Over the Falls Without a Barrel: The Patent Cliff and Prescriber Impartiality

The sound is deafening.

Imagine calling up your old college friend Science and asking her advice. She speaks softly, hesitantly, and with frequent caveats. You strain to hear what she says, but there’s a problem.

It’s a party line.

While you try to hear Science speak, two boisterous rowdies named Marketing are shouting at you, all but drowning her out. They butt in, answering your questions before she gets a chance, claiming to speak on her behalf. It’s tempting to give up and listen to them instead.

This is the situation for any prescriber. “Science” is out there, murmuring in the distance, while the boys from Marketing giggle, whoop, and exclaim in an attempt to attract attention. They sound like 15-year-old boys, and their understanding of Science is about as deep. There is a light at the end of the tunnel, however. At 16, they get bounced off the line.

Umm, what? A Primer on Drug Development.

When a pharmaceutical company discovers a potential new drug, they undertake a mammoth project designed to assess a) whether it really works, and b) whether the risks and side effects outweigh the benefits. The aim is to amass sufficient evidence that the Food and Drug Administration (in the USA) or other national organizations (such as Health Canada in, you know, Canada) will approve the sale of the drug and the type of disorders for which it can be openly prescribed – the so-called “on-label” uses.

The process of gaining approval generally takes 5 to 8 years and can cost from several hundred million to more than a billion dollars. The figures vary widely, in part depending on whether one includes the cost of researching drugs that don’t ever make it to market. For every drug eventually approved, there are four to ten that start human trials and don’t wind up on the pharmacy shelf. So the true cost of development is not just the enormous cost of the trials for successful Drug A, but also the costs of failures B, C, D, E, and F. During the development period, the company is bleeding money and can only get it back once the drug is available in the marketplace.

In order to encourage companies to undertake this risk, governments place a pot of gold at the end of the rainbow. This is patent protection. The company that develops the drug has the exclusive right to produce and market it – in effect, achieving a monopoly on that medication. They can set the price to reflect not only the cost of producing the drug, but also to repay the cost of drug development and testing. If they have a “blockbuster drug” – one that becomes a major seller – they can also make huge profits.

The problem with this system is that patients and governments wind up paying enormous prices for the drug. The solution is to impose limits on patent protection – after which rival companies can produce generic versions of the same drug. Generics companies don’t have the same development costs, and so they price their versions much lower, which the original developers are forced to come close to matching. So when a drug goes off patent, the price drops sharply (often by over 80%) and the advantage to the original developer vanishes.

The period of patent protection is typically 20 years from the date of initial filing of the request. Given the delays in the approval process, the actual period during which a company can market the drug exclusively varies, but is usually around 15 years.

The result is that FDA approval essentially fires the starting gun on a race to recoup development costs and turn a profit. The finish line is the end of patent – often called the patent cliff.

The Expensive Elephant in the Room

There’s one bit of accounting that’s often left off these sketched reviews of the process, and that’s the cost of marketing the drug once it has been approved. Most accounts indicate that pharmaceutical companies spend at least as much on marketing as they do on drug development research. One account (below) suggests the figure is almost twice as high for marketing.

Well, fine. What’s the point of developing a new treatment if no one finds out about it and patients go untreated?

The marketing costs do not include the means by which prescribers are alleged to receive their knowledge about practice: reading journal articles. Here’s an estimate of total costs from Gagnon & Lexchin (2008) – all figures in billions of US dollars:

• Samples (the provision of free packages of medication to prescribers, who can offer them to patients in the office to get them started, after which they will continue on paid prescription): $15.9 b.
• Detailing (essentially, visits by sales representatives to physician offices, plus the provision of pamphlets, swag, and related products): $20.4 b
• Direct to consumer advertising (advertisements in newspapers, magazine, television, and internet that is directed to the general public rather than to healthcare providers, often with the advice to “ask your doctor”): $4 b
• Sponsorships, displays, and the provision of speakers to professional meetings: $2 b.
• E-promotion & mailings (generally to prescribers), promotion-related post-approval clinical trials: $0.3 b
• Journal advertising (advertisements in publications aimed at professionals): $0.5 b
• Unmonitored promotion (estimated; includes amounts that do not appear in other categories including promotion to unmonitored physicians or in unmonitored journals and miscellaneous other marketing strategies): $14.4 b 

Of particular note here for the nonprescriber is the contrast between the amount for direct to consumer advertising (the seemingly ubiquitous and presumably expensive “ask your doctor” ads) at $4 billion, and the marketing to physicians, a much smaller group of people, at a cost 5 times as great at $20.4 billion.

One might be tempted to wonder how the firms can possibly spend so much money marketing to prescribers. Imagine that instead of producing television ads they sent the salesperson directly to your home to act out the advert in person – while making you lunch and providing golfing fees.

But all this ends?

Once a medication “goes off the patent cliff,” profits decline precipitously and the motivation to promote the med to physicians and the public decline as a consequence. The drop can have a major impact on a pharmaceutical firm – just search using the terms “antidepressant patent cliff” to turn up a variety of business analyses like this one:

http://www.insidermonkey.com/blog/eli-lilly-co-lly-what-does-the-patent-cliff-mean-for-this-drugmaker-206308/

Let’s take a look at the names and patent expiration dates of some of the most well-known antidepressants.

• Prozac (fluoxetine), 2001
• Paxil (paroxetine), 2003
• Zoloft (sertraline), 2006
• Remeron (mirtazapine), 2010
• Effexor XR (venlafaxine), 2011
• Lexapro, Cipralex (escitalopram), 2012
• Cymbalta (duloxetine), 2013
• Wellbutrin (bupropion), 2013
• Pristiq (desvenlafaxine), 2022 – of note, desvenlafaxine is marginally different from Effexor and is often regarded as little more than a patent extender on Effexor.
• Viibryd (vilazodone), 2022

Overall dollar sales figures for antidepressants have tended to fall as the medications have gone over the patent cliff. Revenue for antidepressants peaked at about $15 billion per year in 2003, and is projected to decline to $6 billion in 2016. Depression, once a major money-maker for pharmaceutical corporations, is fading as a revenue opportunity.

Why is this important?

Remember our party line? The marketing rowdies drowning out our friend Science get laid off when their drugs go off patent. The drugs are still around, but the distorting influence of their promotional activities (disguised as science) largely end. The air clears, and our prescriber is left undisturbed to examine the literature once more.

Of course, this doesn’t solve all the problems. Prescribers are likely still to have received most of their psychopharmacology education from the marketing team. And having been subjected to endless lectures about the wonders of various drugs, they may feel that they already understand the scientific backing and neglect to look again. As well, most of the articles in the scientific journals are funded and written by (guess who!) the pharmaceutical companies themselves, and there has been a marked publication bias favoring positive studies over negative ones.

Nevertheless, the end of patent means fewer free samples, fewer visits from pharmaceutical reps, fewer paid lunches, fewer “opinion leaders” making the rounds showing the companies’ own slides, fewer conference symposia lavishly funded by patent owners, and less general noise distorting the environment. Medical decision-making is likely to be based at least somewhat more on science than on enthusiasm and hoopla.

What about newer antidepressants?

There are still a few preparations on patent, and in the past there have always been new medications coming online. Once Prozac went off patent, everyone finally shut up about it and more profitable medications picked up the baton and continued the charade. Won’t that continue?

Well, that’s the thing.

The pipeline is just about empty. Some firms have given up on depression, and in the past few years a variety of preparations have bitten the dust before reaching the approval stage. There is a noticeable lack of enthusiasm about upcoming products, though the few that remain on patent will doubtless be promoted to death. So there will still be some rowdies on the line trying to drown out science, but there will be fewer of them and they seem to have become somewhat muted. Not even the pharmaceutical reps seem able to muster much enthusiasm for the newer products, and the usual claims of “revolutionary advances” are not being heard.

So, Science. It’s been a while. At last we’re (almost) alone. Whisper your ambivalence. We can finally hear you.

Resources

Gagnon M-A, Lexchin J (2008) The cost of pushing pills: A new estimate of pharmaceutical promotion expenditures in the United States. PLoS Med 5(1): e1. doi:10.1371/journal.pmed.0050001

York University. "Big Pharma Spends More On Advertising Than Research And Development, Study Finds." ScienceDaily. ScienceDaily, 7 January 2008. <www.sciencedaily.com/releases/2008/01/080105140107.htm>.