Finding Hidden Treasures in Old Drugs: The Challenges and Importance of Licensing Generics

I. Executive Summary

The pursuit of novel therapeutic options is a cornerstone of pharmaceutical research. However, a parallel and increasingly vital approach lies in the rediscovery of existing medications for new purposes, a concept often referred to as finding “hidden treasures in old drugs.” This strategy, known as drug repurposing or repositioning, offers significant advantages over traditional drug development by potentially reducing the time, cost, and risk associated with bringing new treatments to market. Despite its promise, a critical bottleneck exists in translating these discoveries, particularly when they involve generic drugs, into licensed and widely available therapies. This report examines the key challenges associated with licensing generic drugs for new therapeutic uses, focusing on regulatory hurdles, economic disincentives, and intellectual property considerations. It also underscores the profound importance of overcoming these obstacles to enhance public health and improve access to affordable medicines. By addressing these challenges, policymakers and industry stakeholders can unlock the full potential of drug repurposing, turning overlooked assets into valuable treatments for a wide range of diseases.

II. Introduction: Unveiling Hidden Treasures in Old Drugs

The phrase “hidden treasures in old drugs” encapsulates the concept of identifying and developing new therapeutic uses for existing, already approved medications. This process, also known as drug repurposing, drug repositioning, or drug rediscovery, represents a strategic approach to expanding treatment options by exploring alternative applications for pharmaceuticals with established safety profiles.¹ The potential of this approach is exemplified by the story of rituximab, a monoclonal antibody initially developed for B cell lymphoma. Researchers observed its effect on B cells in cancer patients and, recognizing the role of B cell dysfunction in multiple sclerosis, courageously tested it for this entirely different autoimmune disease, leading to a significant therapeutic advancement.² Drug rediscovery holds the promise of creating new treatment avenues while bypassing much of the expense and time typically associated with bringing a novel drug to market.¹ This is particularly important in a rapidly evolving medical landscape where the need for effective therapies often outpaces the traditional drug development pipeline. The challenges and importance of licensing generic versions of these rediscovered drugs are central to maximizing their impact on public health.³

Identifying new indications for existing drugs has the potential to create new therapeutic options for a variety of conditions, including those for which current treatments are inadequate or non-existent.¹ This is especially true for rare and neglected diseases, where the economic incentives for traditional drug development are often limited.⁵ Repurposing generic drugs can have groundbreaking effects for patients suffering from these conditions by offering potential treatments that might otherwise remain undiscovered or inaccessible.⁶ The process of finding new purposes for existing drugs can offer a more rapid and cost-effective route to addressing these unmet medical needs.⁵

This approach stands in stark contrast to the traditional drug development pathway, which is typically a lengthy, expensive, and high-risk endeavor focused on creating new chemical entities.¹ The development of new anticancer drugs through traditional methods, for instance, is known to be a protracted and costly process.⁴ Drug rediscovery offers financial advantages over this traditional route because the drug has already undergone significant study and use, providing extensive knowledge about its safety and quality.¹ This pre-existing knowledge can subsequently reduce the risk of unexpected side effects and shorten the overall development timeline.¹ The ability to leverage prior research and safety data makes drug repurposing a more attractive option in an era where the costs and timelines of bringing entirely new drugs to market continue to escalate.⁷

III. The Landscape of Drug Repurposing

The scientific basis for drug repurposing lies in the fact that many drugs have multiple pharmacological effects and can interact with various biological targets beyond their primary intended target.¹¹ This polypharmacology can lead to therapeutic benefits in diseases seemingly unrelated to the drug’s original indication. The motivations behind pursuing drug repurposing are multifaceted, encompassing both scientific curiosity and the pressing need for more effective and affordable treatments.⁶

Historically, many successful drug rediscoveries were serendipitous, occurring unexpectedly during the initial development or use of a drug.¹ A prime example is sildenafil, which was initially developed for angina pectoris but was repurposed as a therapy for erectile dysfunction due to the unexpected side effect of persistent erections observed during clinical trials.¹ Similarly, minoxidil, initially intended for treating ulcers, was later found to be effective for severe hypertension due to its vasodilator properties, and subsequently repurposed for alopecia treatment after efficacy trials showed unexpected hair growth.¹ These fortunate cases often took place during or before the market exclusivity of the drug.¹

However, the field has evolved to include more rational approaches based on a deepened understanding of disease mechanisms and drug targets.¹ The story of rituximab exemplifies this shift. Researchers observed the depletion of healthy B cell progenitors in cancer patient studies, which, combined with the understanding of B cell dysfunction in multiple sclerosis, led to the insight to test rituximab for this autoimmune disease.² Cancer researchers are also increasingly paying attention to known drugs used in non-oncological situations for their potential anticancer activity.⁴ Advances in human genomics, network biology, and chemoproteomics have significantly benefited drug repurposing by enabling the identification of serious repurposing candidates through the analysis of gene interactions and drug targets.⁶ This has led to more systematic approaches, such as disease-centric methods that identify relationships between old and new indications, target-centric methods that link known targets and drugs to new indications, and drug-centric methods that connect drugs to new targets and associated indications.¹⁸ Computational approaches, including data mining, machine learning, and molecular docking, now play a crucial role in identifying potential repurposing opportunities.⁵

Drug repurposing has emerged as a particularly attractive strategy for rare, orphan, and neglected diseases, which have long been overlooked by traditional pharmaceutical research due to limited patient populations and market incentives.⁵ For these conditions, drug repositioning offers several advantages, including faster development timelines, reduced costs, and the potential for multiple treatment options.⁵ Examples like nitisinone, originally used for tyrosinemia type 1 and as a weed killer, being successfully repurposed to treat alkaptonuria, and sirolimus, a generic transplant drug, finding a new use in treating the rare autoimmune lymphoproliferative syndrome (ALPS), highlight the transformative potential of this approach for rare diseases.⁷

The process of identifying repurposing opportunities is increasingly driven by computational approaches, artificial intelligence (AI), and data mining.⁵ These technologies allow researchers to analyze vast datasets of biological, chemical, and clinical information to predict potential new uses for existing drugs. Network-based approaches, machine learning algorithms, text mining of scientific literature, and molecular docking simulations are among the tools being used to systematically uncover these hidden treasures.⁵

The history of medicine is replete with examples of successfully repurposed drugs, demonstrating the enduring value of this approach. Beyond sildenafil and minoxidil, other notable examples include thalidomide, initially approved for morning sickness, which was later found to be effective in treating multiple myeloma and leprosy.¹ Rituximab, as mentioned earlier, showcases the potential to treat entirely different disease categories.² Aspirin, originally an analgesic, is now widely used as an antiplatelet drug to prevent cardiovascular events.¹³ Azathioprine and mercaptopurine, initially studied for immunosuppressive effects, are now used in organ transplant rejection prevention and the management of chronic inflammatory diseases.¹ More recent examples include levothyroxine being explored for Chagas disease ²¹, metformin showing promise in cancer prevention ²⁰, and dexamethasone and fluvoxamine being repurposed as potential treatments for COVID-19.⁸ The successful repurposing of sirolimus for ALPS and nitisinone for alkaptonuria further highlights the impact on rare diseases.⁷ Even amantadine, originally an antiviral, is now used to treat dyskinesia in Parkinson’s disease patients.³¹ These numerous historical and contemporary successes underscore the significant potential of drug repurposing to address a wide range of medical needs.¹

IV. Navigating the Regulatory Maze: Challenges in Licensing Generic Repurposed Drugs

Despite the compelling advantages of drug repurposing, particularly for generic drugs, significant challenges exist in navigating the regulatory landscape to obtain formal licensure for new indications. In the European Union, there is a notable absence of a defined structured drug regulatory procedure specifically designed for the development and licensing of rediscovered generic drugs.¹ This lack of a clear pathway creates uncertainty for researchers and potential developers seeking to bring repurposed generics to market. In the United States, while the regulatory framework is more established, non-manufacturers such as academic researchers and non-profit organizations face considerable difficulties in obtaining FDA approval for new indications of generic drugs.⁴¹ These challenges often stem from the requirements to provide detailed chemistry, manufacturing, and controls (CMC) data, as well as product samples, which non-manufacturing entities are typically not equipped to fulfill.⁴¹

The European Union recognizes the need for reform in this area, with calls for a dedicated drug regulatory procedure and marketing authorization process for rediscovered generics, including governmental regulation to prevent potential price exploitation.¹ Repurposing strategies, in general, tend to follow a more complex regulatory process compared to reformulations, both in the US and the EU.⁴² This added complexity can create further hurdles for the licensing of repurposed generics. The European Medicines Agency (EMA) has launched a pilot project aimed at supporting academia and non-profit organizations in generating the necessary evidence for the formal authorization of new indications for repurposed generic drugs.²¹ However, this initiative does not address the crucial issue of funding for the required research and regulatory processes.²¹ In the United States, a proposed “labeling-only” 505(b)(2) pathway has been suggested as a potential solution to the challenges faced by non-manufacturers. This pathway would allow them to seek FDA approval for new indications of well-established small molecule drugs when multiple generic products are already available by referencing previous FDA determinations on CMC data and providing commercially available drug product samples.⁴¹ This could significantly streamline the process and unlock the potential of generic drug repurposing by enabling label updates that facilitate wider clinical adoption.⁴¹

Demonstrating efficacy and safety for a new use of an existing generic drug presents another layer of complexity in the regulatory process. Typically, this requires conducting new clinical trials to specifically evaluate the drug’s effectiveness for the new indication.⁴ Researchers may also need to fill gaps in the existing safety, exposure, and preclinical data to support the new use.⁴¹ Defining the appropriate dose for safety and efficacy in the new indication can also be challenging.²¹ Furthermore, regulatory authorities may require access to the original toxicology reports, which can be difficult to obtain, especially if the original manufacturer is not cooperative.²¹ A scientific or medical “bridge” needs to be established to connect the previously approved use of the drug with the proposed new indication.²⁴ In the absence of formal licensure for a new indication, repurposed drugs are often prescribed off-label, meaning they are used for a condition for which they are not officially approved.¹ While this practice is common, it lacks the regulatory validation and standardized labeling that can ensure appropriate use and facilitate insurance coverage.¹ Conducting the necessary clinical trials to gain formal approval for off-patent generic drugs can be particularly challenging due to the lack of significant financial incentives and commercial interest from pharmaceutical companies.⁴

A significant impediment to the licensing of generic repurposed drugs is the lack of both standardized regulatory procedures and sufficient economic incentives.¹ As previously mentioned, the EU currently lacks a well-defined regulatory pathway for this specific scenario.¹ Pharmaceutical companies often exhibit limited economic interest in investing the resources required to pursue new indications for off-patent generic drugs.¹ This is primarily because repurposed generic drugs do not typically guarantee market exclusivity or the ability to recoup the investments needed for new clinical trials and regulatory submissions.¹ The focus of pharmaceutical companies tends to be on diseases that promise higher financial returns, such as cancer and common metabolic conditions, potentially neglecting repurposing options for rare or less profitable diseases.⁴ In cases where repurposed generics are successfully licensed, governmental regulation may be necessary to prevent excessive pricing by pharmaceutical companies.¹ Furthermore, academic researchers, who are often at the forefront of identifying new uses for generics, frequently lack the funding and resources to navigate the complex marketing authorization process.²¹

V. The Interplay of Intellectual Property and Generic Licensing

The intersection of intellectual property (IP) rights and the licensing of generic drugs for new indications presents both challenges and opportunities. While obtaining traditional composition of matter patents for already known generic drugs is generally not possible ¹¹, method-of-use patents serve as the primary route for IP protection in this context.¹¹ These patents protect the specific application of a known compound for a new therapeutic indication.²⁰ However, enforcing method-of-use patents, particularly with the prevalence of generic substitution at the pharmacy level, can be challenging.²⁵ Pharmacists in many jurisdictions can dispense a generic version of a drug even if that generic’s label does not include the newly patented indication, thus undermining the exclusivity intended by the method-of-use patent.⁴¹

Despite this limitation, there is potential for obtaining patent protection for new formulations, dosages, or combinations involving the repurposed generic drug.¹¹ If a repurposed drug requires a novel formulation or a new delivery mechanism for the new indication, this can potentially lead to stronger IP protection, even a new composition of matter patent in some cases.¹¹ However, the patent coverage and market exclusivity periods for repurposed drugs are often more limited compared to those granted for entirely new chemical entities.⁴ This difference in IP protection can impact the economic incentive for investment in repurposing efforts.⁴

The strategies of “evergreening” and building “patent thickets” by original drug manufacturers can also play a significant role in the landscape of generic repurposing.¹⁹ “Evergreening” refers to the practice of making minor modifications to an existing drug, such as changes in formulation or dosage, to obtain new patents and extend market exclusivity beyond the expiration of the original patent.¹⁹ “Patent thickets” involve layering numerous patents on a single drug, covering various aspects like formulations, delivery mechanisms, and even minor improvements, to create a dense web of protection that can deter or delay generic competition, including for new indications.⁵⁸ These practices can effectively extend the period during which the original drug maintains market exclusivity, potentially reducing the incentive for other companies to invest in repurposing the generic versions for new uses.⁵²

Existing patents and market exclusivity granted to original drugs can significantly impact the licensing of generics for new indications.⁴ The market protection afforded to novel compounds often limits the focus on repurposing generics, as pharmaceutical companies prioritize developing and marketing new, patent-protected drugs.⁴ The expiration of the original patent on a drug can reduce the interest of pharmaceutical companies in investing in research for new indications, as the potential for significant profit diminishes.⁴ Patent protection and related legal hurdles can hinder alternative uses for older drugs.⁹ The limited patent coverage generally available for repurposed drugs can also reduce the perceived likelihood of success for such ventures.⁴ Data exclusivity, which prevents competitors from relying on the innovator’s data for a certain period, can also delay the entry of repurposed generics.²⁰ Conversely, orphan drug exclusivity can offer an extended period of protection for repurposed drugs targeting rare diseases, providing a valuable incentive.²⁰ Patent term extensions, which compensate for time lost during regulatory review, can also play a role in the overall IP landscape for repurposed drugs.¹⁹ The 505(b)(2) regulatory pathway in the US offers a potential avenue for streamlining the approval process for repurposed drugs that rely in part on data from previously approved products.²⁰ Regulatory exclusivities, in general, can delay the market entry of generic drugs or biosimilars, including repurposed versions.⁶⁹ The Hatch-Waxman Act in the US governs the FDA approval process for generic drugs and also addresses patent disputes, creating a specific framework for generic entry following patent expiration.⁵⁸

Despite these challenges, strategies exist for pursuing IP protection in the context of generic repurposing.¹⁹ Conducting comprehensive patent searches is crucial to identify potential opportunities and avoid infringing on existing patents.²⁰ Filing patent applications early can help establish priority.²⁰ Robust data collection is essential to support claims of novelty and non-obviousness for the new use, formulation, or combination.²⁰ Focusing on patenting new formulations, specific dosage regimens, and innovative combination therapies can be a successful approach.¹⁹ Highlighting unexpected results or demonstrating a new mechanism of action for the repurposed drug can help overcome potential obviousness rejections during patent prosecution.⁵¹ Finally, the strategic use of secondary patents and a comprehensive life cycle management approach can help maximize the IP protection for repurposed generic drugs.¹⁹

VI. Economic Imperatives: The Importance of Licensing Generic Repurposed Drugs

The licensing of generic repurposed drugs carries significant economic implications, offering substantial cost savings for healthcare systems and individual patients.¹ Generic drugs typically cost significantly less than their brand-name counterparts, often by as much as 80-85%.⁷ This cost differential translates into substantial savings for the US healthcare system, amounting to billions of dollars annually.²¹ Increased utilization of both generic drugs and biosimilars has the potential to generate even greater savings.⁸ Programs like Medicare and Medicaid also experience significant cost savings through the use of generic drugs.³⁴ Furthermore, patients benefit directly from lower out-of-pocket costs when choosing generic medications.⁷⁶ Drug repurposing itself offers a more cost-effective pathway to developing new treatments compared to the traditional drug discovery process, often requiring significantly less investment.¹

Beyond the direct cost savings, licensing generic repurposed drugs plays a crucial role in improving patient access to essential medicines.¹ The increased affordability of generics directly leads to greater access to necessary treatments for a wider population.⁷ Repurposing also expands the treatment choices available to patients, offering new options for conditions that may have limited existing therapies.¹ This is particularly critical for addressing unmet medical needs, especially in the context of rare and neglected diseases.⁵ Lower costs associated with generic drugs can also improve medication adherence, as patients are more likely to take medications they can afford.³⁹ Furthermore, the repurposing of generic drugs can allow for a more rapid deployment of therapies, particularly in response to public health emergencies such as pandemics.⁵

Addressing the lack of economic interest from pharmaceutical companies in pursuing new indications for generic drugs is crucial to realizing the full economic and public health benefits of repurposing.¹ The limited profit potential associated with generic drugs often deters investment in the research and regulatory efforts needed to license them for new uses.¹ To overcome this, a supportive business model and various incentives are needed to encourage the repurposing of generic drugs.⁴ Government funding and public-private partnerships can play a significant role in supporting repurposing research and the regulatory processes.²¹ Exploring differential pricing programs and the use of insurance prior review systems could also help incentivize the use of repurposed generics.³⁵ Furthermore, considering models that delink drug development funding from drug sales could provide a more sustainable approach to exploring the potential of generic drugs for new indications.³⁵

VII. Stakeholder Perspectives

Pharmaceutical companies navigate a complex landscape when considering the licensing of generic repurposed drugs. While their primary focus is often on the development of novel drugs that offer patent protection and higher profit margins ¹, they also recognize the potential for extending product life cycles through reformulation and the discovery of new indications for existing drugs.¹⁵ Licensing agreements between innovator and generic companies can sometimes facilitate the entry of generics into the market.⁷⁵ Additionally, the use of authorized generics, which are identical to the brand-name drug but marketed without the brand name, can be a strategy for managing generic competition.⁵⁴

Regulatory agencies like the FDA and EMA play a critical role in overseeing the licensing of all drugs, including repurposed generics.¹ The FDA has implemented initiatives like the Drug Competition Action Plan (DCAP) to encourage robust and timely market competition for generic drugs.⁷⁴ There are also proposals for dedicated regulatory pathways to facilitate approval for new indications of generic drugs, particularly for non-manufacturers.⁴¹ The EMA has its own pilot project to support the repurposing of authorized medicines.²¹ Both agencies are continuously working to streamline standards for complex generics and improve the overall drug approval process.³¹ Guidance documents are also available to assist with the nonclinical safety evaluation of reformulated drug products ¹²⁹ and to provide considerations for successful reformulation strategies.¹²⁸

Patient advocacy groups play an increasingly important role in advocating for access to affordable and effective treatments, often championing the cause of generic drug repurposing.⁷ These groups raise awareness about the potential of drug repurposing, particularly for rare diseases.⁷ They actively push for policies that would increase access to affordable generic drugs ⁸ and often collaborate with researchers and regulatory agencies to facilitate repurposing efforts.⁷ Sharing patient stories is a powerful tool used by these groups to highlight the urgent need for more treatment options, including those that can be found through repurposing existing medications.¹⁵⁴

VIII. Case Studies and Success Stories

The landscape of drug repurposing is marked by numerous success stories that underscore its potential. Sildenafil’s journey from an angina treatment to Viagra for erectile dysfunction is a prime example of a serendipitous discovery leading to a blockbuster drug.¹ Thalidomide, initially for morning sickness, found new life as a treatment for multiple myeloma and leprosy, demonstrating the potential for drugs with troubled pasts to find valuable new uses.¹ Rituximab’s repurposing from lymphoma to multiple sclerosis showcases the power of understanding disease mechanisms to guide drug discovery.² These examples, among many others ¹, illustrate the diverse therapeutic areas that can benefit from repurposing. While the focus of this report is on generics, many of these initial repurposing successes occurred with patented drugs. The challenge now lies in replicating this success with off-patent generic drugs, where the economic incentives are often lacking.

Reformulation, the development of different formulations for the same drug, is another strategy that can enhance the value of existing medications, including generics.²⁶ Examples include switching from immediate-release to extended-release tablets to improve patient compliance ⁵⁶, developing orally disintegrating tablets for patients who have difficulty swallowing ¹⁰⁵, or changing the route of administration to enhance efficacy or reduce side effects.¹⁰⁵ The reformulation of drugs like amiodarone from an oral to an intravenous formulation ²⁶ and azelastine to improve taste ²⁶ demonstrate how modifications to existing drugs can address specific patient needs and improve treatment outcomes. These examples highlight the potential for innovation even with established generic drugs through strategic reformulation.

IX. Conclusion and Recommendations

Licensing generic drugs for new therapeutic uses, while holding immense promise for public health and economic savings, faces significant challenges. The current regulatory landscape, particularly for non-manufacturers, lacks streamlined pathways for approval. Furthermore, the absence of strong economic incentives for pharmaceutical companies to invest in the necessary research and regulatory processes for off-patent drugs remains a major barrier. Intellectual property considerations, including the difficulty in enforcing method-of-use patents and the impact of evergreening strategies, further complicate the landscape.

Overcoming these challenges is of paramount importance. The successful licensing of generic repurposed drugs can lead to substantial cost savings for healthcare systems and patients, improve access to essential medicines, expand treatment options, and address unmet medical needs, especially in rare and neglected diseases. To unlock the full potential of this approach, concerted efforts from policymakers, regulatory agencies, and the pharmaceutical industry are essential.

Recommendations for Policymakers:

Streamline regulatory pathways: Establish clear and efficient regulatory pathways specifically designed for licensing generic drugs with new indications, particularly for non-manufacturing entities like academic institutions and non-profit organizations. This could involve creating a dedicated pathway similar to the proposed “labeling-only” 505(b)(2) in the US.
Implement economic incentives: Introduce financial incentives to encourage the repurposing of generic drugs. This could include grants, tax credits, extended market exclusivity for repurposed generics (even if limited), or the establishment of “pull” mechanisms that reward successful development and approval of new indications.
Facilitate data access: Improve access to existing preclinical and clinical data on approved drugs to facilitate repurposing research. This could involve creating publicly accessible databases or facilitating collaborations between original manufacturers and researchers interested in repurposing.
Promote international harmonization: Work towards greater harmonization of regulatory approaches for repurposed generics across different regions, such as the US and EU, to reduce duplication of effort and accelerate the global availability of these treatments.

Recommendations for Regulatory Agencies (FDA & EMA):

Further develop and implement dedicated pathways: Continue to develop and refine pilot programs and dedicated regulatory pathways for the approval of repurposed generic drugs, taking into account the unique challenges faced by different stakeholders.
Provide clear guidance on data requirements: Offer clear and specific guidance on the data required to demonstrate efficacy and safety for new indications of generic drugs, including the potential for leveraging existing data and the criteria for accepting real-world evidence.
Enhance communication and collaboration: Foster stronger communication and collaboration with academic researchers, non-profit organizations, and patient advocacy groups involved in repurposing efforts, providing them with regulatory support and guidance.

Recommendations for the Pharmaceutical Industry:

Explore repurposing opportunities: Actively explore the potential for repurposing existing drug portfolios, including off-patent drugs, for new therapeutic indications. This could involve leveraging internal research capabilities or collaborating with external partners.
Collaborate with academia and non-profits: Engage in collaborations with academic institutions and non-profit organizations that are often at the forefront of identifying new uses for generic drugs. These collaborations can bring valuable scientific insights and facilitate the development process.
Develop innovative formulations and delivery mechanisms: Focus on developing new formulations and delivery mechanisms for repurposed generics, which can enhance IP protection and offer additional patient benefits such as improved compliance or targeted drug delivery.

In conclusion, the potential of finding “hidden treasures in old drugs” through the repurposing of generic medications is immense. By addressing the existing challenges in licensing these drugs for new uses through targeted policy changes, regulatory innovation, and collaborative efforts across all stakeholders, we can unlock a wealth of affordable and effective treatments, ultimately transforming healthcare and addressing many of the unmet medical needs that persist today.