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Scientific advice - is drug repurposing missing a trick?

Authors:
Pan Pantziarka at The Anticancer Fund/The George Pantziarka TP53 Trust
Pan Pantziarka
  • The Anticancer Fund/The George Pantziarka TP53 Trust
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Abstract

Scientific Advice meetings are a mechanism to improve communications between drug developers and regulators during the drug-development process. While standard practice for industry, the benefits provided by these meetings are under-utilised by academia. In the context of drug repurposing, can scientific advice, as part of a proposed new R&D tax credits scheme, help to unblock some of the obstacles in the way to clinical adoption?
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Drug repurposing is a drug-development strategy
that seeks new indications for already-licensed medi-
cations—in contrast to the denovo development of new
medicines or the reinvestigation of previously ‘shelved’
compounds. A number of commonly used drugs have
been successfully repurposed for the treatment of
conditions very different to their original indications.
For example, a number of chemotherapeutics are now
being used in clinical fields outside of oncology, includ-
ing methotrexate, which is licensed for the treatment of
patients with rheumatoid arthritis or psoriasis. By con-
trast, the number of non-oncological drugs that have
been repurposed for use as anticancer drugs remains
very low, despite an increasing level of interest in this
drug-development pathway1. The apparent benefits of
drug repurposing, including the availability of existing
data on safety, tolerability, dosing, pharmacokinetics,
and pharmacodynamics, can potentially expedite clini-
cal evaluation and adoption. The potential societal bene-
fits of exploiting an existing source of safe and effective
medicines for new cancer treatments are also widely
acknowledged2; these potential benefits include low drug
costs, well-characterised safety profile and widespread
drug availability.
Despite these apparent benefits, the limited finan-
cial incentives for drug repurposing, particularly of
generic drugs, is an impediment to progress in this area.
Notably, many of the drugs under active investigation for
repurposing in new oncological indications are generic
agents, such as aspirin and metformin. The lack of
patent- protection for generic drugs severely restricts the
potential to make a return on the investment required
for licensing. In the case of rare diseases, orphan drug
designation (ODD) might provide some incentive, most
notably through market exclusivity. Concerns exist that
the ODD creates perverse incentives in which low-cost
generics are transformed into high-priced medicines
when approved for use in small populations of patients,
particularly where indication-based prescribing systems
are used and clinicians are unable to select the lower-cost
generic version of the medication3. Off-label use is not
an ideal solution because many clinicians are reluctant to
prescribe treatment in this manner for fear of potential
legal repercussions, reimbursement might be limited,
and the drug supply might not be guaranteed if the drug
is withdrawn for its original indication.
In the UK, the unsuccessful Off-patent Drugs Bill
2015–16 (REF.4) was pursued in an attempt to create a
legislative solution to these issues. The bill proposed that
a government minister should seek a label extension for
an off-patent drug when sufficient evidence is available
to support its use in a new indication. The Department
of Health has since brokered a number of meetings
on this issue, inviting a broad range of stakeholders to
participate, including clinicians, and representatives of
research charities, patient advocates, the pharmaceutical
industry and regulatory authorities. In this context, the
British Generics Manufacturers Association (BGMA)
has proposed a change to the R&D tax credits scheme
so that any generics manufacturer, with an appropriate
marketing authorisation, can receive tax credits if they
apply for a label extension in collaboration with an aca-
demic or not-for-profit partner. In such a situation, the
manufacturer would receive the tax credit to help fund
the additional work required by going through licensing.
In this scenario, the price of the drug has to remain at the
existing level and no market exclusivity is assigned to the
manufacturer; therefore, the label extension imposes no
additional financial burdens on the health-care system.
Breast Cancer Now and the Anticancer Fund—two of
the organizations active in the campaign to introduce the
Off-patent Drugs Bill—have worked with the BGMA
on two test cases for the proposed amendment to the
R&D tax credits scheme. The first, by Breast Cancer
Now, is on the use of bisphosphonates to prevent breast
cancer recurrence5. The second, by the Anticancer
Fund, is on the use of propranolol in the treatment
of angiosarcoma, a rare soft-tissue sarcoma6,7. As part
1Anticancer Fund,
Brussels, 1853
Strombeek-Bever, Belgium.
2The George Pantziarka
TP53 Trust, London, UK.
pan.pantziarka@
anticancerfund.org
doi:10.1038/nrclinonc.2017.69
Published online 23 May 2017
Scientific advice—is drug
repurposing missing a trick?
Pan Pantziarka1,2
Scientific Advice meetings are a mechanism to improve communications between drug
developers and regulators during the drug-development process. While standard practice for
industry, the benefits provided by these meetings are under-utilised by academia. In the context
of drug repurposing, can scientific advice, as part of a proposed new R&D tax credits scheme,
help to unblock some of the obstacles in the way to clinical adoption?
…the
success rate for
applications that
were compliant
with the scientific
advice on trial
design was
higher than that
for non-compliant
applications
NATURE REVIEWS
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CLINICAL ONCOLOGY VOLUME 14
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AUGUST 2017
|
1
COMMENT
of this process, spokespersons from these organiza-
tions, including this author, supported by a representa-
tive of the BGMA and physicians with relevant clinical
ex perience, have attended ‘scientific advice’ meetings
with the UK drug-regulatory authority, the Medicines
and Healthcare products Regulatory Agency (MHRA).
Engagement with the regulators for scientific or reg-
ulatory advice is standard practice for pharma ceutical
companies, including manufacturers of generic drugs,
but not for the academic and not-for-profit sector.
Scientific advice meetings were initiated in 1996 by
the European Medicines Agency (EMA) to facilitate
improved communications between regulators and
drug developers throughout the drug-development
process. The scientific advice meetings are designed
to address specific questions raised by drug developers
in relation to the levels of evidence required to support
licensing—both for new market authorisations and
variations to existing ones. The drug developers pres-
ent a dossier of information and the questions they wish
to raise. Members of the regulatory team then assess
the evidence presented; the scientific advice meeting
is the forum in which their responses are delivered and a
dialogue takes place. In January 2017, Robin Jones of the
Sarcoma Unit of the Royal Marsden, and I (representing
the Anticancer Fund) attended a Scientific Advice meet-
ing on propranolol and angiosarcoma at the MHRA.
For those of us who had not previously participated in
a scientific advice meeting, the experience proved to be
extremely useful. Preparation of a dossier of evidence
and the selection of our five or six key questions neces-
sitated a thought process that focused not only on the
scientific or clinical issues that are usually within our
purview, but also on the levels of evidence required to
support label extension. This process was a useful exer-
cise, encouraging a change of mind-set to that normally
engaged during the process of designing a research
project. The subsequent meeting and discussion with
the MHRA team was extremely enlightening in that
it provided focused feedback on the levels of evidence
required to propel bisphosphonates and propranolol
through to label extension.
In the case of propranolol, the feedback provided
was very specific with regards to the type of additional
preclinical work required, the definition of the patient
population to be treated, the choice of additional treat-
ments (propranolol is not intended as a monotherapy
for angiosarcoma), the value of the existing published
evidence and ongoing clinical trial data, the choice of
efficacy end points, and the design of subsequent clinical
trials required to support a label-extension application.
Investigators in this area, including clinical research-
ers currently planning trials, have views on all of these
aspects; however, knowing the views of the regulators in
advance means that there is no need to second-guess and
risk getting the investigative approach wrong, which is
often the case in non-industry-ledtrials.
Indeed, the available evidence indicates that the
scientific advice meeting process is an important and
effective tool in ensuring the success of drug licensing.
For example, Regnstrom etal.8 showed that obtaining
scientific advice and complying with the guidance
delivered was an independent predictor of a successful
marketing-authorisation application (compliant with
scientific advice versus no scientific advice: odds ratio
(OR) 14.71 (95%CI 1.95–111.2); non-compliant with
advice versus no advice OR0.17 (95%CI 0.06–0.47,
P <0.0001). In addition, Hofer etal.9 showed that
obtaining early scientific advice before, rather than
during, the pivotal trial phase of drug development was
associated with a higher rate of successful drug licens-
ing (78% versus 64%). Most importantly, the success
rate for applications that were compliant with the sci-
entific advice on trial design was higher than that for
non-compliant applications (84% versus 43%).
The history of drug-repurposing research—and
of clinical oncology research, in general—is littered
with promising clinical results, even from phaseIII tri-
als, that go no further than a high-impact publication.
Many factors are at play in translating promising study
results into clinical practice, not least drug-licensing
issues. Too many clinical researchers are convinced that
positive results from a trial will automatically lead to
changes in standard practice. Sadly, this is not always
the case. Engagement with regulators needs to become
routine practice in non-industry-led trials, particularly
for studies in patients with rare cancers, in which small
trial populations are the norm. An underpowered design
or poor choice of efficacy end point might result in a
trial providing limited evidence to support licensing of
an otherwise promising treatment. Many experts have
expressed concern regarding avoidable waste in clin-
ical research10—by providing specific and rational
guidance in a timely manner, the scientific advice pro-
cess might limit the number of such costly and wasted
opportunities.
1. Pantziarka,P., Bouche,G., Meheus,L., Sukhatme,V. &
Sukhatme,V.P. The Repurposing Drugs in Oncology (ReDO) Project.
Ecancermedicalscience 8, 442 (2014).
2. Bertolini,F., Sukhatme,V.P. & Bouche,G. Drug repurposing in
oncology — patient and health systems opportunities. Nat. Rev.
Clin. Oncol. 12, 732–742 (2015).
3. Davies,E.H., Fulton,E., Brook,D. & Hughes,D.A. Affordable
orphan drugs: a role for not-for-profit organizations. Br. J.Clin.
Pharmacol. http://dx.doi.org/10.1111/bcp.13240 (2017).
4. UK Parliament. Off-patent Drugs Bill 2015–2016. Parliament.uk
http://services.parliament.uk/bills/2015-16/offpatentdrugs.html
(2015).
5. Hadji,P. etal. Adjuvant bisphosphonates in early breast cancer:
consensus guidance for clinical practice from a European panel.
Ann. Oncol. 27, 379–390 (2016).
6. Pasquier,E. etal. Effective management of advanced angiosarcoma
by the synergistic combination of propranolol and vinblastine-based
metronomic chemotherapy: a bench to bedside study. EBioMedicine
6, 87–95 (2016).
7. Chow,W. etal. Growth attenuation of cutaneous angiosarcoma with
propranolol-mediated β-blockade. JAMA Dermatol. 151,
1226–1229 (2015).
8. Regnstrom,J. etal. Factors associated with success of market
authorisation applications for pharmaceutical drugs submitted to
the European Medicines Agency. Eur. J.Clin. Pharmacol. 66, 39–48
(2010).
9. Hofer,M.P. etal. Regulatory watch: impact of scientific advice from
the European Medicines Agency. Nat. Rev. Drug Discov. 14,
302–303 (2015).
10. Yordanov,Y. etal. Avoidable waste of research related to inadequate
methods in clinical trials. BMJ 350, h809 (2015).
Competing interests statement
The author declares no competing interests.
COMMENT
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AUGUST 2017
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VOLUME 14 www.nature.com/nrclinonc
... Another attractive method is redirecting drugs to the CNS, using novel drug delivery methods, undermining disconcerting toxicities seen with systemic therapy [33,34]. In addition, these repurposed drugs used alone or in combination, have the potential of targeting multiple unrelated oncogenic pathways driving tumorigenesis, including undruggable targets, a distinct advantage over single molecularly targeted therapy [35]. ...
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Central nervous system (CNS) tumors are the leading cause of cancer-related mortality in children, with prognosis remaining dismal for some of these malignancies. Though the past two decades have seen advancements in surgery, radiation, and targeted therapy, major unresolved hurdles continue to undermine the therapeutic efficacy. These include challenges in suboptimal drug delivery through the blood–brain barrier (BBB), marked intra-tumoral molecular heterogeneity, and the elusive tumor microenvironment. Drug repurposing or re-tasking FDA-approved drugs with evidence of penetration into the CNS, using newer methods of intracranial drug delivery facilitating optimal drug exposure, has been an area of intense research. This could be a valuable tool, as most of these agents have already gone through the lengthy process of drug development and the evaluation of safety risks and the optimal pharmacokinetic profile. They can now be used and tested in clinics with an accelerated and different approach. Conclusions: The next-generation therapeutic strategy should prioritize repurposing oncologic and non-oncologic drugs that have been used for other indication, and have demonstrated robust preclinical activity against pediatric brain tumors. In combination with novel drug delivery techniques, these drugs could hold significant therapeutic promise in pediatric neurooncology.
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... However, the discovery of a novel anti-cancer compound requires a considerable cost of approximately $648 million and a long duration of several years to more than a decade 4 , resulting in a drug development timeline far slower than anticipated 5,6 . Drug repurposing is a widely acknowledged strategy in the realm of drug development, which exploits potential mechanisms of action and targets genes of existing drugs in old therapeutic areas to explore new therapeutic indications 7,8 . This strategy substantially curtails the cost and time associated with cancer drug development and helps to alleviate drug shortages 9 . ...
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... This methodology presents an *Address correspondence to this author at the Faculty of Medicine, Institute of Immunology, Central University of Venezuela, Los Chaguaramos 1050-A, Caracas, 50109, Venezuela; E-mail: michaelfarmacia@gmail.com advantage compared to the "de novo" drug discovery process by significantly reducing the cost and time to offer a new treatment to patients [16]. ...
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... Many organizations are reanalyzing commercially licensed pharmaceuticals from a drug repurposing standpoint as a unique strategy for overcoming these constraints [6]. Drug repositioning ("creative innovations for old medications") is a strategy to explore new indications for approved or experimental drugs that go beyond the primary medical indication [8,9]. The main advantages of this technique are that the pharmacodynamic, pharmacokinetic, and toxicity profiles of medications have been extensively documented in preclinical and Phase-1 trials. ...
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... These novel techniques aim to surmount the challenges of drug resistance in cancers and enhance patient outcomes. Repurposing drugs for cancer treatment has emerged as an increasingly attractive strategy as it can reduce the time to regulatory approval (Bertolini et al., 2015;Clohessy and Pandolfi, 2015;Corsello et al., 2017;Pantziarka, 2017;Pushpakom et al., 2019) products, Chinese herbal medicines, and antibodies as combinatorial therapies to target drug resistance in cancers ( Figure 1). ...
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Effective Management of Advanced Angiosarcoma by the Synergistic Combination of Propranolol and Vinblastine-Based Metronomic Chemotherapy: A Bench to Bedside Study
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Background: Angiosarcomas are rare malignant tumors of vascular origin that represent a genuine therapeutic challenge. Recently, the combination of metronomic chemotherapy and drug repositioning has been proposed as an attractive alternative for cancer patients living in developing countries. Methods: In vitro experiments with transformed endothelial cells were used to identify synergistic interactions between anti-hypertensive drug propranolol and chemotherapeutics. This led to the design of a pilot treatment protocol combining oral propranolol and metronomic chemotherapy. Seven consecutive patients with advanced/metastatic/recurrent angiosarcoma were treated with this combination for up to 12months, followed by propranolol-containing maintenance therapy. Findings: Gene expression analysis showed expression of ADRB1 and ADRB2 adrenergic receptor genes in transformed endothelial cells and in angiosarcoma tumors. Propranolol strongly synergized with the microtubule-targeting agent vinblastine in vitro, but only displayed additivity or slight antagonism with paclitaxel and doxorubicin. A combination treatment using bi-daily propranolol (40mg) and weekly metronomic vinblastine (6mg/m(2)) and methotrexate (35mg/m(2)) was designed and used in 7 patients with advanced angiosarcoma. Treatment was well tolerated and resulted in 100% response rate, including 1 complete response and 3 very good partial responses, based on RECIST criteria. Median progression-free and overall survival was 11months (range 5-24) and 16months (range 10-30), respectively. Interpretation: Our results provide a strong rationale for the combination of β-blockers and vinblastine-based metronomic chemotherapy for the treatment of advanced angiosarcoma. Furthermore, our study highlights the potential of drug repositioning in combination with metronomic chemotherapy in low- and middle-income country setting. Funding: This study was funded by institutional and philanthropic grants.
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Adjuvant bisphosphonates in early breast cancer: Consensus guidance for clinical practice from a European Panel
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Full-text available
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Bisphosphonates have been studied in randomised trials in early breast cancer to investigate their ability to prevent cancer treatment induced bone loss and reduce the risk of disease recurrence and metastasis. Treatment benefits have been reported but bisphosphonates do not currently have regulatory approval for either of these potential indications. This consensus paper provides a review of the evidence and offers guidance to breast cancer clinicians on the use of bisphosphonates in early breast cancer.Using the nominal group methodology for consensus a systematic review of the literature was augmented by a workshop held in October 2014 for breast cancer and bone specialists to present and debate the available preclinical and clinical evidence for the use of adjuvant bisphosphonates. This was followed by a questionnaire to all members of the writing committee to identify areas of consensus.The panel recommended that bisphosphonates should be considered as part of routine clinical practice for the prevention of cancer treatment induced bone loss in all patients with a T score of <-2.0 or≥2 clinical risk factors for fracture. Compelling evidence from a meta-analysis of trial data of >18,000 patients supports clinically significant benefits of bisphosphonates on the development of bone metastases and breast cancer mortality in postmenopausal women or those receiving ovarian suppression therapy. Therefore the panel recommends that bisphosphonates (either intravenous zoledronic acid or oral clodronate) are considered as part of the adjuvant breast cancer treatment in this population and the potential benefits and risks discussed with relevant patients.
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Growth Attenuation of Cutaneous Angiosarcoma With Propranolol-Mediated β-Blockade
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Full-text available
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Importance: Patients with stage T2 multilesion angiosarcomas of the scalp and face that are larger than 10 cm demonstrate a 2-year survival rate of 0%. To our knowledge, major therapeutic advances against this disease have not been reported for decades. Preclinical data indicate that blocking β-adrenergic signaling with propranolol hydrochloride disrupts angiosarcoma cell survival and xenograft angiosarcoma progression. Observations: A patient presented with a β-adrenergic-positive multifocal stage T2 cutaneous angiosarcoma (≥20 cm) involving 80% of the scalp, left forehead, and left cheek, with no evidence of metastasis. The patient was immediately administered propranolol hydrochloride, 40 mg twice a day, as his workup progressed and treatment options were elucidated. Evaluation of the proliferative index of the tumor before and after only 1 week of propranolol monotherapy revealed a reduction in the proliferative index of the tumor by approximately 34%. A combination of propranolol hydrochloride, 40 mg 3 times a day, paclitaxel poliglumex, 2 mg/m2 infused weekly, and radiotherapy during the subsequent 8 months resulted in extensive tumor regression with no detectable metastases. Conclusions and relevance: Our data suggest that β-blockade alone substantially reduced angiosarcoma proliferation and, in combination with standard therapy, is effective for reducing the size of the tumor and preventing metastases. If successful, β-blockade could be the first major advancement in the treatment of angiosarcoma in decades.
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Avoidable waste of research related to inadequate methods in clinical trials
Article
Full-text available
  • Mar 2015
  • Br Med J
Objective To assess the waste of research related to inadequate methods in trials included in Cochrane reviews and to examine to what extent this waste could be avoided. A secondary objective was to perform a simulation study to re-estimate this avoidable waste if all trials were adequately reported. Design Methodological review and simulation study. Data sources Trials included in the meta-analysis of the primary outcome of Cochrane reviews published between April 2012 and March 2013. Data extraction and synthesis We collected the risk of bias assessment made by the review authors for each trial. For a random sample of 200 trials with at least one domain at high risk of bias, we re-assessed risk of bias and identified all related methodological problems. For each problem, possible adjustments were proposed that were then validated by an expert panel also evaluating their feasibility (easy or not) and cost. Avoidable waste was defined as trials with at least one domain at high risk of bias for which easy adjustments with no or minor cost could change all domains to low risk. In the simulation study, after extrapolating our re-assessment of risk of bias to all trials, we considered each domain rated as unclear risk of bias as missing data and used multiple imputations to determine whether they were at high or low risk. Results Of 1286 trials from 205 meta-analyses, 556 (43%) had at least one domain at high risk of bias. Among the sample of 200 of these trials, 142 were confirmed as high risk; in these, we identified 25 types of methodological problem. Adjustments were possible in 136 trials (96%). Easy adjustments with no or minor cost could be applied in 71 trials (50%), resulting in 17 trials (12%) changing to low risk for all domains. So the avoidable waste represented 12% (95% CI 7% to 18%) of trials with at least one domain at high risk. After correcting for incomplete reporting, avoidable waste due to inadequate methods was estimated at 42% (95% CI 36% to 49%). Conclusions An important burden of wasted research is related to inadequate methods. This waste could be partly avoided by simple and inexpensive adjustments.
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Repurposing drugs in oncology (ReDO)—Cimetidine as an anti-cancer agent
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Full-text available
  • Nov 2014
Cimetidine, the first H2 receptor antagonist in widespread clinical use, has anti-cancer properties that have been elucidated in a broad range of pre-clinical and clinical studies for a number of different cancer types. These data are summarised and discussed in relation to a number of distinct mechanisms of action. Based on the evidence presented, it is proposed that cimetidine would synergise with a range of other drugs, including existing chemotherapeutics, and that further exploration of the potential of cimetidine as an anti-cancer therapeutic is warranted. Furthermore, there is compelling evidence that cimetidine administration during the peri-operative period may provide a survival benefit in some cancers. A number of possible combinations with other drugs are discussed in the supplementary material accompanying this paper.
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The Repurposing Drugs in Oncology (ReDO) project
Article
Full-text available
  • Jul 2014
The Repurposing Drugs in Oncology (ReDO) Project seeks to repurpose well-known and well-characterised non-cancer drugs for new uses in oncology. The rationale for this project is presented, examining current issues in oncological drug development, challenges for health systems, and existing and future patient needs. In addition to discussing the advantages of repurposing, the paper also outlines some of the characteristics used in the selection of drug candidates by this project. Challenges in moving candidate drugs into clinical trial and subsequent practice are also discussed.
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Factors associated with success of market authorisation applications for pharmaceutical drugs submitted to the European Medicines Agency
Article
Full-text available
  • Nov 2009
  • EUR J CLIN PHARMACOL
To identify factors associated with success of Market Authorisation Applications (MAAs) for pharmaceutical drugs submitted to the European Medicines Agency (EMEA), with an emphasis on the Scientific Advice (SA) given by the Committee for Human Medicinal Products (CHMP). MAAs with a CHMP decision (outcome) between 1 January 2004 and 31 December 2007 were included in the analysis. Factors evaluated were: company size, orphan drug (OD) status, product type, existence of SA, compliance with SA, therapeutic area and year of outcome. Compliance with SA was retrospectively assessed with reference to three critical clinical variables in pivotal studies: choice of primary endpoint, selection of control and statistical methods. Of 188 MAAs with an outcome, 137 (72.9%) were approved, whereas 51 (27.1%) were not approved or were withdrawn by the company. In the simple logistic regression analysis, company size [odds ratio (OR) 2.96, 95% confidence interval (CI) 1.92; 4.56, p < 0.0001) was positively correlated with a positive outcome, whereas OD status (OD vs. non-OD: OR 0.38, 95% CI 0.19; 0.77, p = 0.0067) was negatively correlated. A total of 59 (31.4%) MAAs had obtained SA related to one or more of the three critical variables. Thirty-nine of these were assessed as being compliant with SA. Obtaining an SA per se was not associated with outcome (SA vs. no-SA: OR 0.96, 95% CI 0.49; 1.88, p = 0.92), but complying with SA was significantly associated with positive outcome (compliant with SA vs. no-SA: OR 14.71, 95% CI 1.95; 111.2; non-compliant with SA vs. no-SA: OR 0.17, 95% CI 0.06; 0.47, p < 0.0001). Stepwise regression analysis revealed that company size and SA compliance were independent predictors of outcome. The proportion of the MAAs that had received SA increased from 22% in 2004 to 47% in 2007. Company size and product type were associated with the frequency of requesting SA (26, 33 and 46% for small, medium-sized and large companies, respectively; 16, 39 and 48% for known chemical substances, new chemical substances and biologics, respectively). Factors related to compliance with SA were company size and OD status (25, 60 and 84% for small, medium-sized, and large companies, respectively; 77 and 38% for non-OD and OD status, respectively). The strong association between company size and outcome suggests that resources and experience in drug development and obtaining regulatory approval are critical factors for a successful MAA. In addition, obtaining and complying with SA appears to be a predictor of outcome. Based on this analysis, companies, particularly smaller ones and those developing orphan drugs, are recommended to engage in a dialogue with European regulators via the SA procedure. Obtaining SA early in development and at major transition points as well as compliance with the advice given by the CHMP are recommended.
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Affordable orphan drugs: A role for not-for-profit organisations
Article
Aims: The success of the Regulation on Orphan Medicinal Products in the European Union is evidenced by the 127 orphan drugs that have had market authorization since 2000. However, the incentives aimed at stimulating research and development have had the unintended consequence of increasing drug cost, resulting in many orphan drugs not being cost-effective. Orphan drugs command an increasing share of the pharmaceutical market and account for a disproportionate amount of healthcare expenditure. Orphan drug ownership by socially motivated, not-for-profit organizations may facilitate access to more affordable orphan drugs, for the benefit of patients and healthcare systems alike. This study aims to describe opportunities for such organizations to become orphan drug Market Authorization Holders. Methods: We reviewed data on the ownership of EMA designated and approved orphan drugs, identified funding opportunities and business models for not-for-profit organizations, and summarised relevant legal and policy documents concerning intellectual property rights and drug regulation. Results: Using repurposed drugs as a paradigm, this narrative review navigates the regulatory hurdles, describes the legal context and identifies funding opportunities, in a bid to facilitate and encourage not-for-profit organizations to lead on the development of affordable orphan drugs. Conclusions: Although the regulatory steps required to obtain an MA for an orphan drug are numerous and challenging, they are not insurmountable and can be achieved by not-for-profit organizations that are socially motivated to reduce the costs of orphan drugs to the payers of healthcare. Opportunities for orphan drug development resulting in affordable products lie mainly with repurposed drugs.
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Drug repurposing in oncology-patient and health systems opportunities
Article
  • Oct 2015
  • NAT REV CLIN ONCOL
In most countries, healthcare service budgets are not likely to support the current explosion in the cost of new oncology drugs. Repurposing the large arsenal of approved, non-anticancer drugs is an attractive strategy to offer more-effective options to patients with cancer, and has the substantial advantages of cheaper, faster and safer preclinical and clinical validation protocols. The potential benefits are so relevant that funding of academically and/or independently driven preclinical and clinical research programmes should be considered at both national and international levels. To date, successes in oncology drug repurposing have been limited, despite strong evidence supporting the use of many different drugs. A lack of financial incentives for drug developers and limited drug development experience within the non-profit sector are key reasons for this lack of success. We discuss these issues and offer solutions to finally seize this opportunity in the interest of patients and societies, globally.
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