Saturday, April 19, 2008

Big Pharma: hero or villain?

The relationship between pharmaceutical companies, patients and doctors is a complex one. It derives from a mish-mash of motives.

Let's start with the patient. He or she wants to be cured; if not cured, to have a longer life and a better one. Sometimes it's a choice between a longer uncomfortable life and a shorter more comfortable one. Most times neither the doctor nor the patient really knows what the outcome of treatment will be and decisions are made of a basis of statistics, false impressions and wishful thinking. Probably for most things the doctor knows best, but for other things the patient knows better. There is asymmetrical knowledge between doctor and patient. This is common in most professional relationships, but it does not make for a fair market.

When you are perplexed about whether you should buy a Ford or a Toyota there are magazines you can read to give you some insight into the choice. Should you get a Sony or a Samsung, an Epson or a Canon? Buy a "What Car" or a "What TV" or a "Which Printer" and become an instant expert. But it's not like that in medicine. A smooth talking physician may know nothing about your condition; a rude and brusque surgeon may know exactly what's right for you. How can you possibly tell? Trial and error may leave you dead or disabled. Market forces may have calamitous results.

The doctor has many motives. You might think his prime purpose is to cure as many people as possible, but if that were his motive pure and simple, he would be working in Africa and not many are. Why am I not working in Africa? Many reasons. I don't like the heat. I would miss all the mod cons. I don't speak the languages. I would miss all the diseases that are interesting to me and without the facilities I have in Britain I would be pretty useless. I need the money to support my family. And why lay it on a doctor's conscience? Africa needs engineers, accountants, businessmen, teachers and factory owners too.

So although a doctor wants to cure the sick, he wants lots of other things too. He certainly wants paying well. Not many doctors take poorly paid positions. He also wants the good wishes of the community; he likes to be well thought of. He may also want fame. Perhaps he would like the rewards that go with a successful academic career such as foreign travel, smart hotels, and lavish entertainment. Perhaps his real interest is in the science; ferreting out the mechanisms of disease.

Now let's consider the pharmaceutical company. Like any other company its main purpose is to make money. How do they make money? By providing the best product to their customers at the best price. Competition ensures that those who don't perform fail. That's how the market works.

That's how it ought to work, except that the market is deficient. For one thing, it is hard to know whether a particular treatment works or not. Patients often get better from some diseases without treatment. The mere presence of a sympathetic doctor and a pink pill will cure some things. In order to sort this out, we have regulators who apply an expert eye to this thorny question. They regard the randomized controlled trial as the only legitimate way of knowing whether a drug works.

However, even randomized controlled trials (RCT) can be manipulated. For marketing is not just about ensuring that the customer knows that your product is best, but about giving the impression that your product is best. If your marketing is good people can be induced to buy an inferior product.

In an RCT, the new treatment should be compared with whatever has been the best hitherto, not with something that used to be the best. Of course, a drug might have a niche market. There may be some patients for whom what is generally the best is not the best for them. An example of what I mean is this: probably the most effective treatment for CLL is FCR, but not for patients with del 17q, for whom it works very poorly. If a new treatment is worse that FCR for most patients, but better for these patients, then it should be licensed for this exception, but not for the whole gamut of CLL.

Lately, new drugs have been compared with chlorambucil. Now I think chlorambucil is a fine drug, but I do not claim it is the most effective drug in CLL. Until fludarabine came along, chlorambucil was regarded as the standard treatment, but the Rai et al trial in the NEJM in 2000 demonstrated that fludarabine was superior in terms of response rate, complete response rate and length of remission, though not in terms of overall survival. What nobody noticed at the time was that the dose of chlorambucil chosen as a comparator was on the low side - much lower than is usually used in the UK by CLL specialists, though comparable to the dose used by US oncologists who do not specialize in CLL (in other words the dose was a very safe one).

The CLL4 trial published in the Lancet last year demonstrated that fludarabine was no better than chlorambucil when chlorambucil is used in its usual UK dose, and fludarabine is more toxic than chlorambucil used at that dose. That's why fludarabine is not licensed in the UK for first line use in CLL. However, the same trial showed that the combination of fludarabine and cyclophosphamide is superior to both chlorambucil and fludarabine given separately. And the German CLL8 trial, although it has not reported formally, is believed to show that FCR is superior to FC.

Now there may be niches where chlorambucil should be preferred - older patients, frailer patients - and there is still no evidence that any other first line treatment improves overall survival, compared to chlorambucil, but the proper comparator should be FCR now, not chlorambucil, unless one is aiming for a niche market and trying to sell the new drug as an alternative to chlorambucil on the basis that it is less toxic (either short term or long term) or cheaper.

The difficulty anyone has in using FCR as a comparator is that the average length of remission with FCR is very long - perhaps greater than 6 years - and the patent would run out on a new drug before the trial was done. So the pharmaceutical companies try to hoodwink us, by choosing a feeble comparator; not just chlorambucil but chlorambucil in a half-hearted dose.

There is another way that the market is rigged. People don't pay for their own drugs. The cost is borne by the community; either directly by the state or through an insurer who passes the cost on to employers or individuals who don't have the disease. These third party payers have little inkling of whether they are getting value for money. The UK has set up NICE to answer that, but like all bureaucracies it is slow, ponderous and lacking in insight.

So what's the answer? It's not to nationalize the pharmaceutical companies. Leukaemia drugs do occasionally come out of communist countries. Bendamustine came from East Germany, and both ATRA and Arsenic came out of China, but most drugs have come from the big pharmaceutical companies of America, Britain, Germany, France and Switzerland. Paradoxically, my solution would be to extend patent protection for drugs. Currently it is 17 years. I would make it 35 years. This would give the companies long enough to do proper trials, and long enough to recoup their costs without inflicting unnecessarily high costs on third party payers.


Anonymous said...

Your thought about extending the duration of patent protection superficially has some merit, but there are many issues to deal with in the age of technology and it seems most unlikely that all of the worlds governments would ever agree to such a plan (think of Thailand), nor that pharmaceutical companies wouldn't take advantage of such a prolonged free run to sell a product at high prices.

The costs of drug development are very high, but much money also gets spent on drug promotion. Once the benefit of promotion is no longer perceived, the money dries up, and, often, so too, does the availability of the drug in question.

Over my many years of practice I was amused (and disappointed) to see drugs brought to market and heavily, but inappropriately promoted, only to later see the drugs withdrawn after post-marketing problems (which had either not been apparent, or which had been hidden during testing) became painfully apparent (eg, Vioxx, Lotronex).

More disturbing to me, however, was the loss of drugs here and there either because the markets were small, or manufacturing issues made them less profitable to produce and sell.

One of the problems of our modern era is the advent of the "me too' drugs (think of statins, PPIs for heartburn and erectile dysfunction drugs). The costs associated with their development and the outrageous costs associated with their marketing suggest just how much money is in play.

I am not optimistic that there will be many good RCTs going forward, and suspect that the pattern of therapies being adopted after results of small, carefully selected phase II trials being published will persist.

The answers to many questions may not come for many, many years.

certainly, I hope that i am wrong!

Anonymous said...

Thanks for a thoughtful post. I, too, comment on these issues but a patient's voice for some reason is discounted (except at the polls).

You write that for most things, the doctor 'knows best'. I think for run-of-the-mill things, that's what medical school is for. However, for a rare disease such as CLL, I find that I know more about CLL than most hematologists do. Obviously I don't know as much as CLL experts, and I don't know much about the 'over-all' physical system that is the human body, but I think a common theme on the CLL boards is how one can be steered terribly wrong by an all-purpose oncologist.

"How can you tell?" if a doctor knows about CLL, you ask. That's pretty easy. I asked my first HMO oncologist what he would prescribe if I needed treatment years ago. When he gave me an answer that was outdated, then I knew. In other words, the patient needs to do his homework!

I used to be in the occupational testing business. One thing that sticks in my mind years later is what motivates doctors. It is one word above all! They score very, very high on the desire for money. Obviously other factors come into play (personally, I don't like to touch or be around people, esp. sick people. Yuck!), but studies consistently show that the money angle is true.

And this ties into the pharmaceutical business. Most of these companies are publicly traded. Analysts and markets severely punish companies that do not make money, make enough money, or meet expectations. That is probably somewhat different than the environment 50 years ago, when the business world was much more cozy and competition much less ruthless. The 'greed is good' philosophy has changed (ruined?) business by forcing companies to focus on quarterly earnings, not long-term success.

I've long thought that patents are too short-lived. I think in the US it is 20 years from patent (before clinical testing) to expiration. Perhaps the coverage could be extended a couple of years. But you have to be careful; look at the nonsense that Disney and other companies have imposed on the US market and probably others relating to copyright protection. It is there intention (and they are working on this, piecemeal) to make sure NOTHING EVER falls into the public domain.

As long as a buck can be made from 'Snow White' or 'Winnie-the-Pooh', Disney wants to get that last dollar.

Anonymous said...

I feel very sorry for the second commenter. He or she is very cynical. My experience is that physicians may be uninformed, and in some instances, incompetent, but I seriously doubt that money plays a significant role in their motivation, as the study and practice of medicine is simply too hard to do it simply for economic gain.

Most physicians work far longer and earn far less than the public perceives. Most physicians sincerely want to do a good job and many (perhaps not enough) care very much how well their patients do, even when those very same patients are a pain in the nether regions.

The commenter refers to "CLL boards", by which I presume he or she means various on line forums or chat rooms. Much of the information therein is helpful, but everything on such forums should be "taken with a grain of salt" as mis-information and bad advice (often based on incomplete information) are not helpful to anyone.

Terry Hamblin said...

Patent protection has only to hold in the US, Canada and the EU - possibly Japan. Other markets are tivial. The return from India, China, Brazil, Africa and the rest is so small as to not be worth fighting for. Importation of look-alike drugs from countries that don't sign up to patent protection should be a criminal offence.

Marketing costs are at least as high as development costs, but these could be reduced if there were a more secure regulation of clinical trials. Any healthcare system brought in by the Democrats will adopt some measure of cost-effectiveness like NICE, which will limit the value of marketing. I expect that a deal would be done between the companies and the government to limit marketing costs in return for longer patent protection.

I don't think the companies would seriously object to having to give up dishonesty. Like the tobacco companies, they will play on whatever field and according to whatever rules they are furnished with.

I am more concerned with the fact that clinical trials are run by big Pharma. In the UK leukemia trials used to be funded by the MRC and run by academics. However, the MRC has dropped out and now most trials are funded by two charities: CRUK for all cancer studies and the Wellcome trust for all others. Rich though these charities are, they haven't the resources of government. They have to beg free drug from the manufacturers and are unable to get it for head to head comparisons with a rival's product. We need the purchasing power of governemnts to do these head-to head comparisons. But more than this we need trials against current best-available treatment, which the companies are reluctant to do. It is a disgrace that the FDA licensed Campath on the basis of the comparison with low dose chlorambucil, just as it's a disgrace that we have had to wait this long for the German CLL8 results to tell us what we always suspected about FCR.

Some late effects (like those of Vioxx) only become apparent after prolonged use of the drug and prolonged patent protection would give companies added incentives for doing more extensive post-registration studies.

The other thing cost-effective regulation could do would be to shift the bias away from treatment for fairly trivial problems (heartburn and declining sexual prowess in old men) to life and death problems like cancer and stroke.

I have written before (search the blog) on how a patient can become more informed about his or her disease and what questions to ask a doctor. It is unfair to suggest that doctors are driven only by money. Intrinsically, doctors are like other human beings. They are driven by many different forces, just like others. Money is one of them, and sometimes this gets out of hand, but remember, you have to be pretty clever to pass the exams, and in our society cleverer people command higher salaries. But you have to be motivated towards helping people as well. If it's just money you are after go into some sort of financial enterprise. Money sticking to your fingers is one of the perks of thr post.

Anonymous said...

Physicians are always (for some reason) claiming poverty when they constitute one of the highest-paid occupations (at least in the United States). I am a researcher by profession, and it is not difficult to put to rest this claim.

According to the Bureau of Labor Statistics, Department of Labor, United States Government, the average salary of a general practitioner with more than one year's experience is $156,010 per annum. An anesthesiologist with more than one year's experience averages $321,686 per year. No matter who you ask, those salaries are way above average; some may call them extraordinary.

This places physicians in the top 5% of salaried workers in the United States.

Don't believe me? This is the source:

(BTW, I never suggested that a yearning for money was the only thing that motivates doctors; it has been shown to be a major factor that attracts people to the profession. It's just a fact, sorry.)

As to the first poster's lament about 'me-too' drugs, well, so what? You expect Ford or Chevy not to compete in the compact car class just because Japanese automaker Toyota has a model or two so positioned? Hardly!

Pharma is the same. Let's look a the market for acid reflux. It's a large market, and billions can be made here. Do you think we should only have one option? Which one? And says who?