The hills are alive with on-label prescribing

What I’m about to say is likely to result in a loss of subscribers that came to this newsletter from my posts on Radiohead and Batman. But I feel it needs to be said.

In my youth, I was a total musical theatre geek.

I loved musicals. I could quite happily spend my whole school holidays watching old videos of Calamity Jane, Singing in the Rain, West Side Story and Grease on repeat. Andrew Lloyd Weber, not my go to, but I’d still happily go to any production that came to town. Even opera.

Lucky for me, my school gave me an opportunity to get involved in several musical productions. I thought I was too cool to participate in the Oliver production when I was in year 8, and I had some deep regrets about it. The following year I had my debut as the Scarecrow in The Wizard of Oz. My brief theatre career culminated with the role of Maria in The Sound of Music in year 12.

Personally, I’ve never really liked The Sound of Music all that much. However, it was still a fun experience. Except for the whole on stage kiss thing. Nothing against the guy who played Captain von Trapp, I just had someone else I’d rather be kissing at the time, and definitely not on stage in front of my parents and teachers. Awkward.

The original version of The Sound of Music was a stage production in 1959. Most of the stage version is what you’d be familiar with from the movie, released in 1965. The key characters are all the same - Maria, the nuns, Captain von Trapp and his kids, Rolf, and the Baroness. The storyline is also basically the same - nun gets sent off to be a governess to some rich kids with a dead mother, chemistry ignites between the nun and the father, no-longer-nun marries the father and they make a plan to escape Nazi occupied Austria.

When it comes to the songs the classic ones remain consistent between the stage production and the movie. Sound of Music (obviously). How Do You Solve A Problem Like Maria? Do-re-mi. Favourite Things. Eidelweiss. Sixteen Going on Seventeen. Lonely Goatherd. So Long, Farewell. Climb Every Mountain (snore).

However, there are some key differences. The stage production has a couple of extra songs and reprises. The Baroness and Max even get to sing. And, to my dismay, one of the songs that was not in the stage production was Something Good. Instead, it was a song called An Ordinary Couple.

I was gutted. The one and only song that I actually liked. That sat perfectly in my register. Boo.

Thankfully, the teacher in charge of the production agreed, and we got the rights to put it back in. So what we ended up with was a stage production that deviated from the original version. The familiar story still got told, plus, I got to sing my song. Win.

Yeah, that’s cool (not really) Lauren. But what has this got to do with drugs?

I’m glad you asked.

Over the past two posts, we’ve talked about how drug companies bring a drug product to market- how The drug discovery pathway ensures there is sufficient evidence that the drug meets the golden triad of quality, efficacy and safety. The result of this process is that the drug will be registered by the relevant regulatory authority for that particular jurisdiction.

This registration is like the OG stage production.

So lets take a closer look at what regulatory approval actually means.

What’s in a regulatory approval, anyway?

When a drug is approved for the market, it means the regulatory authority have made a formal assessment and decided that the benefits of using that drug to treat a particular condition or disease outweighs the potential risks associated with it, when used in a given population.

There are three bits here that are worth taking particular note of:

• how exactly the drug is used

• what condition(s) or disease(s) the drug is used to treat

• the specific population in which the drug is given

Each of these is specified within the drug’s regulatory registration, or license, based on the evidence provided. This can broadly be described as the ‘on-label’ use of a medicine.

When a medicine is prescribed ‘on-label’ it means it aligns with each of these criteria. Just like a direct replication of the original stage production of The Sound of Music. And in the same way that any variations to The Sound of Music’s song list or dialogue would result in it no longer being considered true to the original production, so too does any variation in these three criteria result in the drug no longer being prescribed ‘on-label’…resulting in ‘off-label’ use.

1. How the drug is used

How the drug is used includes how much of the drug is given (the dose), the product that is used (the formulation), and the way that it gets into the body (the route of administration).

If these terms are new to you, it might be worth checking out my earlier post which covers these concepts and somehow incorporates a discussion about the movie Die Hard:

How do you like your coffee — espresso or enema?

In terms of how much of the drug is given, this is typically expressed as a dosage range - the lowest amount shown to be effective, up to a maximum dose. Any dose exceeding this, is no longer ‘on-label’.

When it comes to the product being used, this seems like something that couldn’t be altered too much, and in most circumstances that’s true. However, there are some times where this isn’t the case. A tablet that gets crushed up and dispersed in water is perhaps the most common example of where the ‘on-label’ formulation is adjusted.

This could have more impact on the safety and efficacy of a drug product than you realise. Crush up a drug with a special slow release coating and you’ll end up with a much higher peak and shorter duration of action. Crush one with an enteric coating and you might give yourself a stomach ache. If you want to understand this further, check out this post:

How to disappear completely

When it comes to route of administration, this is usually pretty closely tied to the product being used. However, there are times that call for doing things differently, particularly in paediatrics and palliative care. Examples that come to mind are injectable formulations used intranasally or sublingually to treat seizures or pain. And, of course, there’s always the oral liquid up the bum situation that is sometimes necessary- it can get sticky though if you’re using a syrup.

2. The condition or disease being treated

A drug approval specifies the condition(s) or disease(s) where it’s been proven the drug has a benefit that exceeds potential risk. The term used to describe this is the Indication.

This sounds pretty straight forward, right? Traditionally, that may be true-ish. However, in recent years as dissemination of information has become more rapid, we’ve seen some examples of where this can get a bit tricky.

One example is where diseases and conditions are poorly understood in terms of their specific pathology. I haven’t done any thorough research on this, but off the top of my head, I’m thinking things like long Covid, ME/CFS, heaps of things involving the immune system and generalised inflammatory response, complex pain syndromes…if there isn’t the solid foundational evidence of what the problem is, it’s harder (read: more expensive) for drug companies to produce strong evidence of the benefit. Unfortunately, the harder it is for a drug company to get their product registered, the lower the return on investment. This has big impact when it comes to getting these drugs onto prescription subsidy schemes, which makes them more expensive and less accessible for the people who might benefit from them.

Another situation is where a drug isn’t really being used to treat a condition or disease per se. Instead, it’s being used to try and ‘optimise’¹ a natural part of life. Like preventing aging, or enhancing cognitive or physical performance. This use of drugs doesn’t fit with the existing regulatory frameworks that are tied to diagnostic codes. Because of this, drug companies don’t really even have an option to get their drugs listed for these indications at the moment.

Given the potential profit to be had from it, I think this is a space we should watch closely. It wouldn’t be the first time normal human experiences are reframed as medicalised conditions to result in greater prescribing of drugs…there’s a really rich ethical and philosophical discussion to be had here but I’m going to have to park it for now, as much as it pains me to do so.

The other circumstances where there’ll often be a period of time where off label use is common is in an area where the evidence evolves faster than the regulatory processes can keep up with. Think cancer care and obesity treatments as obvious examples.

3. The specific population being treated

Finally, a drug approval will specify the population in which it is approved to treat. Again, this seems obvious and not too much of a problem…except of course, if you’re in a group that is excluded from clinical trials. Groups that this is commonly an issue for are children, women who are pregnant or breastfeeding, and people who are medically frail like the elderly and those with advanced terminal illness.

As I’ve already mentioned, it costs a lot of money for a drug company to make a submission to the regulatory authority to have their ‘on-label’ approvals amended. Unless there’s a sufficient market to secure a decent return on investment, they’re probably not going to bother. This is why many drugs that are known to be safe in pregnancy and breastfeeding still have the product information cautioning against their use. It’s a real problem in clinical practice, and a cause of a lot of confusion. Again, another potential for further rich discussion that I’ve got to resist…for now.

If it’s not on, it’s off-label

As we covered in The Golden Triad of Drug Products post, prescription drugs are the Christian Bale of drug products, in that you can take it for granted they meet the necessary standard of efficacy, safety and quality. Now that you know a bit more though, I’d like to add one caveat: this assurance can only be guaranteed if the doctor is prescribing the drug in accordance with the on-label criteria above. Anything outside of that is considered ‘off-label’. This doesn’t make it inherently bad, it just means there’s a bit more work involved.

The reason there’s more work involved is because you and your doctor are now responsible for doing the work of the regulatory authority. Together, you’ll need to identify and understand the evidence required to come to an informed decision on whether this drug is right for you. Especially important as off-label use of medicine will probably mean you’re funding the full cost yourself. Ideally, this is something that the doctor will walk you through during the prescribing process - it’s part of achieving informed consent, which should always happen when prescribing a new medicine. Whether or not this actually happens in practice though? I’m not so sure.

I’m not here to offer advice, but I do think it’s worth pointing out that if you’re putting a drug into your body (or giving it to someone else), you’re the one with the biggest vested interest to understand if the benefit outweighs the harm and associated cost. If your doctor isn’t able to provide you with the information you need, this is where your pharmacist might be able to help. The take home message here is, if you find yourself in this position, don’t be afraid to ask for help - that’s what healthcare professionals are there for!

---

Thanks so much for reading!

If you got this far, I’m guessing you either really liked it or couldn’t stand it - either way, it sounds like something that deserves a comment. Easy to do by clicking the heart and the button below.

Sharing this with someone else is also very useful and greatly appreciated.

Lastly, this is a free weekly newsletter, so if you’d like to hear more please Subscribe!

1. I loathe the term optimise. It’s so overused it’s become meaningless, particularly in medicine. Optimise for what metric? For efficacy? For safety? For patient experience? For cost. It should be banished from our vocabulary when talking about medicines. A rant to park for another day.

Here’s me, circa 1998, belting out The Sound of Music opening number.