Placebo controlled trials, catastrophically ill patients and access to experimental drugs

Here's the long version of a piece I wrote on this topic for  The Conversation where it was published today (sans a few bits and pieces that I would have liked included). Interestingly enough, the site saw it fit to alert readers of my piece to an article expressing a different point of view. Fair enough, except, when you read said article you'll note that it doesn't link back to my piece.

In the last six months Colorado, Louisiana, Missouri, Michigan and, most recently, Arizona have passed “right to try” laws that allow terminally ill patients to access treatments that have only passed FDA Phase I clinical trials. All patients need is permission from a drug company and a prescription from a doctor.
 

Right to try laws are designed to ensure that terminally ill patients taking part in clinical trials are true volunteers and have no incentive to cheat the clinical trials system as has happened in the past.
 

Recently, these laws have been critiqued as misguided, and the ethics of allowing patients to use experimental drugs are still up for debate. These laws do not guarantee access to experimental treatments and patients may have to pay for them out of pocket.

Critics of these laws worry that alternative trial designs, or access to such experimental drugs outside the clinical trials system will significantly delay the development of effective therapies.
 

Right to try laws are ethically defensible because they give desperately ill patients a choice. They can decide to participate in placebo controlled clinical trials or to access experimental agents as a possible last-chance treatment. The clinical trial system demands that participants are true volunteers. But, without right to try laws, terminally ill patients have no choice but to access these experimental treatments through placebo controlled trials.

AIDS and the origins of ‘right to try’

Throughout the 1980s, AIDS activists and patients fought to change the clinical trials system. Dying from what was then a terminal illness, many people with AIDS insisted on the right to access experimental drugs that had successfully passed Phase I clinical trials.

Phase I trials are designed to establish the toxicity profile of a particular drug. A small group of volunteers (often not more than a handful) test the drug to find out whether it has serious side-effects. They don’t have to be patients, because the objective is to determine what negative effects, if any, the short-term use of the experimental agents could have.

The only option for AIDS patients in the 1980s was to join a post-Phase I placebo controlled trial or go without access to experimental agents that might give them a shot at survival. These drugs trials are typically double-blind. Double-blind means that neither the doctors nor the patients know who receives the experimental agent and who receives the placebo. This aims to eliminate any bias that might arise from patients or doctors knowing who receives what.
 

Taking part in clinical drug trials meant that AIDS patients faced the chance of being assigned to the placebo control group, and not the group receiving the experimental treatment. These patients understood perfectly well the steep odds against these drugs working. But at least there was a chance. The same cannot be said of placebos.

There is a sound methodological reason to test a new experimental agent against a placebo control when we have no gold standard of care. We need to know whether the new agent does better or worse than the existing standard of care. Even in cases where there is no effective or well-developed standard of care we are usually, but not always, justified in undertaking placebo controlled trials.
 

But, we expect patients participating in clinical trials to be true volunteers. Patients need to choose to participate and give first person voluntary informed consent.

AIDS patients charged that the clinical trials system was essentially coercive. To access experimental treatments, these patients were more or less forced to take part in these clinical trials. If they did not volunteer to participate in a placebo controlled trial, they couldn’t access experimental treatments.
 

Many patients grew frustrated with this system and, often in collusion with their doctors and pharmacists, lied and cheated to access particular clinical trials. They analyzed who got placebos and who got the experimental drugs, and shared the drugs. Patients dropped out of clinical trials they believed offered trial designs not conducive to their own survival. Controlled trials become nearly impossible under such circumstances.
 

Undoubtedly this made it harder to get a sense of what drugs worked and what didn’t and may have delayed the development of life-preserving anti-HIV medication.

Drug companies control access to experimental treatments. Taiyo FUJII/Flickr, CC BY

Right to try, but not right to access

Since the 1980s special access protocols have been implemented in the United States, Canada and other countries. These protocols meant to ensure that catastrophically ill patients can access experimental agents outside the clinical trials’ system.

At least in theory. In practice, things are different. Right to try laws do not guarantee the right to access experimental treatments. Even with laws in place, access is still controlled by drug manufacturers.
 

In Canada the government permits people with terminal illnesses to access drugs that are in the clinical trials system, and they can do so without having to participate in the trials. In return they promise to have their doctors monitor the impact of the drug carefully and report it back to the manufacturer or whoever runs the clinical trial.

Access to these treatments depends on the goodwill of pharmaceutical companies keen on recruiting patients into their clinical trials. Drug manufacturers effectively coerce terminally ill patients into their trials by refusing access to the experimental agents. Experimental drugs are sometimes released outside of clinical trials on so-called compassionate grounds, but that doesn’t always happen. Here is just one example of a since deceased cancer patient. Adrienne Cotton died earlier this year. She tried to access a particular experimental drug that was already in a phase 3 clinical trial (we had reasonable evidence that it worked against the cancer that was killing her from phase 2 clinical trials). The medication she was successfully denied access to by the drug's manufacturer has since received market approval as a cancer drug in Japan.
 

And who pays for these experimental treatments? For good reasons insurance plans in the US (or, in Canada, government programs assisting uninsured patients) will not pay for drugs that are untested and are not known to work. As a result of this patients in both Canada and the US must pay out of pocket for these experimental agents.
 

Pharmaceutical companies are free to charge whatever they wish for these agents, and so, arguably, are in a situation to exploit financially desperate dying patients. This also gives them an opportunity to deny patients access in order to coerce them into trial participation. Regulators need to look at this problem as a matter of urgency.

 

Ebola patients subjected to placebo controlled trials

FDA officials and influential former NIH staffers are currently falling over one another propagating placebo controlled trials to test experimental agents on Ebola virus infected patients in West Africa. It goes without saying that impoverished catastrophically ill patients there – in the real world – have no alternative other than to accept the deal on the table. There are methodologically sound alternative trial designs available that do not rely on placebos, yet – much like during the 1980s – the FDA remains intransigent to the human suffering caused by its edicts. Remarkably, trial designs that are not acceptable unless alternative access to the experimental agent is offered in a bunch of of US states are foisted so on desperate African trial participants if the FDA has its way.

North Korean health care products

Eish, this is neat. I was on my usual daily shopping trawl on the net to pick up basic health care items, you know, like cancer treatments, viagra, also something against schizophrenia. And, it's not easy at all, to get the necessary equipment or drugs that can help with those issues. Fair enough, viagra is the easiest bit, but still, tad bit pricey, so I naturally shop for serious discounts.

Comrade Kim Jong Il, the current paramount leader of the great great nation of the Democratic Peoples Republic of Korea, also known as North Korea, has been painfully aware of my unsuccessful searches and decided to do something about them. He set up a commercial website featuring state of the art health care products that will be able to deal with the ailments just listed, as well as many others. In fact, the stuff they're selling is so brilliant that some of of the products deal with a whole range of diseases in one go. I cannot recommend them highly enough to you. My personal favorite is the Portable Semiconductor Laser Curer. This amazing health care tool is a laser, basically, but this one cures. What you got to do is to plug it into one of your nostrils and simply laser into the opening for something like 15 min (make sure the battery is fully charged, of course). If you do that, it'll cure for you, and I quote, 'treatment of stenocardia, hypertension, diabetes, cerebral thrombosis, cerebral haemorrhage, schizophrenia, bronchial asthma and canker'. I'm sure it's just a typing error and they meant to say 'cancer'. I tried it, and I can tell ya, ever since I started using it I didn't get cancer, so it seems to be a decent prophylactic, too. My diabetes is also gone, my asthma is seriously retreating, but my schizophrenia takes a while longer to fix it seems (I secretly increased the treatment from Monday this week to 20 min, so I'm sure I'll be cured of that problem, too).

Another tool will be of great interest to geologists and all those of us suffering from the 'harmful influence of transient geomagnetic variations', which causes things like 'hypertension, cerebral thrombosis, neuralgia, inflammation, diarrhea, insomnia, constipation, etc'. I understand that etc means anything those transient geomagnetic variations have caused you. So, the top scientists in North Korea have developed a truly fantastic tool, the Portable Magnetic Treater! Thank goodness for that! All you got to do is press it on the spot where the pain occurs until the pain is gone. I tried it the other day on the spot where my leg was amputated fairly recently, and guess what, it grew back over night. Amazing stuff. Just remember to press the Portable Magnetic Treater on the spot that causes you problems. The etc means it'll help you whatever the problem. I just luv this piece of hi-tech equipment. True genius.

Sadly tho my erectile dysfunction issue cannot also be resolved with that same laser. I pressed the Portable Magnetic Treater for a long time, but no, it seems the etc didn't cover that irksome problem. Bummer. But there's help on the website. Amazing product, it's called Neo-Viagra-Y.R. Like all the other website products it deals with all sorts of problems in one go. This one is particularly cool, and should prove quite helpful to all those of us that are getting on in their years. Especially if our partners are a bit on the tiresome end of things. What this product does, as I said, among many many other things, is to prolong sexual intercourse. So, if you take it, it's not just that you can go on and on and on, but that you will go on and on and on. Again, pretty amazing stuff. You got to control yourself, obviously, because at one point you just got to stop and eat a bit, watch may be the news, sleep occasionally, things like that. The good news is, if the prolonged sexual activity this product triggers causes you a stiff shoulder (no pun intended), Neo-Viagra-Y.R. helps with that problem, too. Of course, you could also deploy the Portable Magnetic Treater. The choice is entirely yours. That's the nice thing about these multi-functional products!

By the way, if you decide to go to that website you will also discover something pretty shocking about capitalism. At the moment at least the Great Leader offers us incontrovertible evidence (photo in top right-hand corner) that the old Mercedes E Class actually isn't the old Mercedes E Class, but a North Korean limousine called 'Junma'. These German bastards really dared to steal the design of the Junma. Pretty incredible stuff! I'm glad that information is in the open now!

On that cheerful note, I leave you to browsing this funny site, the official Economic Website of the DPR of Korea, aka North Korea.

And, if you think, only the North Korean leaders are somewhat nuts, which no doubt they are, there's usually good company for them among the ranks of the South African government. On the same level of idiocy as the portable laser curer is that country's Minister for the Optimal Prevention of Health (MOPH), Manto Tshabalala Msimang. Just to remind the world that she still exists and is up to no good, Manto decided that African traditional medicine doesn't have to prove itself according to the scientific method. She said, 'We cannot use Western models of protocols for research and development. We should guard against being bogged down with clinical trials.' Indeed, and there's a good reason for this, according to Manto 'some of the medicines have been used by traditional healers for thousands of years..'

Quod erat demonstrandum! Now we know indeed.

ADDENDUM 02/03/08: My friend Ray Smith tells me that canker actually exists, so perhaps the laser curer really is meant to deal with canker and not cancer and I got it all wrong :).

Courts and ethicists

You know, I have always been somewhat dismissive of the law as a good means to take forward political causes. I always thought one needed to win the substantive normative argument first, and then, somehow, miraculously the law would fall into line. Well, while I worked in South Africa for a couple of years, the Treatment Action Campaign there gave me much food for thought. They used legal cases to advance usually sensible policy matters. Of course, sometimes the law can be an ass and nothing can be achieved by means of suing one's way through the courts, but there are two cases reported today that suggest that sometimes at least the legal route just might be the more efficient way to achieve particular ethical or policy objectives.

The first case could best be described as: Whales: 1, US Navy: 0. Check it out here.
The second case I reported about on this blog. I learned today that Novartis lost its case in the Indian High Court.

Mind you, none of this shows that critical analysis and argument are not called for, but equally it seems fair to say that in some circumstances a good team of lawyers can replace a lot of academic papers and books and campaign officers, if one is concerned about achieving desireable outcomes at all.