The Benefits and Costs of Compassionate Use Programs (CUPs)

Despite billions of Euros being spent each year in the pharmaceutical industry on research, development and gaining approval for licensed use of ethical medicines, there are still broad areas of clinical needs not being met. Patients who are challenged by relapsed cancer states, a rare genetic disorder or has a life threatening disease yet the preferred drug candidate has not yet been approved by regulatory authorities are just some of the cases where CUPs have potential use. In particular for the latter case, early access for such a cohort of patients who fail to meet clinical trial inclusion criteria and are faced with few other treatment options, may benefit from the CUP.

It stipulates in Article 83.2 of European Union Regulation (EC) No 726/2004 that drug sponsors are permitted to conduct a CUP on a patient only if that patient is faced with a “life-threatening, long-lasting or seriously disabling illnesses” who has not responded successfully to licensed medical treatment, or otherwise has a life threatening disease state for which no clinical treatment has yet been approved. In the US, where CUPs are termed “Expanded Access” (EA), the FDA applies a similar criteria: “Expanded Access is a potential pathway for a patient with an immediately life-threatening condition or serious disease or condition to gain access to an investigational medical product (drug, biologic, or medical device) for treatment outside of clinical trials when no comparable or satisfactory alternative therapy options are available.” The FDA goes on further to identify the objective criteria of EAs:

  • “Potential patient benefit justifies the potential risks of treatment.”
  • “Providing the investigational medical product will not interfere with investigational trials that could support a medical product’s development or marketing approval for the treatment indication.”

Although the European Medical Agency broadly provides regulations and recommendations for CUP implementation, every European Union (EU) member state has developed its own rules and regulations. Moreover products entering these programs are generally not reimbursed, except in France where financing is offered on compassionate grounds.

As in conventional investigational trials, the patient risks against the clinical benefit must be carefully assessed and all CUPs require a multi-faceted approach to the investigation prior to it qualifying as a viable treatment option for the CUP. A particularly important step to adopt would be to profile the risks versus the benefits based on worldwide data of the current clinical trials ongoing and to even exclude it as a CUP treatment option on ethical and safety grounds if no phase I data exists.

There are of course challenges beyond the health outcome of a patient being assessed for CUP. Apart from the healthcare priority of avoiding serious adverse events (AE) which in the case of the patient already in a life threatening condition, holds the high risk of being fatal for the patient, with nowadays active reporting via social media could compromise the marketing launch of the medicine which base their campaign on clinical trial results reported in peer reviewed research journals. Such AEs reported would tend to have a negative impact on the pharmaceutical company’s marketing campaign. Setting up a CUP also tends be a complex process because the responsible organisation is seeking to provide early access to a drug which has not yet been legally registered for clinical use. Therefore this typically involves hiring a legal professional and collaboration across a number of external stakeholders and this inevitably involves much time and administrative input. Needless to say, CUPs are costly undertakings due to the organisation having to outsource to experts beyond their usual sphere of operation in R&D and gaining licensed approval with such external agents charging premium for their “specialised” services. There is the possibility of unrealistic expectations being anticipated by the patient in undertaking a CUP, because the experimental substance may have only shown a proof of principle in phase I clinical trials and this is clinical data taken from subjects in the investigation who are healthy individuals.

Beyond the drawbacks highlighted above, there are a considerable number of benefits associated with CUPs. The key and obvious one is that after all other treatment options have been exhausted, the patient can be thrown a life line with the use of an appropriately selected CUP. Another benefit of CUPs is that it allows a pharmaceutical company to acquire real-evidence data from patients enrolled in the CUP worldwide. Generating such real world evidence, can be used in turn to supplement the conventional clinical trial data acquisition process when seeking regulatory approval. A corporate social responsibility opportunity for the CUP is that it allows the pharmaceutical company to work beyond its conventional mould of merely being a money making organisation by doing the ethical thing for patients and being answerable to an unsolicited patient request for a medical treatment in a regulatory compliant manner. The usual mantra of drug companies is that they will focus on developing and getting the drug candidate approved in countries where there is only a commercial return on that investment and this has impacted on considerable health inequalities in terms of access to medicines. Typically it implies that patients living in less-developed or less well-connected parts of the world, like Africa or South America, for instance, do not have the means to access the clinical trial, unless they are financially and logistically able to relocate to another country where the clinical trial is recruiting subjects. CUPs therefore provide the opportunity for pharmaceutical companies to treat patients with an experimental medicine in what would have otherwise been a hopeless and fatal situation where there are limited medical resources. The anticipation is of course that the patient will switch to the licensed commercial supply of the drug candidate and begin paying.

A final benefit for CUPs is that it offers pharmaceutical companies a wider clinical experience with their pipeline product, not just to patients who would normally be excluded from their clinical trials but also to physicians and related healthcare professionals, prior to its commercial launch. The implications of this are twofold. Firstly, it allows the pharmaceutical company to generate a bigger key opinion network who in turn can potentially advocate for the pipeline product when the company is seeking licensing approval. Secondly, providing treatment to a patient via a CUP prior to its commercial launch, makes it more probable for that particular patient to buy and pay for that product when it does become commercially licensed based on the human element of customer loyalty.