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Prescription Drugs

Conceptual work by Yves Klein at Rue Gentil-Be...

When rules don’t work [Conceptual work by Yves Klein at Rue Gentil-Bernard, Fontenay-aux-Roses, October 1960, photo by Harry Shunk. Le Saut dans le Vide (Leap into the Void) (Photo credit: Wikipedia)]

 

 

 

 

 

 

Sir Andrew Dillon, the erstwhile leader of NICE as said that it is irrational for the Cancer Drug Fund to pay for drugs that NICE has turned down.

 

He’s right of course, it is irrational. But only if NICE’s logic is compelling.

 

The problem for Sir Andrew, and likemined people, is that there is another logic that trumps NICE’s rational world. Don’t get me wrong. NICE performs a useful, but technocratic, function with analytical assessments that any rational person would indeed want to know. Where we part company is believing that NICE’s logic is the final word on the matter. Which it isn’t.

 

Tasked, perhaps unenviably, with parsing the performance of medicines and clinical practice, cannot also mean that they are above challenge. Many of NICE’s rulings fly in the face, not of logic, but of our beliefs as humans. It is why we do things when the odds are against us, because not to do so would be wrong. If we think of the challenges NICE faces as wicked problems, that is complex problems with a multiplicity of solutions, it becomes self-evident that their logic is just one way of deciding and choosing. We could use other rules, other criteria. The Cancer Drug Fund is just such an approach. It is another matter whether we should have in place alternative funding approaches that individuals can avail themselves of (such as co-payments or co-insurance); for extraordinarily costly therapies, co-funding would not apply, so we’ll back to the problem anyway.

 

NICE has a troublesome relationship with the notion of ‘rule of rescue’ and so has decided to ignore it. There replacement, the “end-of-life premium” is really just a reweighting of the logic they use.

 

You see, the rule of rescue is what we might call a meta-rule — it is a rule that tells us if other rules are working properly, and importantly, as a moral imperative which tells us what to do. The rule is often invoked in a particular form: that people facing death should be treated regardless of cost. The rule as originally formulated is really about assisting identifiable individuals facing avoidable death (Jonson, 1986); the bioethicists and economists have shifted this to a cost-effectiveness approach, making it one about trade-offs instead.

 

The problem for healthcare systems is that all patients are becoming identifiable as medicines become personalised (medicines may become orphan drugs). The problem for the NHS is that it does not allow such people to rescue themselves because it prohibits any sort of co-funding or other arrangements. The only option is an opt-out (and private medical insurance has rules about pre-existing conditions). Given the funding priorities of the NHS, we should be reflecting not so much on how to make the pot bigger, but on using the money that is available better (there will never be enough money), and ways to introduce practical co-funding.

 

Since individuals have no other options in the NHS, the rule of rescue as a moral imperative will be violated and we will act, not out of analytical error (i.e. make a technical mistake), but unethically. You see, the NHS must be the healthcare system of last resort and therefore of rescue, otherwise, identified individuals are destined to a death sanctioned by public policy and is that a policy or healthcare system worth having?

 

We have seen a similar challenge to NHS/NICE logic recently with the King family and proton beam therapy, and the NHS will also use NICE logic to determine access. Whether beams or drugs, it is the same argument.

 

But why cancer? The main public policy question is why should cancer patients be given preferential treatment as against any other deserving group? This may in part be driven by the often astronomical costs of new cancer therapies themselves, which demarcate cancer patients decisively from equally deserving patients with less cost-contentious therapies. I have just finished some work on motor neuron disease, for which there is one specific medicine and life expectancy from diagnosis is 3 to 5 years, with median survival rates that are measured in months. NICE reportedly is developing guidelines for this disease. Costs are considerable, and at least in the UK, highlight the bureaucratic illogic of separate healthcare and social care, but that is another story.

 

The moral dilemma that the economists at NICE are trying to reduce to an equation is whether a new therapy is extending life, or delaying death. The Oregon approach collapsed when the hard choices emerged and people were unable to resolve this dilemma, which is not a quantitative issue, but one of how we value our humanity. Kierkegaard’s Concluding Unscientific Postscript speaks of the leap to faith as involving self-reflection and the emergence of scepticism. It is worrisome that NICE is so confident.

Further reading

 

Cookson R, McCabe C, Tsuchiya A. Public healthcare resource allocation and the Rule of Rescue. J Med Ethics. 2008 Jan 7 [cited 2014 Sep 4];34(7):540–4.
Jonsen, AR 1986, Bentham in a box: technology assessment and health care allocation, Law, Medicine and Health Care, Vol 14, pp172–4.
Richardson J, McKie J. The rule of rescue, working paper 112, Centre for Health Program Evaluation, Monash University
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The lost of my trilogy picks up on medicines again.

In the US, not taking medicines correctly is thought to be the fourth leading cause of death – could this be true?

WHO data on mortality captures medicines use in a variety of categories. I ran the data on the categories concerned with medicines-related harm (ICD-10 codes: X40-X44,X60-X64,Y10-Y14,Y45-Y47,Y49-Y51,Y57). It is less than 1% for any European country for the whole population, but breaking it down by age cohorts reveals interesting results that show at different ages, in different EU countries, there are age-related variations in cause of death, rising with age. None, however, emerges as a leading cause of death on its own.

However, medicines use sit within a system of patient care. Therefore, medicines misuse and medication errors may create conditions for a co-morbidity to assert itself. And of course, whether the drugs were toxic for the patient at a particular dose (keep in mind, pills for instance come in standard sizes and may need to be cut in half or so to get an accurate dose for a patient). Working through this data, though, does highlight areas to pay attention to, and in particular countries where there appear to be noteworthy higher risk. I’d like to see better analysis of medication errors.

Once again, before we target the drugs bill as being out of control, let’s get a better understanding of the dynamics of medicines use itself. We may be spending money foolishly or carelessly. What are the incentives in health systems that may actually encourage this sort of professional conduct?

The devil is not just in the detail, but in the data and in clinical practices.

Want to know more?

WHO datasets are here: http://data.euro.who.int/dmdb/

 

In these days of trying to better understand the determinants of rising healthcare expenditure, it is productive to look in the waste bin, to see what is being thrown away. Let’s look in the waste bin and see what medicines we find.

Medicines waste is medicines given to patients that they do not take. But this needs to distinguish between actions taken by the patient, and other factors since not all wastage is patient non-adherence.

The costs include the cost of the medicine itself, but also the changed procedures in pharmacies to reduce patient-related waste (procedural costs drive duplicate medicines ordering on hospital wards, for instance). There is also the costs associated with safe disposal of the medicine waste itself and how patients dispose of unwanted/unused medicines. Environmental contamination by pharmaceuticals is of rising concern. [Pharmaceuticals in the Environment, European Environment Agency, 2010].

Considerable medicines waste arises because the patient has died and correlates with condition: 100% return for anaesthetic drugs, 60% for drugs used in immunosuppression/malignant disease, 26% for cardiovascular conditions, 19% for drugs used for infections. This suggests that gross wastage data needs to be viewed with some care.

Reducing the stock held by patients in the home shifts the stocking costs to pharmacies. UK evidence suggests that “if all repeat prescriptions in 2008 had been issued at just 28 days, then total pharmacy costs would have been even higher – around £2.3 billion, or 28% of the net cost of medicines dispensed.” [Gilmour review on prescription charges, “Medicines Wastage” Prescription charges review: implementing exemption from prescription charges for people with long term conditions, May 2010] This suggests that included in wastage costs are pharmacy dispensing charges.

As in all cases of healthcare expenditure, the challenge involves a complex mix of activities and stakeholders. We need much better tracking of waste, if only to ensure we do not inappropriately target expenditure of medicines without first ensuring that medicines that are being bought are properly used. Industry, healthcare and regulators can usefully work together here.

I haven’t mentioned the environmental impact of flushing unused medicines down the toilet. I’ll let your imagination go to work on that one.

Want to know more?

Evaluation of the Scale, Causes and Costs of Waste Medicines, Final Report, York Health Economics Consortium/School of Pharmacy, London, 2010. This has a good international literature review of costs, but caution is needed in the context of the comments below.

Kummerer K, Hempel M (eds) Green and Sustainable Pharmacy, Springer 2010. See page 170 in for a table of waste by country, but not costed.

Just about every country has identified life sciences in some form or other as a priority for academic and commercial development. But what will characterise the countries that may in the end prevail?

  1. The research community needs a high degree of autonomy. The European University Association released an interesting study,
    Ireland's Highest Peak

    The rigidity and frigidty of state controls. (Photo credit: mozzercork)

    University Autonomy in Europe II: the Scorecard, in 2011, assessing the degree of institutional autonomy universities in the various EU member states enjoyed. The countries with the greatest university autonomy were from northern Europe: Denmark, Ireland, UK, Finland, Sweden Latvia, Lithuania. Those with highly regulated and state controlled systems were from southern Europe, or had systems where the state just likes to intrude: France, Luxembourg, Greece, Italy and others. To be fair, some countries were more or less autnomous on different indicators, but the rough distinction can be drawn. Surprisingly, at least to me, was the middling performance of countries like the Netherlands, Austria and Germany. No doubt various higher control states will endeavour to justify why the state needs to be so intrusive, but as evidence that this is perhaps an unhealthy state of affairs, we see the highly instrusive French state over the past year moving to create greater diversity and differentiation in funding for its universities with greater autonomy (see this news item for instance). Clearly, greater autonomy necessitates greater diversity and differentiation and in the end some will need to become better than others. While we would like to think that all universities are essentially the same, reality suggests that the only real equality lies in the extent to which they all meet minimum standards, rather than all trying to meet some arbitrary ‘gold standard’.

  2. The bulk of significant research results in life sciences is undertaken in centres known as academic health science centres (AHSC). This is a theme I warm too, as it provides an organisational model that drives innovation from the clinical user end, rather than from the research end. Yes, more research funds are always needed, but we also need solutions. Efforts to operationalise translational medicine are doomed to fail if the driving forces are not coupled to the clinical user and innovation policies in general need to start with problems needing solutions, and hence a factor more likely to be evidenced. Only a few countries have AHSCs — such as US (over 50), Canada (about 14), Sweden (1), Belgium (1), Netherlands (8) and the UK (5). (Note: reforms in the UK look set to expand the AHSC model into networks) Germany arguably has at least one as does Italy. France has none. The challenge (and this was the subject of a paper I presented on academic health science centres and entrepreneurialism) is that while universities are more likely to enjoy degrees of autonomy, hospitals are less likely to. The UK was only able to move toward establishment of AHSCs when the state control of the hospitals was relaxed through successive periods of NHS reform. The Netherlands model built on existing relationships. Countries without AHSCs, though, will confront the twin challenge of institutional autonomy of both universities and hospitals.
  3. Not all countries will be able to do everything in life sciences. This entails setting some priorities. National priorities are hard to conceive, because countries usually think of themselves as being able to do everything and so efforts for instance, get diluted and underperform. Cash is tight these days (think debt) and governments just cannot afford everything, so the most difficult challenge is establishing priorities.  There are ways to set research and innovation priorities (I’ve developed some approaches if there is interest), and they help deal with the challenge of deciding where to start. Not all research produces winners, but the state is really bad at picking winners. When it tries to pick winners (aka, national champions), state and political interests dominate over reality; the result is an expensive mistake, and we all know hubris keeps politicians from changing their minds — as it would evidence of having make a mistake.

There is a clutch of small states within the European Union. There are many more small states outside the EU.

TAMPA, FL - JULY 13:  John Winskas, a student ...

Small states? (Image credit: Getty Images via @daylife)

Much can be learned from them, as at least within the EU, some seem more robustly managed and economic productive than their larger debt-laden counterparts.

Healthcare systems are often seen as requiring some degree of economy of scale. This in part is a function of how prevalent diseases are, such that in some small countries they would have one case in 2 years, rather than one case per million of population. Healthcare technologies can be incredibly pricey; for instance, a proton therapy facility will run between €100 and €200 million to set up. Healthcare buildings and research infrastructure are expensive to build and run. Health professionals can be expensive to train and employ and are generally globally mobile.

Associated with investment in healthcare within the EU, we find that almost every region or member state has life sciences, in some form, in their top 5 or so areas of national priority. Life sciences is challenging and demanding, and requires high degrees of global visibility and connectivity to other researchers. Commercialisation of life sciences in Europe is generally appalling; the EU’s research budget focuses on research, not translation and there is precious little to help good ideas bridge the ‘valley of death’ where unfunded good ideas go to die. Financing for life sciences developments consume vast quantities of risk capital, some of which will be unlikely to return any value for a decade or more.

Many EU countries try to avoid downside risks of failure by punishing it, rather than creating opportunities to learn. Countries that encourage risk taking, and make it easy to start and close down companies, with associated flexible labour practices, will outstrip protectionist fearful countries. While many countries fear unemployment, they fail to encourage job creation, which is an economies way of moving work around. Life sciences is one such area that requires particular flexibility owing to the nature of the work.

I recently had the privilege of working with colleagues in one of the EU’s small states, to help develop a life science strategy. National excitement included the construction of a new bioscience research and commercialisation centre (partly funded by the EU, thanks for that). The University is active across its faculties in life sciences areans, and with the College are both keenly extensively in high quality training of health professionals. Local industry is building on past successes in life sciences. The country has a well-developed and well-financed healthcare system.

The main lesson to small countries building life science (or any research-based commercial capacity for that matter) is that setting priorities is more important the smaller you are, as you can’t do everything. That means that some people may be disappointed that they are not on the short list of first projects. It means, too, that infrastructure projects are precious, as they are enablers of future potential — the longer term vision must be sustainable, as getting it wrong can be expensive — research buildings don’t make very good hotels.

Some thoughts:

  1. build on what you already are doing well as that is evidence you have the expertise, networks and working practices in place
  2. keep in mind that life sciences is much, much more than drugs; progress may be quicker in other areas, such as informatics, telecommunications, engineering, materials science, physics, chemistry, agriculture, etc.
  3. you can’t sensibly do life sciences with a weak university, so this may entail some difficult and hard rethinking of priorities and some sensible review of research productivity
  4. you can’t sensibly do life sciences without a teaching hospital; the academic health science centres in the US account for over 80% of productive life sciences research, so think about reorganising your own infrastructure to enable closer collaborations and alignment between university and hospital; this may, by the way, raise real issues for government if the teaching hospital(s) is state run
  5. you can’t sensibly do life sciences without understanding the logic of ‘bench to bedside’; productive work lies in translational research and solving clinical problems; this can challenge academe, which rewards the production of papers and volume of research funding for career progression; in life sciences, solving problems is paramount; understand what the Grand Challenges in life sciences are and see which one(s) you can focus on
  6. you’ll need to consider the economic developments that come with building a life sciences sector as you’ll need to energise high net worth individuals as angel investors to help start and run the small businesses that you’ll create; I’d discourage too much public sector hiring as it disincentivises university graduates from pursuing entrepreneurial careers (there is good global evidence that this can be a problem, so don’t make that mistake); best role for government is ensuring a flexible corporate start-up environment, a non-punitive bankruptcy regime, sensible taxation of start-ups, and seed funding; it might also be a good idea to give away all that publicly owned intellectual property;
  7. finally, the good news is that size doesn’t matter for innovation; there is no correlation between the size of a country and the ability of the country to innovate; many very large countries have clumsy policies that disincentivise and frustrate.

I wrote a paper looking more generally at healthcare systems of small countries (which includes a few remarks on life sciences). Paper on Overview of Small Health Systems

If these issues stir you to think more about life sciences and / or the challenges of smaller states, do make a comment.

One of the real issues facing EU members, particularly those that are having trouble paying their healthcare bills from suppliers, is the way that medicines are priced. The issue of drug pricing is likely to become even more important internationally as the UK pricing system will move to ‘value-based pricing’ in a year when the current arrangement expires. Other EU countries, and elsewhere, all grapple with medicines: whether it is their price, their use, effectiveness, or whether they are not used by the patient. All this adds costs to the system, and particularly in countries where drug prescribing by doctors is not well scrutinised, so that irrational prescribing can occur, influenced more by the reimbursement system, than what is right for the patient. “Big pharma”s’ door-to-door 1950s approach to promoting medicines is well-past its sell-by date.

What is often forgotten in all this is that despite the general view of big pharma, it is not really in their interests (corporate, and profits) for

Development of a rational scale to assess the ...

Evidence of Misuse, from The Lancet, 2007 (Photo credit: Wikipedia)

their drugs to be misused; similarly, it is in their interests, though they seem not to grasp this, and blame sits at in the C-Suite of corporate leadership where they can be disconnected from the real world. Indeed, big pharmaceutical companies are learning, mainly from their own ill-thought out actions, that taking pricing and access to medicines disputes into the courts is, if nothing else, a public relations disaster. [See this item from the LA Times from 2001 on the legal dispute between big pharma and South Africa and this item from the UK’s Independent on protestors outside GSK’s offices]

This week’s British Medical Journal reports on Germany’s Fresenius Kabi’s decision not to supply the drug propofol to the United States if it is to be used for lethal injections for executions within the criminal justice system. The company makes the point that suppling drugs to kill people is inconsistent with their corporate purpose. Similar value language is usually found somewhere in all pharmaceutical companies’ mission statements.

What is interesting here is that the company has indicated what use the drug may be put to and has instructed its wholesalers and distributors to ensure that the product does not end up in the hands of prison officials. This is an important way of thinking and reveals, that when it is necessary, the manufacturer of a drug can stipulate its use and by whom. Granted, the company noted that the use in executions is not part of the product’s licensed use, but doctors can, if they wish, ignore the licensed requirements for medications.

How might this relate to drug pricing?  What we start with is the legitimate corporate (and one hopes healthcare system) concern that medicines should not be misused, or abused. In the case of propofol, we see that a manufacturers could stipulate use and user as a requirement of supply.

What we want is a system that would obligate purchasers (such as healthcare systems) as a condition of supply to ensure proper end use of the medicine. Such conditions might include ensuring that the medicine is not used ‘off label’, ensure that patients are enrolled in medicines management programmes to ensure that the medicines are properly taken, that waste is avoided, that prescribing is rational and follows guidelines, medicines-use audits are conducted, the medicine is appropriately part of care protocols, and so on.

What would it take to do this? Something like the arrangement we should all be familar with when we ‘buy’ software, the End-user Licence Agreement, so-called EULA. With a EULA, we don’t actually own the software, but are licensed to use it. Medicines could also be licensed, and the advantage of such a license-based pricing system would its transparency around proper use. There is some irony in the public perception of the pharmaceutical industry as greedy for money, little thought is given the misuse of medicines by doctors and patients, and that are purchased within the healthcare system. For example, perhaps up to 30% of medicines prescribed and paid for are not used properly or thrown away (disposal of prescription medicines down the toilet of course contaminates water supplies). For country like France, UK or Germany, we are talking in the €/£multi-billions of wasted public expenditure

Licensing has the additional benefit of shifting pricing considerations toward the real value of the product-as-used. The UK’s introduction of value-based pricing will need to develop a view on how to quantify the value of the product-as-used. However, drug pricing and reimbursement arrangements in most countries seem to view medicines a bit like FMCG (fast-moving consumer goods) products, such as cosmetics and candy bars. (While a medicine costs upwards of $1 billion dollars to bring to market, composed of research costs and costs associated with clinical trials and testing, I’m not sure how much it costs to invent a new face cream, but the advertising of such a product seems only to require that 15 of 25 women surveyed agreed that it made their skin appear more youthful, hardly the same standards that apply in clinical trials — accepting of course that clinical trials are not all created equal — see Goldacre’s new book.)

An additional benefit is to show how unhelpful comparative drug pricing (call international reference pricing) is. This approach ignores the innovation value of the product-as-used, in favour of what other countries have got the drug price to be — not much different from comparison shopping on the web.

Licensing would also enable the separation of the innovation value of the product-as-used (the research and development costs), from its production and ingredient costs as it would the innovation value that is licensed, and the drug itself as a product sold (licensing the computer software, but paying for the DVD it comes on). This twin pricing makes it possible to recognise the legitimate costs of production.

Wider benefits are realised in two directions:

  1. the pharmaceutical companies to focus on product development that is truly innovative (and not me-toos or reformulations to extend patent periods);
  2. the healthcare systems to ensure that the medicines they do buy are properly used.
A Mongolian woman condemned to die of starvation

Starvation (Photo credit: Wikipedia)

In June, Mike worked with colleagues in Brussels to develop a range of innovative research and commercial development programmes in the biotechnology, food and agriculture sectors through a research brokerage event hosted by ERRIN.

The KBBE programme — Knowledge-based BioEconomy — is a European Commission programme focused on the food, agriculture, fisheries, biotechnology and oceans. Partnering opportunities for SMEs lie in a number of areas, as some aspects of the call offer specific opportunities to firms in North America, or India for instance. Up to 50% of the call requires SME participation, and they are elegible for 25% of the funding in those programmes.

There were few SMEs at the event, while many universities sent representatives, rather than research principals so brokering opportunities were limited. However, SMEs in this sector should take note of this programme especially firms outside the EU as this offers one way to get into the EU market.

Commercially-minded higher education institutions in Europe are few, given the levels of assured public funding they receive, but noteworthy commercially partnering can be had with institutions from countries that have prioritised this such as the UK, Sweden, Denmark, Finland, Netherlands, Germany, Hungary and Poland for instance. Other countries offer many potentially beneficial relationships, but SMEs may find state bureaucracies difficult, ownership of relevant IP being mainly public sector with little incentive to commercialise, or universities unsophisticated in structuring commercial relationships with industry.

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