From a trickle to a flood: Pipelines fill with psychotropics for children
Pediatric prescribing stands to gain as pharmaceutical companies develop new indications and drugs for younger patients.
Most psychotherapeutic drugs have been studied only in adults and are not approved for use in children and adolescents. Nevertheless, most drugs used in adult psychiatric treatment are widely prescribed to pediatric patients, and prescribing to this young population has increased dramatically (Box). 1-3
Without the benefit of efficacy and safety data, one must rely on anecdotal reports and clinical judgment when choosing medications and determining dosages for children and adolescents. That may be changing soon, as more pediatric information is becoming available on psychotherapeutic drugs approved for adults and on agents under development.
Limited industry attention to pediatrics
The evidence gap between adult and pediatric practice 4 can be attributed partly to child and adolescent psychiatry lagging behind adult psychiatry in embracing psychopharmacologic treatments. The primary reason, however, has been the pharmaceutical industry’s history of limited interest in studying pediatric populations.
An unprecedented step. In 1986 at Ciba-Geigy, I and colleagues Richard Katz, PhD, Phyllis Landau, MD, and Georges Moroz, MD, began developing clomipramine, the first drug approved in the United States to treat obsessive-compulsive disorder (OCD). Knowing that OCD onset is common in childhood or adolescence, we proposed doing a pediatric study concurrent with the adult studies that would provide the basis for regulatory approval.
DESPITE LIMITED DATA, PEDIATRIC USE OF PSYCHOTROPICS IS GROWING
Researchers have documented a dramatic increase in psychotropic prescriptions to children and adolescents in recent years.
Olfson et al1 reviewed national trends across 10 years. They found the overall annual rate of prescription of psychotherapeutic drugs to children increased from 1.4 per 100 children in 1987 to 3.9 per 100 in 1996. Stimulant and antidepressant drug prescriptions mostly accounted for this nearly threefold increase.
Rushton and Whitmire 2 reviewed a North Carolina Medicaid population and found the number of children prescribed stimulants increased from 6,407 in 1992 to 27,951 in 1998; the corresponding numbers for selective serotonin reuptake inhibitor (SSRI) prescriptions were 510 and 6,984. These represent a fourfold and greater than tenfold increase, respectively, across 7 years.
Zito et al 3 reported increases of 1.3- to 3.1-fold for stimulant and antidepressant prescriptions to preschool children (aged 2 to 4) between 1991 and 1995 in three healthcare settings.
This approach was unprecedented and was initially met with considerable resistance. Ultimately, however, Ciba-Geigy included the pediatric study in the drug development program. As a result, clomipramine became the first psychotropic drug to be simultaneously studied—and eventually approved—for children and adolescents as well as for adults. 5,6
Clinical development programs at other pharmaceutical companies followed suit when designing studies of selective serotonin reuptake inhibitors (SSRI) for OCD (SSRIs were just reaching the market as antidepressants). In some programs, pediatric studies were done after initial successful studies in adults with OCD. Even so, the industry continued to show little interest in including children and adolescents in routine clinical development of new drugs or in seeking regulatory approval for this population. This changed several years later, thanks to initiatives from the National Institute of Mental Health (NIMH) and the Food and Drug Administration (FDA).
RUPP and beyond
During the 1990s, NIMH convened meetings with the American Academy of Child and Adolescent Psychiatry (AACAP) and others that brought together representatives from academia, government, industry, and clinical practice, as well as patient advocates. 7 Attendees discussed the need for new drug development to treat psychiatric disorders in children and adolescents and the obstacles to be overcome for progress to occur. As a result, NIMH in 1996 established Research Units in Pediatric Psychopharmacology (RUPP).
RUPP is a network of centers of excellence in child and adolescent psychopharmacology based in academic medical centers. Its purpose is to provide definitive studies of psychotropic drugs that are being used routinely in children and adolescents and to provide an infrastructure to support complicated multicenter trials. RUPP’s focus is practical, evaluating treatments used in clinical practice.
To date, RUPP has completed and reported the results of two significant studies:
Other studies are under way, and RUPP has advanced the field substantially.
Even so, RUPP has limitations. Its network cannot conduct studies on all psychotropic drugs that are in use today, and it is not positioned to evaluate investigational drugs (in development but not yet approved).
As a result, RUPP’s network can only partially satisfy psychiatrists’ need for information to guide the prescribing of psychotropics to children and adolescents.
FDA initiatives. Concurrent with the NIMH efforts, the FDA implemented the Pediatric Rule of 1994, which applied to all classes of drugs that might be used in younger patients. Under this rule, pharmaceutical manufacturers:
- were required to review existing data for using their drugs in a pediatric population
- could extrapolate efficacy data from adults to children, if the course of disease and effects of drug treatment were sufficiently similar in adult and pediatric patients and if appropriate pharmacokinetic and safety data were provided for younger patients.
The rule did not require them to conduct new studies to obtain labeling of products for pediatric use.
FDAMA. The FDA’s next step was included in the FDA Modernization Act (FDAMA) of 1997, which allowed the agency to ask pharmaceutical manufacturers to generate safety and effectiveness data for drugs likely to be used in pediatrics. In exchange, manufacturers received 6 months’ marketing exclusivity (in addition to existing patent protection) for those drugs.
Many companies did sponsor additional safety and efficacy studies, although the incentive’s structure clearly favored drugs with high sales volume. For example, consider two products with annual sales of $200 million and $800 million, respectively. Six months of exclusive marketing rights would generate $400 million in additional revenue from the $800 million product—double the annual revenue of the $200 million product. The pharmaceutical company could obtain this benefit even if total pediatric use were quite small because the 6 months of exclusivity applied to all product sales, including pediatric and adult use.
The FDAMA had several other weaknesses:
- A manufacturer could obtain its benefit even if studies failed to demonstrate the product’s efficacy in the pediatric population.
- The regulation provided no incentive to develop pediatric data for drugs that had lost patent protection.
- It did not induce pharmaceutical companies to include pediatric studies early in drug development.
Final Pediatric Rule. These concerns led to FDA’s Final Pediatric Rule of 1998, which requires pediatric studies:
- for all new chemical entities (drugs in development and not yet approved)
- and for development programs seeking new indications, dosage forms, treatment regimens, or routes of administration for approved products.
For drugs in early development, this rule allows data to be collected from pediatric studies well before the manufacturer submits a New Drug Application (NDA) seeking marketing approval. Information on the new drug’s efficacy, safety, and prescribing for pediatric use will then be available when it is marketed or very shortly thereafter. For drugs in late-stage development and nearing approval, the required pediatric data might not be available as quickly because pediatric studies will be conducted long after the development program in adults.
DRUGS IN DEVELOPMENT FOR CHILDREN, AS REPORTED BY MANUFACTURERS
- 32 drugs for cancer
- 24 vaccines
- 16 for cardiovascular disease
- 16 for cystic fibrosis
- 16 for infectious diseases
- 11 for psychiatric disorders
- 11 for respiratory disorders
- 10 for AIDS
- 10 for asthma
- 10 for genetic disorders
Source: Pharmaceutical Research and Manufacturers of America 10
Drugs in development
As a result of these regulatory changes, the Pharmaceutical Research and Manufacturers of America (PhRMA) reports that nearly 200 drugs and vaccines are in development for children, (Box 2). In addition to the 11 drugs identified by PhRMA for treating psychiatric disorders in children and adolescents, at least another 10 were in the pipeline through the first 6 months of 2002 (Table). 11 By the time you read this, some of the drugs may have been terminated from development, new drugs may have been added, and others will have emerged from the development process to receive FDA approval for pediatric use.
Indications. Among the 21 compounds listed in development for 10 different psychiatric indications, 16 are already approved for adult use. One—donepezil—is marketed for management of Alzheimer’s dementia symptoms, but for children and adolescents the agent is being developed for treatment of attention-deficit/hyperactivity disorder (ADHD).
Four other approved drugs appear to be in development for new indications, including mania (topiramate), autism (secretin), Tourette’s syndrome (mecamylamine), and ADHD (modafinil). Among the five new chemical entities (NCEs—investigational drugs not yet marketed with any indication), four appear to be in development for ADHD and one for a disorder of childhood listed only as behavioral disorders.
PSYCHOTROPICS IN DEVELOPMENT FOR CHILDREN AND ADOLESCENTS, LISTED BY INDICATION
Drugs in development
Eli Lilly and Co.
Layton BioScience, Inc.
Shire Pharmaceuticals Group
Eli Lilly and Co.
Brystol-Myers Squibb Co.
Eli Lilly and Co.
Bristol-Myers Squibb Co.
Layton BioScience Inc.
Johnson & Johnson Pharmaceutical Research and Development
Johnson & Johnson Pharmaceutical Research and Development
Posttraumatic stress disorder
Development programs. Twenty-four development programs are geared toward creating medications for children and adolescents, including 10 for ADHD, 5 for depression, 3 for OCD, and 1 each for anxiety, Tourette’s syndrome, schizophrenia, mania, autism, and posttraumatic stress disorder (PTSD). Nearly one-half these agents are already approved for similar indications in adults.
The pharmaceutical companies’ decisions to conduct clinical trials in children and adolescents for this group of drugs may be attributable, to some extent, to incentives and the potential for financial gain. Whatever the reasons, the regulatory changes that stimulated this work will have accomplished their goal if they produce evidence of efficacy, safety, and tolerability of these marketed drugs in children and adolescents.
Noncommercial reserach. In addition to industry-sponsored drug development, much pediatric psychopharmacology research is also being conducted in academic and government settings. NIMH and the AACAP are sponsoring trials for a range of pediatric disorders, including ADHD, autism and other pervasive development disorders, bipolar disorder, body dysmorphic disorder, depression, OCD, PTSD, schizophrenia, social phobia, and Sydenham chorea. 12,13
The breadth of indications being investigated in pediatric psychopharmacology clinical trials shows that progress is being made. Missing are NCEs being developed for indications other than ADHD, but the FDA’s Final Pediatric Rule does create the expectation that pediatric studies will be included in all future new drug development programs.
- Food and Drug Administration pediatric Web site. www.fda.gov/cder/pediatric
- American Academy of Child and Adolescent Psychiatry. Pediatric Psychopharmacology Initiative. www.aacap.org/research/ppi.htm
Drug brand names
- Busipirone • BuSpar
- Clomipramine • Anafranil
- Donepezil • Aricept
- Fluoxetine • Prozac
- Fluvoxamine • Luvox
- Imipramine • Tofranil
- Mecamylamine • Inversine
- Methylphenidate • MethylPatch, Ritalin QD
- Mirtazapine • Remeron
- Modafinil • Provigil
- Nefazodone • Serzone
- R-methylphenidate • Attenade
- Risperidone • Risperdal
- Secretin • SecreFlo
- Sertraline • Zoloft
- Topiramate • Topamax
- Venlafaxine • Effexor XR
The author reports that he receives grant/research support from Synaptic Pharmaceutical Corp., is a consultant to GlaxoSmithKline, Elan Corp., and Cytospect, and owns stock in GlaxoSmithKline. No GlaxoSmithKline products are mentioned in this article.
1. Olfson M, Marcus SC, Weissman MM, Jensen PS. National trends in the use of psychotropic medications by children. J Am Acad Child Adolesc Psychiatry 2002;41(5):514-21.
2. Rushton JL, Whitmire JT. Pediatric stimulant and selective serotonin reuptake inhibitor prescription trends 1992 to 1998. Arch Pediatr Adolesc Med 2001;155:560-5.
3. Zito JM, Safer DJ, dosReis S, Gardner JF, Boles M, Lynch F. Trends in the prescribing of psychotropic medications to preschoolers. JAMA 2000;283:1025-30.
4. DeVeaugh-Geiss J. OCD: A model for closing the “gap” between adult and pediatric psychiatry. In: Maj M, Sartorius N, Okasha A, Zohar J (eds). World Psychiatric Association series, Evidence and experience in psychiatry (vol. 4). Obsessive-compulsive disorder. Chichester, UK: John Wiley & Sons, 2000:192-4.
5. DeVeaugh-Geiss J, Moroz G, Biederman J, et al. Clomipramine hydrochloride in childhood and adolescent obsessive compulsive disorder: a multicenter trial. J Am Acad Child Adolesc Psychiatry 1992;31(1):45-9.
6. Clomipramine Collaborative Study Group. Clomipramine in the treatment of obsessive compulsive disorder. Arch Gen Psychiatry 1991;48:730-8.
7. Vitiello B, Jensen P. Medication development and testing in children and adolescents: current problems, future directions. Arch Gen Psychiatry 1997;54:871-6.
8. Walkup J, Labellarte M, Riddle M, et al. Fluvoxamine for the treatment of anxiety disorders in children and adolescents. N Engl J Med 2001;344:1279-85.
9. RUPP Autism Network. A double-blind, placebo-controlled trial of risperidone in children with autism. N Engl J Med 2002;347:314-321.
10. Pharmaceutical Research and Manufacturers of America list of new medicines in development. Available at: http://www.phrma.org/searchcures/newmeds/. Accessed Aug. 26 2002.
11. R&D Directions, e-Knowledge Base online databases 2002 (a subscription database). Available at: www.pharmalive.com.
12. National Institute of Mental Health clinical trials. Available at: http://www.nimh.nih.gov/studies/index.cfm. Accessed July 2002.
13. American Academy of Child and Adolescent Psychiatry clinical trials and surveys. Available at: http://www.aacap.org/research/ctvn.htm. Accessed July 2002.