Introduction

This topic, while eliciting much interest today, remains a very controversial area. The controversies include (1) the fact that these uses are not subject to the rigorous approval process; (2) that such uses may be perceived as experimental in nature; and (3) that such uses may impede incentives to evaluate the drug for its off-label use. With the emphasis on curbing health care costs, coverage and reimbursement for off-label use of drugs also have become issues.

The package insert (label) is intended to provide all of the information judged to be necessary for the drug or biological to be used safely and effectively for the approved indication(s). Special groups, however, such as children and pregnant women, have commonly been excluded by disclaimers in the label because substantial evidence of safety and efficacy has not been submitted to the FDA. Three fourths of the prescription drugs currently marketed in the United States lack pediatric use information and are labeled with such disclaimers.₁,₂ Most drugs have not been adequately studied in the pediatric population. Recent regulations and legislation have been introduced to improve this situation.

Drug Safety Concerns

Modern drugs, by and large, have provided enormous benefit to humanity in improving their health status and thereby ensuring a better quality of life. The morbidity and mortality rates, as well as life expectancy figures vouch for the contributions that modern medicines have made during the last half a Century. However, there have been concerns regarding the usefulness of several drugs, the way they are used and the role that commercial considerations play in the in the promotion of at least some of the drugs in current use.

Among many of these concerns, the safety aspects of drugs are the ones, which attract a great degree of anxiety in the minds of many of the stakeholders including the Regulatory Agencies, the patients and society in general. Absolute safety can never be guaranteed for any product launched in the market, since potential serious side effects when a drug is used by a large population can never be fully predicted in spite of all efforts at the drug development stage to ensure maximum safety based on pre-clinical and clinical investigations in animals and humans respectively. Judgments on the safety and efficacy of drugs by the innovator companies and the Regulatory Agencies have to be necessarily made on a fair assessment of the risk to benefit ratio, sometimes referred to as the therapeutic index.

Real concerns about unexpected safety issues of drugs surfaced for the first time in 1962 closely following the Thalidomide tragedy where the use of this drug, approved as a sedative and marketed by Chemie Gruenthal resulted in the birth of several thousand malformed babies to mothers who had taken the drug during the first trimester of their pregnancy. Even though the drug was never approved in U.S., this tragedy led to the Kefauver-Harris Amendments to the U.S. Drug Laws which made it mandatory for all new drugs to pass through ever so stringent testing for toxicity, safety and efficacy before they are even taken up for the first use in clinical trials in humans.

In addition, the Investigational New Drug (IND) Application for clinical trial, generally stipulates restriction of the trials for specific age groups leaving out paediatric (below 12 years), women in the reproductive phase (17 to 45 Years), lactating mothers and even geriatric patients (60 years). Consequently when the drug goes for approval on the basis of an New Drug Application (N DA), the use of the drug will be initially restricted to patients belonging to the class and type on which clinical trials have been completed and the drug found to be both safe and effective for the indication for which the drug was tested.

Getting Supported Off Label Uses On The Label

As we know, a drug is approved for its initial indications via a new drug application, which includes data on the drug's safety and efficacy. A subsequent indication is added via a supplemental new drug application, which usually needs to present only efficacy information to support that new use. After review and approval by FDA, the new use is added to the approved labeling and can be promoted by the drug's manufacturer.

There are several good reasons for drug companies to submit these “efficacy supplements”:

• Approval usually ensures that third-party payers will reimburse for the use, as insurance. companies virtually always pay for approved uses of drugs and devices.

• As health maintenance organizations continue to grow in size and number, a sponsor's ability to get their drug included in the HMO's drug formulary will be significantly enhanced.

• The physician, via the approved labeling, is given more complete information about the drug's uses, contraindications, adverse effects, and other important information about the manufacturer's product.

• Drug companies can present the FDA findings to drug approval bodies in other countries, thus enhancing their ability to gain approval (and reimbursement) for uses in other markets.

• And, of course, the manufacturer can promote the use, whether through the use of journal articles or other means.3

Dangers Of Off-Label Use

The approval of a new drug is based on evidence gathered at various pre-clinical and clinical evaluations for efficacy and safety against specific diseases for which the drug is indicated. The results are pertinent only for that particular disease condition and the trials delineate the dosage required for treatment, the frequency and duration of treatment, and the adverse reactions that could possibly manifest when used by the population segment (age, gender, physical condition etc) selected for the clinical trials. All these parameters change when the same drug is administered for a new indication for the treatment, for which no data has been generated. Thus the treatment schedules , the dosage and the duration of treatment in off-label use could be very different from the approved schedules and such ad-hoc approaches could result in serious adverse reactions or may have even fatal outcomes

Some of the important tips: The patient should discuss with doctor these questions about the medication:

• How will this help me?

• What are the risks and side effects?

• How long will it be before I see results?

• What happens if I take too much?

• What should I do if I miss a dose?

• Are there any foods, medications or supplements that I should not take with this drug

FDA Obstacle

The latest FDA guideline (1994) does little to protect the nation's children. The continued “off-label” use of medications by practitioners for pediatric clients can lead to dangerous outcomes. Examples of poor outcomes due to the absence of pediatric data include tetracycline-induced dental dysplasia and neonatal deaths due to chloramphenicol-induced “gray baby” syndrome 4.

Role of The Pharmacist

What is a pharmacist to do when a drug is prescribed for off-label use? Years ago, pharmacists simply did not question why a drug was prescribed, or whether it was for use unapproved by the FDA. Pharmacists now realize that they must ask why a medication was prescribed and must question its appropriateness before it is actually dispensed. Naturally, pharmacists also must realize that a prescription for an off-label use does not produce an automatic refusal to dispense.

• The drug is approved by the FDA

• The drug is recognized by the American Hospital Formulary Service Drug Information, the US Pharmacopoeia Dispensing Information, vol I, or 2 articles from major peer-reviewed journals that have been validated supporting the proposed use for the specific medical condition as safe and effective

• It is medically necessary to treat the specific medical condition, such as a life-threatening or chronic condition

• The off-label use is medically necessary and “non-investigational”

The Indian Scenario

In the absence of data on off-label use of drugs in India, it is difficult to quantify such use and evaluate the damage caused to patients in the process. There have been recent reports that have attracted public attention such as the use of Sildenafil citrate (Viagra) on paediatric cardiac cases and the more recent use of Tetrozole, an anti-cancer drug as a fertility enhancer. It was claimed that at least in the latter case, the drug was being promoted with the full knowledge of the Companies marketing management. The most extensive case of off-label drug use which has been in practice ever since Antibiotics were introduced, is the case of their use against viral diseases, even though it is well-known that they have no effect on viruses per se. In fact the use of antibiotics for such cases perhaps far exceeds their legitimate use as anti-bacterials.

Conclusions

It is surprising that there have been very few attempts to control the menace of off-label Drug Use and it is strange that even the Indian Medical Association, which should be fully seized of the inherent dangers of this practice stated that off-label drug use may be necessary to ensure optimal patient care. The philosophy appears to be that “Let Doctors prescribe as they see fit”, even if it means that they prescribe without adequate knowledge of the benefits as well as the risks involved in indiscriminate use of drugs for indications where neither benefits nor risks have been unambiguously established by scientific methods.