Not a MyNAP member yet? Register for a free account to start saving and receiving special member only perks. Major components of the Food and Drug Administration FDA statutory authority have evolved in response to drug-related public health crises and in response to a changing environment. FDA needs considerable new resources to perform optimally in a fast changing, challenging environment, including resources to support its regulatory activities, such as regulatory oversight of direct-to-consumer DTC advertising and staff with training and expertise in drug regulation see Chapter 7 for more discussion of resources.
In keeping with other consumer product laws, it focused on postmarketing remedies only. That is, if a drug already on the market was proven to be a hazard, it could be seized and further sales halted. The requirement was a major advance in drug regulation, but it was nonetheless still somewhat weak, as marketing could begin 60 days after submission of the information to the FDA unless the FDA affirmatively found the drug to be unsafe. The statutory scheme for drug regulation went through yet another revision in , after thousands of European children with limb defects were born to mothers who had been administered thalidomide Kaplan, ; FDA, The Drug Amendments of shifted the burden of proof from FDA which previously had to prove harm to keep a drug from being marketed to manufacturers, who now were required to demonstrate both safety and efficacy prior to receipt of marketing approval Hutt, The early s also marked the crystallization of clinical trials into the sequence of phase 1, 2, 3 trials still in use today and described in greater detail in Chapter 2 DHEW, As a result, the statutory scheme governing drug approval in the United States has also included a series of measures to provide an incentive for third parties to develop safety and efficacy data for use by FDA.
Thus, the statutory scheme is characterized by carrots rather than sticks, in that the development of new information on drug safety and efficacy is achieved more by creating incentives than by issuing mandates. The statute empowers FDA to bring enforcement actions through administrative procedures warning letters, adverse publicity, recalls, and withdrawals of product approvals and judicial procedures seizure, injunction, and prosecution Bass, ; Levine, The statutory authority for drug regulation was constructed decades ago, and it remains largely unchanged.
The existing regulatory framework is structured around the premarketing testing process; few tools are available for addressing postmarketing safety issues, short of the blunt instruments to respond to clear-cut adulteration and misbranding. As described in Chapter 1 , the sciences of drug discovery and development, the practice of medicine and the extent of drug use, and the information environment in which health care providers practice and patients learn about drugs and interact with the health care delivery system have all changed.
The carefully controlled clinical trials currently conducted premarket under the existing statutory framework consists of study populations that are commonly different in composition and health status from populations that will use the marketed drug.
Study populations are chosen for a legitimate reason: After approval, drugs are used by larger and more heterogeneous populations, and by people who have comorbidities or are taking multiple prescription and over-the-counter drugs and dietary supplements.
Furthermore, the promotion of drugs has moved beyond health care providers, and substantial industry investment goes into directly targeting consumers. Every effort must be made to monitor the performance of drugs on the market, to identify safety problems early, and to address them effectively.
This suspends further progress in the study until the underlying reasons for the hold e. Center review teams can also ask sponsors to develop and submit for review, when appropriate, plans for postmarketing safety surveillance and study to monitor previously undocumented, unexpected risks, and a risk management program when there are known risks. Other risk management measures and data from epidemiologic studies may be needed if safety signals are identified and confirmed when a drug has been on the market, including label changes, communication to health care providers, restriction of marketing, and public health advisories.
In recent years, CDER has developed guidance for industry on preparing and evaluating risk minimization action plans RiskMAPs , which may include an array of educational and administrative activities to address risks that are known at the time of approval.
There appear to be several conditions FDA can impose at the time of approval, for example, requiring distribution limited to a specific medical specialty, distribution with required periodic screening to avoid contraindicated use, and distribution with mandatory enrollment in a registry. Certainly such conditions have been imposed in the past, for example with teratogenic drugs such as thalidomide and isotretinoin.
And in general, such conditions are even more difficult to put in place after the drug has been approved for marketing, as efforts to impose such conditions nearly always depend upon voluntary compliance by the manufacturer rather than on the threat of withdrawal of the drug from the market as an imminent health hazard.
The desire of patients and the general public for more rapid access to important drugs was among the primary drivers of congressional action to speed up the drug approval. The enactment of PDUFA secured user-fee funds dedicated to enabling FDA drug review divisions to retain the staff and other resources needed to shorten the length of the approval process.
PDUFA has clearly expedited agency decision making and has probably led to efficiencies in distinguishing important from less important issues in the final stages of the review process. Patient expectations and misperceptions about drugs, the ever broader array of drugs, the complexity of actual drug use in the real world, and the intense pace of preapproval activities all suggest that FDA needs stronger authority postapproval to conduct adequate surveillance and oversee and enforce safety studies.
As described in Chapter 4 , postmarketing studies are often planned and designed as an afterthought late in the review process, just before approval, and sometimes the study designs may not be the most useful, necessary, or even practicable IOM, In , the Review Panel. The bill included a provision to allow FDA to require postapproval studies Dorsen and Miller, However, PDUFA provided no resources or new authorities to enable the agency to enforce that provision.
FDA was required to develop and publish a rule on the reporting format and to report annually on sponsor performance in the Federal Register. The report also found that postmarketing study commitments do not have a high priority in FDA, the agency lacks a system for managing postmarketing study commitments and the existing database of commitments is not consistently populated with information from commitment letters or from annual status reports, one-third of annual status required by FDAMA reports on postmarketing commitments are not submitted or are incomplete, and many completed reports lack useful information.
It is clear that FDA authority to require postmarketing studies in cases other than accelerated approval, etc. During the drug development process and up to the point of approval, FDA has a great deal of power. Doing nothing implies not acting on potential threats to the health of the public, and precipitating withdrawal implies taking the drug from patients who need it, so neither is a satisfactory option. Currently, most actions involve softer remedies negotiated with a drug sponsor; FDA cannot unilaterally compel label changes, addition of boxed warnings, or fulfillment of postmarketing study commitments.
Nor can it unilaterally restrict marketing, change the content of a package insert including Medication Guides 2 , or change the content of other documents intended for the public. The process of negotiation works well in many cases, but for some products the process can be long and have potentially adverse repercussions for safety. FDA takes several approaches to monitoring postmarketing safety. CDER staff members review Adverse Event Reporting System AERS reports using data mining techniques for automated monitoring of the AERS database, conduct retrospective and observational studies using external administrative databases, and track the status of phase 4 studies.
Withdrawals are almost always voluntary rather than mandated by FDA. According to its statute, FDA can institute recalls only for devices and baby formula Adams et al. Such actions may include additional study, label changes, and risk communication including Dear Health Professional letters.
If safety problems are identified, FDA can ask the sponsor to propose label language but cannot require specific language to describe the newly identified risks. Often, companies argue strongly against label changes, limitation of marketing, boxed warnings, and so on.
Pharmaceutical companies engage in various activities to promote their products to the public and to health care providers. An increasing proportion of promotional funds goes toward DTC advertising, which is an increasingly contentious area of drug regulation GAO, a. Around the turn of the 20th century, some analysts became concerned that regulation of DTC advertising was not keeping pace with the rapid evolution in advertising, and the debate that began with the introduction of DTC advertising became multifaceted Hunt, Consumer groups, insurers, providers, and others have identified several interrelated concerns about DTC advertising, such as its influence on drug pricing, patient behavior, and prescriber behavior.
A report from the Government Accountability Office concluded that DTC advertising appears to increase spending on prescription drugs and drug utilization GAO, a. One concern is that advertising may lead to more rapid uptake of a new drug, which, in cases where the drug in question is later found to present greater risks than older drugs in the same class, could potentially dramatically increase the exposure to that particular drug, even among patients who are not good candidates for it.
That exemplifies the continuing tension between safety concerns and benefits that outweigh the risks for certain patients. Also, DTC advertising may distort use patterns within classes of drugs, often driving. As a communication or educational tool, DTC advertising appears to have mixed effects. There is evidence that advertisements have raised awareness about certain health conditions and led people to visit their health care provider and in some cases, receive needed diagnosis and treatment Ostrove, ; Calfee, ; Aikin, ; Almasi et al.
Advertisements about drugs may increase consumer familiarity with products available to treat their particular condition s , perhaps empowering them to initiate discussion about therapy with their health care provider, and in some cases, to alert a less well-informed provider to a particular therapy Wilkes et al.
On a potentially more negative note, viewers of television prescription drug advertisements may learn more about the benefits than about the risks. Also, DTC advertising has been shown to have an effect on physician prescribing patterns Aikin, ; Mintzes et al.
FDA can regulate advertising that is false or misleading, but its regulatory actions must harmonize with First Amendment protections of truthful commercial speech. FDA does not have the authority to approve drug advertisements or require that advertising materials be reviewed prior to their use.
The agency can require and enforce corrective action only after a drug advertisement has been broadcast Woodcock et al. The history of court challenges to restrictions on DTC advertising is lengthy and instructive.
Attempts to ban DTC advertising have foundered due in part to uncertainty as to whether such a prohibition is constitutional. Drug advertising has been held to be commercial speech deserving First Amendment protection Virginia State Board of Pharmacy v.
Virginia Citizens Consumer Council, Inc. As a variety of social changes began to transform the passive patient into an empowered seeker and contributor of knowledge and information, the patient-provider relationship and other interactions and spheres of influence around it changed as well.
As early as , FDA developed the first patient package insert in recognition of the need to instruct patients on the use of a drug, the inhalational product isoproterenol Pines, As FDA and the industry reoriented some of their communication activities to target patients, the agency worked in two different directions: Current statutes give FDA and FTC overlapping and concurrent authority over the labeling of FDA-regulated products and over advertising of prescription drugs and devices.
FTC is responsible for regulating false or deceptive claims about products other than prescription drugs and FDA has primary jurisdiction over false and misleading labeling of all jointly regulated products and, on the basis of the definition of advertising as an extension of labeling, over DTC advertising Adams et al. Public Service Commission U.
If the government cannot demonstrate that it meets all three prongs of the Central Hudson test, the speech restriction is unlawful. Western States Medical Center, U. Advertisements that talked about the disease, but not the drug, or about the drug without mentioning the indication left viewers confused and led FDA to reconsider the entire subject of DTC advertising Pines, How the court would react to restrictions short of outright ban on DTC advertisements is unclear, but it is worth noting that in the western states decision the court was unsympathetic to the argument that DTC advertisements of compounded drugs might affect physician prescribing practices, to the detriment of their patients.
The same court cases are relevant to whether FDA can require prior approval of the advertisements. It has been suggested that DTC advertising is associated with the transformation in the role of patients from passive to actively contributing to the health care encounter shared decision making.
The study also found that consumers believe advertisements are more effective in communicating benefits than risks of prescription drugs.
In response to the debate about the effects of DTC advertising on prescription drug use and, ultimately, on drug safety, Senator Frist called for a 2-year moratorium on DTC advertising Pharma Marketletter July 6, One of the principles called for submitting advertising material to FDA prior to broadcast, and informing the agency about the intended time of initial airing.
The principles also urged companies to cooperate with FDA to alter or remove DTC advertising when safety issues about an advertised prescription drug arise. Twenty-three drug companies agreed to the new guidelines, and at least two, Bristol-Meyers Squibb and Pfizer, announced moratoria for 1 year, and 6 months, respectively on DTC advertising for newly approved drugs.
Whether or not an advertisement is reviewed in a timely manner depends on the resources available for review activities—DDMAC is small and has limited resources. When a company submits material, the appropriate DDMAC staff members including a social scientist, regulatory counsel, and others meet to review the proposed promotional material and make a decision.
Warning letters, issued to sponsors for more serious violations than those addressed by untitled letters i. Educate providers about new medicine or new indication for an appropriate given all facts about the drug, the condition, etc.
DTC TV and print advertisements should inform about non-drug options e. DTC advertisements that identify a product by name should include indications and major risks.
The committee learned in conversations with and from literature about several former FDA leaders that even in cases where authority was not clear-cut, the. However, consumer organizations, legislators, scientists, and others who have called for strengthening and clarifying FDA regulatory authority have provided numerous examples of cases where the agency was unable to effect desired changes.
The committee asserts that the bully pulpit route leaves potentially critical regulatory action vulnerable to a subjective and highly variable process of exercising individual or agency influence, and to the vicissitudes of changing attitudes toward regulation.
Pediatric drugs and accelerated approval drugs provide two important incentive mechanisms with which to circumvent the imbalance in regulatory authority pre- and postapproval, and may be instructive as models for strengthening the statutory authorities available to FDA. The FDA Modernization Act of included patent exclusivity provisions as an incentive for sponsors who conducted studies of approved drugs in pediatric populations, and the Best Pharmaceuticals for Children Act renewed those incentives.More...