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MAPs during a global pandemic

pharmafile | February 26, 2021 | Feature | Business Services, Manufacturing and Production, Medical Communications, Research and Development, Sales and Marketing | COVID-19, MAPS

Early and managed access programmes provide opportunities for patients to get the treatments they need faster – but the COVID-19 pandemic has taught us that the balance between efficacy and speed in the approval and rollout of medicines can be a treacherous pathway, Jack Goddard writes

COVID-19 has thrown light on several new phenomena over the last year: wearing a face mask just to grab a meal deal, constant cries of “you’re on mute” during every single work meeting, and a genuine horror at the thought that, once upon a time, you were ever less than a metre away from someone you didn’t know.

In the pharmaceutical world it’s also brought to the fore the world of early and managed access programmes (EMAPs) – local systems put in place to allow patients access to drugs that aren’t yet publicly available. They are most commonly used on seriously ill patients who have no other treatment options left.

In the middle of a global pandemic, governments and institutions were able to use EMAPs to their advantage. Of all institution or government managed access programmes (MAP) requests made to pharmaceutical company Novartis last year, 77% were for COVID-19-related use.

Novartis’s managed access programme (MAP) allows an institution or physician to contact patients to request an investigational treatment before it is approved by a local authority. As long as the request complies with local law and certain conditions are met, Novartis can supply the treatment.

As such, governments were able to use unapproved or repurposed drugs to help them manage a pandemic that was rapidly unfolding before them, without having to wait for that drug to go through three phases of clinical trials.

Dr Myriam Mendila, Global Head of Medical Affairs Oncology and Oncology CMO at Novartis, explained: “Novartis MAPs provide an opportunity to access innovative unapproved therapies for patients who are in need, such as in instances where a patient has a serious or life-threatening disease or condition, for which all currently available treatment options have been exhausted and enrolment into a clinical trial is not possible.

“The decision on whether access via a MAP is appropriate is based on a thorough evaluation of the potential benefits and risks of each compound requested in the respective disease.”

Novartis received and reviewed 10,670 MAP requests in 2020, of which 94% (more than 10,000) were approved.

The concept sounds like a win-win. Pharma companies get a chance to test their treatments in the real world, while patients who may have exhausted all their other options get the opportunity to try a new treatment. However, considering these are pre-approval treatments, how effective are they actually? And how much does the patient really benefit?

It’s important to understand that efficacy in pre-approved treatments can be difficult to measure. Pharmafocus spoke to Brad Groves, Associate Director for Managed Access at NICE, a public body that assesses the clinical and cost effectiveness of treatments licensed by the MHRA.

He explained: “What we tend to see, outside of cancer, in some of the patients is a clinically meaningful improvement in their ability to perform the normal daily activities that you might expect someone to be able to do.

“What drugs in managed access typically do is halt the progression of the disease, rather than improve someone’s functional capability. Even when we do see those improvements in patients who do have them, although clinically meaningful, [the treatments] aren’t restoring them to what you’d expect someone without the condition to have.”

This isn’t the case for everyone. Some patients do fully recover but, because MAP treatments are so diverse, it is difficult to quantify what factors contribute to higher effectiveness. Groves continued: “For some diseases we do see patients be what you expect someone without the disease to be like but that’s in really small numbers.

“Typically, the way I could describe it is the patients who are diagnosed at the youngest time [recover best] because these are often congenital or progressive diseases. The earlier the diagnosis, the better the patient will perform.”

Efficacy isn’t the only concern for a patient, of course. MAPs primarily exist to benefit them, and in many cases they do, but there are other, more intangible negatives to receiving treatment in this way.

“These treatments are often delivered in what we call highly specialised centres, and are not always close to where the patient lives,” said Groves. “The very first issue is the patient, who has quite severe mobility issues, has to travel across the country. And then be back in quite alien places, to get the treatments that they need.

“One treatment that occurs to me involved a lumbar puncture to deliver the treatment. So, these are patients who are really quite poorly, having to undergo that procedure, and even with that procedure in the best of situations, there are side effects that patients have. With almost any treatment you have side effects, a headache or flu-like symptoms or things like this for a few days afterwards. They’re not described as major in clinical terms but when you’ve got a patient who already has a poor quality of life, you’re adding to that.

“The trade off though is that these patients know that potentially their condition is either going to be halted, and they’re not going to get worse, and that’s a sacrifice some are willing to make, but often what we see is minimal improvements in the conditions that we are treating.”

Of course, MAP treatments are still only used on patients where there is a good chance that the drug will be effective. The medicines used will in most cases have gone through Phase II or Phase III trials and will have had to show benefit in these trials too. Novartis, for instance, will consider issuing a drug earlier in the development cycle, if the need is severe, but these are considered on a case-by-case basis according to the scientific evidence – MAP treatments aren’t a shot in the dark.

Nicky Wisener, Vice President of Business Development and Unlicensed Medicines at Clinigen, offered further detail. “If required, the physician will have to seek approval from their local competent authority or other relevant local committee to utilise an unlicensed drug. This would typically be granted on the basis that there is no alternative option approved and available in country and that there is enough evidence to extrapolate a level of confidence around perceived benefits to the patient,” she said.

“Only once they’ve gone through these regulation mechanisms and provided evidence that approval has been granted, can we ship the drug to them.”

Wisener explained that efficacy is almost impossible to measure as the treatments aren’t being trialled when used in an MAP, but there are indications as to how effective a medicine could be.

She explained: “Prior to requesting access, the physician will have reviewed the available data for the product and may have even acted as an investigator in a clinical trial, and would have enough faith in the perceived benefits to his or her patient to make an educated treatment decision.”

However, COVID-19 has changed the landscape somewhat. A new disease, unheard of until just over a year ago, leaves little time for clinical trials or marketing authorisation elsewhere to establish efficacy. Dr Mendila explained how it made Novartis streamline their approach. They used technology to speed up the process and reduced the number of questions physicians needed to answer to submit a request.

Nicky Wisener told Pharmafocus that to meet the sudden need for COVID-19 therapies, competent authorities in various countries sped up the regulatory process. This meant that pharma and biotech companies, rather than open MAPs, would prioritise the clinical programme to enable robust data capture with the aim of approval. Then, as soon as the data became available, companies were able to allow access through a MAP, while waiting for product approval. “Clinigen is actively supporting companies in this situation to enable treatment to sick patients where there is no approved option available to them in the short term,” she said.

Remarkably, however, pharma companies are finding it hard to find enough patients to do trials so they can start testing out their treatments. Wisener said: “One of the challenges is that clinical trials clearly rely on there being a required number of patients available to be recruited, but what we found with COVID patients presenting to hospital was that there was a significant demand for the patients to be enrolled into a number of sponsored trials to enable the required robust data capture, and ultimately product approval. This created a kind of competition for patients and if the required number of patients were not available, recruitment was delayed and this then has a knock-on effect to the time it takes for the trial to reach robust conclusions.”

This isn’t the only problem that MAPs have thrown up, with more general problems meaning the system doesn’t run as smoothly as some may like.

One of the biggest problems for companies such as Clinigen is getting products out to countries where there are no MAPs or clear regulations around early access, especially in cases of unmet medical need. The company have struggled in the past to get medicine to patients, due to regulatory restrictions or importation issues; although this doesn’t prevent early access medication entirely, it can delay the process of delivering treatment in what can often be a time-sensitive scenario.

Wisener added: “In these cases we find a real inequality by which patients aren’t always able to access products that in some cases can be life-saving. Clinigen goes to great lengths to work with regulators and healthcare professionals to enable access in as many countries as possible, a number which is consistently growing. But in some cases, the onus still lies with the patient or carer to engage authorities or travel to other countries or regions for access.

“Clinical trial is vitally important and has to happen, and patients should access drug and clinical trials or else you can’t ever commercialise it. [But] the global inequality of access to drugs is just huge. Sorting inequalities globally across access to medicine full stop, whether that’s early access, commercial or otherwise is really key.”

Groves of NICE believes that the pricing of treatments could be changed to better reflect the impact they have. “Companies just need to price the drug at a level that is commensurate with the benefit that they can demonstrate patients,” he said. “I think what we could do within the health system is make sure that the data are available on these patient groups, so that we can track the natural history of these diseases and companies have that as a baseline, when they start. They know what they’re comparing their trial data to.”

However, Dr Mendila was keen to sing the praises of MAPs. She said: “Over the years, MAPs have enabled Novartis to provide access to innovative treatments to a larger patient population, i.e., outside of a clinical trial, prior to obtaining local regulatory approval, collect high level data that could support the regulatory filing, and inform the clinical development programme.

“Primarily,” she added, “the MAPs are set up for the benefit of patients who are in need.” Indeed, Novartis sent out 6,000 unapproved or repurposed medicines to treat COVID-19 patients between March and August last year. In a system where a treatment can take several years to get authorisation, MAPs allowed pharma companies to step in and save lives.