Embracing Early Access

Compassionate use programs offer hope to patients who have ran out of options. But the benefits must be weighed against the risks.



Over the last decade a host of novel drugs and biological agents with potential to cure serious illness has been developed by the pharmaceutical industry.

These innovations have not yet reached a broad swathe of patients, however, as they still require regulatory approval. There is a path to early access for a sub-section of the population however, many of whom do not meet clinical trial criteria and often have few options left.

Article 83.2 of European Union Regulation (EC) No 726/2004 allows pharmaceutical companies to run compassionate use programs (CUPs) for patients with “life-threatening, long-lasting or seriously disabling illnesses” who cannot be treated satisfactorily with licensed medicines, or who have a disease for which no medicine has yet been licensed.

But there is no mandate on companies to develop CUPs and the reality is that there are currently only a limited number of EMA-endorsed programmes, including ledipasvir/sofosbuvir, daclatasvir/sofosbuvir combinations for hepatitis C (see below) and IV zanamavir for confirmed pandemic H1N1 infection.

It is a highly complex and sensitive area and one where there are many unanswered questions. Providing early access through programmes such as compassionate use (CUP) or expanded access have some benefits but there are myriad risks and challenges too. Striking a balance between risk and opportunity can be tricky.

Christine MacCracken, director of patient support in the office of the chief medical officer at Janssen, believes all pharmaceutical companies with therapies in development that have the potential to meet unmet medical needs, or are transformative, should consider their approach to CUPs “early and often”.

She maintains that “providing early access is a principled and patient focused consideration, not a business consideration, to help patients who often have no other treatment options available to them.”

Florence Penicaud, head of market access, Switzerland, at UCB, says CUPs can also be beneficial in terms of increasing “real life” knowledge of the drug beyond clinical trials, can increase awareness of the drug and build constructive interactions with different stakeholders including key opinion leaders (KOLs), payers, regulators and patient associations.

But there have been several high-profile cases in recent years, some of which have been played out very publicly on social media, where patients in the advanced stages of illness have been denied early access to life-saving drugs.

The companies involved have cited reasons including a lack of data on safety and efficacy or a lack of supply to accommodate requests.

Dimitar Tonev, senior medical director at IQVIA, believes these cases have shone a light on an inherent paradox and a “deeply embedded controversy” within the pharmaceutical industry.

“In the credos of each and every pharmaceutical company there is of course a strong philosophy that everything is being done to benefit the patient in need. So, you would think that compassionate use programmes (CUP) would be an archetype of this,” he says.

“But there is a reluctance to develop these programmes. Pharmaceutical companies are not driving this agenda.”

He believes there are numerous reasons for this.

During his time as Medical director of Bristol Myers-Squibb (BMS), he was involved in a CUP that was jointly run in 2016 by BMS, Gilead, NHS England and HCV Research UK for patients with chronic hepatitis C and decompensated cirrhosis.

The programme involved 406 patients with advanced liver disease being given a 12-week course of free of charge NS5A agent-either ledipasvir (Gilead) and daclatasvir (BMS) in combination with sofosbuvir (GILEAD) - anti-virals which were at the time all still in development.

The results of the programme, which was funded by a £12m grant from NHS England, found that antiviral therapy in patients with decompensated cirrhosis led to a very high Sustained Virological Response rates and prolonged improvement in liver function, with no evidence of paradoxical adverse impact nor increase in liver malignancy.

It was a success, says Tonev, and greatly benefited the companies involved in terms of data generation and marketing but, he says, it was a far from easy journey to get the CUP up and running.

“There was some confusion initially around methodology and a general lack of knowledge of the internal rules that apply for early access programmes,” he says.

“As a result of this lack of knowledge, many CUPs use the same protocol as for clinical trials but in this case that presented a problem. There is a clinical trial mantra which states, for example, that it is unethical to include prisoners in clinical trials. In the BMS/Gilead CUP this was not acceptable because NHS England was funding the programme and could not be seen to be discriminating against any British citizen.

“There were also other rules to consider. For example, when you treat advanced patients in a programme such as this the regulatory authorities will normally forbid the collection of data, other than safety data, because they fear the company could mask the compassionate use programme as a clinical trial and run it under less stringent conditions.

“This eliminates one of the very few benefits pharmaceutical companies gain from running CUP programmes – that of generating real-world data.

“The model in this case was beneficial because HCV Research UK, a not-for-profit organisation, was mandated by NHSE to collect the data and evaluate it.”

MacCracken says the risks and benefit must be carefully examined and all CUPs require a multi-dimensional assessment before they can be considered viable.

“Establishing that the clinical trial program, the preferred form of access, will not be jeopardised by providing early access is essential,” she says. “This is important for a few reasons – first, clinical trials are the foundation of how medications are studied to evaluate efficacy and safety and the data from them will be submitted to health authorities for review. Because of this, items such as a drug or biologic supply must be considered to ensure the clinical trial programme is adequately supplied.”

She adds that a risk/benefit profile must be carried out on the medication before it is allowed to be used in a CUP setting.

“If it is determined to be appropriate to provide early access for any one agent, it should be done equitably and consistently,” she adds.

And she stresses the importance of transparency: “It is incumbent on those developing agents as described above, to be transparent about their approach and policy around early access even if that position is such that early access is not possible. This transparency in communication to patients, providers and caregivers is paramount to supporting people who are seriously ill as well as the physicians who may seek to make a request on their behalf.”

Providing early access requires a significant investment in time and collaboration across an organisation.

Penicaud highlights some of the more general challenges.

“CUPs can be complex to put in place and take a lot of administrative effort,” she says.

“The major objective is to avoid the risk of a serious adverse event (AE) which could first be dramatic for the patient and compromise the launch of a product beyond the positive results in the clinical programme or could generate negative feedback even if used in a very specific situation.”

She adds that consideration should also be given to whether a CUP could complicate the process of price setting later on.

MacCracken spells out the need for a robust infrastructure to address patient eligibility which allows for consistent decision making.

“This is one of the reasons we initiated a first in industry pilot in 2015, the Compassionate Use Advisory Committee (CompAC) to support Janssen decision making for compassionate use requests. This model ensures evidence-based, transparent, patient-centric, fair and timely framework for independent evaluation of our early access strategies as well as single patient requests by an international group of medical experts, bioethicists and patient representatives.”

Pre-launch access to a curative treatment could also reduce the pool of eligible patients for commercially available treatment later, reducing the potential revenue in a country, adds Tonev.

He also highlights the considerable costs involved in such programmes, mostly driven by the fact that many companies don’t have the necessary man power and use a specialised intermediary which see this ‘a substantial commercial opportunity’ for them.

He points out that many companies fear that CUPs could compete with and slow down the clinical trials recruitment, especially in orphan indications. There are concerns that patients would prefer to get access to drugs through CUPs, instead of enrolling in clinical trials for fear of being given a placebo.

Expectations about experimental drugs can also be unrealistically high. There is no guarantee they will work, and the issue is further complicated by the fact that there is no legal framework for CUPs across Europe. Each of the 28 Member States is required to coordinate and implement its own individual programme with its own rules and procedures.

For the reasons set out above, says Tonev, it is crucial that companies considering CUPs should begin developing a clear strategy as early as after Phase 1 clinical trials. The strategy should be a company-wide endeavour and should involve medical and commercial. The ultimate solution to square the circle, he believes, is electronic data records.

“If the healthcare system used a linkable, traceable Electronic Medical Records (EMR) system it would enable the NHS to know how effective products are (in CUPs). This is the ultimate solution to address the real-world efficacy paradox and could eventually result in pharma companies actually buying data from a third party-ideally an academic consortium as HCV Research UK.”

In April 2017, EURORDIS – Rare Diseases Europe published a new position paper on compassionate use. It called on:

  • Patients to engage in early discussions with medicines developers to agree on if and when a CUP could be relevant, and for which patients
  • Industry to plan for an adequate supply of the product to be provided through the CUP
  • National authorities to improve transparency of the CUPs they authorise in their Member State, so that clinicians and patients are aware of programmes and how to join them
  • The European Commission to compare different national schemes for CUPs in Europe.

Given the challenges and the risks involved many companies must understandably question whether it is worth having an early access strategy at all.

MacCracken says it absolutely is.

“’Worth’ is relative to where you sit at a given time but as a company, it’s important for us to help those we can where appropriate and in accordance with our principles.

“It must be done thoughtfully, considering each unique group of potential patients and requires significant effort by multiple stakeholders across a company,” she says.

“Is it worth it? To help patients in need? Yes. It’s worth it. I’m fairly certain that you or I, if we found ourselves in the extremely difficult and emotionally charged position of being out of treatment options but then were presented with something that may help us, we’d say it was worth it.”