivalent Samples Act of 20162017, or the CREATES Act of 20162017 (S. 974, H.R. 2212).89 The FAST Generics Act and CREATES Act use the term covered product to refer to any drug approved under FFDCA Section 505(b) or 505(j), a biologic licensed under PHSA Section 351, or a combination thereof "when reasonably necessary to demonstrate sameness, biosimilarity, or interchangeability," excluding drugs and biologics that appear on the drug shortage list under FFDCA Section 506E, as specified; eligible product developer to refer to a person that seeks to develop a product for approval pursuant to an application for approval under FFDCA Section 505(b)(2) or 505(j), or for licensing under PHSA Section 351(k); and license holder to refer to the sponsor of an approved NDA, ANDA, or BLA for a covered product.90
The FAST Generics Act of 2017 (H.R. 2051)
The FAST Generics Act seeks to generally limit a license holder of a covered product from restricting its availability for testing purposes by an eligible product developer. Among other things, it would allow the (S. 3056). As of the date of this report, neither of these two bills has been reintroduced in the 115th Congress.
However, in the 115th Congress, two bills addressing generic drug development have been introduced—H.R. 749, the Lower Drug Costs through Competition Act, and S. 297, the Increasing Competition in Pharmaceuticals Act. Both bills contain a provision titled "Study on REMS," which would require GAO to conduct a study on REMS and its implementation, examining, among other things, the "burden associated with REMS," including on generic drug manufacturers."
The House bill sought to generally limit a "license holder" (defined as the holder of an approved new drug or biologics license application) of a covered product (i.e., a drug, biologic, or combination thereof, as specified) from restricting its availability for testing purposes by an eligible product developer78 (e.g., a generic drug manufacturer). Among other things, the bill would have
In addition, the bill would have generally prohibitedprohibit a license holder from taking any steps to impede the development of a single, shared system of ETASU or the entry of a product developer into a previously approved system of ETASU. Moreover, the bill would have requiredIt would require license holders to negotiate in good faith toward a single, shared system, but it would have allowedwould allow the Secretary to waive the requirement for a single, shared system if the product developer wasis unable to finalize terms with the license holder. Further, the legislation would have allowedalso allow an eligible product developer that wasis injured based on certain violations of the legislation to have suedsue the license holder for injunctive relief and damages.
The Senate bill would have likewise established of 2017 (S. 974, H.R. 2212)
The CREATES Act would likewise establish a mechanism for an eligible product developer to obtain the covered product for testing. The legislation would have allowedallow the product developer to bring a civil action against the license holder for failure to provide the coveredeligible product developer sufficient quantities of the drug on "commercially reasonable, market-based terms." If the eligible product developer prevailedprevails in the case, the license holder would have generally beenbe required to (1) provide to the product developer, without delay, sufficient quantities of the product, as specified, and (2) award to the developer attorney fees and costs related to the lawsuit, as well as a monetary amount, as specified.
In addition, the Senate bill would have allowed an eligible product developer to bring civil action against the license holder for failing to reach a single, shared system of ETASU, or for refusing to allow the product developer to join into a previously approved system. If the product developer prevailed in such a lawsuit, the license holder would have been required to (1) with the approval of the Secretary, enter into a single, shared ETASU with the developer or allow the developer to join a previously approved system, or (2) demonstrate that the Secretary has waived the requirement for a single, shared system. It would have also required the license holder to award to the developer attorney fees and costs associated with the litigation and a monetary amount, as specified. The Senate bill contains the same limitation of liability provision as the House bill.
Although legislation aimed at reforming FDA The CREATES Act would allow the Secretary to require modification to an approved REMS to accommodate different approved REMS for the RLD and generic product. It would provide the Secretary with additional flexibility to waive the requirement for a single shared system of ETASU, unless the Secretary determines that no different, comparable aspect of the ETASU would satisfy the statutory requirements. Like the FAST Generics Act, the CREATES Act also contains a limitation of liability provision.
REMS Reform and Cost-Savings
Although legislation aimed at reforming REMS has been discussed as a means of reducing health care spending, CRS is not aware of any formal cost estimates (from CBO or other entities) that indicate how H.R. 2841 or S. 3056 would function as such. However, while CBO has not scored these two bills (as of the date of this report), the agency has scored thethe FAST Generics or the CREATES Act would function as a cost saving measure. Some entities have shared informal cost estimates.
CBO had formally scored a similar provision from the 112th Congress—Section 1131 "Drug Development and Bioequivalence Testing" of S. 2516—an early version of the FDASIA legislation (later version S. 3187 passed as P.L. 112-144). Like H.R. 2841 and S. 3056,.91 Section 1131 would have generally prohibited the use of ETASU to restrict availability of a covered drug for BEbioequivalence testing by an eligible product developer, as specified, and it would have allowed the developer to seek authorization from the Secretary to obtain a covered drug;. However, it would not have addressed the issue of developing a single, shared system of ETASU. Unlike H.R. 2841 and S. 3056REMS and unlike the FAST Generics and CREATES bills, the definition of "covered drug" under Section 1131 iswas narrower and would have included only a drug or biologicdrugs and biologics subject to a REMS with ETASU, compared to H.R. 2841 and S. 3056, which seek to generally limit a license holder from restricting for BE testing (1) covered products subject to REMS with ETASU and (2) covered products. The FAST Generics Act and CREATES Act seek to also limit the brand manufacturer's ability to restrict the availability of samples of drugs and biologics not subject to REMS with ETASU. In May 2012, CBO estimated that the implementation of Section 1131, with other provisions in S. 2516 aimed at reducing barriers to market entry for lower-priced drugs, would have reduced direct spending for mandatory health programs by $753 million over the 2013-2022 period.7992 Section 1131 was ultimately not included in the final version of the bill signed into law as FDASIA.
In July 2017, FDA held a public meeting and provided the public with the opportunity to comment "on the appropriate balance between encouraging innovation in drug development and accelerating the availability to the public of lower cost alternatives to innovator drugs."93 Various comments submitted to the docket have addressed the REMS issues raised in this CRS report. recently renamed as the Association for Affordable Medicines [AAM]now called the AAM) estimated that misuse of REMS and other restricted distribution programs costs the United States $5.4 billion annually, with the federal government bearing a third of this burden.8094 The AAM has expressed support for the CREATES Act, stating it would "provide a clear solution to abusive, anticompetitive business practices that increase costs to the American health care system by impeding patient access to generic medicines."8195 Opponents of changes to the REMS program argue that REMS are rare and that a forced sale provision "would undermine necessary drug safety precautions and create disincentives for the future development and marketing of higher-risk drugs, especially to treat rare disorders, due to liability concerns."8296 At a June 2016 hearing, a witness representing brand companies testified that the CREATES Act would result in safety concerns, and that the bill would not "establish robust criteria that eligible product developers seeking to obtain such a drug must satisfy in order to protect patients and other individuals who come into contact with the drug during its distribution."8397
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Health care providers who prescribe and dispense Mifeprex must: |
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To be able to prescribe |
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Before dispensing |
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Patients who are prescribed Mifeprex must: |
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Before receiving |
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Distributors that distribute Mifeprex must: |
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To be able to distribute |
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At all times |
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Materials |
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Source: FDA, Approved Risk Evaluation and Mitigation Strategies (REMS) database, https://www.accessdata.fda.gov/scripts/cder/rems/index.cfm?event=IndvRemsDetails.page&REMS=35.
Note: The REMS specifies that Mifeprex must be dispensed to patients only in certain health care settings, specifically clinics, medical offices, and hospitals, by or under the supervision of a certified prescriber. Mifeprex may not be distributed to or dispensed through retail pharmacies or other settings not described above.
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Health care providers who prescribe extended-release long-acting opioid analgesic products |
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Materials |
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Source: FDA, Extended-Release and Long-Acting (ER/LA) Opioid Analgesics Shared System REMS, https://www.accessdata.fda.gov/scripts/cder/rems/index.cfm?event=RemsDetails.page&REMS=17.
Author Contact Information
| 1. |
See CRS Report R41983, How FDA Approves Drugs and Regulates Their Safety and Effectiveness. |
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| 2. |
A biologic is a preparation, such as a drug or a vaccine, that is made from living organisms.
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In the 1930s, the drug Sulfanilamide, in tablet and powder form, was used to treat streptococcal infections. In 1937, a company in Bristol, Tennessee compounded a liquid form of the drug and sent shipments all over the country. This new formulation called "Elixir Sulfanilamide" had not been tested for toxicity and at the time, the law did not require safety studies for new drugs. More than 100 deaths in 15 states were linked to Elixir Sulfanilamide. See, FDA, "Taste of Raspberries, Taste of Death The 1937 Elixir Sulfanilamide Incident," FDA Consumer Magazine, June 1981, https://www.fda.gov/AboutFDA/WhatWeDo/History/ProductRegulation/SulfanilamideDisaster/ucm2007257.htm. |
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FDA, "A History of the FDA and Drug Regulation in the United States," https://www.fda.gov/downloads/drugs/resourcesforyou/consumers/buyingusingmedicinesafely/understandingover-the-countermedicines/ucm093550.pdf. |
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See CRS In Focus IF10463, Regulation of Over-the-Counter (OTC) Drugs. |
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See CRS Report R41983, How FDA Approves Drugs and Regulates Their Safety and Effectiveness. |
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Bioequivalence is defined as the absence of a significant difference in the rate and extent to which the active ingredient/moiety in pharmaceutical equivalents or pharmaceutical alternatives become available at the site of drug action when administered at the same molar dose under similar conditions in an appropriately designed study. See 21 C.F.R. 320.1(e). 10.
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See CRS Report R44703, Generic Drugs and GDUFA Reauthorization: In Brief. 11.
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An early version of the Food and Drug Administration Safety and Innovation Act (FDASIA; P.L. 112-144), S. 2516, contained a provision—Section 1131 "Drug Development and Bioequivalence Testing"—that would have generally prohibited the use of REMS to restrict availability of a covered drug for bioequivalence testing by an eligible product developer, among other things. 12.
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For information about FDA user fees and the 2017 reauthorization, see CRS Report R44750, FDA Medical Product User Fee Reauthorization: In Brief, and CRS Report R44961, FDA Reauthorization Act of 2017 (FDARA, P.L. 115-52). |
PDUFA (P.L. 102-571); PDUFA II, Title I of the FDA Modernization Act of 1997 (FDAMA; P.L. 105-115); PDUFA III, Title V of the Public Health Security and Bioterrorism Preparedness and Response Act of 2002 (P.L. 107-188); PDUFA IV, Title I of the FDA Amendments Act of 2007 (FDAAA; P.L. 110-85); and PDUFA V, Title I of the FDA Safety and Innovation Act of 2012 (FDASIA, P.L. 112-144). For additional information about each reauthorization, see CRS Report R42366, Prescription Drug User Fee Act (PDUFA): 2012 Reauthorization as PDUFA V. |
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| 9. |
CRS Report R44750, FDA Medical Product User Fee Reauthorization: In Brief. |
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U.S. Congress, House Committee on Energy and Commerce, |
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U.S. Congress, Senate Committee on Health, Education, Labor, and Pensions, Implementation of the Generic Drug User Fee Amendments of 2012 (GDUFA), |
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The Fair Access for Safe and Timely Generics Act of 2015, or the FAST Generics Act of 2015 (H.R. 2841), and the Creating and Restoring Equal Access to Equivalent Samples Act of 2016, or the CREATES Act of 2016 (S. 3056). These bills are discussed later in the report. |
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U.S. Congress, House Committee on Energy and Commerce Markup, June 7, 2017, Amendment to H.R. 2430 filed by Rep. Welch (WELCH_01), http://docs.house.gov/meetings/IF/IF00/20170607/106096/BILLS-115-2430-W000800-Amdt-10.pdf. 17.
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U.S. Congress, House Committee on Energy and Commerce Markup, June 7, 2017, Final Vote Sheet, http://docs.house.gov/meetings/IF/IF00/20170607/106096/CRPT-115-IF00-Vote002-20170607.pdf. |
FDA, Guidance for Industry: Development and Use of Risk Minimization Action Plans, March 2005, see https://www.fda.gov/downloads/RegulatoryInformation/guidances/ucm126830.pdf. |
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J Wilkins Parker, FDA Division of Risk Management, Presentation, "Risk Management in the United States," http://www.fda.gov/downloads/drugs/resourcesforyou/healthprofessionals/ucm473163.pdf. |
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A teratogen is an exposure in pregnancy that can affect fetal development (e.g., cause birth defects). |
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Roche, Accutane® (isotretinoin) Capsules, "Pregnancy Prevention Program: A Risk Management Program to Reduce Pregnancies during Accutane Treatment", https://www.fda.gov/ohrms/dockets/ac/00/backgrd/3639b1c_06.pdf. |
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Ibid. |
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Ibid. |
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L. Choe, Consumer Safety Officer, Division of Drug Information, FDA Office of Communication, Presentation "Risk Evaluation and Mitigation Strategies (REMS) |
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FDA CDER, Manual of Policies and Procedures (MAPP) 6700.1, https://www.fda.gov/downloads/AboutFDA/CentersOffices/CDER/ManualofPoliciesProcedures/ucm082058.pdf. |
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In 2005, FDA issued three such guidance documents: Premarketing Risk Assessment (Premarketing Guidance), Development and Use of Risk Minimization Action Plans (RiskMAP Guidance), Good Pharmacovigilance Practices and Pharmacoepidemiologic Assessment (Pharmacovigilance Guidance). |
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FDA, Guidance for Industry: Development and Use of Risk Minimization Action Plans, March 2005, see https://www.fda.gov/downloads/RegulatoryInformation/guidances/ucm126830.pdf. |
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| 24. | FDA, "FDA's Role in Managing Medication Risks," https://www.fda.gov/Drugs/DrugSafety/REMS/ucm592672.htm. 73 Federal Register 16313, March 27, 2008. The list included 28 NDAs, ANDAs, and BLAs. Drugs that had RiskMAPs prior to FDAAA that have transitioned to a REMS include Thalomid (thalidomide), Accutane (isotretinoin), Mifeprex (mifepristone), and Clozaril (clozapine). |
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FFDCA §505-1(a)(1) |
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FFDCA 505-1(d) |
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21 CFR part 208. |
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FDA, Questions and Answers on Guidance for Industry: Medication Guides - Distribution Requirements and Inclusion in Risk Evaluation and Mitigation Strategies (REMS), https://www.fda.gov/Drugs/DrugSafety/ucm248459.htm, and FDA Guidance, Medication Guides—Distribution Requirements and Inclusion in Risk Evaluation and Mitigation Strategies, November 2011, https://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM244570.pdf. |
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Ibid. |
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FFDCA §505-1(f)(4) |
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This does not mean there are |
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FDA, Approved Risk Evaluation and Mitigation Strategies (REMS), "REMS Data Files and Historic REMS Information," |
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M Cronin, S. Berger, and P. Seligman, "Risk Evaluation and Mitigation Strategies with Elements to Assure Safe Use: Alignment of the Goals with the Tools to Manage Risk," Therapeutic Innovation & Regulatory Science, (2014), vol. 48, no. 6, pp. 724-733. S. Worthy, "Don't sell out to safety: a call to preserve evaluation and mitigation strategies to reduce harm to patients and the public in the U.S.," Journal of Pharmaceutical Policy and Practice, (2016), vol. 9, no. 2. |
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| 34. |
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FDA, Mifeprex (mifepristone) Information, https://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/ucm111323.htm. |
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Some drug applications approved before the effective date of the FDAAA REMS provision contained elements to assure safe use and were deemed by FDA to have, in effect, an approved REMS, including Mifeprex, see 73 Federal Register 16313, March 27, 2008. |
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NDA 020687 MIFEPREX (mifepristone) Tablets, 200mg, REMS, https://www.accessdata.fda.gov/drugsatfda_docs/rems/Mifeprex_2016-03-29_REMS_full.pdf. |
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Ibid. |
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FDA, |
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See CRS Report R43559, Prescription Drug Abuse. |
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Ibid. |
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49.
FDA, Risk Evaluation and Mitigation Strategy (REMS) for Opioid Analgesics, https://www.fda.gov/Drugs/DrugSafety/InformationbyDrugClass/ucm163647.htm. |
Extended-Release (ER) and Long-Acting (LA) Opioid Analgesic Risk Evaluation and Mitigation Strategies (REMS), Reference ID: 3992743, https://www.accessdata.fda.gov/drugsatfda_docs/rems/ERLA_2016-09-30_REMS_Document%20.pdf. |
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See CRS Report R44703, Generic Drugs and GDUFA Reauthorization: In Brief. 52.
|
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The majority of biologics are regulated under Section 351 of the PHSA [42 U.S.C. §262] 53.
|
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For additional information about the regulations of biologics and biosimilars, see CRS Report R44620 Biologics and Biosimilars: Background and Key Issues. 54.
|
|
The BPCIA of 2009 was enacted as Title VII of the Patient Protection and Affordable Care Act (ACA, P.L. 111-148). 55.
|
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PHSA §351(k). See also CRS Report R44620 Biologics and Biosimilars: Background and Key Issues. 56.
|
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FFDCA §505-1(f)(8) [21 U.S.C.§355-1(f)(8)]. |
The REMS for Thalidomide was approved in August 2010, Accutane in October 2010, and Clozapine in September 2015; see FDA Presentation, "Risk Management in the United States," http://www.fda.gov/downloads/drugs/resourcesforyou/healthprofessionals/ucm473163.pdf. |
| 45. |
Bioequivalence is defined as the absence of a significant difference in the rate and extent to which the active ingredient/moiety in pharmaceutical equivalents or pharmaceutical alternatives become available at the site of drug action when administered at the same molar dose under similar conditions in an appropriately designed study. See 21 CFR 320.1(e). |
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| 46. |
See CRS Report R44703, Generic Drugs and GDUFA Reauthorization: In Brief. |
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| 47. |
The brand product is called the reference listed drug (RLD) because the generic product ANDA refers to the clinical data in the brand-name drug's NDA. |
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| 48. |
FFDCA §505-1(f)(8) [21 U.S.C.§355-1(f)(8)] |
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U.S. Congress, Senate Committee on Health, Education, Labor, and Pensions, Implementation of the Generic Drug User |
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D. Tucker, G. Wells, & M Sheer, "REMS: The Next Pharmaceutical Enforcement Priority?" |
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| 51. |
U.S. Congress, Senate Committee on the Judiciary, Testimony prepared by Peter Safir, Senior Counsel at Covington & Burlington LLP, 114th Cong., 2nd sess., June 21, 2016 https://www.judiciary.senate.gov/imo/media/doc/06-21-16%20Safir%20Testimony.pdf. |
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|
Federal Trade Commission, Amicus Brief, Case No. 1:12-cv-05743-NLH-AMD, https://www.ftc.gov/sites/default/files/documents/amicus_briefs/actelion-pharmaceuticals-ltd.et-al.v.apotex-inc./130311actelionamicusbrief.pdf. |
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|
FDA, Guidance for Industry, How to Obtain a Letter from FDA Stating that Bioequivalence Study Protocols Contain Safety Protections Comparable to Applicable REMS for RLD, draft | ||||||||||||
| 61.
|
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Ibid. 62.
|
|
Ibid. |
U.S. Congress, Senate Committee on the Judiciary, |
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U.S. Congress, Senate Committee on the Judiciary, |
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Ibid. |
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FFDCA §505-1(i) [21 U.S.C. §355-1(i)] . |
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FFDCA §505-1(i)(1)(B) [21 U.S.C.§355-1(i)(1)(B)]. Drug Manufacturers have been able to patent their REMS programs "by describing these programs as innovative methods of safely distributing dangerous drugs that are 'new and useful methods of conducting business'... Because thalidomide is a well-known teratogen, Celgene developed a System for Thalidomide Education and Prescribing Safety and obtained numerous patents related to that system, including one claiming exclusivity for a method of 'delivering a drug to a patient while restricting access to the drug by patients for whom the drug may be contraindicated.'" See A Sarpatwari, J Avorn, & A Kesselheim, "Using a Drug-Safety Tool to Prevent Competition," NEJM, vol. 370, no. 16, (April 2014), http://www.nejm.org/doi/pdf/10.1056/NEJMp1400488. |
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Elaine Lippman, FDA, CDER, Office of Regulatory Policy, Development of Single, Shared System REMS, October 26, 2016, https://www.gphaonline.org/media/wysiwyg/Meetings/Fall_2016/Elaine_Lippmann.pdf, and Elaine Lippman, FDA, CDER, Office of Regulatory Policy, Development of Shared System REMS, http://www.fda.gov/downloads/Drugs/DrugSafety/InformationbyDrugClass/UCM539368.pdf.
69 | ||||||||||||
| 60. |
U.S. Congress, Senate Committee on the Judiciary, Testimony prepared by Beth Zelnick Kaufman, Assistant General Counsel at Amneal Pharmaceuticals, 114th Cong., 2nd sess., June 21, 2016. |
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Elaine Lippman, FDA, CDER, Office of Regulatory Policy, Development of Shared System REMS, http://www.fda.gov/downloads/Drugs/DrugSafety/InformationbyDrugClass/UCM539368.pdf. |
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71.
U.S. Congress, Senate Committee on the Judiciary, testimony prepared by Beth Zelnick Kaufman, Assistant General Counsel at Amneal Pharmaceuticals, 114th Cong., 2nd sess., June 21, 2016. |
Ibid. |
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Per FFDCA §505-1(i)(1)(B) [21 U.S.C.§355-1(i)(1)(B)], the Secretary may waive the requirement if "the burden of creating a single, shared system outweighs the benefit ... taking into consideration the impact on health care providers, patients, the applicant for the abbreviated new drug application, and the holder of the reference drug product; or an aspect of the elements to assure safe use for the applicable listed drug is claimed by a patent that has not expired or is a method or process that, as a trade secret, is entitled to protection, and the applicant for the abbreviated new drug application certifies that it has sought a license for use of an aspect of the elements to assure safe use for the applicable listed drug and that it was unable to obtain a license." |
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| 64. | FDA, Draft Guidance, Use of a Drug Master File for Shared System REMS Submissions," November 2017, https://www.fda.gov/ucm/groups/fdagov-public/@fdagov-drugs-gen/documents/document/ucm584202.pdf. FDA, Press Announcement, "Statement from FDA Commissioner Scott Gottlieb, M.D. on new steps to improve FDA review of shared Risk Evaluation and Mitigation Strategies to improve generic drug access," November 8, 2017, https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm584259.htm. FDA, "Guidance Agenda New & Revised Draft Guidances CDER Plans to Publish During Calendar Year 2018," January 19, 2018, https://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM417290.pdf. |
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A. Pollack, "New York Attorney General Examining Whether Turing Restricted Drug Access," October 12, 2015, see http://www.nytimes.com/2015/10/13/business/new-york-attorney-general-examining-if-turing-restricted-drug-access.html?_r=0. |
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D. Lowe, "Martin Shkreli has one idea, and it's a bad one," Science Translational Medicine, September 21, 2015, http://blogs.sciencemag.org/pipeline/archives/2015/09/21/martin-shkreli-has-one-idea-and-its-a-bad-one. M. Carrier and A. Kesselheim, "The Daraprim Price Hike and a Role for Antitrust," Health Affairs Blog, October 21, 2015, http://healthaffairs.org/blog/2015/10/21/the-daraprim-price-hike-and-a-role-for-antitrust/. |
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U.S. Congress, House Committee on Oversight and Government Reform, Subcommittee on Health Care, Benefits and Administrative Rules, Examining the Impact of Voluntary Restricted Distribution Systems in the Pharmaceutical Supply Chain, 115th Cong., March 22, 2017. |
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D. Tucker, G. Wells, |
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|
Ibid. |
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|
Ibid. |
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See, for example, Complaint at 4, Mylan Pharm. Inc. v. Celgene Corp., No. 2:14-CV-2094 (D.N.J. April 3, 2014); Complaint for Declaratory Judgment at 7–8, Actelion Pharm. Ltd. v. Apotex Inc., No. 1:12-cv-05743-NLH-AMD (D.N.J. September 14, 2012) |
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U.S. Congress, Senate Committee on Health, Education, Labor, and Pensions, Implementation of the Generic Drug User Fee Amendments of 2012 (GDUFA), | ||||||||||||
| 73. |
|
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U.S. Congress, Senate Committee on the Judiciary, |
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Elaine Lippman, FDA, CDER, Office of Regulatory Policy, Development of Shared System REMS, http://www.fda.gov/downloads/Drugs/DrugSafety/InformationbyDrugClass/UCM539368.pdf. |
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U.S. Congress, Senate Committee on the Judiciary, Subcommittee on Antitrust, "The CREATES Act: Ending Regulatory Abuse, Protecting Consumers, and Ensuring Drug Price Competition," Grassley Statement, 114th Cong., 2nd sess., June 21, 2016, |
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Although Congress did consider draft language that would have required manufacturers to provide samples to generic product developers, such language was not included in the final bill. The earlier draft of FDASIA stated that "if a drug is a covered drug, no elements to ensure safe use shall prohibit, or be construed or applied to prohibit, supply of such drug to any eligible drug developer for the purpose of developing, or conducting bioequivalence testing necessary to support, an application under [FFDC Act §505(b)(2) or §505(j) or PHS Act §351(k)]." Id.; Food and Drug Administration Safety and Innovation Act, S. 2516, 112th Cong. §1131 (2012). |
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Earlier versions of both bills were introduced in the 114th Congress: the Fair Access for Safe and Timely Generics Act of 2015 (or the FAST Generics Act of 2015 [H.R. 2841 ]) and the Creating and Restoring Equal Access to Equivalent Samples Act of 2016 (or the CREATES Act of 2016 [S. 3056]). 90.
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Although the term application holder is generally used to describe the sponsor of an approved NDA or ANDA, and the term license holder is used to refer to the holder of a BLA, the bills do not make this distinction. 91.
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A later version, S. 3187, was enacted as FDASIA (P.L. 112-144). |
An eligible product developer is defined as a person that seeks to develop a product for approval pursuant to an application approved under FFDCA section 505(b)(2) or 505(j) or for licensing pursuant to an application under section 351(k) of the Public Health Service Act. |
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Congressional Budget Office (CBO) Cost Estimate, S. 2516 Food and Drug Administration Safety and Innovation Act, May 11, 2012, https://www.cbo.gov/sites/default/files/112th-congress-2011-2012/costestimate/s25160.pdf. |
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| 80. | FDA, "Administering the Hatch-Waxman Amendments: Ensuring a Balance Between Innovation and Access; Public Meeting," https://www.fda.gov/Drugs/NewsEvents/ucm563986.htm. |
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GPhA, Letter to Senators Grassley, Leahy, Lee, and Klobuchar, June 14, 2016, http://www.gphaonline.org/media/cms/CREATES_Act_Group_Letter.pdf . |
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S. Worthy, "Don't sell out to safety: a call to preserve evaluation and mitigation strategies to reduce harm to patients and the public in the U.S.," Journal of Pharmaceutical Policy and Practice, (2016), vol. 9, no. 2. |
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U.S. Congress, Senate Committee on the Judiciary, |