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Innovative medicines: miracle drug or bitter pill?
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Research

Innovative medicines: miracle drug or bitter pill?

If you’re told tomorrow that you’re seriously ill, and there is a new drug, or one is in development, would you have access to that drug?

13 minutes
20 May 2021

Belgium has excellent healthcare, which also happens to be one of the most affordable in the world for patients. Nevertheless, Professor Isabel Spriet, hospital pharmacist at UZ Leuven, is regularly confronted with patients who need medicines that are not reimbursed by health insurance. This might be, for example, because their condition is very rare. “Pharmaceutical companies must take the initiative themselves to request reimbursement for their products via a procedure that costs money and time. Sometimes they consider the Belgian market to be too small to do that; for certain conditions only a handful of patients are concerned. A medicine may therefore come to the market in our country, but it’s would not be reimbursed by health insurance.”

One widely known story is that of Baby Pia, who needed the most expensive drug in the world to stop the degenerative muscle disease from which she suffered. Eventually her parents raised the necessary 1.9 million euros through crowdfunding. Such situations are fairly common, involving less enormous but still very problematic amounts, says Professor Spriet. “We’re seeing more and more patients whom we have to charge thousands or tens of thousands of euros per month. Take, for example, a patient who is pregnant with a child with a certain autoimmune disease. To save the child, the only option is a non-refundable treatment that will cost around 30,000 euros. You’re actually not allowed to put people in such a situation.”

And it's not just about drugs for rare conditions. “For patients suffering from infections of multi-resistant germs, we sometimes have to resort to antibiotics that have been on the market for years in say the Netherlands or Germany, but for which reimbursement has never been requested in our country. We have to import those medicines and the patient has to cough up the full price for them. For this sort of antibiotic treatment, that can amount to hundreds of euros per day, for weeks at a time.” Sometimes this involves medicines that were previously available and reimbursed here, but for which the manufacturer now prefers markets where the product can be sold for a higher price. According to Professor Spriet, the prices for medicines are quite low here compared to other countries.

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© Belga image

Strict criteria

The decision of whether or not to reimburse a new medicine can sometimes take a long time. In oncology, for example, new products are constantly being developed and generally put into use once they have been approved by the European Medicines Agency (EMA). Belgium is usually relatively out front in the reimbursement of innovative medicines, and especially cancer medicines, says Professor Minne Casteels, who like Professor Spriet is affiliated with the Department of Clinical Pharmacology and Pharmacotherapy. However, that repayment can sometimes take up to a year. The Minister of Social Affairs and the manufacturer must reach an agreement on the price of the medicine in our country, and the Drug Reimbursement Committee (CTG) of the RIZIV/INAMI must advise on reimbursement.

Professor Minne Casteels was chair of the CTG for many years until 2010: “When deciding whether or not to reimburse a medicine, the committee takes into account the evidence, the allocation available in the budget and the expected number of patients. Reimbursement is usually also subject to very strict rules. For example, a medicine may only be prescribed to a patient in a clearly determined state of illness; those who fall outside this criteria will not be reimbursed for the medicine. If you want to be treated with that medicine, it can cost you tens of thousands of euros per month, an amount that most people can't afford.”

If an expensive medicine is not reimbursed, a patient can apply to the RIZIV/INAMI Special Solidarity Fund (BSF). This procedure is time consuming and the result is unpredictable, says Professor Casteels. And there are, unsurprisingly, a host of necessary requirements to be met, e.g. it must be a rare condition. In addition to this fund there is also an internal solidarity fund within UZ Leuven, founded on contributions from doctors, which assists in certain cases according to strict criteria.

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© KU Leuven - RS

Free

There are number of other mechanisms to ensure that as few people as possible slip through the net, says Professor Casteels. “For medicines that are in the EMA approval track, the manufacturer can set up a compassionate use programme for patients under certain conditions. The pharmaceutical company then submits a request to the Federal Agency for Medicines and Health Products (FAMHP) to make the product available free of charge pending approval and reimbursement.”

Professor Spriet is a member of the medicines committee at FAMHP that considers these applications. Such a compassionate use programme is not just a nice gesture, she explains. “A pharmaceutical company has to pay to obtain approval, but this also ensures a guaranteed market, as it often involves long-term therapies. This way they get the medicine ‘in the hand of the prescriber’.”

The medical need programme is somewhat similar. Suppose, for example, that a drug for ovarian cancer is being tested for efficacy against late-stage thyroid cancer. Whilst the studies are ongoing, the company can set up a medical need programme for the use of that drug for thyroid cancer. This is also free for the patient until the medicine is approved for the second indication and is reimbursed.

Another scenario: if a particular drug is on the market for condition X and there are indications that it could also help with condition Y, a doctor may decide to prescribe that drug off-label, i.e. for a different indication than it says in the package insert. That does not mean that it is not scientific – there may already be a great deal of relevant literature – but it means that the medicine is not officially registered for that indication. And sometimes it will never happen because it doesn't benefit the company. Off-label use of a drug is common, but liability rests with the prescribing doctor and is not reimbursed in Belgium. Here too, the costs for the patient can amount to tens or hundreds of thousands of euros.

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Faster approval

And then there is the case of unmet medical need: a doctor who no longer has options to treat a particular patient – but has good reason to believe that a specific new, not yet approved, drug could be useful – requests free samples for that patient from the manufacturer. Here, too, liability rests with the doctor. Professor Casteels, as chair of the Ethics Committee for Research within UZ Leuven, checks whether the applications meet the conditions, for example, whether there is the proper informed consent of the patient. Programmes for compassionate use and medical need are also submitted to an Ethics Committee.

To speed up the approval of medicines so that patients have faster access to them, you increasingly see conditional market authorisation (CMA), says Professor Isabelle Huys, head of the Department of Clinical Pharmacology and Pharmacotherapy. Here, a medicine is approved early and conditionally by the EMA. This happens when there is a high medical need and the first data from the clinical studies are sufficiently promising. “The condition is that the manufacturer will continue to collect further data on efficacy and side effects. Typically, such a CMA occurs when phase two of a clinical trial has been completed, i.e. the first phase in which patients are involved, and after which a third phase on a larger scale will usually follow.”

Belgium is usually relatively early for the reimbursement of innovative medicines. However, that repayment can sometimes take up to a year.”

Desperate

Pharmaceutical companies often choose Belgium for their clinical studies, says Professor Casteels. This is to the advantage of patients, who can sometimes have relatively early access to possible new medicines. Hundreds of clinical studies are conducted every year at UZ Leuven, says Jean-Jacques Derèze, a lawyer at the Clinical Trial Center (CTC). “Participating in a study is the last resort for some patients, but of course we have to always check whether a patient meets the inclusion criteria in order not to jeopardise the scientific value of the study.”

Moreover, participation in a study does not automatically mean access to the experimental drug: in a randomised study, who will receive which treatment is decided by chance. Half or a third of the participants will not receive the standard therapy plus the trial drug, but will receive the standard therapy and a placebo. The patient usually does not know group to which they belong, and often the same applies to the treating physician or researcher. The study is then “double blind”. This makes it easier to compare the results between the different groups.

The Declaration of Helsinki ­–­ an ethical statement of principle regarding clinical research on humans – is taken into account when concluding contracts for clinical studies, says Derèze. Amongst its stipulations is one stating that study participants must continue to have access to the active drug after completion of the trial, pending approval and reimbursement.

It sometimes happens that the development of a promising drug is stopped prematurely, says Professor Huys. This despite promising results, and despite patients willing to enter a clinical trial. “A company may no longer have the financial resources, or there may be other reasons. There are non-profit organisations, such as the Anticancer Fund, that invest in clinical research that pharmaceutical companies are no longer interested in, often at the initiative of patient organisations.” This does not happen very often, because clinical research is so risky, and the continuing procedures for approval and registration are also complex and expensive. This usually involves research into new indications for existing medicines.“ For example, the effectiveness of aspirin against a certain type of cancer is now being researched. Sometimes these sorts of non-profit organisation enter into a partnership with industry, or a public-private partnership, as in the case of the Innovative Medicines Initiative (IMI). At the European level, the expertise group STAMP – Safe and Timely Access of Medicines to Patients – is working on setting up a legal framework.”

Policy choices may have to be made to guarantee both the accessibility for the patient and the sustainability of the system.

Pressure on the system

For the time being, we have a system in our country in which your financial capacity usually does not play a role in the therapy you receive, says Professor Casteels. “Most treatments are reimbursed and you don’t have to pay a patient contribution for cancer medication. But in the case of effective drugs that are not reimbursed, there is a possible risk of a two-tier medical system.”

The problem is well known, says Professor Spriet. Last autumn, in the Chamber of Representatives, the Health and Equal Opportunity Commission held a session on financial accessibility to medicines in which she participated as a delegate for the professional association of Belgian hospital pharmacists. “We must ensure that we maintain a sufficiently solidarity-based reimbursement system that leaves no one out.”

But the pressure on the system is enormous, says Professor Casteels. “The figures for relatively cheap medicines, such as biological medicines for inflammatory bowel disease and rheumatoid arthritis, are also increasing every year, because they are now also – rightly – offered to patients with milder forms. The cost of, and budget for, cancer drugs is also rising sharply. How long can we sustain this as a society? Political choices may have to be made to guarantee both patient accessibility and the sustainability of the system.”

As long as you're spending money on things that aren't strictly necessary, you can't really say there isn't money to pay for life-saving treatments.

Joining forces

In addition, more and more extremely expensive treatments, such as gene therapy and bespoke medications, will appear on the market in the coming years. Professor Huys is researching systems that could make it affordable for the government to reimburse these very expensive medicines. “Increasingly, the contracts concluded between pharmaceutical companies and the government are temporary and conditional. It almost never happens that complex medicines are immediately reimbursed for a longer period.”

Today, it is mainly the pharmaceutical companies that are in charge of marketing a medicine and determining a price, says Professor Huys. “It would therefore be good if a small country like ours joined forces with other European countries. Take the Beneluxa consultation group, for example, wherein the Benelux countries and Austria are already trying to pursue a joint policy to make innovative medicines available to patients at affordable prices.”

Some see a possible solution in abolishing patents for medicines. But Professor Huys does not agree with this at all: “That would remove a very important drive to invest in – very risky – research.” Health economist Professor Jeroen Luyten, head of the Leuven Institute for Healthcare Policy, poses a caveat: “As a society, you give a manufacturer a monopoly on sales via a patent to offset the costs associated with developing a drug. But then it is only fair to ask for transparency about this. We’ve conducted research which shows that the development costs are often much lower than stated. Drawing up such a cost estimate is of course not easy. Many costs are general costs, and there are also costs that are incurred without ever yielding anything. But the fact that it’s difficult may not be a reason not to do it.”

Lottery

The manufacturer of Zolgensma, the medicine needed by Baby Pia, wanted to raffle free doses a few years ago. This is, of course, not an ethical approach, any more than leaving it to the patients to find a solution themselves through crowdfunding. But how far should we as a society go toward reimbursing medicines? That question reveals a dilemma, says Professor Luyten. “On the one hand, there is a deep-seated compelling ethical intuition that says you should rescue a person in need if you can. If there’s medication available and you don’t offer it, it feels unjust, even negligent. On the other hand, from a societal perspective it’s clear that there are limits to what we can do for each other. This also applies to other issues, such as migration. At an individual level, it’s always about tragic stories, yet from a social perspective borders need to be maintained, otherwise the system will collapse.”

“If you ask people for their opinion in a concrete situation, they’ll generally spontaneously make the choice for the short term: saving a life in the here and now. Letting an individual patient die in the interest of a system that helps as many people as possible in the long term is something we cannot justify to ourselves.”

“Moreover, the key question is not so much ‘can we afford it’ as ‘will we pay for it’? What do you prioritise as a society? As long as you spend money on things that are not strictly necessary, sometimes even on trivialities, you can't really say that there is no money to pay for life-saving treatments ….”

The last word has yet to be said on this issue, according to Professor Luyten. “We have to find a solution to this as a society. But what that should look like isn’t yet clear.”

(ivh)

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Sonar

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