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Figure 139–1 is a schematic overview of the process for drug development of a new molecular entity (NME). The process begins with the preclinical evaluation of the candidate drug. During this evaluation, preclinical toxicologic testing is performed in more than one animal species, and other testing includes product stability, good manufacturing methods, purity, and potential carcinogenicity. Dose–response relationships in animal models and in vitro receptor binding or surrogate marker effects are often determined at this phase of the evaluation. At this time many manufacturers determine the metabolism of the drug in animal and in vitro human systems. Following this preclinical testing, the sponsor submits an IND application to the FDA for approval to initiate human testing. This application contains all relevant data concerning animal and in vitro toxicology testing, product manufacturing and purity, and a protocol for using the drug in initial human investigation. Within 30 days, the FDA must review the IND application and either allow the proposed human study to proceed or inform the sponsor that additional data or preclinical (eg, animal) study is required before clinical testing of the candidate drug can begin.
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The clinical study of new candidate drugs is divided into four basic phases.
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Phase 1 clinical testing involves a relatively small number of participants with the primary aim of determining the safety and toxicity of the drug. Many phase 1 studies will also determine the human pharmacokinetics and metabolism of the drug. Phase 1 studies are normally conducted in 20 to 100 healthy volunteer participants, with the notable exception of phase 1 studies for cancer chemotherapeutics, which enroll only patients with cancer.
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Phase 2 clinical testing is designed to determine the potential efficacy of the drug product in humans, usually at varying levels of exposure to the drug candidate. In this phase, approximately 100 to 300 participants are usually studied. In phase 2 clinical trials, participants generally have the diseases for which the drug is intended or are capable of demonstrating the appropriate, validated, biologic surrogate marker to indicate response to the drug. An example of this would be when a drug intended for early treatment of acute coronary syndrome is tested to show that it can inhibit in vivo platelet function after oral dosing in human study participants.
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Phase 3 clinical drug studies usually involve large scale clinical trials in the actual population for which the drug is intended for use. Typically, this phase of drug development will involve testing a treatment cohort versus a control treatment of several hundred to several thousand patients who have the target disease, depending on both the prevalence of the disease and effectiveness of the drug. The primary goal of phase 3 studies is to determine the safety and efficacy of the candidate drug in the actual intended patient population in question, under conditions similar to the anticipated medical use. At the completion of phase 3, an NDA (request for approval to market) is submitted to the FDA. A candidate drug completing phases 1, 2, and 3 can thus be approved for marketing after study in only 2000 to 4000 patients. In the setting of a fast-track approval or under the Orphan Drug regulations, substantially fewer patients will receive the drug before its approval for marketing. The relatively small number of human exposures to a new chemical or biologic entity prior to approval for marketing is an important factor that limits the sensitivity of the drug approval process to detect uncommon ADEs.
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Toward the end of the review cycle, the FDA often seeks the external advice of its constituted advisory committees prior to their approval decision, especially in the setting of an uncertain risk–benefit profile of a candidate drug. FDA advisory committees generally are organized by therapeutic areas and are composed of medical professionals, primarily from academia, as well as biostatisticians, a patient representative, a consumer representative, and a nonvoting industry representative. These same advisory committees also convene to consider postapproval safety or efficacy data when FDA is considering an important change to a drug label or other postapproval regulatory action. Generally, the FDA prepares questions for the committee members and provides an FDA briefing document containing a detailed data analysis and background of the issue from the FDA perspective as well as a briefing document prepared by the drug sponsor containing corresponding information. Committee members comment and vote on the FDA questions during the proceedings. For a new drug approval, one question generally includes a yes or no answer as to whether or not the committee member believes that the drug can be marketed with an adequate risk–benefit profile. The advisory committee vote is technically nonbinding for the FDA, but the FDA generally follows the advice of the committee. A recent issue of concern is the fact that some members of FDA advisory committees with perceived conflicts of interest are granted waivers by FDA to participate.23 The appearance of conflict of interest on an advisory committee can have a significant impact on the drug approval process, and the FDA has begun to decrease the number of committee member waivers.
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At the conclusion of the NDA review process and, at times, following an Advisory Committee meeting on the application, the FDA may issue an approval for marketing the new product. On occasion, the FDA issues an “approvable” letter, indicating that the product is potentially approvable but additional data will be needed before final approval can be granted. Examples of additional data required in this setting include further clinical study of a specific drug interaction, use of the drug in a specific patient population, or extension of the submitted drug stability testing. Once approval of the drug is given by the FDA, the next phase of drug development begins as discussed separately below.
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Phase 4 Drug Development: Postmarketing Surveillance
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Every drug, therapeutic biologic product, or medical device carries with it some potential risk. If society required that only “completely” safe drug products could be marketed, the drug approval process would likely take decades and few if any new drugs would be made available. Therefore, the FDA and the pharmaceutical industry rely significantly on postmarketing surveillance for further safety information regarding the toxicity of a medical product after approval. A postmarketing surveillance system is in place to monitor postapproval drug safety. These systems are intended to detect unanticipated or previously unrecognized adverse events or to identify an at-risk population in whom the safety profile differs from that which was expected prior to marketing. Individual pharmaceutical manufacturers are responsible for monitoring the safety of their products and regularly reporting any detected ADEs to the FDA. The FDA postmarketing surveillance program (MedWatch) for all medical products is a parallel system in place to monitor drug and medical device safety. This system relies on spontaneous reports by health care professionals or patients regarding the occurrence of deleterious effects associated with the use of a medical product.
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Because manufacturers are also required by law to report ADEs associated with use of their products to MedWatch, the FDA database contains one complete data set called FDA Adverse Event Reporting System (FAERS), that was renamed from AERS in 2010 following its enhancement and integration of device-related data.34 Because the MedWatch system is passive in nature, the estimated overall rate for adverse event reporting is estimated at only 1% to 10%. Despite this, the number of serious adverse events reported to MedWatch increased between 1998 and 2005,26 although the completeness of the reports remains poor.13 Improved attitudes toward reporting, perhaps due to an appreciation of the risk of error and adverse drug effects, leads to better MedWatch reporting.12 Both, the adverse event reports from MedWatch and those that are submitted from product manufacturers are entered into the FAERS database. This database is fully computerized and therefore easily searchable and contains adverse event reports from human drug and biologic products. The system contains more than 7 million reports, entered since 1969, and is growing substantially. In 2012 there were nearly 1 million reports submittedto FAERS. Approximately 95% of the total reports in the system are generated by the manufacturers and the remaining 5% are submitted via the MedWatch system.
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The primary goals of the MedWatch system are the following:
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To increase awareness of drug- and device-induced disease.
To clarify what should (and should not) be reported to the agency.
To facilitate reporting of adverse effects by creating a single system for health professionals to use in reporting ADEs and product problems to the agency.
To provide regular feedback to the health care community about safety issues involving medical products.9
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Establishing causality for a specific medical product is not required before submission of a MedWatch report. The FDA is primarily interested in the reporting of serious adverse events, or an ADE previously not associated with the drug being administered, whether or not a causal relationship is established. Although any potential ADE should be reported, an event is considered serious and must be reported when the patient outcome is one of the following:
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Death: If the death is suspected to be a direct result of the adverse event
Life threatening: If the patient was considered to be at substantial risk of dying at the time of the adverse event or the use or continued use of the product would result in the patient’s death (eg, gastrointestinal hemorrhage, bone marrow suppression, pacemaker failure, and infusion pump failure that permits uncontrolled free flow and results in excessive drug dosing)
Hospitalization (initial or prolonged): If admission to the hospital or prolongation of a hospital stay resulted from the adverse event (eg, anaphylaxis, pseudomembranous colitis, bleeding that causes or prolongs hospitalization)
Disability: If the adverse event resulted in a significant, persistent, or permanent change, impairment, damage, or disruption in the patient’s body function/structure, physical activities, or quality of life (eg, cerebrovascular accidents caused by drug-induced coagulopathy, toxicity, peripheral neuropathy)
Congenital anomaly: If there is a suspicion that exposure to a medical product before conception or during pregnancy resulted in an adverse effect on the child (eg, vaginal cancer in female offspring from maternal exposure to diethylstilbestrol during pregnancy or limb malformations in the offspring from thalidomide use during pregnancy)
Requires intervention to prevent permanent impairment or damage if use of a medical product is suspected to result in a condition requiring medical or surgical intervention to preclude permanent impairment or damage to a patient (eg, acetaminophen overdose–induced hepatotoxicity requiring treatment with N-acetylcysteine to prevent permanent damage, burns from radiation equipment requiring drug therapy)
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MedWatch reports are easily done through the MedWatch Web site, or by facsimile, telephone, or mail. Physician reports are given priority for review by the FDA in the MedWatch system. A well-documented case of a serious adverse event is a significant and useful contribution to the MedWatch system.
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Reports of serious ADEs to the FDA or to the manufacturer can become an epidemiologically detectable signal that can trigger a more detailed investigation, several examples of which are provided later in this chapter. On occasion, serious ADEs detected in the AERS database have led to the withdrawal of products from the US market without conducting additional studies.
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Reporting serious ADEs has periodically been encouraged by various health care groups in conjunction with the FDA. Currently, the MedWatch program is supported by more than 140 organizations, representing health care professionals and industry collaborating as MedWatch Partners to help achieve these goals. These organizations include medical societies and organizations such as the American Medical Association (AMA), the American College of Medical Toxicology (ACMT), and the American Academy of Pediatrics (AAP) that have encouraged their members to report to the MedWatch system. As a requirement for hospital accreditation, The Joint Commission mandates hospitals to collect, analyze, and report significant and unexpected ADEs to the FDA.
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The primary limitation of the MedWatch system is the exclusive reliance on spontaneous reporting of ADEs. The system is passive in nature and therefore has several important limitations. Significant underreporting is known to occur in such systems. The uncertainty about the significance of a signal in the AERS database is exacerbated by the low estimated rate for adverse event reporting and the fact that the true incidence of the reported ADE is almost never precisely known because the denominator, which is the number of actual exposures to the drug, is rarely accurately known. Despite these limitations, the MedWatch system has detected significant ADEs during the postmarketing period.
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Drug regulators must rely on passive surveillance systems like the AERS database to detect potential uncommon or rare but serious ADEs postapproval. This is primarily because a relatively small number of patients or participants are exposed to the drug during phases 1 to 3 prior to approval for marketing. For example, to detect an uncommon ADE occurring in approximately 1 of 5000 individuals exposed to a drug with 95% probability that the ADE resulted from exposure to that drug, approximately 15,000 patients would have to be exposed to the drug. In a balanced (equal numbers of drug and placebo recipients) placebo-controlled clinical trial, 30,000 participants would need to be enrolled. Premarketing clinical studies (phases 1, 2, and 3) are usually inadequate to detect rare ADEs, ADEs that are incorrectly diagnosed, or ADEs that result from a drug interaction that may not have been tested in the development program.
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An example of a rare ADE not detected until postmarketing involves the drug felbamate, which was approved by the FDA in September 1993 and subsequently found to be associated with aplastic anemia during postmarketing surveillance. Felbamate induced aplastic anemia had not been detected during the drug development program. By July 1994, nine cases had been reported from an estimated 100,000 patients exposed to felbamate in the United States.28 Most of the aplastic anemia cases occurred in patients who had taken the drug for less than 1 year. The nine cases represented an approximate 50-fold increase in aplastic anemia over the expected rate in the population with the very low background rate of two to five cases per million per year allowing the FDA to attribute this rare condition to exposure to felbamate.
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The primary role of the MedWatch system is to generate a hypothesis for potential association of an ADE with a specific drug. These hypotheses are sometimes further tested in subsequent phase 4 investigations. An example of this “hypothesis generation” function of MedWatch was the question of whether phenylpropanolamine (PPA) caused hemorrhagic stroke in patients using nonprescription diet suppressants or cough and cold preparations containing PPA. In the early 1990s, the Spontaneous Reporting System (SRS; now AERS) detected a potential association of hemorrhagic stroke and nonprescription use of PPA. An industry-sponsored prospective, case-controlled study was designed to determine if such an association existed. The multicenter study demonstrated that an association did exist, especially for women aged 18 to 49 years. The Nonprescription Drug Advisory Committee (NDAC) of FDA reviewed this study and the associated MedWatch data in the fall of 2000 and decided that the evidence supported such an association. The committee advised the FDA to remove PPA from the market, which occurred a short time later. Although the entire process of signal identification from MedWatch to presentation of results from the prospective epidemiologic study required nearly a decade for PPA, the process demonstrates the value of the hypothesis-generating ability of the MedWatch system.
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Potential outcomes of a safety signal detection for a marketed drug include dose reduction in all or certain high risk patient populations, restriction of the sale of the specific drug to a more medically supervised environment or the development of a patient registry to more closely monitor use, and removal of the drug from the market. These options are further discussed later in this chapter.
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Other types of phase 4 safety investigations include clinical studies, comparative studies with the new drug versus a competitor, or a special population study or drug interaction study when suspicion is raised that there may exist a different risk–benefit relationship in certain clinical settings. The enhancement of safety information is the primary goal of most phase 4 studies. Other than the specific prospective study in patient subpopulations, the methods by which phase 4 safety studies are usually conducted are primarily observational and epidemiologic. Main sources of data for the postapproval monitoring of the safety of a drug are the spontaneous reports gathered by both the pharmaceutical manufacturer and FDA. The fields of pharmacovigilance and pharmacoepidemiology are typically employed in the conduct of phase 4 studies. Attributing a serious ADE to a drug solely from MedWatch reports does occur, but it is much more common for the AERS database to produce a signal, suggesting a possible drug-related safety problem.