Is It Safe? 15th of August 2020

Older versus new drugs, Science Fictions, and formulation choices can kill

Welcome to the second edition of ‘Is It Safe?’, a newsletter about medicines and their harms.

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Old versus new drugs

For most things in life humans tend to have an attraction to the new. If someone offered you an iPhone 11 for free and you had an iPhone, you’d likely swap. Buying news things is often not based on entirely rational decision making, and neophilia seem inbuilt to what we are. But does this apply to drugs?

A paper published in Psychology and Marketing by Yun Jie suggests not. Pharmaceutical marketing often plays on the alleged benefits of new drugs over existing therapies. These can be overplayed, due to well known issues within clinical trials. Many new drugs offer marginal benefits over established drugs, and also come with the problem that safety on first approval is provisional. Clinical trials only find the common side effects, and the novel problems with drugs that lead to drug withdrawals are only found after widespread prescribing of a drug in the population.

In a series of six experiments, 5 in the lay public (1 group of university students, 4 MTurk groups), and one control group of doctors (n=34), Jie found a bias towards older medications, rather than new ones. Without critiquing the study methods, I just thought the perspective in this article was interesting, and in fact quite reassuring. Jie notes:

This current research project builds on the notion that, in reality, many newly launched drugs are no better than existing ones. In such a situation, although these newer medications have been tested and shown as efficacious and safe, we found that new drugs are at a disadvantage. This study is among the first in the marketing literature to study the effect of drug launch time on consumer perception and drug choices. We identified a robust oldness preference that has important implications for consumers and medical practitioners. Theoretically, we identified the regulatory focus and risk attitude as antecedents of consumers' choices. Finally, at the time when the entire world is confronted with the challenge of COVID-19, studies in psychology and marketing on how people perceive medical products may help marketers and policymakers to make better decisions. Indeed, the identification of a decision bias toward an oldness preference serves as the first step to de-bias it. We encourage further interest in chronological cues, in general, and in medical domains, in particular, among researchers in marketing and psychology.

He also gives a few ideas on how this might be done and how marketing practitioners might use this to help sell new medicines.

This raises the question of how marketers can persuade consumers. One obvious way is to show that newer drugs offer benefits over older drugs. Appeals of “first‐in‐class” (i.e., mechanisms of action different from those of existing therapies) may help, as many newly developed drugs belong in this category. A second way is to explain in detail the new drugs' safety benefits to address consumers' potential safety concerns. We speculate that, if consumers are more aware of the FDA approval process, it may alleviate some of their safety concerns about new medicines.

Contrast that with how evidence-based medicine practitioners frame things. To a very large extent mechanism does not matter. Does the drug show increased efficacy compared to current standard treatments? What is the safety record? If the mechanism doesn’t lead to solid outcome in those areas, than the mechanism is less important. The mechanism may even lead to novel adverse effects once marketed. Consumer confidence in regulatory systems is of great importance, as we have seen in the UK, but it still does not address the information gap on the first marketing of a drug.

Interestingly, people’s inferences about older drugs seem to lead to a healthy skepticism about new drugs that could have a beneficial effect in preventing overly rapid widespread uptake of new drugs. As a marketing academic, Jie doesn't quite frame it that way.

Because we told our participants that both medications were equally safe and effective, one would expect that they would rate both options as equal in efficacy and safety. On the contrary, we found a consistent pattern in which, on average, participants thought that older products were both more effective and safer, even when they were clearly informed (and they know they were informed) otherwise (Study 2). This means that they disregarded the declarative information and made choices based on their inferences.

Having sections of the population who are more risk averse, and others who are willing to try new drugs, is useful. A slower uptake of new drugs provides time for post-marketing surveillance systems to analyse real world data to discover new adverse reactions before widespread prescribing. This reduces the overall harm to the population if they are later found to exist. Given the often marginal gains in efficacy for most new drugs, this seems a sensible balance to have.

Neophobia has it uses sometimes. I’m not sure this is a bias that needs addressing. Unless you are trying to sell something.

Deprescribing

Of course, despite those inferences made to reduce new drug use, drug use accumulates in the population. Like a snowball rolling down a hill, patients with multiple health issues can quickly accumulate a number of drugs, leading to polypharmacy and drug-related problems.

Deprescribing has become a bit of a social movement within healthcare to address this. Doherty et al have a nice systematic review of the barriers and facilitators to deprescribing practise.

These are summarised in the figure below.

Like all issues around medicines use the various drivers are complex. One of the many specific considerations they have is:

The UK’s incentive schemes for GPs have rewarded general medical practices for quality care provision, but primarily focus on single-disease management, for example, cardiovascular disease management utilising therapeutic interventions. However, GPs could be rewarded for rationalising inappropriate polypharmacy, and a broader view is needed on what constitutes 'quality care' in medication management, which must include patient-centred measures.

Incentives drive behaviours, and single disease state management incentives have arguably been one of the drivers of polypharmacy in some patients. A holistic view of the patient, and their views, is important to provide the best care. Caution is needed taken when developing rewards for rationalising medication. Goodhart’s law is easily invoked.

Formulation matters

Over ten years ago Baljit Sunner and Paul Richards, both cancer patients in their mid-thirties died about an overdose of intravenous amphotericin in Birmingham UK. This was caused by the use of the wrong dose, based on confusion around different formulations of amphotericin (lipid and non-lipid). In July, the UK’s regulator issue new naming recommendations for liposomal and lipid-complex formulations and conventional formulations. The differences in dosing and drug release characteristics of these formulations can lead to huge variations in drug effect, and there have been fatal cases with both doxorubicin and amphotericin B.

As an example with amphotericin B, Abelcet 5mg/ml Concentrate for Suspension for Infusion will now be Abelcet LipidComplex 5mg/ml Concentrate for Dispersion for Infusion (my emphasis).

It is a reminder that formulation matters, and if you are involved in the prescribing, dispensing, and administration of these products, do read the MHRA advice.

Is there evidence that this will help? Who knows, but it would be hard to design an RCT for such relatively rare events. However, it is an entirely rational move, that at least gives an extra flag to trigger awareness of the formulation you have in front of you.

Book review

I’ve written a short review of Science Fictions by Stuart Ritchie on my blog. It is a great read, and extensively footnoted, and I would recommend it for undergraduates, anyone entering a PhD programme, and for reasons I go into in my blog, senior leaders in science and politicians. A lot of the problems identified in the book feed directly into some of the issues seen in drug safety as well.

Quote

“This is an age of science, but sometimes it doesn’t feel that way. “

Bill Gates on hydroxychloroquine.

That’s all, and don’t forgot to tell any anyone you think might be interested about the newsletter. See you in a couple of weeks.

Stay safe.

Anthony

Don’t forget to report your suspected adverse effects from medicines. In the UK, this is the Yellow Card Scheme