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In September 2022, RARE Revolution and Tanner Pharma Group co-hosted a RARE Rev-inar that brought together stakeholders to discuss early access pathways to medicines. The themes included the role of patient groups and healthcare professionals, communication strategies, real-world data collection, equitable access, ethical issues and patient pathways to access

Medicines that treat a particular rare disease may only be available commercially in a limited number of countries. In Europe, for instance, where there is a centralised approval process, there is wide variation in the availability of approved medicines among the various European countries.

A patient with a rare disease who cannot access a medicine commercially or through a clinical trial may sometimes be able to access treatment through an early access pathway. Increasing numbers of pharmaceutical companies are now willing to make their innovative medicines available in this way.

Most countries have a pathway for patients to get access to a medicine that isn’t available in their country or is still in clinical development. However, legislation varies significantly by country. Typically, the patient’s physician needs to provide clinical justification for why the patient needs access and obtain permission to have the medicine imported for their patient.

Existence of a pathway does not guarantee access and may ultimately depend on whether funding to purchase the medicine is available.

Early dialogue

Patient advocacy groups (PAGs) play a critical role in early access pathways (EAPs).

Roberta Smith (Alagille Syndrome Alliance) believes that pharma should engage with PAGs as early as possible in the development of a therapy—pre-clinical trial even. She explains that PAGs are ideally placed to distribute information that educates families about EAPs and to help identify patients. Their reach extends to parts of the world where there is less access to approved medicines and where there may be greater demand for early access pathways. PAGs can open the door for patients internationally, creating opportunities for patients, healthcare professionals (HCPs) and pharma companies to connect one-on-one.

“We monitor our support groups very closely. We hear what people are saying and reach out to them.”

Roberta

Keep and maintain dialogue

Establishing and maintaining dialogue between companies and PAGs is vital for the smooth running of EAPs.

David Caponera (Novo Nordisk) explains the benefits of dialogue. First, it enables companies to engage with the patient group to understand what patients’ needs are. Second, companies can share information about clinical trials and EAPs with the HCPs who work with the PAG. Last, companies can keep PAGs abreast of the progress of clinical studies.

Because drug development can take many years, ongoing communication is key, through things like press releases and sharing a company’s successes within the community, Roberta adds. “Patients lose sight of the companies and their progress, if we don’t stay connected and informed.”

“It is truly such a disservice to the patient community if there’s not a great relationship between the patient advocacy group and the company.”

Roberta

Making connections

In the US, the 21st Century Cures Act obligates any pharma company, regardless of its location, to include information about early access on its website if it is conducting clinical trials in the US. This is a first step in opening communication between stakeholders.

Dawn Sullivan (Ultragenyx) explains that companies should also make it clear “who to contact within the company about early access and how”. Beyond that, pharma companies need to have internal clarity, so that questions about EAPs are routed appropriately and responded to quickly.

David adds that we should not discount the “old-fashioned way” to respond to people making enquiries: “pick up a telephone and talk!”

“If you have an internal advocacy team, have them go ahead and connect with the patient; connect your medical teams with inquiring physicians. Just don’t be afraid to communicate.”

Dawn

Overcoming obstacles

Naturally, there can be challenges to be overcome in achieving effective communication between the many stakeholders involved in early access pathways.

From his clinical perspective, Prof Anibh Das (Hannover Medical School) found that he and a pharma company had different expectations around how frequently and to what extent data on patients in an EAP would need to be fed back. Not too much information can be expected to be provided by busy physicians.

Dr Femida Gwadry-Sridhar (Pulse Infoframe) feels that pharma companies need to understand the clinician workflow in different specialties and make the process of data collection as easy as possible.

Roberta, too, finds complexity within some of the processes around EAPs. There can be a lot of paperwork involved for physicians and the processes aren’t always perfect, which sometimes creates significant difficulties for patients waiting for the EAPs to move forward. Having communication with patients within the community, PAGs often hear from patients when the EAP processes get stuck and can then highlight the issue to the company involved, she says. Effectively, they become “EAP counsellors”, mediating between patients and the company, helping patients while also managing their expectations and helping the process along.

Sometimes communication needs that little bit of extra effort, Dawn notes. “Sometimes, for instance, that might mean finding a translator. Sometimes that might mean working with other partners, such as companies like Tanner Pharma Group, who may know people who can help us answer questions.”

John Lagus (Tanner Pharma) emphasises the importance of a collaborative approach to communication and getting the mechanisms and process right, not least when the patient is in an underserved country. “The beauty is that stakeholders oftentimes are very aligned in terms of wanting to do good for patients,” he says.

As Nicola Miller (RARE Revolution) says, “putting in work at the front end to manage expectations and have really good communication helps iron out pitfalls that can come further down the line”.

EAP data have significant value

EAPs not only potentially help patients who may otherwise lack access to medication but also provide real-world data (RWD) about a drug’s effectiveness, safety and outcomes for a wider population than the clinical trial, for which patients must meet tight criteria to enrol. The value of that broad knowledge is significant in influencing payors, Femida says. After all, “if you get a drug approved, it doesn’t mean anybody is going to pay for it.”

EAPs also help companies understand how a drug will fare in different jurisdictions and help them with their future marketing and targeting, she adds.

“We know that in real life, a drug that’s approved is going to be used in patients who don’t necessarily fit the eligibility criteria for a trial… The EAP becomes very attractive as a mechanism to actually get a product into people’s hands and to collect information about how patients do, including quality of life data, not just the clinical and biomarker data.”

Femida

Thoughtful data collection

One of the most important things for companies is having clarity about the real-world data that they want to capture in an EAP. Companies needs to take a very pragmatic approach and think about “a minimal data set”, says Femida.

John has found that companies can sometimes seek to collect a level of information that would be more appropriate for a clinical trial than for an EAP. In such cases he recommends dialogue with key investigators in the clinical trial and with PAGs to clarify what real-world data should be captured to bring maximum benefit.

How the data are collected is important too. Femida underlines the importance of mapping data to a regulatory standard so that it is usable and she draws attention to the recently published FDA guidance on the topic.

Asking patients to consent to taking part in a registry or real-world data registry when they first register for a clinical trial is a useful approach, Femida says. Then, patients who don’t meet the eligibility criteria for the clinical trial can still contribute their real-world data to research. This proactive approach means that patients do not have to be approached again for consent and that there is not the scramble for real-world data that often happens towards the end of a clinical trial.

John adds some practical tips for encouraging the participation of clinicians in real-world data collection. In some countries it is possible to offer them a small stipend to remunerate them for the time they spend capturing real-world data; they can also be offered the opportunity to be part of any publication that follows.

“You want to think about what the regulator is going to want. What do we need to find out from patients in terms of their lived experience with a particular condition as well as how the drug is affecting them… their preferences and their quality of life?”

Femida

Partnering with PAGs to collect RWD

“Looking at some of the failures that we’ve seen in treatments, in some cases, it’s because we haven’t really understood the natural history.”

Femida

Scientists have a perceived view of a disease based on what they know from science and what’s been published, Femida says. She believes that it is necessary to sit down with patients and find out what is important to them. “When we were building the CDKL5 data dictionary, we sat down with patients first, before we sat down with clinicians.”

Roberta, too, is clear on the need for such an approach: “We have had situations where what was seen in the clinical setting was completely different to families’ daily experiences. We have been able to offer companies creative ways to collect data directly from patients so they can correlate, refine and align the data that they see.” She says this was instrumental in the progress of one EAP, helping researchers to see patients’ experience outside the clinic.

Measuring a disease’s impact

Measuring the true impact of a disease is a challenge because sometimes the instruments used are too generic. For instance, some instruments used in rare oncology were developed decades ago and don’t reflect subsequent advances in treating the conditions. Femida says that ascertaining whether new instruments are required for effective data capture should be a consideration early on. Regulators should also be aware of this issue when reviewing data, she adds.

Patient groups have a key role in advising on the data to be collected and on whether data sets truly reflect a disease.

Companies can capture a more balanced view of the patient population if they collaborate with multiple patient organisations, including those in different countries This can be especially helpful where patient numbers are particularly low, Nicola adds.

In the rare disease space, patients are often keen to contribute their real-world data to companies, but it can become a drain, Femida says. “A patient doesn’t have time to enter the same data into four different portals for four different organisations… We’ve used memoranda of understanding, where if the patient consents, we will share those data in a de-identified, GDPR-compliant way with other researchers.” This collaborative approach to research means that the “burden is no longer on the patient and they don’t feel they’re letting anybody down”.

“It’s really important to have dialogue so that you capture what the patient values in a treatment, or what it means to them to slow or halt the progress of their disease… One PAG leader told me ‘I’m not the biomarker. My symptoms are so important and sometimes they’re not captured correctly.’”

David

Low- and middle-income countries

Even within Europe, access to approved medicines can vary greatly. In a low- and middle- income country, the likelihood of access decreases even more, but there are pathways to make it happen. In countries where regulatory pathways are not well defined, discussions with the respective ministry of health are needed to discuss the route to get medicines to patients in need.

Crucially, patients in low- and middle-income countries may not have health insurance, Prof Das observes. So, even if a drug is approved or licensed, patients may not be able to get it without an early access pathway, such as a compassionate use programme.

In these countries there may be complexities in terms of politics, importation and customs, supply chains, storage and patient monitoring for safety and effectiveness. John explains how Tanner Pharma is working in partnership with other companies to find sustainable approaches to use pathways in these countries. Many stakeholders—pharmaceutical companies, ministries of health, patient groups, NGOs—need to be brought together to help patients in these areas, he says.

Dawn elaborates on some of the specific challenges she has seen. One of the difficulties for a patient is finding a physician who is not only able to treat their indication but also willing to take on the added responsibility of getting early access to medication: “Depending on a particular country’s local regulations and governance, some of those hurdles can be quite challenging, even nearly impossible.”

She adds that some challenges are “out of the company’s hands, the physician’s hands and definitely out of the patient’s hands”, such as when drugs are kept sitting in customs for a long time, potentially not in a temperature-controlled environment, or when the facility for administering a compassionate use treatment, such as an infusion, is so distant to the patient’s home that the logistics become a barrier to access.

The challenges in achieving equitable global access to medicine are clearly considerable and cannot be overcome overnight. However, John is encouraged by the progress that he has seen during the last 16 years.

“It gives me great hope to think about where we could be in 20 years’ time if a coalition of the willing come together and ask ‘how can we make a difference?’”

John

Sharing information

“Everyone, every company involved in considering supporting access to a drug for a patient should adhere to the ethical standards of what is in the best interest for the patient. Access in this framework—early access, expanded access, compassionate access—is treatment, not research.”

Dawn

Roberta believes that setting expectations about the timeframe in which a drug may be available is important, “…working to maintain hope that it will be there, but never making promises.” Families may become desperate as they wait years for a treatment that is bringing benefit to patients elsewhere. Companies need to work closely with PAGs to give them as much clarity as possible, she says.

When a drug becomes available for early access, limited supply can sometimes be a challenge, John notes. Companies may want to respond to requests for early access but need to prioritise treating patients enrolled in the clinical trial. “Companies will sometimes set up external ethics boards that can look at each case individually and make a decision about how to allocate that medicine,” he says.

“There should never be any false illusion given to the patient, there should never be any guarantees.”

Dawn

When an HCP is accessing a drug through an EAP to treat a patient, companies should give all the pertinent information to the HCP, who must share that with the patient, so that the patient can make an informed decision, Dawn says. She adds that the patient’s decisions about their treatment need to be respected at all times: “Sometimes there can be concerns that they might be making the wrong decision; for example, when the choice is to not move forward with utilising a potential treatment. But that’s not for us to judge.”

A spectrum of desperation

Prof Das illustrates the importance of early access pathways in conditions such as inborn errors of metabolism, where patients are in desperate need of treatment: their condition is lethal and may deteriorate within a short space of time, so they simply do not have time to wait until a drug is approved.

As Roberta puts it, this creates a “spectrum of desperation” for patients and their families. She recalls having a patient with a rare skin condition who travelled overseas to get a cream that was not available in the United States. “When they were no longer able to travel, they purchased every ingredient in that cream to make it themselves”, she says.

Patients may try to acquire a medication that is not available in their own country through overseas contacts, like friends and family members, Roberta says. These efforts can result in long chains of people transporting a medication across national borders. Some people attempt to smuggle medications or enter countries illegally. For them, the potential benefit outweighs the considerable risks. “People are losing their homes, their livelihoods, in order to pay for medications that they would not be able to afford otherwise, if their insurance isn’t covering them—which we see quite often.”

Roberta’s organisation works hard to share information with patients in its network and communication channels about the different ways they may have to access to medicines, but she knows that this information does not reach all parts of the world. She believes, it is “important to find the clinicians who can spearhead the communication and share information directly”.

“Patients sell their homes, their cars—everything they have—and will move in with another family in order to try to keep their child or their family member on a drug that they don’t know if they’ll have the next day.”

Roberta

Practical tips for patients

David advises that patients be persistent in reaching out to relevant pharma companies and that they stay close to their PAG. HCPs can also be approached because they may have useful contacts who can share information.

It is also a good idea to keep an eye on the information available through regulatory body websites and umbrella organisation websites, like NORD, Eurordis, CORD and Global Genes, he says. These umbrella organisations may have useful connections with pharmaceutical companies.

David’s final piece of advice is to not be afraid to use the different terms for EAPs, including expanded access, compassionate use, early access, special access, named patient, and so on. This can help bring the full picture into focus.

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