Diverse approaches to off-label drug regulation: A global regulatory perspective

*Corresponding author: Sudha.Diddi. Copyright © 2025 Author(s) retain the copyright of this article. This article is published under the terms of the Creative Commons Attribution License 4.0. Diverse approaches to off-label drug regulation: A global regulatory perspective Sudha Diddi *, Raghu Chandra Miryala, Aqib Ahmed Md, Krupa Parimala Kavilikatta and Sankeerthana Singam Department of pharmacy practice, at St Mary’s college of pharmacy, India. World Journal of Biology Pharmacy and Health Sciences, 2025, 22(02), 254-258 Publication history: Received on 02 April 2025; revised on 10 May 2025; accepted on 12 May 2025 Article DOI: https://doi.org/10.30574/wjbphs.2025.22.2.0433 Abstract This retrospective study probes Off-label drug use, or prescribing drugs for unapproved patient groups, dosages, or purposes, is a common but continuous practice around the world. In contrast to other regions with well-defined rules, India lacks comprehensive and unambiguous guidelines for off-label prescribing and promotion, even though many other regions have developed legal structures to do so. The legal implications of off-label drug usage and promotion are examined in this comparative study in a number of nations, including the US, the EU, Australia vs India. It considers important regulatory variations, moral dilemmas and enforcement strategies and examining how many regions strike a balance between patient safety, medical innovation and pharmaceutical marketing laws. The legal environment in India is given special attention, as the lack of official regulations leaves medical personnel in the dark and uncertainty for healthcare professionals and potential risks for patients. The study provides insights into effective practices for ethical pharmaceutical promotion and responsible off-label prescribing by comparing global regulatory models. The results highlight the necessity that India must set up organized legislative frameworks to guarantee patient-centered, ethical and evidence-based off-label medication use while halting abuse and uncontrolled marketing tactics. Keywords: Off Label Drug Use; Global Regulatory Frameworks; India; FDA; EMA; TGA; Off Label Promotion 1. Introduction The term Off-label can be viewed in different ways in different regions, although they are same at an ultimate level there are little variations in defining it, for example a drug can be considered on-label in a country while the same drug can be considered off-label in a different country or same country for different condition [3,7,9]. This is a study which aims to analyse ethical conundrums, policy gaps, and worldwide regulatory frameworks, with a focus on India, in order to emphasize the need for organized norms that ensure patient safety and medical innovation. Off-label drug use is defined generally as a drug prescribed for a use that is not in the regulatory framework of the corresponding country or region, for instance in USA the drug use which is not registered in the USFDA database is considered off-label drug, same goes for the European Union and Australia but in their cases the drug use is deemed offlabel when it is not enlisted in EMA and TGA respectively[3,7]. Off-label drug use, in which drugs are administered for unapproved patient groups, dosages, or indications, is a common and crucial practice in contemporary healthcare. It is especially prevalent in areas with few approved medicines, such World Journal of Biology Pharmacy and Health Sciences, 2025, 22(02), 254-258 255 oncology, paediatrics, psychiatry, and uncommon disorders. Off-label prescribing raises questions about safety, efficacy, ethics, and regulatory control even while it can offer important treatment possibilities. Off-label prescribing is widespread in several medical specialties because there aren't any authorized substitutes. Research indicates that over 90% of prescriptions in paediatrics and 40% in adult populations are written off-label (Mukherjee, 2018) [5]. Off-label medication is commonly used for conditions such as cancer therapies, pain management, mental health issues, and respiratory ailments. Notable examples of Off-label applications are given in table-1. Table 1 Drugs/groups with approved and off-label use Drug name/group Approved use Off-label use/uses Albuterol Asthma Bad cough Aripiprazole Antipsychotic Dementia, Alzheimer’s disease Antianxiety drugs Anxiety disorders Sleep aid Bumetanide Diuretic Neonatal seizures, temporal lobe seizures, autism, schizophrenia Clonidine Hypertension ADHD Gabapentin Antiepileptic, postherpetic neuralgia Depression, nerve pain, migraine Propranolol Hypertension, prophylaxis of angina, migraine Performance anxiety Tiagabine Antiepileptic Depression, mood stability 1.1. Inclusion and exclusion criteria This study uses a retrospective comparative analysis. Data was sourced from regulatory bodies such as USFDA, EMA, TGA, and CDSCO [3,7,9]. Literature was reviewed via PubMed and Scopus focusing on off-label drug use, safety, and legal framework [4,5]. 2. Materials And Methods This study is a retrospective comparative analysis that looks at off-label drug use across various regulatory regimes and medical specialties. The study entails a thorough analysis of patient outcomes, prescribing patterns, and safety issues related to off-label medication use. Prescription practices in different healthcare systems, such as the US, Europe, Australia and India, were compared using data gathered from regulatory reports and previously published studies. 2.1. Data Sources and Collection Regulatory Data: To assess the moral and legal implications of off-label prescribing, policy documents from the FDA (United States), EMA (Europe), TGA (Australia) and CDSCO (India) were examined. Published Literature: Using databases including PubMed, Scopus, and Google Scholar, thorough literature analysis was carried out with an emphasis on research that addressed the prevalence, dangers, and regulatory frameworks of off-label medication. 2.2. Roles and Responsibilities of Regulatory Bodies in different regions 2.2.1. USA In USA, FDA plays significant role in ensuring safety, efficacy and quality of the drug. However, FDA doesn’t regulate the practice of the medicine, allowing physician to prescribe approved drugs for unapproved uses. Once a drug is approved for marketing by the FDA health care providers are generally free to prescribe it for any purpose, they deem medically appropriate even if that use isn’t on the approved label, this is known as OffLabel use. In addition, it does regulate the marketing of those drugs, prohibiting manufacturers from promoting them for unapproved uses [9]. Under the FDA Authorities, a firm’s communication about unapproved uses of its approved/cleared medical product could be evidence of the firm’s intended use for such product, and, depending on the facts and circumstances, may be relevant to World Journal of Biology Pharmacy and Health Sciences, 2025, 22(02), 254-258 256 establishing that the firm has distributed a medical product that fails to comply with applicable premarket requirements or is otherwise misbranded or adulterated. In an effort to guide professional practice, a few medical organizations have issued policies on off-label prescribing. The American Medical Association supports off-label use “when such use is based on sound scientific evidence and sound medical opinion”. Similarly, the American Academy of Paediatrics (AAP) Committee on Drugs endorses off-label prescribing “based on sound scientific evidence, expert medical judgment, or published literature” and “done in the best interest of the patient”. The AAP Committee on Drugs also recognizes an obligation to promote knowledge about offlabel uses. Physicians who choose to prescribe a medication with limited paediatric data have a public and professional responsibility to assist in the systematic development of the information about that drug for the benefit of other patients [4,5]. Implicit in these advisory statements are two ethical considerations relevant to off-label prescribing: [1] evaluating the existing evidence for off-label prescribing: [2] collecting information and conducting research when there is inadequate evidence about an off-label use. 2.2.2. Europe and australia In both Europe and Australia Regulatory bodies like European medical agency and Therapeutic goods administration does not regulate clinical factors. However, off-label use is a clinical decision made at the discretion of the treating clinician. Off-label prescribing is not prohibited by EMA and TGA but, they strictly regulate off-label promotion ensuring patient safety and maintaining the integrity of regulatory process. The EMA , in conjunction with national regulatory authorities , oversees the evaluation, supervision and safety monitoring of medicines, including the matters related to off-label use and promotion in the same way Australian Health Practitioner Regulation Agency( AHPRA) and national boards provides ethical and professional guidelines regarding appropriate prescribing including off-label drugs, ensuring patient safety and provides disciplinary oversite (take action against practitioners who misuse off-label prescribing or promote it unethically). Health care providers are informed by EMA and TGA that they should abide to their policies and make sure that off-label prescribing be done with informed concern from patient [3,7]. Figure 1 Penalties paid by pharmaceutical companies for illegal promotion of off-label drugs From the above bar diagram, it is evident that USA, Europe and Australia take stern actions against pharmaceutical companies that promotes drugs for off-label indications. As the data indicates Pfizer had paid the most penalty in 2009 among all the companies mentioned. Eli Lilly, Jhonson-Jhonson Services Inc, Glaxo smith Kline plc, Abbott Laboratories World Journal of Biology Pharmacy and Health Sciences, 2025, 22(02), 254-258 257 Inc, Sereno are some companies which had paid penalty to USFDA even though not as much as the Pfizer. The chart depicts that USA has taken actions against pharmaceutical companies to a greater extent. Although both European Union and Australia has taken lesser actions compared to USA. It should be noted that both regions have not published the cases regarding off-label promotion to the public. Considering this we can say that USA has firm actions against promotion of off-label. Even though it is not evident in the graph the European Union and Australia also takes firm stance whenever it is about promotion of drug for off-label use. Notable examples for the pharmaceutical companies and the penalty paid for off-label promotion is given in Table-2. Table 2 List of companies and the amount of penality paid [8] Companies Penality paid Ab: Abbott Laboratories Inc. (2012) 800 million USD E: Eli Lilly (2009) 1.45 billion USD G&N: GSK and Novartis (2017) 4.5 million AUD G: Glaxo smith Kline plc (2012) 1.043 billion USD J: Jhonson-Jhonson Services, Inc (2013) 1.391 billion USD N: Natco Pharmaceuticals (2015) 9.8 million EURO P: Peterson and Merck Sharpe and Dohne Pvt Ltd (2010) 300,000 AUD P: Pfizer Inc. (2009) 2.3 billion USD S: Sereno (2005) 704 million USD W: Wockhardt Ltd (2010) 360,000 EURO 3. Results Diverse approaches to off-label drug use and promotion exist across the world-wide pharmacy market, however compare to USA, EU and Australia the Indian off-label use guidelines is under developed, Whereas there is a clear concept of informed consent across the EU’s member states and USA permits the use of off-label drug and also evolves it regulatory regime to potentially benefit from the use of off-label drugs. Australia also as its own consideration and legal system in place to avoid confusions about off label drug use and promotion. Where USA, European Union and Australia have a clear systemic process for promoting and usage of off-label medications, which limits the promotion and in some regions the promotions of off-label use completely prohibited. On the contrary India lacks distinct rules and regulations regarding off-label drug use and marketing which may cause physicians in India to get confused when prescribing off-label drugs. Even though the risk benefit ratio of off label drug is high it is proven useful in case of conditions with limited medication (for example, conditions like cancer, dementia, advanced lung, heart, kidney and liver diseases). So, all the regions are trying their best for secure regulation of off-label drugs but India still needs to develop a regulatory model for the safe guard of patients in case of off-label drugs and remove any cloud judgement among physician by providing proper information on drug uses. Insight, by developing a model where physicians, healthcare providers can get access to the information on off-label drug, Indian regulatory bodies can clear up the doubt of prescribing the off-label drugs in physician and it may decrease the potential side effects caused by off-label drugs. But this information should not be shared to pharmaceutical companies as it may lead to misuse, so Indian regulatory bodies should keep in mind when designing guidelines that false promotion of off-label drugs should not be done by any pharmaceutical companies or else they should be punished legally [5,7,10]. 4. Discussion This study deals with diverse approaches of off-label prescribing and promoting according to various regulatory bodies around the globe. A brief comparison was done in the following regions of USA, European Union, Australia and India to study the pattern of actions taken regarding off-label drug marketing and use. Although, there is a complete ban on offlabel promoting a number of pharmaceutical companies took the risk of off-label promotion and paid a hefty penalty. World Journal of Biology Pharmacy and Health Sciences, 2025, 22(02), 254-258 258 This trend is seen is all the mentioned regions but only USA, EU, Australia took serious measures not sparing anyone as mentioned in the table-2. However, in India there was a lack of strict amendments and actions in case off-label use and promotion as it is evident from the case of Letrozole misuse in India, originally approved for breast cancer but controversially used for infertility (Gupta & Nayak, 2014) [3,4,9]. A classic example of off-label use in recent times was Hydroxychloroquine (an anti-malarial drug) which was prescribed to the patients who were suffered from corona virus during Covid-19. Yet the pharmaceutical took it as a chance to promote Hydroxychloroquine as the treatment for corona to generate finance. However, Hydroxychloroquine showed its pharmacological action to treat covid only when it is taken with the combination of zinc as suggested by US government’s top corona virus expert Dr. Anthony Fauci. Nevertheless, in India no clear instruction on the use of Hydroxychloroquine to physicians by regulatory authorities [8]. 5. Conclusion This study offers a comparative analysis of off-label drug use regulations in the USA, EU, Australia, and India, highlighting the pressing need for India to establish a structured legal framework. It emphasizes that while off-label prescribing can be medically valuable, its misuse—especially through unethical pharmaceutical promotion—poses risks to patient safety and clinical integrity. If the recommendations of this study are implemented, outcomes may include enhanced patient safety, reduced medication misuse, increased physician confidence through clear guidelines, and strengthened public trust in healthcare systems. Furthermore, it would curb unethical marketing practices by pharmaceutical companies through strict legal enforcement. This work benefits society by encouraging evidence-based, ethical, and transparent off-label drug use policies that support both medical innovation and public health protection. Compliance with ethical standards Disclosure of conflict of interest No conflict of interest to be disclosed. References [1] American Academy of Pediatrics. Uses of drugs not described in the package insert (off-label uses). Pediatrics. 2002;110(1):181-3. [2] American Medical Association. AMA Code of Ethics Opinion 9.6.6: Off-label use of pharmaceuticals. 2020. [3] European Medicines Agency. GVP Module V: Risk Management Systems. EMA; 2017. [4] Gupta S, Nayak RP. Off-label use of medicine: Perspective of physicians, patients and regulatory authorities. J Pharmacol Pharmacother. 2014;5(2):88-92. [5] Mukherjee R. Off-label use of drugs: an overview. Indian J Pharm Pract. 2018;11(3):123-7. [6] National Institutes of Health. COVID-19 Treatment Guidelines Panel. 2020. [7] Therapeutic Goods Administration. Off-label use of medicines: Information for health professionals. 2020. [8] U.S. Department of Justice. Justice Department Announces Largest Health Care Fraud Settlement in Its History. 2009. [9] U.S. Food and Drug Administration (FDA). Guidance for Industry: Good Reprint Practices for Distribution of Medical Journal Articles and Publications. [10] World Health Organization. Promoting Rational Use of Medicines: Core Components. Geneva: WHO; 2002.