Background
Methods
Participants
Interviews
Data analysis
Results
Attitude towards off-label prescribing of OMPs
“I’m against under the current conditions, data are hardly being collected.” ( BNY31102 )
“I think it’s too simplistic to be “against” off-label use, but I do think that it has to happen in the context of study projects as much as possible.” ( BES14101 )
“Of course you have to check first whether there is no approved medicinal product for that indication. But if there isn’t, then off-label prescribing should have to be possible.” ( BNS11101 )
“I think OMPs need to be prioritized here, because they treat rare diseases. The clinical evidence will always be limited, but if you have a proof of concept, an idea of how a medicinal product works, then I agree that it should be available for patients as quickly as possible. It would even be unethical not to!.” ( BTY14102 )
Factors influencing off-label prescribing
Safety and tolerability
“The most defining factor is the safety of the medicinal product and whether or not it causes severe side effects. You don’t want to make a patient even sicker than he already is.” ( AET13091A )
“Once you go off-label, I think safety is the most important thing. Safety and tolerability. (…) Medicinal products with a good safety profile have a better chance of getting prescribed off-label.” ( ANS02101L )
Effectiveness
“You hardly ever have guarantees about the effectiveness of a medicinal product in the off-label indications. (…) But you need to have some sort of scientific indication that it actually works. You can’t just prescribe medicinal products and hope that they will have an effect.” ( AET13091A )
“I always consider: has this medicinal product been tested in randomized studies? And I try to discuss it with my assistants: why are we choosing this medicinal product?” ( AES14103A )
“There is a forum for questions about effectiveness and cost-effectiveness of medicinal products used for metabolic diseases. You can even add your own questions. (…) That’s how you get feedback from physicians worldwide. Sometimes is somewhat subjective or not always based on objective criteria from the literature, but along the way you learn to distinguish between what is relevant and what is not.” ( AES14103A )
Mechanism of action
“These medicinal products [enzyme replacement therapies] are used exclusively for very specific indications, so I guess they are not used for any other indications.” ( ANS10101A )
“You can of course, based on the mechanism of action of a medicinal product presume that it will probably also be effective for a similar disease and just try it. That is how it is often done.” ( ANS10101A )
Place in clinical practice
“At the end of what is feasible, or what is reimbursed, or what is “standard”, then you resort to off-label prescribing.” ( ANS02101L )
Disease indication
“There are 1001 medicinal products to treat heart arrhythmia. If product A fails, then try product B. And all these are registered and reimbursed. There is no such thing in hemato oncology! Additionally, medicinal products in hemato oncology are mostly expensive, monoclonal antibodies and small molecules. Off-label use is a lot more frequent in hemato oncology.” ( ANS02101L )
Patient population
“Yes, in neonatology intensive care, I think it will be up to 80 or 90 % off-label. Almost every leaflet states that the medicinal product can’t be used in children.” ( AET07111C&N )
Disclosure of information towards the patient or family
“We basically don’t have a choice, if it isn’t a registered indication. It’s something between an experiment and standard common practice, so we ask for permission.” ( AET1309A )
“The decision to prescribe an off-label medicinal product is made in consultation with the patient.” ( BNS02101 )
“Yes, we need informed consent. A patient HAS to say: ‘I share responsibility’. Provided of course that the patient has been informed correctly.” ( BTY14102 )
“The specific jargon is sometimes incomprehensible to the patient, so it needs to be explained very clearly. And I’m not saying that the information should be trivialized or popularized, but still… (…) Patients are sometimes desperately looking for a last remedy, so it’s not uncommon that they agree too easily or too quickly.” ( BTY14102 )
“Also, the physician needs to have the information himself! I think there is a role there for the industry. They know their medicinal product, they can say ‘these are the limitations’.” ( BTY14102 )
“If there aren’t any alternatives, and the patient is very sick, he is likely to be happy with any alternative. Most patients don’t oppose.” ( AET13091A )
“We mustn’t forget that, these days, patients are well informed! They scan the internet, find a product and suggest it to ME. And if it is not available, we try to get it.” ( ANS02101L )
“At a certain point, we stopped using the medicinal product and the family agreed. They also had the impression that that was for the best. We had discussed this on beforehand.” ( AES14103A )
“If it doesn’t have the desired effect after a certain time, then you stop the treatment. But we have this in mind in the beginning. For example, after four courses of treatment, if it doesn’t have an effect, we stop trying.” ( ANS02101L )
Financing and budget for reimbursement
“Reimbursement is limited to the indications mentioned in the SpC. Sometimes it is even more limited, but never more broad. So off-label use is not reimbursed. But the physician can prescribe it for another reimbursed indication of course.” ( BNS11101 )
“I think we should be very careful with reimbursement of off-label use. If too much is ‘allowed’, then companies no longer will be motivated to apply for new indications and to perform their own studies. But sometimes, there is no other choice, just to help patients!” ( BES14101 )
“The patient feels no financial burden, because we make sure of it! We want to avoid that people do crazy things, like selling their house, to pay for a treatment that won’t necessarily benefit them.” ( ANS0201L )
“We mostly try to get the product from the company. Other options are national or internal solidarity funds. But these are exceptions! The odds of getting a positive response there are very small.” ( ANS02101L )
“We [at the hospital] have an internal solidarity fund, but there is hardly any money available. I think if we were to treat one patient with an enzyme replacement therapy, well that would drain the fund completely for the rest of the year.” ( AET13091A )
“Off-label use is not reimbursed, unless we claim that the product will be used to treat a reimbursed indication. For example if one subgroup is reimbursed, but the other is not, then you can prescribe everything for that first subgroup. But if you get caught… you can pretend you made a mistake once, but not ten times! I’m not going to deny that we sometimes bend the rules like that.” ( ANS02101L )
“Sometimes companies send delegates to physicians to explain how they can by-pass the law, which boxes to check on the application form. Of course it’s cheaper for them! And in the end, they are not responsible; when problems arise, well they say ‘it’s off-label use’.” ( BES14101 )
“It can be high, I would guess up to 50 % of the total orphan medicinal product budget. But there is no way to determine it, it’s a speculation.” ( BES14101 )
“You could map it, but that would be very difficult! I guess because orphan medicinal products are only used for a limited number of patients the off-label budget will be limited.” ( BTY14102 )
Reporting of off-label use
“Well I have to admit that the pressure to publish positive results is bigger than to publish bad results. Bad results do not get published, period.” ( ANS02101L )
“Case reports are just cast reports with little scientific value. (…) I’m more in favor of organizing clinical studies or registers or systems in which results are somewhat grouped.” ( BES14101 )
“Yes, I think we have to report it for these rare conditions simply because the medicinal products are so expensive. (…) It would even be best to organize it on a European level. For example, everybody using an orphan medicinal product off-label, registering that use in a European database.” ( AES14103A )
“Anonymizing, that’s an option. It can possibly help to also publish negative experiences.” ( BNS11101 )
“That the physician is anonymous? Well yes of course! (…) But, if someone else wants more information, how would that work? Why would physicians want to remain anonymous? I can imagine that all of us are trying to achieve improvements in medical science, and that you stand by your own decisions and take responsibility for them.” ( AET13091A )
“Of course it’s useful! You want to spare others the mistakes that you made. Well it doesn’t necessarily even have to be a failure, but just a ‘lack of effect’, I think it’s also useful to report that. So others won’t try the same thing.” ( AET13091A )
“Absolutely, those negative experiences give you a much bigger picture! Nowadays everybody has a feeling of ‘wow this works well off-label’, but in fact, you don’t know about all the failed attempts.” ( ANS02101L )
“We simply don’t have the time to do all that publishing and reporting.” ( AEY11101L )
“This database, it won’t be easy to implement. At the moment there is no legal framework, and I think that is needed first.” ( BNS11101 )
“For some conditions, or groups of conditions, there are international registers. I try to participate in those. It gives me a lot of information! If everyone has five patients, that’s not informative, but all together, well there might be 500 and then you learn something from it.” ( AET13091A )
Risks and consequences
Therapeutic failure
“Based on the literature we thought, we have to do something and this looks promising. In practice, it didn’t play out well.” ( AES14103A )
“It isn’t always 100 % clear what the effects and the adverse events will be.” ( AET13091A )
Accountability
“A physician has therapeutic freedom and can prescribe off-label. But it is a risk! Companies and pharmacists will not cover the physician’s back if anything goes wrong.” ( BNS11101 )
“It is not a risk, it’s based on the literature and you discuss it with patient beforehand. Everybody knows what the risks are. In my opinion, the only risk is the reimbursement of the product.” ( ANS02101L )
Funding problems
Incentives for future development
“But I think you have to be careful to extend an indication, because that’s a practice that companies strive for. They put a product on the market in a small niche market, but their actual target group is much wider to be able to make profits.” ( AES14103A )
“Why don’t they [pharmaceutical companies] file for additional indications? Because when that happens, they have to lower the price! It’s an odd situation of course.” ( BNS02101 )
“Companies are not interested. Why would they be? Their product is the only one on the market… If they change the application, then it has to be based on clinical studies. And the evidence is already there, because physicians are collecting it. Is it worthwhile to trouble children again?? There is a lot more behind it than the motivation of the company.“ ( AET07111C&N )
“It is not easy to collect data in these very small patient populations! This implies that the number of phase II and III clinical studies is limited, and that the duration of these studies may be limited.” ( BNS02101 )
“From a societal point of view it is sometimes frustrating that we can’t force a company to extend an indication.” ( BES14101 )
Future perspectives
“I don’t think everybody should be allowed to prescribe everything. We trust expert centers, we determine their expertise, they fulfill all our conditions. Then they also should be able to prescribe off-label in a responsible way.” ( BNS02101 )
Discussion
Conclusions
1. Presence of a severe, life-impairing or life-threatening condition; 2. Absence of authorized treatment or repeated treatment failure; 3. Absence of alternative treatments authorized for the condition; 4. The off-label use is supported by strong evidence in scientific literature; 5. The patient has been educated and has given his or her informed consent; 6. Presence of established reporting routes for adverse events and linked to off-label use. |