Pharma Pieces

Thanks for visiting www.pharmapieces.com.  My blog and corporate site have now moved to www.bluespherehealth.com.  See you there!

Africa is awash with counterfeits of all types, to a level not easily appreciated unless you see it with your own eyes.  In one African capital a government official showed me boxes and boxes of different confiscated products such as shoes, pens, razors, batteries, shampoo and medicines.  These items are usually shoddy at best – the ‘leather’ shoes are made of cardboard and dissolve in the rain, the pens only last two days. Sometimes the products are injurious – fake razor blades often have blunt or jagged edges.  Counterfeits can also be lethal: fake artemisinin therapy may be a death sentence for a three-year-old whose malaria remains untreated.

The industrial rise of many developing nations has led to a hierarchy of product safety: Developed > Fast Developing > Africa.  In European and US markets we are concerned about fake products when we find them,  but we have sophisticated monitoring and law enforcement systems that can spot even low levels of fake or sub-standard product.  The true problem lies largely unreported in Africa which is at the bottom of the heap, deluged by low cost, poor quality goods and counterfeits.  The same low-wage countries used by western brands to reduce production costs are now dumping large quantities of manufactured garbage into Africa.  This does not just affect international brands.  An African entrepreneur told me how he was put out of business when his locally-made toiletry products were copied by Asian counterfeiters.  Even cheap items can be counterfeited profitably if the volume is high and the quality of the fake is low. 

Africa is now living with an epidemic of counterfeits to add to its other problems.  This erodes daily life with petty inconveniences and wasted money but in the case of fake drugs the effect is much more severe.  Some of the bigger, richer nations such as Nigeria can fight back on their own with some success.  Regional coordination is also improving but the seizure of huge quantitities  of fake medicines in coordinated operations such as Interpol’s recent Mamba III is probably only the tip of the iceberg. It doesn’t matter which statistics you believe about the global level of fake drugs.  Personally I don’t believe any one number because they are all built on the sand of poor data rather than on solid statistical foundations.  The average prevalence is not the point.  One percent, ten percent, fifty percent, whatever. All just irrelevant numbers if your child is dead from a treatable disease because the drugs you bought in good faith turned out to be worthless fakes.

The long-term success of health initiatives such as the Medicines for Malaria Venture, aimed at one of the major causes of death in Africa,  will depend not just on scientific innovation and ensuring wider access to medicines but on protecting Africans from fake medicines. Some of the things Africa needs to combat counterfeit drugs are low profile, unglamorous and probably hard to excite donors about: customs support, anti-counterfeiting technology, better retail systems, pharmacist training, consumer education.  Some of it is happening, but not enough and not quickly enough.  African governments do not have the finances or the resources to cope on their own.  Many Africans will remain trapped in poor health unless we in developed nations attach as much importance to securing the African healthcare system as we do to providing innovative new drugs.

Photo by John Steven Fernandez from flickr Creative Commons

Does pharmaceutical medicine concentrate too much of its effort on exploring outer (chemical) space at the expense of finding out more about our own backyard?  The costs of finding and launching a new drug are in the same billion-dollar-plus bracket as a space mission , according to independent research.  Yet we are still metaphorically trying to send people to Mars rather than thoroughly exploring the potential of resources closer to home.

A recent Novo Nordisk survey found that more than 1 in 3 diabetics do not take their insulin as prescribed.  This has worrying problems for their health since poorly controlled blood glucose is linked to many long-term complications such as heart attacks, blindness, amputations etc. Since these outcomes are well-known, especially to diabetics, and the administration of insulin is very effective in controlling glucose levels, we have to ask ourselves what is preventing 100% adherence to the therapy. There are probably many reasons.  The process of checking glucose levels and injecting insulin is not a pleasant one (although using the side of the head as an injection site is especially not to be recommended).  The report says that the risk of hypoglycaemia also makes some patients reluctant to get down too close to the ideal level in case they overshoot.  But the main finding is that diabetics find the dosing regimen and route inconvenient.  If there were better delivery technologies then maybe adherence would be better.  Now if this was easy then it would have been done by now. Pfizer, no less, failed with an inhaled insulin programme that would have meant much less invasive treatment for diabetes.

However, many other big adherence problems are in areas with proven, oral therapies. Hyperlipidaemia, hypertension, and HIV (just to take three widespread examples) all have big issues with people not taking effective medication.  Pills only work if you swallow them.  By improving adherence, pharma companies could improve patient health outcomes and increase their own sales revenue as repeat prescriptions are filled. But pharma spends only a tiny fraction of its R&D budget on adherence-promoting technologies.

Maybe it is time we switched focus from manufacturing new health inputs (drugs) to producing efficient health outcomes (wellness) and started educating the financial community, regulators and patent offices to reward those companies who explore their own planet as well as launching the occasional moonshot.

Photo by skippyjon from FlickR

‘User-generated content’ has never been a popular concept in medicine.  Traditionally the patient’s role was to sit there in awe as the doctor dispensed whatever drugs and information he felt they needed. Apart from taking a medical history, most doctors routinely ignored any information the patient provided.  It was difficult for anyone to get any information anyway, unless they had access to rare and expensive textbooks. The paternalistic approach suited the medical profession and patients didn’t have much choice.

Things are different these days, or at least the availability of raw information is no longer a limiting factor.  Many patients go to their doctor armed with reams of Googled material on what they think might be wrong with them.  The problem now is not where to find information but how to separate the useful and reliable material from the terabytes of garbage.  Much of the chaff is not generated by doctors or anyone affiliated to the medical profession, or even by the myriad quacks and vested interests out there, but by patients.  Chat rooms, forums, blogs, Twitter, Facebook etc all provide a place for anyone to share their opinion with the world.  If you think that broccoli cures baldness then your ’fact’ can be out there in seconds (it doesn’t work for me, by the way). 

This swirling mass of user-created information presents problems for the pharmaceutical industry.  How to engage in meaningful conversation with their customers without having to rebut every piece of nonsense or misinformation?  Most companies have opted to keep their heads down.  One of the more active corporate twitterers is Pfizer, although @pfizer is an unofficial site and the corporation had to make do with @pfizer_news, a neat example of the relative uncontrollability of the social networking space from a corporate branding perspective. 

The drug industry should persevere in trying to find its voice in this unfamiliar landscape.  Firstly, social networking and the associated media channels are not going to go away so it makes business sense to join in.  Better to surf the wave than to wait for it to knock you off your feet.  Secondly, a better dialogue with customers could give new and unique types of information.   One of several areas where I think audience participation might be really helpful to patients, doctors and the drug industry is in anti-counterfeiting.  By encouraging people to report suspected fake drugs direct to the maker through a quick, easy and familiar channel, we can probably reach a lot of people who wouldn’t bother to go through the hoops of the formal system. Some of the reports will be false alarms, but the increased transparency will be worth it. Companies prepared to be open about the fake drug problem and to trust their customers enough to enter a dialogue will project a more caring image which will pay off in the longer term.

Despite the rearguard actions of paper-loving Luddites, we are slowly inching nearer to e-medicine.   The ‘paper-is-good, computers-are-bad’ movement seems to be stoked by tabloid newspapers but like the death of newsprint the eventual demise of the fat, yellowing, cellulose medical record is inevitable.  Yes, there will be problems and big challenges along the way.  The systems to secure the data and maintain confidentiality will need constant vigilance and there will be occasional lapses and leaks but by and large the advent of the digital age is a huge opportunity. 

With the increasing digitisation of medicine will come a host of new healthcare possibilities that we haven’t even begun to realise yet.  Some of these will come from the universe of ’unknown unknowns’ - things that are undreamable today.  A radical new way of delivering health may emerge as if out of nowhere to become ubiquitous.  Some of these new business opportunities may be as unexpected as Monty Python’s Spanish Inquisition.  However,  I suspect that a lot more progress will come from the ‘known unknowns’ area.  For example, there are things we should be able to do much better if only we could link up existing data sources more creatively and effectively. The governments and insurance companies of the world sit on huge quantities of medically-relevant data.  So do supermarkets. And phone companies. If we could get over the hang-ups (and genuine security concerns) about patient confidentiality then a whole new vista opens up.  Linking information about personal movements with supermarket loyalty card information about purchased food items could give interesting correlations and there are probably many other diamonds waiting to be excavated from the layers of government sediment.

Joined up datasets would also provide a practical path towards ‘health payments’.  This is the idea of giving people cash (or other incentives) if they make good lifestyle choices (stop smoking, eat healthily, take exercise etc).  The UK government is currently holding a public consultation about this, which is either pragmatic realpolitik or another example of the nanny state, depending on your point of view.  If le grand public can’t or won’t tackle their avoidable health problems individually then anything that society can do might help. The system, if it works, will more than pay for itself in prevention of healthcare costs and reduction in sickness benefit payments.  Personally (and only slightly tongue-in-cheek) I would put low cost RFID readers in lamp-posts and RFID tags in the personal incentive cards. By noting the time between reads it should be possible to distinguish between someone walking, cycling or driving, and by setting a minimum qualifying trip distance some element of cheating could be prevented.

But this brings me to the other practical issue of health incentives. If the government goes ahead, the headline technical problem in the media will be the system implementation challenge – wherever you live, try naming a government IT scheme that came in early and under budget.  However, the prevention of crime is equally important.  In my day job I help companies to protect their systems and products from fraud and counterfeiting, and I can see any new health payment scheme being rapidly targeted by those looking for a quick buck.  Fraudsters, whether lone or organised, are amazingly creative and quick to exploit a vulnerability. Whatever the UK government decides to do in e-healthcare, health incentives or any other system-based initiative, the cardinal rule is to expect the unexpected. Their chief weapon is surprise…

Just wanted to let everyone know that I haven’t decided to stop blogging, despite appearances.  I’ve recently put everything else to one side to prioritize finishing the draft of a book on anti-counterfeiting – due to be published by Wiley-Blackwell in the next few months. That’s now done and submitted, so normal blog service will resume soon.

As poor countries get richer, their growing middle classes develop expanding waistlines and increasingly “western” disease patterns.  Demand for branded medicines is rising in many developing countries and the drug industry is waking up to the potential for profit growth.  They see an opportunity to globalise the same drugs that have been such money-spinners in the west.

Developing economies have also driven cost reduction.  The rate of industrialisation has exceeded the growth in labour costs and several countries now now offer cheap, high-quality pharmaceutical manufacturing. Many drug companies have moved production out of the USA and Europe and into low cost countries. The new sales opportunities make this strategy doubly attractive.

Although there is huge commercial potential, the globalization of the western pharmaceutical industry also carries a number of risks which, in my view, have not yet been fully addressed.  Two of the key issues lie in the drug development area.

Drugs for Patients not just Shareholders

If the pharmaceutical market is now global, then the output of the drug industry must reflect that shift.  Otherwise, pharmaceutical development will become detached from patient needs. In marketing terms, the industry is in danger of being product-driven rather than market-led. The neglect of anti-infectives research is a good example of this.

Advances in healthcare and nutrition over the past hundred years have led to an approximate doubling of average life expectancy worldwide, according to World Health Organisation (WHO) statistics. Most people in rich nations now avoid or survive the infectious, early life illnesses that killed many of their forebears.

The progress in the developing world has not been so clear. Despite the rise of relatively affluent middle classes, there are still millions of poor people who cannot afford even basic medical care.  WHO data reveal that the number one killer in low income regions is lower respiratory tract infection and six of the top ten causes of mortality involve infection of some type.  Together they cause more than two-thirds of deaths in children under five.

The pharmaceutical industry has developed effective treatments and preventative vaccines for many diseases, but in recent years very few new anti-infective drugs have been developed and few companies are investing in this area.  Why not, if there is clearly an urgent unmet medical need? 

In high income countries only one of the top ten killers is an infectious disease (leaving aside the fact that some cancers are virally-triggered). Most drug company headquarters are in high income countries, as are most of the people who can afford branded, patented antibiotics. Ironically, they are the least likely to need them.

The relative lack of demand for new antibiotics in the developed markets is only one reason for the lack of research.  The real commercial and development issues, which perpetuate under-investment in these major causes of death, are buried deeper in the business model of global pharma and in the conflicting needs of doctors and shareholders.

Most infections can be successfully eradicated with existing cheap generic medicines (assuming the drugs are not fake – see below). Even when powerful new drugs are used, a course of antibiotics usually lasts no more than two weeks or so.  Paradoxically, curing the patient is generally a bad thing for sales revenues.  The most profitable drugs tend to control chronic symptoms over a long period of time (diabetes drugs, statins, anti-psychotics etc) thus ensuring continued revenue.  Even worse, from a drug company point of view, the more effective the antibiotic the lower its sales potential is likely to be.  To prevent the rapid emergence of resistance, doctors reserve powerful new anti-infectives for cases where other therapies have failed.

Finding molecules with the necessary selectivity to cure infectious disease without causing unacceptable side effects is a difficult and expensive task, and the payback may not be great in direct revenue terms.  The majority of drug companies are publicly traded corporations whose executives have a legal duty to act in the best interests of their shareholders.  Antibiotic research is a tough way to make money so until we change the way society prioritizes and rewards biomedical innovation new anti-infectives will remain a rarity. 

But are we viewing the issue much too narrowly? The relative neglect of infectious diseases in developing countries is short-sighted and risky as well as unjust.  If we ignore the health needs of millions of poor people, we in the west are also endangering our own wellbeing.  Global migration, both legal and illicit, allows diseases which originate in poor countries to spread quickly to developed nations.  The world is now essentially one disease pool, as recent influenza and SARS epidemics have shown.

One answer might be to encourage not-for-profit research, perhaps by offering tax breaks to drug companies prepared to invest in this area or by granting longer periods of patent exclusivity on “lifestyle” drugs in return for increased development effort on neglected diseases of the poor and the distribution of anti-infectives at very low cost to those who need them.  There are some movements in this direction but we need to do more.

History teaches us that infectious disease is never defeated, only kept at bay. New global pandemics could emerge at any time, probably from poor, densely populated countries which cannot help themselves.  Climate change may accelerate this process, perhaps allowing malaria back into southern Europe for example. For the sake of patients worldwide, we must retain and enhance the capacity to develop new anti-infective drugs before they are needed. 

Real Drugs in the Right Places

A smaller world has led to the emergence of global trade and global crime as well as global disease.  Many medicine donation programmes have had unintended consequences: drugs which pharmaceutical companies provide cheaply or free to poor countries but which normally sell at higher prices in developed countries can be stolen and diverted back to these markets very profitably. Corrupt middlemen and criminals make a killing and the poor still don’t receive the medicines they need.

As well as diversion and theft, there is now widespread copying of drugs. Some of these counterfeits are genuine, albeit unauthorised, attempts to produce “generic” versions of effective medicines, often coming from countries which do not recognise the originator’s intellectual property.  The pharmaceutical industries of nations such as India and China are no longer just domestic suppliers or sub-contractors for international corporations.  They are looking for new outlets for their cheap drugs. 

In Africa, many counterfeit drugs are sub-standard and ineffective and often contain dangerous contaminants.   The criminals who produce them cynically exploit the illiterate poor who are unable to differentiate between genuine and fake medicines. However, the problem is not confined to Africa, and very sophisticated fake drugs have penetrated the highly-controlled supply chain of many developed nations. Even brand owners sometimes struggle to differentiate their genuine drugs from counterfeit product. 

This is where drug development comes in.  In the past, it was enough to differentiate a pharmaceutical brand using trademarks: a memorable name, a logo, and the borrowed brand attributes of the company itself.  Nowadays, these product elements can be quickly and easily copied. Copies of almost any dosage form can be obtained in bulk on the open market, with as much or as little purity as the buyer wishes to pay for. Packaging can be replicated or simply recycled from hospital waste. Counterfeiting of pharmaceutical products is now a huge parallel industry.  Visually at least, the output is often of superb quality.  More than one manufacturer has identified counterfeits because the packaging quality was higher than that of their own product. 

The legitimate pharmaceutical industry has fought back, but their focus has generally been on the addition of distinctive features to packaging.  This has some merit, since it has been tried and tested on bank notes and value documents (passports, cheques etc) around the world.  We can think of drug packaging as a value document, since it represents the main way in which the consumer can discern the authenticity and value of the contents. In the same way that central banks have used colour-shifting inks, holograms, watermarks and the like to protect their currency, so some drug companies have added similar features to their packaging. 

The problem is that these security measures are mostly retro-fitted onto existing packaging designs, making them easier to locate and to copy, rather than integrated into the design and fabric of the product itself as they are in bank notes.  The level of investment in pharmaceutical packaging security is often lower than that needed for adequate protection, and therefore the results have been patchy.  This is a non-core business area for drug companies and product security is often still seen as a manufacturing cost.  In the relative absence of big counterfeiting incidents in their major western markets, most companies have invested the minimum necessary for legal compliance.  This is slowly improving with the emergence of initiatives to “serialise” (add a unique code to) each pack, but other approaches are also needed.

A better way to protect patients is to concentrate on what the drug industry does best: formulating and testing innovative drugs and novel delivery methods.  By incorporating unique security features into the products themselves during drug development, and by designing integrated packaging that is harder to copy and (where appropriate) cannot be re-used, the drug companies can make counterfeiting economically unattractive without making their products prohibitively expensive to produce.  In the same way that the car industry has incorporated passenger safety into every facet of automobile development and production, the pharmaceutical industry needs to re-evaluate anti-counterfeiting from first principles.

The US Food and Drug Administration (FDA) issued guidance in 2009 on what they term “physical-chemical identifiers” and how they can be incorporated into pharmaceutical products.  There are many available ingredients which are “Generally Regarded As Safe” or GRAS in the FDA jargon. Using GRAS substances as markers provides a way of adding safe, traceable components into new pharmaceutical products without huge extra cost. Making the shape and appearance of the pill or capsule more distinctive is another simple option – it is surprising how many products are still produced in standard, easily-copied formats.

The dosage form itself is only one element of an integrated product, and there is great scope for innovation in drug delivery and integrated packaging. Not all of this innovation need add major costs. Early planning by development teams allows anti-counterfeiting approaches to be integrated with usability, patient adherence and other physical features at little additional expenditure and may even identify process savings.

This new way of thinking needs to be sponsored at board level because it may occasionally run counter to prevailing cost-cutting and “lean” initiatives.  For example the manufacturing division – incentivized by management to save money – may decide to use cheap, easily available, industry-standard vials rather than developing or specifying a product-specific design. They reduce direct costs but give the counterfeiters an immediate head start in copying the product.  The ultimate cost to the business may be much greater than the saving on materials.

Providing high-quality anti-infectives at a low, uniform global price would help to remove the incentive for criminal activity in this area and would save millions of lives. Designing robust security features into all products during the development phase would serve the needs of patients whilst safeguarding the assets of the drug industry as it globalises.

The pharmaceutical development process could better serve the needs of all patients (not just those of us in the rich world) if we take a more globally-integrated view of disease burden and criminal threats. We should view the development and supply of genuine, effective drugs to treat the diseases of the world’s poor as enlightened self-interest.  

Photo: US Army Africa from Flickr

Yesterday, I chaired the online “Walpole Lecture“, a webinar entitled:  ’To what extent can pharmaceutical counterfeiting ever be contained?’ Various interesting perspectives on this issue were provided by Marisa Matias MEP, Rapporteur for Counterfeit Medicines at the European Parliament, Janice M. Soreth, Deputy Director at FDA’s Europe Office, Guy Villax, CEO of Hovione and Board member of CEFIC’s European Fine Chemicals Group and of RX-360, and Hans Bijl of Siemens.

The ninety or so attendees got an understanding of what the legislative priorities are in Europe and the USA.  No real surprises in the content, but it looks like transatlantic coordination is bearing fruit.  One of the interesting parts of the discussion for me was a clarification from Marisa that the amendment to dilute the traceability requirement, that I previously commented was a bad development for patient safety, is to be edited out again.  It was apparently only one of many interventions at the draft stage and will be dropped during the legislative clean up process.  So it looks like traceability will be at the heart of the regulations, which is critical if we are to make headway quickly in getting to grips with counterfeit drugs.

Guy Villax made the interesting point that the counterfeit API cases that we know about could be the tip of an iceberg. Since some API batches can be composed of multiple originating suppliers , and the bulk product is dispersed so widely, it is hard to trace API.  We do not have a mechanism to tally adverse events with fake drugs so our data is almost non-existent. If someone dies and it doesn’t look overly suspicious then the autopsy (if one is conducted) is unlikely to consider fake drugs as a contributing cause.

It was clear from the discussion and the presentations that we have the political will, and we have the tools – now we need to get on with the job of protecting the drug supply.

Photo: Mykl Roventine from Flickr

Product authentication is the aspect of anti-counterfeiting which has received the most attention from regulators and the public, but it is worthwhile examining how we verify that the person requesting a prescription medicine is genuine.  This is important because prescription medicines are dangerous in the wrong hands and because in many subsidized healthcare systems access to drugs needs to be controlled in order to keep a lid on costs.  Before allowing an individual access to medical products, the answers to the following questions should be known:

• Are they who they claim to be? Do they have valid personal identification?
• Do they have an authorized prescription from their physician (where applicable)?
• If they are asking for medicines which are normally given long-term for a chronic condition, are they already “known” to the healthcare system? 

Some of these precautions may be impractical in some situations but, by ensuring that healthcare professionals consistently take simple measures to verify their patients’ personal identities and healthcare entitlement, much of the unauthorized acquisition and resale of medicines can be prevented. 

Informal transactions and anonymity are the tools of the criminal in all areas of life, and this is equally true with counterfeit or diverted drugs.  The problem is exacerbated where the state provides much or all of the funding for prescription drugs, and reimbursement fraud is common where controls are lax. Therefore, to reduce fraud and ensure that only those entitled to free or subsidised medication receive it, some governments have begun issuing medical cards.  These are identity cards for the specific purpose of validating personal entitlement to subsidised healthcare. The system in the Republic of Ireland, for example, uses a credit card size format.  The Irish system is means-tested (only those on low incomes are entitled to support) and is carefully controlled to ensure that only eligible patients are able to receive subsidised healthcare.

Some drug companies have also started to develop longer-term relationships with their consumers, using similar methods.   The aim is to get more information about their patients, and thus enable greater control over who is using their drugs and where they are getting them from. The quid pro quo usually takes the form of a price reduction to the consumer. Such schemes often involve product-specific payment cards, which the patient can present to the pharmacist in order to receive approved discounts on his medication, financed by the drug company. Consumers in many markets are already comfortable with the loyalty card concept and these pharmaceutical schemes seem to be proving successful.

The added benefit of a closer relationship between patient and drug company is that it can improve the likelihood that the patient takes the required medication correctly and for the correct time period. It provides a mechanism to remind them to take their medication as prescribed – so-called “compliance”, also known by the less loaded term “adherence” – and to come back at regular intervals for repeat prescriptions (known as “persistence”). By increasing adherence and persistence in this way, additional health benefits can be realised, particularly for chronic, largely asymptomatic conditions such as diabetes, hypertension, and hypercholesterolaemia.  The reduction in hospitalisation rates may also offset the cost of the extra drugs to the state, the insurer or the patient. Critics would say that these “loyalty cards” are purely profit-driven schemes which put too much sensitive patient information into the hands of drug companies, but with appropriate safeguards a closer link between patient and manufacturer has the potential to provide financial and product security benefits to both sides as well as improving patient health.

Counterfeit drugs can never be tolerated, and we must continue to use the full force of the law to stamp them out.  However, in my opinion, the most effective long-term approach for society and drug companies to use when dealing with counterfeits is one of demand reduction. We can do this by education, relationship development, imaginative product marketing and providing real service benefits to customers.  This may require regulatory flexibility as well. The more that legitimate products can be sustainably differentiated from the competition (whether legitimate or counterfeit) the easier it is to defend their market position and therefore by extension to reduce the threat from fakes. The gradual move towards the delivery of pharmaceutical healthcare as a continual service, rather than an intermittently-purchased product, will make it harder for counterfeiters to infiltrate and subvert the medical system.

Photo: Thanks to jimbowen0306 from Flickr

*If patient safety is the driver, then any counterfeit ingested substance is equally hazardous - regardless of its price or sales volume. 

**In a moving situation, what was counterfeited last year is not a good guide to what will be targeted next. 

***Neither is the severity of the condition to be treated.  Many incidents have involved things like Panadol, a common painkiller for headaches.    

The opportunity exists to implement a strong-minded Directive that puts patients first, is fair to all parties and provides clear, shared responsibilities. I hope the politicians don’t screw it up.