Current Drug Approval Framework
Since the 1962 amendments, new drug development has become an increasingly costly, time-consuming endeavor (DeMasi, Hansen, & Grabowski, 2003). Estimates on the amount of time it now takes for a new compound to reach approval are as high as 12 to 13 years (Figure 28-1).
Generally speaking, new drug discovery and development proceeds in a sequence of phases, sometimes overlapping (DeMasi et al., 2003). Prior to any human testing, a new drug’s sponsor, typically a pharmaceutical company, but sometimes, a non-governmental organization or government agency, tests a new compound in assays and animal models. If encouraged by the results, the sponsor submits to the FDA an investigational new drug application (IND) that contains all known information about the compound, including manufacturing information to demonstrate that the test article can be produced consistently with high quality. The IND also specifies the clinical research plan and protocol for phase 1 studies. Unless the FDA affirmatively objects, the IND is automatically allowed after 30 days, and human clinical trials can begin. In accordance with federal regulations, local institutional review boards (IRBs) charged with protecting research participants must approve these trials (FDA Protection of Human Subjects Regulations, 1980; FDA Institutional Review Board Regulations, 1981). IRBs review protocols relative to their scientific merit, risks and benefits, and procedures for gaining informed consent. They are also expected to review plans for recruiting volunteers to avert inappropriate incentives or coercive tactics (FDA Protection of Human Subjects Regulations, 1980; FDA Institutional Review Board Regulations, 1981).
A drug’s premarket clinical testing must proceed through three successive phases consistent with the required safety and efficacy standards. In Phase 1, a small number of usually healthy volunteers are given the drug to establish safe dosages, and characterize the absorption, distribution, metabolic effects, and excretion (ADME) of the drug. These data help determine the drug’s pharmacokinetic (PK) profile (the way the body processes a drug), its tolerability and safety profile, and pharmacodynamics (PD), the way the drug works in the body. Phase 2 trials include a few hundred volunteers who have the targeted disease or condition to determine an effective dose and to begin to evaluate efficacy and short-term risks. In Phase 3, studies are conducted to evaluate safety and efficacy in several hundred to several thousand patients or volunteers at risk for the drug’s targeted condition (e.g. a new female contraceptive is tested in women at risk for pregnancy; a colon cancer treatment is tested in people with this condition). Depending on a drug’s indication, testing occurs in hospitals and/or outpatient settings. Phase 3 studies are usually randomized, controlled multicenter trials with results of the new drug tested against an approved standard therapeutic agent (sometimes referred to as the “gold standard”). The goal of these studies is to gather precise information on a drug’s effectiveness for specific indications, determine whether or not the drug produces a broader range of adverse events (AEs) than those exhibited in the smaller Phase 1 and 2 study populations, and identify the best way to administer and use the drug for its intended purpose. These studies also can uncover infrequent side effects.
Once a sponsor has finished preclinical and clinical testing, analyzed the data, and written reports in accordance with regulatory guidelines, it can compile and submit a new drug application (NDA) to the FDA, which will assess it for completeness before filing and initiating its review. In addition to the aforementioned components, the NDA must also include detailed chemistry, manufacturing and quality controls (CMC) documentation to ensure that the marketed product will adhere to consistent safety and purity standards.
In accordance with a time frame mandated by the Prescription Drug User Fee Act (PDUFA) that took effect initially in 1993, the FDA must complete its review in a timely fashion. The approval process for most new drugs takes 12 months on average, while priority applications are generally reviewed within 6 months.
During the review period, the FDA may seek clarification of data contained in the NDA or ask for new information. To augment its internal review, the FDA sometimes will convene an advisory “expert” panel to discuss the NDA publicly and advise the agency regarding the new drug’s approvability. These panels are comprised of health professionals with expertise in the therapeutic area applicable to the drug under review, including statisticians and/or epidemiologists, and generally a consumer and industry representative. Historically and currently, physicians compose the majority of health professional representatives to these panels. On occasion, nurses are invited to serve, but often as consumer representatives who may or may not be voting members.
As part of the approval process, information gleaned during the phases of drug testing forms the basis for product labeling information. The FDA’s guidance on drug labeling ensures that package inserts include the same types of information in a standardized format, although the titles may vary according to manufacturer preference. Developing this label is a lengthy process that often includes heated negotiation between sponsor representatives and FDA staff regarding the exact wording of an approved drug label. Every single word is important. Adding an indication or removing a contraindication can have a several-million-, even billion-dollar impact for a sponsor as well as significant health consequences for the medication-taking public. The addition of a “black box” warning (the strongest warning the FDA issues in its drug labeling) on antidepressants prescribed to children and adolescents, for example, not only reduced prescriptions for selective serotonin reuptake inhibitors (SSRIs) by an estimated 22% in the U.S., but also was associated with reducing aggregate rates of diagnosis and treatment of pediatric depression (Gibbons et al., 2007; Libby et al., 2007). A label’s contents, therefore, are of paramount importance to nurses who care for patients and/or are responsible for updating other nurses on labeling changes.