Implications of using drugs ‘off-label’

November 2002

One of the most concerning medication-related issues facing clinicians caring for infants and children is the relative lack of pediatric-specific information and approval by FDA for many drugs. Using a drug in an infant or older child when the drug is not officially approved by the FDA for use in the age group of the child is common in pediatrics and presents certain implications.

A review of the Physician’s Desk Reference (PDR) – a compilation of product package inserts (ie, the drug’s labeling) – in 1991 found that more than 80% either had no approval or restricted approval (to specific age groups) for use in children.

Without such approval, information about using a drug in an infant or child may be limited or nonexistent. Or, if information is available, it may be available only with a literature search and review. Information such as dosing, adverse events, contraindications or special precautions is obviously vital for appropriate use of the drug.

Prescribing the drug, but proportionately reducing the dose based upon the child’s weight is potentially dangerous, for this simplistic dosing method does not consider changes in the drug’s pharmacokinetics that often differ in the pediatric population. Additionally, drugs can differ in their adverse-effect profile in children as compared with adults – tetracycline and aspirin are well-known examples. From a practical viewpoint, administering a drug without pediatric labeling to an infant or young child when a liquid dosage form, or chewable tablet, is not commercially available has obvious implications. Optimally then, it is desirable for drugs used in children to be well studied, with approval for such use by the FDA, and available in dosage forms compatible with administration to young children.

When reviewing the drug approval process it is helpful to consider the regulatory processes surrounding it. The history of the drug-approval process is an interesting one. Nearly a century prior, in 1906, the first laws governing drug use were written. The Federal Food and Drug Act was enacted in 1906 to prevent the transport of adulterated drugs. The Food and Drug and Cosmetic Act of 1938 was established to ensure the safety of medications, largely as a result of the deaths of more than 100 children, who died from ingesting sulfanilamide elixir, which incorporated diethylene glycol as a diluent. Diethylene glycol was not pretested for toxicity in this age group prior to commercial marketing of the drug. Unfortunately, tragic effects again upon children resulted in additional regulations in 1962. It was found that thalidomide given during pregnancy resulted in severe teratogenic effects. These effects eventually led to the requirement that drugs must be proven safe and effective in the population for which it is intended to be used.

Over the past several decades pharmaceutical manufacturers avoided testing many drugs in children, unless the drug was specifically indicated for pediatric disorders. The term “therapeutic orphan” was used over 25 years ago by Harry Shirkey, MD, to describe the lack of effort given to studying drugs in children to gain official approval and the attendant implications of efficacy and safety. However, many of these drugs were used in children, despite their lack of pediatric-specific FDA approval. Thus, manufacturers often had no major incentive to conduct pediatric clinical trials.

Recently, however, leaders in the pediatric community have begun to approach this issue, with the intent to improve the available information on many of these drugs. Within the past decade considerable efforts have been made, with significant results. The Pediatric Rule of 1994 established that drugs with the potential for use in the pediatric population must be evaluated for dosing and safety information for approved labeling. These data may be, in part, extrapolated from adult data. Economic incentives were given in 1997 through the Modernization Act of 1997, whereby patent extensions of six months were given for manufacturers conducting clinical trials with pediatric subjects. Overall, the Pediatric Rule has been assessed as effectively increasing the amount of information available for pediatric dosing and therapeutic use. However, the courts recently struck down the rule. (See related story.)

Drug approval process

It is also interesting and important to review how the drug approval process occurs. Such a review may extend an appreciation for the complexity involved with bringing a drug to the commercial market. Thousands of chemical entities are tested each year by the pharmaceutical industry for their potential as useful therapeutic agents. After screening and testing in various animal models for toxicity and pharmacologic effect, human testing may begin. A treatment investigational new drug (IND) application is then submitted to the FDA. This explains and outlines plans the company or research institution has for testing the potential drug in humans. Phase-1 studies are then completed in healthy volunteers. The goal of these studies, often conducted in no more than 100 people, is to study and verify the adverse effects and pharmacokinetic profile of the agent in humans.

Phase-2 studies may then proceed in a larger number of patients with the major emphasis focusing upon efficacy. Phase-3 studies, even larger still (up to several thousand patients with the disorder), are used to gather additional information on safety and efficacy of the agent. Different doses may be compared. These studies are more commonly published in peer-reviewed journals. Once sufficient information is obtained from these studies that proves the agent is relatively safe and effective for the intended disorder, a new drug application (NDA) is submitted by the sponsor to the FDA. If the FDA is satisfied that the studies were conducted in an appropriate manner, and the data prove the agent’s safety and efficacy, the agent will be approved for commercial marketing. The manufacturer must also demonstrate that the drug will be produced with appropriate manufacturing techniques.

Thus, the entire process of screening, preclinical animal testing, human testing and manufacturing is highly regulated, and is time-consuming and expensive. The period for IND submission to final drug approval may be six years or more. It is estimated that only 20% of all chemical entities entering clinical studies are eventually approved for use and commercial marketing. This explains, in part, the expense pharmaceutical manufacturers endure when bringing a drug to market.

Implications of off-label use

Using a drug outside of the approved indications, dosing guidelines and age groups as set forth in the drug’s labeling is termed off-label use. The AAP Committee on Drugs recently published a statement on this issue in Pediatrics. Because of the relative lack of information about specific drug use in children, off-label use is common. The drug label, or package insert, is a reflection of the clinical study data submitted by the manufacturer to the FDA for approval. Thus, without specific study of an agent in the pediatric population, the drug label will not include information about its use in children. Because of the above regulations, however, this concept is changing. Using a drug off-label does not universally imply unethical use, for some drugs are commonly used as accepted medical practice despite official lack of pediatric labeling. For example, albuterol solution for nebulization, commonly used in young children and infants, is approved for use only for ages 12 years and above. Despite this, dosing information for younger ages can be commonly found in dosing handbooks. Fluoxetine (Prozac, Eli Lilly), also used in children and adolescents, is not approved for use in any child younger than 18 years of age. Despite common uses of such drugs off-label, it remains desirable for drugs used in pediatric patients to have pediatric labeling, for such labeling affords clinicians essential information about appropriate use of the drug. It is important to consider that the FDA does not, in large part, regulate how prescribers use a drug once it is approved for marketing.

Conclusions

The off-label use of drugs in pediatrics is common. Prescribing a drug off-label in an infant or child carries ethical, legal and scientific implications that may not be easy to comprehend. It is important for pediatric clinicians to have an appreciation for the drug approval process and the implications of off-label drug use. The recent committee statement by the AAP is an important summation of this issue.

For Your Information:

• Meadows M. The FDA’s drug review process: ensuring drugs are safe and effective. FDA Consumer. 2002;36(4):19-24.
• Committee on Drugs, AAP. Use of drugs not described in the package insert (off-label uses). Pediatrics. 2002;110(1):181-183.
• Wilson JT. An update on the therapeutic orphan. Pediatrics. 1999;104(Suppl):585-590.
• Blummer JL. Off-label uses of drugs in children. Pediatrics. 1999;104(Suppl):598-602.