Drugs Taken Off the Market: Important Lessons Learned

Introduction

The goal of drug development is to provide safe and effective pharmaceutical products for use in the treatment of clinical diseases and conditions. The vast majority of approved drug products remain on the market, with routine revisions to labeling, as needed. In some instances, new safety information may provide a basis for significant safety labeling changes or considerations for market withdrawal. This chapter will focus on tools that can be used to communicate risk and benefit, and provide examples of products whose risks were considered to outweigh the benefits.

Q8.1 Product (drug) labeling (including the physician package insert, patient package insert, carton/container labeling, medication guide) is a summary of the essential scientific information needed for the safe and effective use of the drug. The approval of original New Drug Applications (NDA) and Biologics Licensing Applications (BLA) results in product labeling intended to define and describe the conditions under which the product has been determined to be safe and effective, with the benefits outweighing the risks. This original labeling provides a baseline for continued risk management activities for the product. As new indications are proposed for marketing approval, or as new safety information becomes known, the risks and benefits of the product may change. Drug product labeling is dynamic and intended to be amended via supplemental labeling applications that keep abreast of new safety and efficacy information. This capacity for labeling changes allows new information regarding product risks and benefits to be provided for physicians and patients.

Presentation of Risk–Benefit in Labeling

Product labeling describes the conditions under which a product has been determined to be ‘safe and effective’: in other words, it describes the conditions under which the product has been determined to provide a reasonable balance of risks and benefits. Although considerations of risk–benefit assessment are ultimately informed by the totality of available information, product labeling provides safety information in discrete sections with levels of interest. Q8.2 The Clinical Studies section contains primarily efficacy information describing the adequate and well-controlled studies that provided the primary support for effectiveness, including the study design and efficacy outcomes, without an emphasis on safety information. The Adverse Reactions section is intended to contain information that would be useful to healthcare providers making treatment decisions, monitoring and advising patients, including adverse events (AE) where a causal relationship exists, and also rare serious reactions unusual in the absence of drug therapy. Exhaustive lists of every reported AE, including those not plausibly related to drug therapy, are not considered relevant in this section, as such lists are not informative and tend to obscure more clinically meaningful information. Warnings and Precautions sections include adverse reactions that are serious or otherwise clinically significant relevant to the indication, events that may require discontinuation of the drug or dosage adjustment, or may interfere with a laboratory test. Unobserved yet expected adverse reactions based on pharmacology, chemistry or animal data or related to unapproved uses may be included in this section.

Q8.2 The Contraindications section describes instances in which risks clearly outweigh any possible benefit and is intended to capture known hazards only, not theoretical possibilities.

Q8.3 Two additional instruments, the ‘Boxed Warning’ and a Risk Evaluation and Mitigation Strategy (REMS), may be implemented to address a safety concern. Certain contraindications or serious warnings, particularly those that may lead to death or serious injury, may be required to be presented in a boxed warning. The Boxed Warning (traditionally known as a ‘ black box warning ’) ordinarily must be based on clinical data, but serious animal toxicity may also be the basis of a boxed warning in the absence of clinical data. This warning is intended to highlight for prescribers an event that is: (1) so serious with regard to the potential benefit from the drug (i.e., a fatal, life-threatening or permanently disabling adverse reaction) that it is essential, that it be strongly considered in assessing the risks and benefits of using the drug; or (2) there is a serious adverse reaction that can be prevented or reduced in frequency or severity by appropriate use of the drug (e.g., patient selection, careful monitoring, avoiding certain concomitant therapy, addition of another drug or managing patients in a specific manner, avoiding use in a specific clinical situation). Boxed warnings may be updated as new information becomes available. In mid-2011 the FDA Adverse Event Reporting System (AERS) database and published medical literature provided postmarketing information on the tumor necrosis factor-α (TNF-α) blockers (infliximab, etanercept, adalimumab, certolizumab, golimumab) to inform a revision of the Boxed Warning to include the risk of infection from the bacterial pathogens Legionella and Listeria .

In some instances, REMS may also be necessary to ensure that the benefits of a drug outweigh the risks. Q8.4 These programs (REMS) are intended to provide for continued availability of products that have been determined to have significant risks that must be mitigated to continue marketing of the product. Isotretinoin is marketed with a REMS, including Elements to Assure Safe Use (ETASU), implemented as the iPledge program. A summary of ETASU may be required if a drug has been shown to be effective, but is associated with a serious AE, and can be approved only if, or would be withdrawn unless, such elements are required as part of a strategy to mitigate the specific serious risk(s) listed in the labeling of the product. ETASU may be required for approved products when an assessment and Medication Guide, patient package insert, or communication plan are not sufficient to mitigate these risks. The goals of the iPledge program are to: (1) prevent fetal exposure to isotretinoin, and (2) inform prescribers, pharmacists, and patients about isotretinoin serious risks and safe-use conditions.

Product Label ‘Lifecycle’ Changes

To change existing labeling, the drug company submits a supplemental application to the FDA for approval. There are various types of supplements, but generally these are either: (1) efficacy supplements (intended to add a new indication for an already marketed product), or (2) safety/labeling supplements. An applicant may submit labeling supplements for review at any time and without prior notification to the FDA; however, the FDA was recently given the authority to require safety-related labeling changes based on new safety information (such as information derived from a clinical trial, AE report(s), peer-reviewed literature, or other scientific data that becomes available after product approval). Q8.5 AE reports (spontaneous case reports) have proved to be a primary mechanism by which drug regulatory agencies detect ‘signals’ regarding emerging postmarketing safety concerns. In general, applicants will work voluntarily with FDA to incorporate labeling changes related to new safety information, and the appropriate labeling changes will be proposed by the application holder and approved by the agency. Important safety information will be communicated to physicians and patients by the agency, and the FDA currently uses one safety communication, the ‘Drug Safety Communication,’ to provide the public with easy access to important drug safety information. These communications also provide recommendations for action that can be taken by patients or caregivers to avoid or minimize the potential for harm from a drug, and are issued when FDA has information that would help doctors and patients make better treatment choices. This type of communication is part of FDA efforts to communicate early with the public when the agency is still evaluating data and has not reached a conclusion. FDA shares information in the interest of informing doctors and patients about the issues under review, and when FDA experts anticipate completing their review. Before ordering a safety labeling change, FDA would generally form a multidisciplinary team to evaluate the information. If the safety information is relevant to more than one member of a drug class, the affected class would be identified and the review staff in all relevant review divisions and offices would participate. Team discussions and evaluations of new safety information may include internal FDA meetings, Drug Safety Oversight Board, or FDA Advisory Committee meetings. Public meetings and safety communication venues are used by FDA to outline available data, obtain public input, and explain the FDA decision-making process.

Risks and Benefits: US Food and Drug Administration Safety Information

Q8.6 FDA provides information regarding drug safety in multiple venues. Some examples of physician and patient communications for drug safety information include:

• 1.

  An online ‘Index to Drug Specific Information’ includes only drugs that have been the subject of a Drug Safety Communication or equivalent (previously known as Early Communication/Health Care Professional Information Sheet ), and provides direct access to the content of each communication.

• 2.

  MedWatch Alerts contain actionable information that may affect both treatment and diagnostic choices and provide timely medical product information. The MedWatch gateway provides opportunities to sign up for MedWatch email updates, subscribe to RSS Feed safety alerts, and follow MedWatch on Twitter.

• 3.

  Daily Med, a website developed with the National Library of Medicine, gives physicians and patients electronic access to FDA-approved drug labels. The presentation includes a ‘tabbed’ format, providing quick access to specific portions of product labeling, including reproductions of the carton and container.

• 4.

  Drugs@FDA, an online database of approved drug products, allows a search for information regarding drugs and biologic products by drug name or active ingredient. Electronic links to the product approval history, approval letters, reviews and related documents, labeling information, REMS information and medication guides are provided.

• 5.

  Complete transcripts of FDA Advisory Committee meetings, and schedules of upcoming meetings and agendas, are available online.

• 6.

  Please also see the Bibliography for various links for additional drug safety information.

The Dermatologic and Ophthalmic Drugs Advisory Committee (DODAC) is convened to obtain independent expert advice on scientific, technical, and policy matters. The committee convenes to discuss approval of new molecular entities proposed for use in dermatology, and has provided substantial input and advice concerning risk management programs for isotretinoin and thalidomide.

Drug Withdrawal

In rare cases, FDA may need to reassess and change its approval decision on a drug. A conclusion that a drug should no longer be marketed is based on the nature and frequency of the AE and how the drug’s risk–benefit balance compares with treatment alternatives. Considerations regarding risk may include assessments of whether the benefits outweigh the risks for some defined population, and whether this can be addressed in labeling. Q8.7 Discussions concerning risk–benefit and the decision to keep a drug on the market could include:

• What is the magnitude of the benefit compared with known therapy or to alternatives?

• Does the drug add to existing therapy?

• Is there a subgroup of high responders?

• Is the product effective for patients who failed other therapies?

• Is the product tolerated by patients who cannot tolerate other treatments?

• Is there a substantial convenience factor (frequency, dosage, administration)?

When FDA believes that a drug’s benefits no longer outweigh its risks, the agency will ask the manufacturer to withdraw the drug. Q8.8 Specific examples of drugs withdrawn and the associated category of complication are given in Tables 8.1 to 8.4 .