Drug repurposing: Clinical practices and regulatory pathways

Abstract

Drug repurposing, also known as drug repositioning or reprofiling, involves identifying new therapeutic uses for existing drugs beyond their original indications. Historical examples include sildenafil citrate transitioning to an erectile dysfunction treatment and thalidomide shifting from a sedative to an immunomodulatory agent. Advocates tout its potential to address unmet medical needs by expediting development, reducing costs, and using drugs with established safety profiles. However, concerns exist regarding specificity for new indications, safety, and regulatory exploitation. Ethical considerations include equitable access, informed consent when using drugs off-label, and transparency. Recent advancements include artificial intelligence (AI) applications, network pharmacology, and omics technologies. Clinical trials explore repurposed drugs’ efficacy, with regulatory agencies facilitating approval. Challenges include intellectual property protection, drug target specificity, trial design complexities, and funding limitations. Ethical challenges encompass patient autonomy, potential conflicts of interest due to financial incentives for industries, and resource allocation. Future directions involve precision medicine, AI, and global collaboration. In conclusion, drug repurposing offers a promising pathway for therapeutic innovation but requires careful consideration of its complexities and ethical implications to maximize benefits and minimize risks.

INTRODUCTION

In the domain of pharmaceutical innovation, drug repurposing has emerged as a notable strategy, encompassing the identification of new therapeutic uses for existing drugs beyond their original indications. Known also as drug repositioning or reprofiling, this approach leverages existing pharmacological knowledge and clinical data to accelerate the development of novel treatments for various diseases and conditions.[1] Historical instances of drug repurposing include the accidental discovery of sildenafil citrate, initially developed as an antihypertensive and later approved to treat erectile dysfunction, and thalidomide’s shift from a sedative to an immunomodulatory agent for multiple myeloma and leprosy.[2]

Advocates highlight drug repurposing’s potential to address unmet medical needs by expediting development, reducing costs, and utilizing drugs with established safety profiles.[3] By bypassing many challenges of traditional drug discovery, repurposing offers a streamlined path to clinical translation. However, concerns persist regarding the target specificity of repurposed drugs for new indications, which raises safety issues and ethical dilemmas such as informed consent for off-label drug use, proprietary interests, and intellectual property protection.[4] Financial incentives to pharmaceutical companies and developers such as extended patent rights, market exclusivity periods, or expedited review processes by regulatory agencies may also lead to regulatory exploitation, potentially jeopardizing patient safety.[5] As drug repurposing evolves, evaluating its benefits and risks is imperative. By scrutinizing evidence, regulations, and ethics, stakeholders can harness its potential as a boon for global health advancement while mitigating risks.

HISTORICAL PERSPECTIVE OF DRUG REPURPOSING

The historical roots of repurposing drugs for new therapeutic uses span centuries, rooted in ancient medical practices and serendipitous discoveries.[6] Before modern pharmacology, healers recognized the multifunctional properties of remedies, laying the groundwork for drug repurposing. Ethnopharmacological studies shed light on how traditional medicines repurposed natural substances for diverse therapeutic purposes.[7]

Early pharmacological endeavors were marked by chance discoveries, such as aspirin evolving from analgesic to antiplatelet therapy.[8] As science advanced, systematic investigations into repurposing gained traction, leading to breakthroughs such as sildenafil citrate’s repurposing for erectile dysfunction.[9] Recent decades have seen traditional knowledge guiding drug discovery, with ethnobotanical studies revealing plant-derived compounds for repurposing.[10] Technological strides, such as high-throughput screening (HTS) and computational modeling, have accelerated repurposing by streamlining compound screening and predicting new indications. Today, repurposing offers a cost-effective, time-efficient approach to drug discovery, promising to address unmet medical needs and hasten treatment delivery.[11]

Despite challenges such as regulatory hurdles and intellectual property issues, interdisciplinary collaboration and technological innovation signal a bright future for drug repurposing, with potential improvements in patient care and public health outcomes.[12]

ADVANTAGES OF DRUG REPURPOSING

Drug repurposing offers several advantages over traditional drug discovery and development processes. One primary advantage is its facilitation of rapid clinical translation. Unlike traditional drug discovery, which entails extensive preclinical research and clinical trials, repurposing utilizes existing clinical data and safety profiles, accelerating candidate progression into human studies.[1,5] Moreover, repurposing significantly reduces costs and time compared to de novo drug development,[4] bypassing early-stage processes such as compound synthesis and toxicity testing. As a result, development costs are lower, and time to market is faster.[3] Repurposing also boasts lower failure rates in clinical trials, given the drugs’ established safety profiles, minimizing trial failures due to safety concerns.[2,4]

In addition, drug repurposing expands therapeutic opportunities by uncovering new uses for existing drugs across various medical conditions. By exploring approved drugs’ pharmacological properties, researchers identify potential applications beyond their original indications, discovering novel treatment options.[2] This approach improves patient access to new treatments by utilizing existing drugs, eliminating the need for costly manufacturing and regulatory processes.[13] Furthermore, it enables exploring novel drug combination therapies, enhancing efficacy and reducing side effects, especially in complex diseases such as cancer and infectious diseases.[3] Repurposing aligns with sustainability principles by minimizing the need for new chemical synthesis and reducing pharmaceutical waste, optimizing resource utilization.[12] Moreover, drug repurposing broadens clinicians’ therapeutic options, particularly in disease areas with limited alternatives, quickly bringing additional treatment options to patients.[6]

In summary, drug repurposing offers numerous advantages in clinical trials, including accelerated timelines, reduced costs, increased success probabilities, expanded therapeutic options, streamlined regulatory processes, and improved patient access, ultimately enhancing health-care outcomes.

ETHICAL ADVANTAGES OF DRUG REPURPOSING IN CLINICAL TRIALS

From an ethical standpoint, drug repurposing offers several advantages. Since repurposed drugs have already been extensively studied in humans, researchers can minimize the risks associated with clinical trials, ensuring that participants are exposed to well-characterized and safe therapeutic agents.[3] Repurposing existing drugs can reduce the burden on patients participating in clinical trials. Since repurposed drugs have known safety profiles, participants are less likely to experience adverse effects or unforeseen complications during the trial period, enhancing their overall experience and compliance.[12]

By maximizing the utility of existing drugs, drug repurposing promotes sustainable health-care practices. Repurposed drugs reduce the need for extensive resources and investments in new drug development, allowing health-care systems to allocate resources more efficiently and address a broader range of medical needs.[6] Drug repurposing in clinical trials offers compelling ethical advantages, including enhanced patient access, ethical considerations, reduced patient burden, and promotion of sustainable health-care practices. By harnessing the potential of existing drugs for new therapeutic indications, drug repurposing represents a boon for both patients and health-care systems alike.

EXAMPLES OF DRUG REPURPOSING

Drug repurposing involves identifying new therapeutic uses for existing drugs beyond their originally intended indications. This section explores several notable examples of drug repurposing, highlighting the diverse range of therapeutic applications and the potential benefits for patients and health-care systems.

We have compiled examples of drugs with repurposing potential in Table 1, highlighting their initial indications and possible new applications. These examples underscore the versatility and potential of drug repurposing in addressing unmet medical needs across various therapeutic areas, offering novel treatment options, and improving patient outcomes.

Table 1.

Examples of repurposed drugs and their indications

Drug name	Original indication	Potential indication
Aspirin[8,39]	Analgesic, antipyretic	Antiplatelet*
Sildenafil[40]	Hypertension, angina	Erectile dysfunction*
Thalidomide[41]	Sedative	Multiple myeloma*, lepra reaction*, Behcet’s disease
Metformin[42]	Type 2 diabetes mellitus	PCOS, anticancer, psoriasis
Ivermectin[43]	Antiparasitic	Antiviral (COVID-19), scabies
Clozapine	Schizophrenia	Treatment-resistant bipolar disorder
Ezetimibe[44]	Hypercholesterolemia	NAFLD
Minoxidil	Hypertension	Androgenic alopecia*
Bupropion[45]	Depression, smoking cessation	SAD, obesity, ADHD
Cimetidine	Peptic ulcer	Prevention of gastric cancer recurrence
Aripiprazole	Schizophrenia, bipolar disorder	Tourette syndrome*, augmentation therapy for depression*
Propranolol	Hypertension, angina	Migraine prophylaxis*, anxiety
Amantadine[46]	Parkinson’s disease	Fatigue in multiple sclerosis
Misoprostol	Gastric ulcer	Medical abortion, induction of labor
Hydroxychloroquine	Malaria	Rheumatoid arthritis*, lupus erythematosus
Colchicine	Gout	Familial Mediterranean fever*
Tamoxifen[47]	Breast cancer	Prevention of breast cancer in high-risk women*, gynecomastia
Methotrexate[48]	Cancer chemotherapy	Psoriasis*, rheumatoid arthritis*, ectopic pregnancy
Disulfiram	Alcohol dependence	Cocaine dependence
Naltrexone	Alcohol dependence, opioid dependence	Fibromyalgia
Topiramate[48]	Epilepsy, migraine prophylaxis	Obesity*, alcohol dependence, bipolar disorder
Olanzapine	Schizophrenia, bipolar disorder	Chemotherapy-induced nausea and vomiting, anorexia nervosa
Acetylcysteine	Acetaminophen overdose antidote	Contrast-induced nephropathy
Dapsone	Leprosy	PJP
Pioglitazone	Type 2 diabetes mellitus	NASH, prevention of cardiovascular events in high-risk patients
Celecoxib	NSAID	FAP*
Minocycline	Antibiotic	Leprosy, rheumatoid arthritis
Chlorpromazine	Antipsychotic	Intractable hiccups*, nausea and vomiting
Semaglutide[49]	Type 2 diabetes mellitus	Obesity*

*Approved FDA. PCOS=Polycystic ovary syndrome, NAFLD=Nonalcoholic fatty liver disease, SAD=Seasonal affective disorder, ADHD=Attention deficit hyperactivity disorder, PJP=Pneumocystis jirovecii pneumonia, NASH=Nonalcoholic steatohepatitis, FAP=Familial adenomatous polyposis, NSAID=Nonsteroidal anti-inflammatory drug

RECENT ADVANCES IN DRUG REPURPOSING

Drug repurposing has witnessed significant advancements in recent years, propelled by innovative approaches and technological breakthroughs. This section explores several key developments in drug repurposing research, highlighting promising strategies and novel insights into the repurposing landscape.

Recent years have seen a surge in the application of artificial intelligence (AI) and machine learning (ML) algorithms in drug repurposing. These technologies enable large-scale data analysis, prediction of drug–disease interactions, and identification of potential repurposing candidates based on shared molecular pathways and biological targets.[13] Leveraging advanced computational algorithms and big data analytics, AI offers unprecedented opportunities to uncover hidden relationships between drugs and diseases, streamlining the drug discovery process and enhancing clinical outcomes.

AI algorithms analyze vast repositories of biological, chemical, and clinical data to identify potential drug candidates for repurposing. By integrating diverse data sources, including genomics, proteomics, and electronic health records, AI-driven platforms can uncover novel drug-disease associations that may have been overlooked using conventional methods.[13] ML models enable predictive modeling and virtual screening of large compound libraries, allowing researchers to prioritize promising candidates for further experimental validation. By learning from patterns in existing data, AI algorithms can predict drug–target interactions, identify off-target effects, and optimize drug repurposing strategies with unprecedented accuracy.[14] Network pharmacology approaches leverage AI techniques to map complex interactions between drugs, targets, and biological pathways, offering insights into the underlying mechanisms of drug action and disease pathophysiology. By analyzing drug–target networks and signaling pathways, network pharmacology facilitates the identification of repurposing opportunities based on shared molecular mechanisms.[15]

AI-driven approaches enable the development of personalized therapeutic strategies tailored to individual patient profiles. By integrating genomic, clinical, and lifestyle data, AI algorithms can identify patient subpopulations likely to benefit from repurposed drugs, optimizing treatment outcomes and minimizing adverse effects.[16] Collaborative initiatives and consortia harness the collective expertise of researchers, pharmaceutical companies, and technology partners to accelerate drug repurposing efforts. By sharing data, resources, and computational tools, these consortia facilitate the discovery of new indications for existing drugs and drive innovation in the field of AI-driven drug repurposing.[17] As AI-driven approaches gain prominence in drug repurposing, regulatory agencies face new challenges in evaluating the safety, efficacy, and quality of repurposed drugs. Robust validation of AI models, transparent reporting of data sources and methodologies, and collaboration between regulators and industry stakeholders are essential to ensure the responsible deployment of AI in drug repurposing.[18]

Looking ahead, AI holds immense potential to transform drug repurposing into a more efficient, cost-effective, and patient-centric endeavor. By harnessing the power of AI-driven approaches, researchers can accelerate the discovery of new therapeutic uses for existing drugs, address unmet medical needs, and improve patient outcomes on a global scale.[19] The integration of AI into drug repurposing offers unprecedented opportunities to accelerate therapeutic innovation, optimize treatment strategies, and improve health-care outcomes. By embracing AI-driven approaches, researchers and clinicians can unlock the full potential of existing drugs, transforming the field of drug repurposing from a promising concept into a tangible reality.

Network pharmacology has emerged as a powerful tool for elucidating the complex interactions between drugs, targets, and diseases. By integrating data from multiple sources, including genomics, proteomics, and drug databases, network pharmacology enables the identification of repurposing opportunities and the exploration of synergistic drug combinations.[20] Advances in HTS technologies have accelerated the discovery of repurposing candidates by enabling the rapid testing of large compound libraries against diverse biological targets. HTS platforms, coupled with innovative assay designs and automation, facilitate the identification of lead compounds with desired pharmacological activities.[21] Omics technologies, including genomics, transcriptomics, proteomics, and metabolomics, have revolutionized drug repurposing by providing comprehensive insights into molecular mechanisms underlying disease pathophysiology and drug response. Integration of omics data with computational modeling enhances target identification and validation in repurposing studies.[22]

Innovations in clinical trial design and methodology have facilitated the evaluation of repurposed drugs in diverse patient populations and disease contexts. Adaptive trial designs, real-world evidence studies, and collaborative platforms enable efficient and cost-effective repurposing trials, expediting the translation of preclinical findings into clinical practice.[23,24]

REPURPOSED DRUGS UNDER TRIAL

In recent years, numerous drugs have entered various phases of clinical trials for repurposing, presenting promising opportunities for the treatment of diverse diseases. This section provides an overview of some of the notable drugs undergoing repurposing trials across different phases. In Table 2, we present examples of drugs under research along with the conditions for which they have been repurposed.

Table 2.

Examples of repurposed drugs under research and their indications

Drugs	Repurposed indications
Thalidomide[41]	Cancer chemotherapy
Nitroglycerin	Wound healing and tissue repair
Baclofen[50]	Alcohol use disorder
Doxycycline	Parkinson’s disease
Metformin[51]	PCOS
Amitriptyline[52]	Fibromyalgia
Rapamycin[53]	Neurodegenerative disease, cancer chemotherapy
Ezetimibe[44]	NAFLD
Methylene blue[54]	Alzheimer’s disease
Cimetidine[55]	Cancer chemotherapy
Diclofenac[56]	Actinic keratosis
Mefloquine[57]	Glioblastoma multiforme
Metformin[51]	Cancer, prevention of cardiovascular disease
Losartan[58]	Parkinson’s disease
Atorvastatin[59]	Alzheimer’s disease
Pioglitazone[60]	Parkinson’s disease
Disulfiram[61]	Glioblastoma multiforme
Aspirin*[39]	Antiplatelet
Propranolol*[62]	Infantile hemangioma
Allopurinol[63]	Heart failure
Gabapentin[64]	Hot flashes in menopausal women
Bisphosphonates [65]	Reducing the risk of breast cancer
Minocycline [66]	Multiple sclerosis, amyotrophic lateral sclerosis

*Drugs under postmarketing surveillance. NAFLD=Nonalcoholic fatty liver disease, PCOS=Polycystic ovary syndrome

Several global initiatives and consortia, such as the repurposeful medicines initiative, aim to accelerate drug repurposing efforts by fostering collaboration between academia, industry, and regulatory agencies. These collaborative platforms facilitate the sharing of data, resources, and expertise to expedite the identification and validation of repurposing candidates.[25] Biomedical informatics and computational modeling play a crucial role in identifying potential repurposing candidates by analyzing large datasets and predicting drug–disease interactions. ML algorithms and network pharmacology approaches enable the systematic exploration of drug repurposing opportunities, guiding the selection of candidates for further evaluation.[26] Regulatory agencies, such as the U. S. Food and Drug Administration (FDA) and the European Medicines Agency (EMA), play a pivotal role in facilitating drug repurposing by providing pathways for accelerated approval and regulatory incentives. Expedited review processes, orphan drug designations, and repurposing-specific guidelines streamline the development and approval of repurposed drugs, promoting innovation in drug discovery.[27] The advancement of these drugs through different phases of clinical trials underscores the potential of drug repurposing to address unmet medical needs and expedite therapeutic innovation.

CHALLENGES AND LIMITATIONS OF DRUG REPURPOSING

Despite its numerous advantages, drug repurposing also faces several challenges and limitations that may impact its effectiveness and feasibility. This section discusses some of the key challenges associated with repurposing existing drugs for new therapeutic indications.

One of the primary challenges of drug repurposing is the lack of robust intellectual property protection for repurposed drugs. Since many repurposed drugs are no longer under patent protection, pharmaceutical companies may be less incentivized to invest in repurposing efforts due to the limited potential for exclusivity and profitability.[20] Another challenge in drug repurposing is the biological complexity and lack of specificity of many drugs. While some drugs may exhibit broad-spectrum activity against multiple targets, others may have narrow therapeutic windows or off-target effects that limit their utility for repurposing.[12] Designing clinical trials for repurposed drugs can be challenging due to the heterogeneity of patient populations and disease conditions. Repurposed drugs may require novel trial designs that account for differences in dosing, treatment duration, and patient selection criteria, which can complicate the regulatory approval process.[28]

Navigating regulatory pathways for repurposed drugs can be complex and time-consuming. While repurposed drugs may benefit from existing safety data, they still need to undergo rigorous evaluation to demonstrate efficacy and safety for their new indications. Regulatory agencies may require additional clinical trials or real-world evidence to support approval, adding to the time and cost of development.[29] Securing market access and reimbursement for repurposed drugs can be challenging, particularly in health-care systems with strict formularies and cost-containment measures. Payers may be reluctant to reimburse for off-label uses of repurposed drugs, limiting patient access and commercial viability.[5] Drug repurposing efforts may struggle to attract funding and investment compared to traditional drug discovery projects. Investors may perceive repurposing as less innovative or risky, leading to a lack of financial support for research and development initiatives in this area.[30]

ETHICAL AND SOCIAL CONSIDERATIONS OF DRUG REPURPOSING

One ethical consideration in drug repurposing is ensuring equitable access to repurposed drugs for all patient populations. While repurposed drugs may offer cost savings compared to newly developed treatments, there is a risk that access disparities could persist, particularly in low-resource settings or marginalized communities.[31,32] Maintaining patient autonomy and obtaining informed consent when using off-label drugs are critical ethical principles in drug repurposing research. During the drug repurposing trial, Patients must be adequately informed that the drug used is not approved for the intended indications (The trial was done to get approval for that indication), its potential risks, benefits, and the uncertainties associated with repurposed treatments, and their consent should be obtained voluntarily and free from coercion.[33] Robust regulatory oversight and safety monitoring are essential to ensure the ethical conduct of drug repurposing trials and protect patient safety. Regulatory agencies play a crucial role in evaluating the evidence supporting repurposed indications, assessing the quality of clinical trial data, and monitoring postmarket safety and efficacy.[34]

Promoting transparency and data sharing is vital to enhance the ethical integrity and scientific validity of drug repurposing research. Open access to clinical trial data and research findings facilitates independent scrutiny, replication of results, and broader participation in scientific discourse, ultimately advancing public trust and accountability.[35] Managing conflicts of interest, which arise from financial incentives for pharmaceutical companies, and mitigating commercial pressures represent ethical challenges in drug repurposing. Industry sponsorship of repurposing research may introduce biases or prioritize commercial interests over public health considerations, highlighting the importance of transparent disclosure and independent oversight.[36] Ethical considerations also extend to the stewardship of limited health-care resources in drug repurposing. Allocating resources to repurpose drugs with the greatest potential for public health impact requires careful consideration of comparative effectiveness, cost-effectiveness, and the burden of disease.[37] Drug repurposing can have broader social implications for health equity and public health policy. Policies and incentives that promote equitable access, foster innovation, and prioritize health outcomes can help address disparities in access to repurposed treatments and advance health equity goals.[38]

CONSIDERATIONS BEFORE INITIATING DRUG REPURPOSING INITIATIVES

Drug repurposing, a promising avenue for new therapeutic interventions, requires careful consideration to ensure success and maximize benefits. Understanding the target disease’s pathophysiology is crucial for selecting candidate drugs that modulate relevant pathways.[1] Systematic approaches, including computational methods and data mining, aid in identifying drugs with desired profiles. Assessing safety and toxicity through preclinical studies mitigates risks.[5] Optimizing dosing regimens is essential for efficacy and safety.[6]

Regulatory compliance is paramount, with agencies such as the FDA and EMA providing guidelines for drug repurposing. Well-designed clinical trials are crucial for evaluating safety and efficacy, incorporating appropriate endpoints and statistical analyses.[12] In addition, a patient-centric approach ensures drugs meet patient needs, achieved through stakeholder engagement.[3] Drug repurposing accelerates therapeutic innovation and addresses unmet needs. By considering these factors, stakeholders can enhance success and maximize benefits.

CONCLUSION

The landscape of drug repurposing embodies a nuanced interplay of opportunities and challenges, shaping its trajectory in therapeutic innovation.[6,12] From its origins in serendipitous discoveries to the evolution of systematic approaches, drug repurposing offers a promising avenue for expedited treatment development. By using what we already know about how existing drugs work, repurposed drugs can move through clinical trials more quickly, allowing new treatments to reach patients faster and address a wider range of diseases.[3] However, among its potential, drug repurposing encounters hurdles concerning safety, efficacy, and regulatory pathways that demand rigorous evaluation of candidates.[12]

Ethical and social dimensions loom large in drug repurposing discussions, touching on equity, access, and patient autonomy. Prioritizing patient welfare and ethical standards is paramount, necessitating equitable access to repurposed treatments.[5] Looking forward, collaborative endeavors, technological innovations, and patient-centric approaches are pivotal for maximizing drug repurposing’s impact on public health outcomes.[6]

In summary, drug repurposing presents a dual narrative – a catalyst for therapeutic advancement alongside a terrain fraught with ethical and logistical intricacies.[12] By navigating these complexities judiciously, stakeholders can steer drug repurposing toward responsible and impactful therapeutic discoveries.

Conflicts of interest

There are no conflicts of interest.

Funding Statement

Nil.