Drug repurposing: a systematic review on root causes, barriers and facilitators

The most frequently cited reason for why drug candidates are abandoned was inadequate efficacy for the studied indication or target population (n = 59) or a lack of superiority to alternative therapies (n = 11). Thymitaq™, an experimental cancer drug, for example, was discussed as shelved by Agouron Pharmaceuticals after studies showed it was "clearly active," but "not sufficiently superior to alternative therapies to justify the required investment [8]." Similarly, imagabalin was discussed as discontinued by Pfizer because it appeared unlikely to “provide meaningful benefit to patients beyond the (then) current standard of care [9].” Capravirine was also discontinued after two Phase IIb studies sponsored by Pfizer failed to show a statistically significant difference between standard triple-drug HIV therapies and the same therapy combined with Capravirine [10].

After efficacy challenges, strategic business reasons were the second most commonly discussed reason for why a promising drug candidate might be abandoned (n = 35). Specifically, poor market prospects (n = 14), incompatibility with company disease priorities (n = 7), industry consolidation (n = 5), and type II decision-making errors that can cause a manger(s) to underestimate a drug’s value (n = 6) were discussed as leading reasons for a company abandoning development of a promising drug candidate.

Poor market prospects were discussed as a top factor in decisions around whether to shelve an asset (n = 14). For example, vaccines were discussed as often abandoned due to their smaller markets and lower projected revenues, as generally the federal government is their largest purchaser, and due to their lower frequency use and higher manufacturing costs than drugs [11]. Drugs may be used every day, while a vaccine may only be used a few times throughout a person’s lifespan [12]. One article discussed how the highest revenue generating vaccine, Prevnar 13®, a pneumococcal vaccine for children, grossed $1 billion in annual U.S. sales, in comparison to individual drugs which were grossing around $7 billion in annual US sales, such as those for high cholesterol, hair loss, heart disease, obesity, and neurology [12]. To further put this in perspective, the revenues for Lipitor®, a cholesterol drug, were described as “greater than revenues for the entire worldwide vaccine industry,” according to an article published in 2005 [12]. Articles did not generally elaborate on the amount of profits or returns on investments (ROI) needed to sustain investment in an asset and avoid shelving risks [11, 13, 14]. Instead, companies were described as needing to make prioritization decisions about which compounds to advance at every stage of development, given limited resources and in light of current and future projects [15]. If a late-stage compound does not meet set endpoints it is often shelved for the next lead candidate. Re-evaluating a drug’s activity for use in multiple indications is not generally considered economical [16].

Companies often focus on developing products for specific categories of diseases and conditions and can abandon drugs targeting conditions outside their research priorities. For example, AstraZeneca sold the rights to its shelved schizophrenia drug candidate to Millendo therapeutics. While the drug was ineffective in schizophrenia, hormonal side effects seen in testing suggested a potential use in polycystic ovary syndrome (POS), which was not a priority therapeutic area for AstraZeneca at the time [17]. Pagoclone (PGC), is another drug that was discussed as abandoned after multiple unsuccessful repurposing efforts by different companies. Studied in 1994 for anxiety by Rhone-Poulenc Rorer, now Sanofi, the drug was later licensed and abandoned by Pfizer due to a lack of robust efficacy data. The drug was then pursued by Endo Pharmaceuticals for stuttering and discontinued for reportedly not fitting into the company’s defined R&D priorities and for having low projected commercial potential [9].

Industry consolidation, through for example mergers and acquisitions, can also lead to culling of promising development programs, merging of portfolios, and rivaling factions of scientists [13, 15, 18]. Pfizer, for instance, cut nearly 20% of its development pipeline after acquiring Wyeth in 2009, to help ensure its key disease priority areas were dominant in the new portfolio and to consolidate resources post-merger. This included abandoning imagabalin, under development by Pfizer, reportedly because Pfizer and Wyeth both already had other successful and popular drugs with anxiolytic activity, including Pfizer’s pregabalin and Wyeth’s venlafaxine [9].

After the merger, Pfizer also withdrew its supplemental marketing application for Lyrica, a drug already approved to treat seizures, fibromyalgia, and nerve pain, among other projects, to treat anxiety because these did not fit within their disease and condition priority groups of oncology, pain, inflammation, Alzheimer's, psychoses, and diabetes. Most abandoned drugs were in phase 1 of development, though three drugs in Phase 2 were also culled. Similarly, Merck cut multiple programs across its pipeline after acquiring Schering-Plough [13].

The literature also noted that managers allocating resources inevitably make errors in their assessment of which projects to continue and which to terminate, especially “type 2 errors,” defined as false negative decisions that underestimate a drug’s value; had the organization found the right target and business model, it may have had therapeutic value. These types of judgment errors, where managers underestimate therapeutics’ potential, were discussed as resulting in fewer drugs for patients than would arise in an ideal world [13]. Type 2 errors, that is false negatives, were described as harder to mitigate in comparison to type 1 errors, false positives, which may be caught and or addressed through a rigorous regulatory review. Examples of such errors include the “class effect” (that is negative results for one drug affecting value judgments for others in the same class) and a “felt inferiority” for a compound or “assumption that the compound could be too late to enter the market [19]”. Dalcetrapib, for instance, was abandoned by Roche after an independent group stated the drug lacked clinically meaningful efficacy in a late-stage trial. The drug targeted cardiovascular risks, and its failure was discussed as potentially having repercussions for other companies studying similar drugs, like Eli Lilly [20].

Selection of the wrong indication, endpoints, populations to enroll, or patient stratification methodologies in a trial, as well as suboptimal dosing or insensitive biomarkers were discussed as potential drivers of drug abandonment, which we have classified as “research design decisions” (n = 12) [21, 22]. One paper, for instance, suggested Nelivaptan, a treatment for major depressive disorder and generalized anxiety disorder, may have appeared ineffective because it was studied in the wrong population and for the wrong indication. Study authors noted Nelivaptan, an AVPR1b antagonist, would be best utilized in acute stress conditions, as V1b receptors are particularly activated, with limited efficacy for the chronic stress states in which it was tested [21].

In terms of dosing decisions, after initially declaring Aducanumab ineffective for treating Alzheimer’s disease after phase III trials, Biogen found statistically significant improvements in cognitive decline in a subset of the sample who had received the highest doses and thus revived the nearly abandoned therapy with new dosage selections [23‐25].There have been over 200 failed Alzheimer’s drugs and candidates, reflecting poorly understood etiology and deficiencies in development and methodology, including issues with dosing, biases, and protocol violations [26]. Papers by Becker described how researchers found several trial related factors in Phenserine’s development, also an Alzheimer’s-related drug, that suggested they did not provide fair and unbiased conditions for the drug to demonstrate efficacy, including variance on assessment scores, improvement in the placebo groups, and unaddressed errors [26, 27].

In general, placebo-based trials were discussed as possibly having higher risks for drug abandonment. Comparing a new compound with a placebo was discussed as having a higher risk of a false negative trial, particularly in diseases like irritable bowel syndrome and mild depression, where the placebo responder rate can be as high as 40–50%. Inability to pick a correct dose can also lead to a false-negative effect with placebos, as often the highest acceptable dose, not the most optimal dose, is chosen in order to emphasize the difference versus a placebo [19].

An inadequate understanding of therapeutic pathways in complex diseases (n = 8)- such as Alzheimer’s disease, cardiovascular disease, psychiatric conditions, and stroke- was discussed as a contributor to trial design challenges [22]. In psychiatric disease, for example, inferences from animal research remain limited in scope [28]. In addition, indication selection is relevant as repurposing aims to find new uses for shelved drugs. Importantly, a lack of efficacy for the original indication does not mean a lack of efficacy in other indications. An illustrative example is Nelivaptan, which was found to be ineffective as a treatment for major depressive disorder (MDD) and generalized anxiety disorder (GAD). However, nelivaptan is an AVPR1b antagonist and V1b receptors are particularly activated during acute stress, not chronic stress in which it was tested. Thus, Nelivaptan is an attractive option for anxiety and disorders of sociality; despite this promising evidence, a company contact suggested that Nelivaptan is not available [21]. Lack of efficacy is multifactorial, and interrogating causes of drug abandonment is crucial to demonstrate the potential of repurposing.

Companies were described in the literature as recently drifting away from CNS drug development, as it is now perceived to carry a high risk of failure, despite a high potential reward with a market valued at over $40 billion [29]. High attrition rates in this area reflect issues in translation due to a lack of knowledge of disease etiology and pathology and thus a lack of predictivity of animal models. For example, understanding of the neurophysiology associated with schizophrenia is limited and thus there have been high-profile drug development failures such as the Roche GLYT1 glycine uptake inhibitors. Additionally, despite costly clinical trials of more than 15 neuroprotectant drugs for ischemic stroke, the results were negative [29].

Regulatory hurdles (n = 2), such as regulators requesting additional studies and a sponsor unwilling to comply, were also discussed as potential drivers for the abandonment of promising drugs [30].

Organizations require financial resources and personnel with relevant expertise on the compound and studied indications to advance a shelved drug candidate. Because pharmaceutical research and development is often organized around specific therapeutic areas within an organization, it can be hard to internally realize the repurposing potential of compounds outside this focus [14, 16]. As such, multi-partner collaborations in repurposing are often needed [32]. Academic researchers may have the expertise to study compounds, but not have access to a pool of deprioritized pharmaceutical compounds [33]. Likewise, small biotechnology companies and academic institutions may need to find commercial partners to address a lack of resources [34]. Additionally, companies often lack sufficient staff dedicated to out-licensing discontinued compounds, and thus most are abandoned [35].

Despite the promise of repurposing being a cheaper and faster alternative to de novo development, bringing a repurposed compound to market was described as still costing hundreds of millions to billions of dollars, despite early cost savings from not having to conduct preclinical research [21, 32, 36]. Although many of the compounds have existing data and are well understood, repurposing only reduces, not eliminates drug development risks. Ultimately, repurposing can still require substantive testing, and repurposed compounds must still undergo the same approval process and meet quality, efficacy and safety standards.

Repurposing can result in millions of dollars’ worth of savings, given its potential to save 6–7 years of time spent on preclinical and early-stage research [36, 37]. However, in the later stages of clinical research, repurposed compounds can still have the same failure rate as any other compound, if not higher, after failing in a primary indication [14, 34]. Repurposed drugs can still require phase 2 and 3 clinical trials, which eliminate 68% and 40% of compounds, respectively, which make it that far, for their new indications [38].

Even when out-licensing a compound, there can be burdensome “in-kind” costs from remanufacturing the active product and placebo, completing study reports and regulatory documentation, pharmacovigilance, monitoring and reporting on patient safety, and coordination [39, 40]. It is challenging to persuade management to allocate resources to compounds that were initially unsuccessful, especially if the new indication is not a strategic focus [14].

The second most common barrier to drug repurposing discussed in the literature was IP related. Pharmaceutical companies were described as patenting many compounds, even if they are later abandoned, and thus prevent others from developing these compounds without a license [13]. There can also be limited patent time left for compounds that failed in later stages, limiting return on investments (ROI) in drug repurposing. The threshold companies use to determine if an ROI is worth their investment varies by company size. Larger companies may require a greater ROI than smaller ones. What may not be a sufficient ROI for a large company may be enough for a small company and result in a new medication for patients [35].

Further discussed is a lack of traditional IP protections for repurposed compounds, though products can still be economically successful without this type of protection. Composition of matter (COM) claims are among the most powerful IP protections for newly synthesized compounds. But COM claims can be difficult to gain for repurposed compounds, as the patentee must somehow differentiate their patent claims over what is in the public domain and present data that the drug is a credible candidate for the new indication [41, 42].

Entanglement with core IP is another issue. The literature states it can be common for developers to patent a number of compounds in development, which protects not only the final candidate, but the semi-finalists as well [13]. Thus, shelved compounds from the same family cannot be developed by another party without a license of access to the relevant patents that protect the compounds.

As IP protects pharmaceutical investment and disallows competitors from building upon original research and repurposing compounds, it poses a difficult barrier to address [11, 43]. Material transfer agreements (MTAs) pose a particularly challenging and time-consuming barrier. Negotiations on MTAs are most heated around issues of limiting compound use to non-commercial research, limiting company liability, delaying academic publications to protect confidential information, and IP provisions. IP terms were described as difficult and time-consuming to negotiate as companies often want to protect their freedom to operate using their own compounds, while universities want to maintain ownership of inventions, receive consideration, and make compounds available to the public [44].

Barriers to accessing shelved compounds and their trial data were the second most commonly discussed challenge to drug repurposing. Compounds were described as “disappearing” once their development is abandoned, with trial data and results left unpublished [19, 38]. Several factors were described as influencing trial publication practices around shelved drugs, including the difficulty of publishing negative trial results, that many trials end up terminated abruptly after a company merger or acquisition [9], and the lack of commercial benefit in dedicating time and resources to publishing results on a discontinued project, and no legal requirement to do so [30]. Moreover, data are sometimes sequestered if considered a “trade secret” or of potential commercial value.

Gaining knowledge about and access to shelved industry compounds was often described as difficult and, in many cases, requiring an internal company champion for success [40]. Companies were cited as expressing reluctance to share shelved compounds with other companies in case they turn out to be blockbusters. Nonprofits and government-funded bodies, on the other hand, have a lower risk of commercial embarrassment [13].

Furthermore, a lack of repositories to transparently register abandoned compounds and a reluctance from companies to release compounds to a shared resource were cited as reasons shelved drugs can “disappear [44]”. Within companies, paper records need to be digitized and often the company’s experts on the compound move on and teams responsible for the regulatory and safety data are disbanded [31]. Additionally, mining large datasets poses a logistical hurdle and integration of different types of data in a user-friendly manner is challenging [42, 45].

Developers make assumptions on the value of reinvestigating shelved compounds. Some critics have expressed concern that focusing on repurposing detracts from innovation and the pursuit of novel drugs and therefore poses a disservice to the possibility of finding new cures [46]. Some experts also disagree with the notion that shelved drugs represent a significant opportunity for development and report believing there has been “an awful lot of hype” regarding repurposing programs [44, 47]. Addressing value biases was discussed as requiring a great deal of information and is a process that is described as time-consuming and expensive for all involved parties.

The “not sold here” and “not invented here” syndromes were discussed. The “not sold here” syndrome refers to the unwillingness of companies to out-license compounds that may be promising for other indications [13]. Business units argue that if they do not sell a product, no one else should, leading to a waste of human talent in research and development as compound attrition rates are quite high. The “not invented here” syndrome refers to the bias that external research and technology are inferior to a company’s own R&D capabilities and standards and therefore not worth pursuing. External parties may also assume a seller is keeping the best compounds for themselves and offering lesser value compounds for out-licensing [13].

Pharmaceutical companies were generally described as employing few, if any, staff to aid in out-licensing shelved compounds, thus limiting outside companies’ evaluation of shelved drugs.

Drug companies may also face liability risks (n = 5) when out-licensing abandoned compounds, which include risks of adverse patient events, a need to continuously supply the compound to the licensee, and litigation [13]. Testing compounds for new indications and populations may reveal new adverse events or unforeseen toxicities [48]. For externally sponsored studies, the investigator must report back safety data to the parent company.

The high cost of liability insurance was discussed as a reason pharmaceutical companies discontinue development of lower-revenue products like vaccines. To meet the demand for increased liability insurance, the cost of the pertussis vaccine rose from 17 cents to 11 dollars per dose, and the number of companies making the vaccine reportedly decreased [12].

Multi-partner collaborations between pharmaceutical companies and academic institutions, non-profit organizations and biotechnology companies was the most commonly discussed facilitator for drug repurposing cited in the literature (n = 38). Pharmaceutical companies have the resources as well as a pool of shelved compounds and data while biotechnology companies and academia have knowledge and expertise on emerging areas to study compounds and contribute to innovation [49]. A staff dedicated to out-licensing discontinued compounds was described as a facilitator for collaborative partnerships [13].

Several examples of collaborative initiatives focused on drug repurposing were discussed in the literature, including the NIH National Center for Advancing Translational Sciences (NCATS) program: Discovering New Therapeutic Uses for Existing Molecules (n = 23), the Medical Research Council (MRC) and AstraZeneca (AZ) Mechanisms of Human Disease Initiative, (n = 16), the AZ Open Innovation program (n = 6), European College of Neuropsychopharmacology (ECNP) Medicines Chest Program (n = 5), The Clinical and Translational Science Award (CTSA) Pharmaceutical Assets Portal (n = 2), Pfizer’s SpringWorks Program (n = 2), the AstraZeneca/National Research Program for Biopharmaceuticals(NRPB) partnership in Taiwan (n = 2), the Clinical Development Partnerships Initiative (n = 1), the Roche/Broad Institute Collaboration (n = 1), and the Drugs for Neglected Diseases Initiative (DNDI) (n = 1).

The NIH NCATS’ Discovering New Therapeutic Uses for Existing Molecules program was initiated in 2012 to help scientists explore new treatments for patients by matching NIH-funded researchers with a selection of 58 compounds previously discontinued from development due to lack of efficacy, selectivity, or strategy [36, 39, 50]. Co-launched with AstraZeneca (AZ), Eli Lilly, and Pfizer, the initiative required that compounds had prior evidence and manageable tolerability in humans and that companies publicly posted online template confidentiality disclosure agreements (CDAs) and collaborative research agreements (CRAs) to enable rapid implementation [39, 51]. In the program, the NIH acts as a trusted intermediary, facilitates deals between researchers and companies that are often characterized by prolonged negotiation, and moves promising compounds into the private sector [36, 42, 52, 53]. Organizations maintain IP on the original compound, but the repurposed use belongs to the researchers. However, companies can license the IP from researchers, and researchers can request licenses for additional studies [52]. In short, the NIH NCATS initiative facilitates the availability of compounds, data, human, and financial resources, and addresses issues of intellectual property and data sharing in drug repurposing [31].

Another partnership between the MRC and AZ, the Mechanisms of Human Disease Initiative, launched in 2011 and provided researchers with what was described as “unprecedented access” to clinical and pre-clinical AstraZeneca compounds. It accepted proposals for novel research projects with a focus on understanding human disease [38]. The MRC posted data on 22 compounds on its website, and over 100 proposals were submitted from across the UK. Full proposals were developed by UK researchers and AZ scientists, and selected proposals were funded by the MRC [39]. AstraZeneca also launched another program with the National Research Program for Biopharmaceuticals (NRPB) in Taiwan to facilitate translational research locally, which included live compounds [42]. As a result of the success of pilot programs, AstraZeneca launched an Open Innovation program that seeks to make a range of unwanted molecules readily available to university researchers who can propose novel repositioning ideas [39]. In doing so, AstraZeneca gains a competitive advantage when the same scientists are looking for companies to share breakthroughs with [17].

The European College of Neuropsychopharmacology (ECNP) Medicines Chest Program was set up to provide academic and small company researchers access to promising compounds for experimental medicine studies. Similar to the NIH NCATS program, the compounds are placed on the ECNP website, and researchers are invited to submit a 2–3-page proposal outlining a clinical study. After the ECNP vets the study, a contract, of which a sample is publicly available, is drawn up between the company and academic institutions and access to confidential information is provided for grant applications to fund the study [40].

The Clinical and Translational Science Award (CTSA) Pharmaceutical Assets Portal facilitates industry-academic collaborations for discovery of new indications for shelved compounds by providing a foci-of-expertise tool that identifies investigators with complementary interests, access to resource-management tools, facilities to house, maintain and distribute the discontinued compounds, management of IP and material transfer agreements, and selection of projects for funding [44, 52].

Likewise, The Clinical Development Partnerships Initiative presents a cost-effective, rapid means by which pharmaceutical companies can boost their product lines. Companies retain IP rights to their original molecule and the first option to view trial data if they loan their compounds to Cancer Research UK, which will conduct early phase I and II clinical trials. The company retains the option to develop and market the drug, and the charity receives a share of any revenue [15].

The Roche/Broad Institute Collaboration made 300 compounds that failed to meet critical phase II milestones or were shelved for strategic reasons available to researchers who could suggest experiments. If collaborators uncovered any shared findings, Roche and the partner would agree on next steps, including publishing results, further experimentation, or a development plan [52].

Lastly, the Drugs for Neglected Diseases Initiative (DNDI) is an open-source collaborative endeavor that partners the expertise and assets of pharmaceutical companies with networks of public and private scientists to support repurposing and investigation of novel treatments for neglected tropical diseases. Merck entered a collaboration with DNDI in which it would provide small molecule assets and respective intellectual property through socially responsible licensing agreements to develop, manufacture and distribute cost-effective treatments for NTDs to resource-poor countries. The pharma company would share joint IP rights on candidates in early development, with an opportunity to continue late clinical development and registration of successful candidates. In doing so, collaboration is incentivized and resident expertise and contributions in later stages of development help maximize the drug’s potential [54].

Compound access is another important facilitator for repurposing. Many initiatives serve to create databases that provide target and drug profiles, including protein and active site structures and associations with related diseases and biological functions, to interested researchers. Databases discussed in the literature include PubChem (7), DrugBank (6), Promiscuous (5), ChEMBL(5), the NIH clinical collection (2), the Open PHACTS Initiative (2), DisGeNet (1), the Drug Repurposing Hub (1), DrugSig (1), and the US FDA’s Orange Book of discontinued drug products list (1).

Compound-specific databases include: PubChem, which is administered by the NIH and holds data from several hundred biochemical and phenotypic screens, with more deposited each month [55], ChEMBL, an open target platform that enables investigation of evidence-associated targets and diseases in an accessible manner by presenting molecules with drug-like properties [56] and the US FDA’s Orange Book of discontinued drug products.

DrugBank is the most comprehensive publicly available database of approved, experimental and withdrawn drugs which are annotated by indication and intended targets [57]. The Promiscuous database provides an exhaustive set of drugs (25,000), including withdrawn or experimental drugs with drug-protein and protein–protein relationships annotated, allowing researchers to identify prospective new uses by examining predictive interaction points [52]. The NIH clinical collection presents a library of drugs that passed safety tests but for various reasons did not reach the market [38]. The Open Phacts initiative allows for multiple sources of publicly available pharmacological and physicochemical data to be intuitively queried, with 28 partners from public and private sectors [52]. DisGeNet offers associations between genes and diseases, as well as disease-variant associations.

The Drug Repurposing Hub is a database of approved, clinical-trial tested, and pre-clinical compounds that are annotated with literature-reported targets, and DrugSig is a public resource for signature-based drug repositioning that builds off the Connectivity Map from the Broad Institute [57]. Open-source databases allow for efficient sharing of resources and drug profiles to cost-effectively advance shelved compounds, and provide a public relations benefit for pharmaceutical contributors who are not locked into long-term commitments.

Many novel methods have been developed and applied to help identify and validate repurposing targets, greatly advancing repurposing endeavors (n = 32). Computational approaches coupled with open-access databases were described as central in identifying potential repurposing opportunities by predicting drug-disease responses and validating targets and pathways [21].

Of these newer methods, signature-based approaches (n = 5) were commonly employed for drug repurposing. These include investigating published GWAS data from institutes like the US National Human Genome institute to systematically and rapidly identify alternative indications for existing drugs and exploring how many genes are amenable to pharmacological intervention using biopharmaceuticals or small molecules [58]. However, key limiting factors are the expertise and time required to develop such assays and integrating databases that identify known drugs among confirmed activities [55].

In-silico screening of compound libraries (n = 4) is useful in both significantly reducing wet-laboratory work and lowering the cost of experimental determination of drug-target interactions [59]. Additionally, public access to high throughput screens (HTS) of small molecules (n = 3), particularly mining of phenotypic screens, was described as an effective and economical strategy for repurposing drugs [55].

Computer-aided approximations include bioinformatics-based approaches (n = 3) which employ domain similarity prediction tools and sequence alignment to discover novel protein–protein similarities, identifying closely related targets and new repurposing opportunities, and chemoinformatics-based approaches (n = 2) which involve molecular representations of candidate compounds which are submitted to computational algorithms which rank and prioritize compounds for experimental testing.

When 3D structures are available, molecular docking (n = 1) can be used to screen a large number of compounds against a target protein. When they are not, ligand and network-based approaches can be utilized [59].

Network modeling (n = 1) and systems-biology approaches (n = 1) were also discussed as helpful. Network modeling reconstructs a biological network and simulates its interactions to reveal potential drug targets [60, 61]. A systems-biology approach was described as the use of omics data, signaling pathways, metabolic pathways and protein interactions to come up with a new pathway for a proposed disease [43].

While most network-based approaches are limited in their predictions of how drugs and targets interact, machine learning approaches (n = 3) can go further in accurately predicting drug-target interactions and inferring modes of action and novel drug-target relationships [59].

Finally, Artificial Intelligence (AI)-driven technology (n = 1) can integrate diverse types of data and look for connections. For example, Biovista has developed an AI solution called Project Prodigy which does not limit itself to machine learning but rather is capable of building entirely new clinical scenarios and has led to internal repurposing successes in multiple sclerosis and epilepsy. Their AI system has been used in collaboration with major pharmaceutical companies, patient advocacy groups, and the FDA [62].

Tax incentives and certain regulatory modifications may further facilitate drug repurposing. Tax incentives such as allowing for the deduction of residual product value upon donation of a compound or for sharing trial data to a third party could help advance development of shelved compounds. Regulatory modifications to the FDA’s 505(b)(2) pathway could allow for use of previously compiled safety data. Use of the FDA’s safety findings could expand the number of drugs available without adversely impacting risk benefit [21].