Drug Repositioning

– An Underused Strategy for Cancer Drug Development and Access to Next-line Cancer Treatment?

By Peter Nygren, Uppsala University, Department of Immunology, Genetics and Pathology and Uppsala University Hospital, Department of Oncology, Stefan James, Uppsala University, Department of Medical Sciences and Uppsala Clinical Research Centre


This workshop will focus on a less conventional way to develop new cancer drugs, i.e. ‘drug repositioning’: the use of a drug already approved for another indication. In the light of several successful examples of this strategy, along with the often-modest benefit from and low cost-effectiveness of new cancer drugs, drug repositioning is seemingly a promising approach that could, in theory, provide new cancer drugs more rapidly and at considerably lower costs for the development phase. Randomized clinical trials based on national registers are one approach that have proved to be successful and could be developed. In addition, drugs that are candidates for repositioning into cancer drugs could be offered as ‘last-line’ treatments to patients with disease progression while on established treatment.

However, both drug development based on repositioning and individual patient use of drug repositioning candidates outside of clinical trials within routine healthcare run into problems from scientific, economic, ethical and healthcare resources points of view. This workshop will address these issues from the perspectives of the different parties mainly involved: patients, healthcare staff, medical authorities and pharmaceutical companies.

Workshop key issues to be addressed

  1. Assess the overall potential and limitations of ‘drug repositioning’ for development of new cancer drugs and in ‘innovative practice’.
  2. Discuss if there are ways to make cancer clinical trials less complicated, resource-demanding and expensive with the overall aim to allow for more patients to participate in drug development based on the principle of drug repositioning and, thus, to more rapidly move cancer drug development forward. Furthermore, are there ways to make cancer drug development based on drug repositioning more attractive for pharmaceutical companies?
  3. Elaborate on ways to use ‘innovative practice’ based on drug repositioning and within a scientific context to the potential benefit of the individual patient and as a starting point for more definitive clinical trials and preclinical research.
  4. Consider the ethical, scientific and healthcare issues of drug repositioning and ‘innovative practice’.

New drugs, high costs, unclear benefit

Despite considerable progress in basic cancer biology knowledge in recent years, the development of new, more efficient cancer drugs has, with some exceptions, not been very succesful ( Davis C., Naci H., Gurpinar E., et al, 2017, Prisad V., 2017) Thus, newly introduced drugs, mostly categorized as ’targeted’, for the most common solid cancer types have typically provided little benefit and meant nothing more than adverse effects and very high costs (Workman P., Guilio F., Schellens J., et al., 2017). This situation increases the need to look into complementary drug development strategies, e.g. drug repositioning, exploiting the possible use of substances on the market that, if properly investigated, can propose additional treatment options.

The cancer patient’s ‘last-line’ dilemma

For cancer drug treatment in advanced disease settings, the evidence cumulated through randomized trials in the major cancer diagnoses typically results in the recommended use of a limited number, up to a handful but often fewer, ‘lines’ of treatment that can be used in sequence, with the use of a ‘next-line’ treatment following on from the previous one. After the last line of recommended treatment, or its cessation for other reasons, e.g. intolerance, the performance status of many cancer patients does not allow for consideration of new treatments directed towards the disease itself and the best option from a quality-of-life perspective is to provide symptom-guided palliative care.

When palliative care is not the only option

However, more than a few patients still have a good performance status following guidelines directed by the last-line treatment and are not in need of advanced palliative care. For very understandable reasons, these patients and their relatives frequently ask for additional treatment attempts.

If the treatment centre has an active clinical trial in which the patient could participate, this may be an alternative to providing the patient with yet another ‘line’ of treatment hopefully for a treatment benefit while at the same time contributing to the accumulation of new knowledge that might benefit future cancer patients.

But when no clinical trial protocol is available or the patient status does not fit with an active protocol, the patient could be said to be in ‘no man’s land’: too fit for advanced palliative care but with no cancer treatment options left.

Many patients and relatives accept this situation while others turn to alternative, unscientific treatments or try to find clinical trials at other hospitals, in their own country or abroad, with the hope of travelling there and participating. Often these strategies are felt to be very unsatisfying, both from the point of view of the patient and relatives and from that of the physician in charge of the patient. In addition, for many these alternatives are beyond reach.

Drugs approved for other medical conditions offer new possibilities

A physician would still be allowed to prescribe an ‘old’ drug to an individual patient, provided there is sufficient scientific evidence behind such a decision. Such a procedure could be beneficial for the individual patient. But to drive the development of healthcare forward, benefitting the global cancer community, a clinical trial procedure would be needed.

For the sake of patient safety, a clinical trial has to be preceded by numerous safety studies. Even if the drug substance is already on the market, such pre-clinical studies may need to be performed in order to evaluate potential risks and benefits related to the specific disease in question. The actual clinical trial will typically need a large number of patients, recruited, treated and monitored according to a standardized protocol.

An additional challenge for setting up clinical trials is, of course, that the number of patients suitable to be included will most surely be very small if data and patients cannot be gathered from a very large community of healthcare centres.

Considering the complexity of clinical trials, why not just continue with individual patient-based prescriptions of old drugs?

A more structured approach to evaluating the effects of old drugs for new indications can provide knowledge on how to treat cancer that, if successful, can benefit a much larger patient group. If unsuccessful, the results should also be shared with the research community.

A structured evaluation for repositioning of drugs would also be necessary for most healthcare systems to include the treatment in standardized care plans.

From an ethical point of view, leaving patients in the no-man’s land between approved treatments and palliative care, or risking ‘losing’ them to unscientific programmes, is, of course, most unsatisfactory.

Finally, considering the increasing pressure on healthcare budgets, repositioning of old drugs may be a cost-efficient contribution to the selection of cancer treatments.

Even if much new knowledge and data needs to be gathered when repositioning an approved drug, an advantage is that basic knowledge and investigations are already there and, that the drugs are immediately available for testing in patients for the new indication (Pantziarka P., 2017.45).

The starting point for a drug repositioning project is mostly findings in preclinical research using various cancer models but can also be based on epidemiological data or serendipitous findings of unexpected anti-cancer effects in patients starting drug treatment for a concomitant disease. Going through published data thus provides a great number of reasonably well-founded ideas for the repositioning of available drugs for use in cancer.

The quest for an alternative to conventional clinical trials

The process for starting and performing clinical trials has been criticized for becoming not only over-regulated, but also slow and very expensive. This makes cost-effectiveness so low that the use of some of the approved drugs is prohibited in many healthcare systems. The complexity of the process limits the performance of pivotal, game-changing clinical trials to those initiated or supported by major pharmaceutical companies.

Clinical trials for new substances are mostly sponsored by a commercial pharma company, with the financial and administrative resources available to conduct the pivotal clinical trial.

However, when it comes to a possible repositioning of already available drugs, there are rarely such actors to support and drive a clinical study.

The pharmaceutical industry has however little interest in supporting and financing such clinical trials. Among the obstacles are, e.g. the risk that the trial reveals new adverse effects or simply because the patent is about to, or has, expired. Thus, most cancer drug repositioning candidates will never move beyond the status of being promising based on preclinical and in some cases also very preliminary clinical findings.

A strategy for drug repositioning?

Thus, given the relatively modest progress in cancer drug development based on completely new molecular entities and the complexity of this process, as described above, there is an increasing interest in this much simpler repositioning strategy that, at least, could be considered as a potentially fruitful approach which is complementary to the traditional one.

National registries offer opportunities for a new approach

Pioneering work has been done by Uppsala Clinical Research Centre on the concept of building prospective randomized trials based on the Swedish national clinical registries, using the existing hospital networks and the registry infrastructure for patient identification, trial enrolment, randomization and follow-up. These registry-based randomised clinical trials (R-RCT) are now well developed as a type of pragmatic trial and a number of studies have been successfully concluded and changed international guidelines.

The new R-RCT concept provides the means for a faster and more cost-effective process for bringing approved drugs into use for new indications and at the same time limiting the cost and some of the burden for the investigators. The trial concept has been developed in the cardiovascular field but is moving on to other areas of medicine. Oncology is a field with a considerable need for more extensive evaluation of pharmaceutical agents in large representative patient cohorts.

However, some challenges and hurdles remain, regulative as well as practical. A guideline document has been written explaining how to design and run such trials and there is a belief that they have the potential to revolutionize the way future prospective trials are conducted. It is possible to design studies for building evidence for drug repositioning of already approved drugs for new indications. In this way we can avoid having to go through the costly and time-consuming work of building trial platforms, extensive safety testing and repeated patient visits and instead focus on the efficacy of the new indication.

Healthcare as an arena for research and development

Closely related to the problem of selecting drugs for repositioning into evidenced-based options by means of the generation of data from clinical trials, is how to deal with patients in ‘no man’s land’. How can we help when clinical trial protocols are not available but there are published scientific data, preclinical, clinical or epidemiological, that one or more established drug in use for other purposes could have beneficial effects for the cancer type in question? If such a drug is inexpensive and known to be well tolerated, it is tempting to let the patient try it in what could be denoted ‘innovative practice’. Such treatment of an individual or even a few patients would be in agreement with the Declaration of Helsinki, provided that patient-informed consent is obtained and that the information so generated is documented and, as applicable, made publicly available and then made the focus for research.

However, this would potentially be in conflict with the basic principle that healthcare should always be based on scientific evidence and/or extensive experience and mere preclinical data will probably be considered insufficient for this in most healthcare systems. There is, of course, also a risk that individual physicians set the level of scientific evidence for individual ‘repositioning treatment’ too low, putting the patient at risk and undermining the confidence in healthcare. In addition, this kind of treatment very soon comes close to research and would then run into conflict with the principle of committee and authority approval to safeguard ethics and scientific quality.

There is an obvious bridge from healthcare to science here if the experience and outcome of treatment of individual patients based on a scientifically based ‘repurposing’ rational are made public as ‘N of 1 or few’ studies. Such case studies could then form a basis for the selection of treatments which are worthwhile to investigate more thoroughly in adequately powered and controlled clinical trials.

Overall, this sensitive grey zone between healthcare, science and unacceptable use of unjustified beliefs seems relevant to discuss with the aim of finding ways forward to benefit individual patients while simultaneously satisfying scientific and ethical principles.


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Davis C., Naci H., Gurpinar E., et al. Availability of evidence of benefits on overall survival and quality of life of cancer drugs approved by the European Medicines Agency: retrospecitve cohort study of drug approvals 2009–13. Br Med J 359:1–11, 2017.

James S., Rao S.V., Granger C.B., Registry-based randomized clinical trials – a new clinical trial paradigm, Nature Reviews Cardiology 12:312–316, 2015.

Pantziarka P. Scientific advice – is drug repurposing missing a trick? Nature Rev Clin Oncol 14:455–456, 2017.

Prisad V. Do cancer drugs improve survival or quality of life? Br Med J 359:4528, 2017.

Workman P., Guilio F., Schellens J., et al. How much longer will we put up with 100.000 dollar