Off-label medicine use refers to the use of medicines outside the conditions of the product license in terms of dose, patient age, route of administration, indications and contra-indications. Off-label use of medicines is relatively common in medical practice, even if it’s often not supported by strong scientific evidence. The key agencies and acts related to regulation of medicines in India include the Drug Controller General of India (DCGI), Drugs and Magic Remedies (Objectionable advertisement) Act (1954) and the Central Drug Standard Control Organization (CDSCO) which prepares the National Formulary of India (NFI). The DCGI is the regulatory authority for granting approval for new medicines but, unfortunately, there are no clear-cut guidelines on the off-label use of medicines. Indian law does not currently allow medicines to be prescribed for indications for which they have not been approved. In 2002, amendments to the Indian medical council act made off-label prescribing illegal. Off-label marketing by pharmaceutical companies are regarded as a violation of law in India, and it is an offense under the drug and magic remedies (objectionable advertisements) act, 1954.
The criteria for inclusion of medicines in NFI includes drugs in the National List of Essential Medicines (NLEM), drugs used in national health programmes, drugs listed in Indian pharmacopia, drugs not covered but recommended by panel of experts or Indian pharmacopia commission. However, neither the DCGI nor the CDSCO regulate the practice of medicine. The practice of medicine is regulated by the Professional conduct, etiquette and ethics regulations (2002) of the Indian Medical Council. This regulation states that. “Physicians should try continuously to improve medical knowledge and skills and should make available to their patients and colleagues the benefits of their professional attainments.” Therefore, doctors are expected not to avoid legal restrictions like the Drugs and Cosmetics Act and not to violate human rights as well.
In 2002, amendments to the Indian medical council act made off-label prescribing illegal. The issue of off-label use was debated in India in 2003 when it was found that letrozole, an anti-breast cancer drug was being promoted for infertility. Subsequently, the DCGI authorized a probe into media reports that few pharmaceutical companies had endorsed letrozole for treating infertility in women, without the valid regulatory permission. Following this controversy, the DCGI asked the Indian Medical Association (IMA) to prepare a report about the various attributes related to off-label use of medicines. The IMA submitted their report recommending that doctors in India should be allowed to prescribe off-label indications if there is scientific evidence and medical basis for the same. Despite the IMA’s positive opinion about off-label prescribing, currently there is no rule regarding offlabel prescription in India.
While off-label use may be associated with a greater number of side effects, the benefits may outweigh the risks. Again, off-label practices based solely on intuition are unlikely to be effective as against off-label use supported by clinical evidence. Therefore, audits of off-label practices should include these metrics in the overall assessment of the utility of such practices. The approval process for a new medicine includes a clinical trial, which costs time and money. It is practically impossible to identify all potential uses of a product while it is under process of approval initially. This makes it impossible for a product getting approved for all indications, dosage forms, routes of administration, and covering all age groups (such as children, pregnant women and lactating mothers). This makes the practice of off-label use common. Off-label use of medicines has several advantages in cancer treatment, and therefore, the government in close association with the DCGI should look at ways and means to streamline the practice. Such measure would enlarge the armamentarium for the treatment of cancer.
Although some off-label therapies can be beneficial and even lifesaving for some patients, in many cases, off-label use can be problematic, especially if there is inadequate data regarding drug safety and effectiveness for the off-label use. Ideally, the use of drugs in clinical practice should be based on rational scientific theory, expert medical opinion and well-controlled clinical trials (i.e., evidence-based) rather than the package insert.
Review of studies in India show off-label prescription in the areas of neonatal care, pediatric age group, peri-operative indications and cancer. Off-label medicine use in India is high among the pediatric and neonatal age groups in the form of altered dosage, different indications and different route of administration. Common clinical conditions for off-label use of medicines in India include respiratory diseases and anti-infectives. Research initiatives are very limited and should be developed with the involvement of all key stake holders. There are many potential area of research in use of offlabel medicines in India. These include evidence-based approach to improve rationality of pharmacotherapy (especially pediatrics). developing dosage guidelines. pharmacovigilance for causality assessment of adverse events and risk benefit assessment and a potential role of HTA for studying cost- effectiveness.
Off-label medicines regulation in India remains a grey area and the legal implications are unclear.
The good reprint practices guidance of the Food and Drug Administration (FDA) in the USA can be a starting point and provides guidance on the dissemination of medical journal articles about off-label uses. Manufacturers should not be protected from state persecution when their promotional activities are fraudulent. Hence, off label prescription laws in India should focus not only on the health care provider but also the manufacturers promoting off label use without scientific evidence.