Fig. 26.1
Phases of drug development. NDA New Drug Application, IND Investigational New Drug Application
Initial studies in humans (Phase 1 trials) are the first stage of testing in human subjects. Often, during this phase of development, a small number (e.g., 20–50 people) of healthy adult volunteers will be tested in trials designed to assess the first time use in humans for safety, tolerability, proof of concept for efficacy, and pharmacokinetics.
Pharmacokinetic (PK) parameters are often assessed in Phase 2 studies. PK studies provide information on the systemic exposure of a drug after administration. Important PK measurements include area under the curve (AUC) and maximum concentration (C max), clearance (C), half-life (T 1/2), and volume of distribution (V d). These parameters are all used to characterize a drug’s absorption (A), distribution (D), metabolism (M), and elimination (E). The overall process (ADME) ultimately controls the systemic exposure to a drug and its metabolites after administration. Pharmacokinetic parameters must be considered when establishing the appropriate dose of a drug.
Once the first human exposure has been completed, and some PK parameters assessed, additional studies (Phase 2 studies) are performed on a larger number of participants (e.g., 20–300 patients) to assess the treatment effect size, provide safety assessments, and test the response to different doses in a larger group of volunteers and patients. The information obtained from Phase 2 studies is critical in designing the definitive Phase 3 studies.
The Phase 3 studies should leverage the data from all other nonclinical and clinical trials to determine an appropriate dose(s), and to estimate the number of patients required to demonstrate efficacy based on the expected treatment effect size. The clinical trials must also include sufficient numbers of patients with sufficient length of exposure to adequately assess the safety of the product for its intended use. Phase 3 studies are intended to provide substantial evidence of safety and effectiveness of the product and should therefore be designed as adequate and well-controlled studies [2].
A marketing application, or New Drug Application (NDA),2 is submitted to the FDA once all required studies have been completed to support a new drug for marketing. A supplemental NDA (sNDA) may be submitted if the industry seeks to change the indication or population for a pharmaceutical product that has already been approved. The application must contain all information necessary to market the product including:
A technical description of methods used in manufacturing (good manufacturing practice, GMP) and data on the drug’s quality (supporting the drug’s identity, strength, stability, and purity)
Complete data from preclinical and clinical studies to support the safety and effectiveness of the drug in its proposed use(s)
The drug’s proposed labeling (package insert)
The product labeling describes the conditions of study, to include the patient population(s) studied, the dose(s) used, and the end point(s) assessed. Use(s) of the product under the specific conditions described in the product labeling is known as “on-label use.” Uses of the product outside of these parameters, including any conditions or diseases, populations, or dosages not found in labeling, are known as “off-label” use.
Pediatric Legislation
Historically, many drugs, including those used in sedation, were not studied in pediatrics, and thus, the majority of drugs used in pediatric practice were “off label.” Approximately 75 % of medicines used in children did not include specific pediatric prescribing information prior to implementation of legislation encouraging and requiring the study of medication in the pediatric population [3]. While the number of drugs with specific pediatric labeling information has improved under this process, the majority of commonly used sedatives continue to lack specific pediatric labeling or robust efficacy and safety data in children (Table 26.1).
Table 26.1
Common sedatives and their use for children
Agent | Approved indication(s)a | Pediatric information |
|---|---|---|
Chloral hydrateb | Manufacturing of chloral hydrate oral solution discontinued in 2012 | Drug not approved by the FDA |
Dexmedetomidine | • Sedation of initially intubated and mechanically ventilated patients during treatment in an intensive care setting | The efficacy, safety, and pharmacokinetics in patients less than 18 years of age have not been established. Therefore, this product should not be used in this population |
• Sedation of nonintubated patients prior to and/or during surgical and other procedures | ||
Diazepam, injectable | • Adjunct for relief of skeletal muscle spasm due to reflex spasm to local pathology (such as inflammation of the muscles or joints, or secondary to trauma) | • Although anxiolytic indication appears in labeling for adults, pediatric approval and dosing information are limited to use in tetanus and status epilepticus and recurrent convulsive seizures |
• Spasticity caused by upper motor neuron disorders (such as cerebral palsy and paraplegia), athetosis, stiff-man syndrome, and tetanus | • Not approved below 30 days of life | |
• Adjunct in status epilepticus and severe recurrent convulsive seizures | ||
• Premedication (intramuscular) for relief of anxiety and tension in patients who are to undergo surgical procedures. Intravenously prior to cardioversion for the relief of anxiety and tension and to diminish the patient’s recall of the procedure | ||
Etomidate | Induction of general anesthesia | There are inadequate data to make dosage recommendations for induction of anesthesia in patients below the age of 10 years; therefore, such use is not recommended |
Fentanyl citrate, injectable | • For analgesic action of short duration during the anesthetic periods, premedication, induction and maintenance, and in the immediate postoperative period (recovery room) as the need arises | • The safety and efficacy of fentanyl citrate in children under 2 years of age have not been established |
• For use as a narcotic analgesic supplement in general or regional anesthesia | • Rare cases of unexplained clinically significant methemoglobinemia have been reported in premature neonates undergoing emergency anesthesia and surgery, which included the combined use of fentanyl, pancuronium, and atropine. A direct cause-and-effect relationship between the combined use of these drugs and the reported cases of methemoglobinemia has not been established | |
• For administration with a neuroleptic as an anesthetic premedication, for the induction of anesthesia, and as an adjunct in the maintenance of general and regional anesthesia | ||
• For use as an anesthetic agent with oxygen in selected high-risk patients, such as those undergoing open heart surgery or certain complicated neurological or orthopedic procedures | ||
Fospropofol | • A sedative–hypnotic agent indicated for the monitored anesthesia care (MAC) sedation in adult patients undergoing diagnostic or therapeutic procedures | Safety and effectiveness in pediatric patients have not been established because fospropofol has not been studied in patients <18 years of age. Fospropofol is not recommended for use in this population |
Ketamine | • Sole anesthetic agent for diagnostic and surgical procedures that do not require skeletal muscle relaxation | Safety and effectiveness in pediatric patients below the age of 16 have not been established |
• Induction of anesthesia prior to the administration of other general anesthetic agents | ||
• To supplement low-potency agents, such as nitrous oxide | ||
Lorazepam | • Treatment of status epilepticus | • Pediatric pharmacokinetic data included in labeling |
• In adult patients for preanesthetic medication, producing sedation (sleepiness or drowsiness), relief of anxiety, and a decreased ability to recall events related to the day of surgery | • No pediatric dosing included in labeling | |
• There are insufficient data to support the efficacy of injectable lorazepam as a preanesthetic agent in patients less than 18 years of age | ||
• Information in labeling about the “gasping syndrome” associated with benzyl alcohol, polyethylene glycol, and propylene glycol, components of lorazepam injection | ||
Methohexital | In adults as follows: | Methohexital can be used in pediatric patients older than 1 month as follows: |
• IV induction of anesthesia prior to the use of other general anesthetic agents | • For rectal or IM induction of anesthesia prior to the use of other general anesthetic agents | |
• IV induction of anesthesia and as an adjunct to subpotent inhalational anesthetic agents for short surgical procedures | • For rectal or IM induction of anesthesia and as an adjunct to subpotent inhalational anesthetic agents for short surgical procedures | |
• Along with other parental agents, usually narcotic analgesics, to supplement subpotent anesthetic agents for longer surgical procedures | • The safety and effectiveness of methohexital in pediatric patients below the age of 1 month have not been established. Studies of methohexital intravenously in pediatric patients have been reported in the published literature. The literature is not adequate to establish the safety and effectiveness in pediatric patients | |
• IV anesthesia for short surgical, diagnostic, or therapeutic procedures associated with painful stimuli | • Pediatric dosing information is included in labeling | |
• As an agent for inducing a hypnotic state | ||
Midazolam | • IM or IV for preoperative sedation/anxiolysis/amnesia | • The safety and efficacy of midazolam for sedation/anxiolysis/amnesia following single-dose intramuscular administration, intravenously by intermittent injections, and continuous infusion have been established in pediatric and neonatal patients |
• IV as an agent for sedation/anxiolysis/amnesia prior to or during diagnostic, therapeutic, or endoscopic procedures, such as bronchoscopy, gastroscopy, cystoscopy, coronary angiography, cardiac catheterization, oncology procedures, radiologic procedures, suture of lacerations, and other procedures either alone or in combination with other CNS depressants | • Midazolam should not be administered by rapid injection in the neonatal population. Severe hypotension and seizures have been reported following rapid IV administration, particularly with concomitant use of fentanyl | |
• IV for induction of general anesthesia, before administration of other anesthetic agents. IV midazolam can also be used as a component of intravenous supplementation of nitrous oxide and oxygen (balanced anesthesia) | ||
• Continuous intravenous infusion for sedation of intubated and mechanically ventilated patients as a component of anesthesia or during treatment in a critical care setting | ||
Nitrous oxideb | This drug has not been found by the FDA to be safe and effective, and this labeling has not been approved by the FDA | Drug not approved by the FDA |
Safety and efficacy not established in children | ||
Pentobarbital, injectable | • Sedatives | • No adequate well-controlled studies have been conducted in pediatric patients; however, safety and effectiveness of pentobarbital in pediatric patients are supported by numerous studies and case reports cited in the literature |
• Hypnotics, for the short-term treatment of insomnia, since they appear to lose their effectiveness for sleep induction and sleep maintenance after 2 weeks | • The recommended pediatric dosage ranges from 2 to 6 mg/kg as a single IM injection not to exceed 100 mg | |
• Preanesthetics | ||
• Anticonvulsant, in anesthetic doses, in the emergency control of certain acute convulsive episodes, e.g., those associated with status epilepticus, cholera, eclampsia, meningitis, tetanus, and toxic reactions to strychnine or local anesthetics | ||
Propofol | • IV sedative–hypnotic agent that can be used for both induction and/or maintenance anesthesia as part of a balanced anesthetic technique for inpatient and outpatient surgery | • Approved for induction down to 3 years of age and maintenance of anesthesia down to 2 months of age |
• Not recommended for induction of anesthesia below the age of 3 years or for maintenance of anesthesia below the age of 2 months because its safety and effectiveness have not been established in those populations | ||
• Not indicated for use in pediatric ICU sedation since the safety of this regimen has not been established | ||
Thiopental | Manufacturing of thiopental discontinued in 2011 | No pediatric use or dosage information |
Prior to the passage of important pediatric legislation, many pharmaceutical manufacturers were reluctant to study drugs in children due to ethical and financial constraints or trial design challenges [4]. However, the pediatric population accounts for 25 % of the US population and, therefore, represents a population that must be addressed during product development [5].
Because of the historic lack of data from adequate and well-controlled clinical trials, medications were often administered to children empirically, assuming that they were “little adults.” This simplistic and often erroneous assumption resulted in pediatric dosing recommendations derived solely as fractions of adult dosing rather than on intrinsic factors based on known differences in growth and development (e.g., volume of distribution and maturation of metabolic pathways). Safety and efficacy were also simply assumed to be the same in the pediatric and the adult populations and did not take into account both known and potential safety and efficacy differences that may be present in a growing and developing pediatric patient.
The Food and Drug Modernization Act of 1997 (FDAMA) created an incentive program known as pediatric exclusivity. This provision allowed the FDA to issue a formal request, known as a Written Request, outlining the studies needed on a specific drug for one or more conditions or indications. The Written Request includes details of study design, number of patients needed, and important safety and efficacy endpoints to be measured. The Written Request also includes a due date for submission of the study data to the FDA. The FDA can grant 6 months of marketing exclusivity to sponsors who complete the voluntary pediatric studies using good scientific principles, blocking the approval of generics for the entire product line and all indications already approved, resulting in financial return for the sponsor who performed the studies [6]. Although FDAMA was to sunset on January 1, 2002, the incentive was reauthorized by the Best Pharmaceuticals for Children Act (BPCA) of 2002, 2007, and again in 2012. The most recent reauthorization of BPCA was permanent and does not sunset. Additionally, the ability to obtain pediatric exclusivity was extended to biologic products under the Patient Protection and Affordable Care Act of 2010.
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