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Can We Make Old Drugs Great Again? The Relevance Of Licensing Generics

Throughout a drug’s life cycle, there is a continuous development of drug features and new uses beyond the initial or approved drug indication. Identifying new applications for existing drugs, a process also known as drug rediscovery, repositioning, or repurposing, may create alternative treatment options while bypassing costs and time involved with bringing a new drug to market.

A great example of a rediscovered drug is “sildenafil.” This drug was initially explored for the management of cardiovascular diseases, but due to persistent erections as an unexpected adverse event, sildenafil was repurposed as a therapy for erectile dysfunction (Viagra┬«).1

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Drug rediscoveries generally happen before or during the period of drug market exclusivity. Already approved drugs, such as generics, however, may also be repositioned for new indications. Thalidomide, for example, got repositioned for the treatment of multiple myeloma five decades after its initial use for morning sickness in pregnant women in 1950s.2

Relevance of relicensing generics

Drug rediscovery has multiple advantages over traditional drug development, which is costly and time-consuming. There is broad knowledge about the safety and quality of the repurposed drug, since the drug has been studied and used before.

From a public health perspective, it may be valuable not to only develop new uses for old drugs but also to license the new indications. A licensed drug, manufactured by a pharmaceutical company, has the benefit of guaranteed standardized drug quality and safety control. Yet in clinical practices, rediscovered medicines are commonly prescribed off-label (in up to 20 percent of the time), and are, thus, unlicensed.3

It is believed that off-label drug use might be associated with unknown safety risks since they are under-evaluated for the new indications.4 An official product leaflet with accurate information about drug usage for the new indication is often non-existent. Moreover, data regarding the safety, efficacy, and quality of the off-label used drug are not always accurately recorded, but these are crucial to evaluate drug usage for the new indication.

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Challenges in rediscovering generics

Concerning protected drugs, there are several routes in the European Union (EU) and the United States (US) to extend the market exclusivity period.5 Enlarging the patient population or adding therapeutic indications are standard practice in pharmaceutical economics. When it comes to the successful rediscovery of generics, however, a standardized regulatory approach or marketing regulation is unavailable. In particular, the lack of interest by pharmaceutical and other stakeholders in drugs with an expired patent is unprofitable, since repurposed drugs do not guarantee market exclusivity or recoupment of investments.

In the US, the Food and Drug Administration (FDA) offers market exclusivity for three years for the development of new indications for an already approved drug; however, this short period is often not tempting enough for pharmaceutical companies to invest in repurposed generics.6

Generic drug regulation in the EU provides even less support for drug rediscovery. In the EU, the European Medicines Agency (EMA) does not have the final word, and drug policies differ among European countries. A generic rediscovered drug application can be submitted via several ways (e.g.  the Mutual Recognition Procedure (MPR) and Decentralized Procedure (DCP)), but each of them are long-lasting and unharmonized between different European countries.7 If procedures are successfully conducted, one-year market exclusivity can be obtained for the repurposed generic drug. This limited timeframe together with the lack of standardized regulatory procedure makes rediscovery and relicensing of generics, especially in Europe, a very challenging pursuit.

Personal experiences in licensing a generic drug

Since 2001, our research team (from the VU University Medical Center in Amsterdam, The Netherlands) has been involved with the rediscovery of thioguanine, a drug originally developed for leukemia in 1950, for the treatment of inflammatory bowel diseases (IBD).8

Thioguanine had shown promising results in several early trials, especially in IBD patients who did not benefit from (multiple) previous therapies. However, there were several concerns regarding treatment with thioguanine in IBD. There was no standardized thioguanine dosage for IBD, and as a result, various dosages were prescribed leading to (preventable) drug toxicity (when dosed relatively high). Additionally, data on safety and efficacy of thioguanine was not nationwide collected, therefore the evaluation of thioguanine for IBD was difficult. Lastly, the official product leaflet about thioguanine (for leukemia) provided incorrect drug information, challenging the therapy adherence of patients.

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To reach the full rediscovery potential of thioguanine for IBD and provide a qualified treatment, relicensing of this drug was proposed. Initially, pharmaceutical and regulatory authorities showed no interest due to a lack of standardized generic drug regulation and pharmaceutical (an expired patent), as well as financial (reimbursement) and medical issues (controversial results of this drug in early clinical trials). Within years, attention was drawn to these obstacles and open dialogue between the research team, regulatory authorities and pharmaceutical applicants occurred. The initiation of multicenter studies on thioguanine in IBD was supported and the benefit-risk profile of this drug was demonstrated.

After a 14 years period (2001-2015), thioguanine got conditionally relicensed for the treatment of IBD. Interestingly, the costs of this whole procedure were in keeping with prevailing market price trends. This unique development created awareness about the importance of further development of old drugs and the need for a standardized protocol for the rediscovery of generics in the Netherlands as the EU.

These findings are described in the article entitled Finding hidden treasures in old drugs: the challenges and importance of licensing generics, recently published in the journal Drug Discovery Today. This work was conducted by Melek Simsek, Berrie Meijer, Adriaan van Bodegraven, Nanne de Boer and Chris Mulder from the VU University Medical Center in Amsterdam, The Netherlands. 

Footnote: The views and experiences expressed in this article are the personal views of the authors and may not be interpreted as being made on behalf of ScienceTrends nor the health authorities or medical associations involved in the procedure of relicensing generics.

References:

  1. Goldstein I, Lue TF, Padma-Nathan H, et al. Oral sildenafil in the treatment of erectile dysfunction. 1998. J Urol 2002; 167(2 Pt 2): 1197-203; discussion 204.
  2. Mercurio A, Adriani G, Catalano A, et al. A Mini-Review on Thalidomide: Chemistry, Mechanisms of Action, Therapeutic Potential and Anti-Angiogenic Properties in Multiple Myeloma. Curr Med Chem 2017.
  3. Radley DC, Finkelstein SN, Stafford RS. Off-label prescribing among office-based physicians. Arch Intern Med 2006; 166(9): 1021-6.
  4. Eguale T, Buckeridge DL, Verma A, et al. Association of Off-label Drug Use and Adverse Drug Events in an Adult Population. JAMA Intern Med 2016; 176(1): 55-63.
  5. Sandner P, Ziegelbauer K. Product-related research: how research can contribute to successful life-cycle management. Drug Discov Today 2008; 13(9-10): 457-63.
  6. Administration FaD. Patents and Exclusivity. 2015. https://www.fda.gov/downloads/drugs/developmentapprovalprocess/smallbusinessassistance/ucm447307.pdf (accessed June 20. 2017).
  7. Kim D. Transparency Policies of the European Medicines Agency: Has the Paradigm Shifted? Med Law Rev 2017.
  8. Simsek M, Meijer B, van Bodegraven AA, de Boer NKH, Mulder CJJ. Finding hidden treasures in old drugs: the challenges and importance of licensing generics. Drug Discov Today 2017.

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