Recent reports of the use of drugs, mainly by physicians, in indications other than those for which the drug has been approved by the Drugs Regulatory Authorities raise important issues regarding the legitimacy of such use and even more importantly the possible consequences of such action on the safety of the patients who have been prescribed drugs which have not been approved for that indication. Legislative and other measures need to be considered for avoiding such practices in the interest of safety to the patients.
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.
Extension of the use to the paediatric and other populations would be possible only after the drug has been tested for such populations in specially conducted trials which in many cases will mean at least a couple of years more after the first approval. In practice until use in these populations is approved, no claims can be made on the safety and / or efficacy of the drug in such populations.
As a corollary to this, such use cannot only be indicated in labels and product literature, but also cannot be promoted directly or indirectly by the manufacturer and / or the distributor, to the medical profession.
Labeling of Drugs
No drug can be sold or distributed unless it is labeled in accordance with rules prescribed under the various regulatory systems, which are amended from time to time. Accordingly, the label should contain the name and address of the manufacturer, name and address of the marketing Company if different from the manufacturer, name of the drug (Brand & Generic both in same size lettering), specifications (IP, BP, U.S.P. etc), batch number, date of manufacture, date of expiry, if any, the dosage, the schedule under which the drug is classified, the colours used, storage conditions if any and the maximum retail price (MRP).
While it is not obligatory to put the indications and contraindications on the label and the statement 'as indicated by the physician' would suffice, that information should be available in the medical literature in package inserts or in their absence in official drug directories of the Companies. Under Section 9 (b) of the Indian act, a drug is considered to be misbranded if it is not labeled in the prescribed manner and if the label or container or anything accompanying the drug bears any statement, which makes any claims for the drug, which is false or misleading.
Off-Label Drug Use
Use of a drug for an indication for which it has not been approved and hence is not part of it's labeled indication is defined as "Off-label Use". The problem of use of drugs for Off-label indications is universal, with even Countries with very strong regulatory controls having identified it as a major problem. Some of the appalling statistics have indeed come from the U.S. and U.K., partly because of the systems of documentation available from these markets.
In 1990, the then FDA Commissioner David Kessler said that most off-label uses are based on anecdotes rather than clinical evidence and indeed posed a major problem. For example, Thalidomide which got resurgence as a drug for leprosy is mostly used for treatment of Multiple Myeloma, an indication for which there is still no FDA approval. One report mentions that 8 out of the 10 prescriptions written for the anti-epilepsy drug Topamax is for an off-label use. Some anti-depressants are prescribed for premature ejaculation, nocturnal enuresis and pain, while some anti-psychotics are used for insomnia and attention deficit disorder in children, all unapproved indications. In a study conducted by Knight Ridder in U.S.A it was reported that around 8000 people fell sick in 2001 after taking some of the most popular drugs for off-label use.
Use of Off-label or Unlicenced drugs to treat children is widespread. In a study published in BMJ in 2000, it was reported that of the 2282 prescriptions for 624 children in 5 hospitals, 1036 was for either unlicenced or off-label indications. In yet another retrospective study on 536 prescriptions, 159 were for off-label use. The most commonly used drugs were Piroxicam, Methotrexate, Salbutamol, Lisinopril and others. It was also revealed that most Doctors did not even know the meaning of off-label use and the drugs were prescribed on the basis of unsubstantiated hearsay and usage by peer groups rather than reports of clinical validation.
Legal Status for Use Of Off-Label Drugs
Practically no Country in the World has formal legislation forbidding the off-label use of drugs by clinicians, nor are there measures to monitor and control such uses. However, if a manufacturer promotes a drug for an indication for which there is no approval from the drugs control agencies, it would be violative of the provisions under the Drugs and Cosmetics Act of that Country. Pfizer was reprimanded by FDA for promoting unlicenced indications for some of their drugs by executives and detailing representatives. The drugs concerned included Ziprisidine (anti-psychotic), Atorvastatin , Sildenafil and Gabapentin. It is thus clear that the controls on the manufacturer are very different from those on the Clinicians. In fact, according to FDA, if a drug maker knows that it's drugs are used for off-label indications, it is required to inform the agency of such use even if the Company had no role in the promotion for that use.. According to FDA officials this rule has never been strictly enforced so far. In one of the few litigations on the issue, a former employee of Warner-Lambert filed a law suit against the Company for promoting Neurontin, a drug approved for epilepsy for being promoted for treatment of bipolar disorder, pain etc.
In the U.K., licensed drugs can be used legally in clinical situations that fall outside the remit of the licence , eg., for different age groups, different indications, different doses etc. However in such cases the liabilities for any damages caused as a result of such use will rest with the Doctor and not the manufacturer and the issue of informed consent would be involved as in the case of drugs for clinical investigations.
In the U.S. such uses fall under the status of an IND (to be approved by the FDA) or as compassionate use with the informed consent of the patient.
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. Testing for a new indication calls for fresh clinical trials and sometimes even repetition of toxicology studies to ensure that the doses used for the new indication do not result in toxic manifestations and adverse drug reactions.
It is thus imperative that there has to be a legislative control to prevent widespread off-label use of drugs.
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 exceed their legitimate use as anti-bacterials..
Seized of the real major health hazards that off-label use can lead to, there is currently a move in India to enforce rules to curb this practice at all levels and the Government has appointed a Committee to go into this issue. To what extent a practical and implementable legislation can be brought in as an amendment to the Drugs And Cosmetics Act is a moot point.
Conclusion
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.
-- The author is a senior research scientist and industry observer.