On the science and ethics of Ebola treatments

[Jim__]

Note: I can only link to Scientia salon and from there you can select the article that matches the thread title.

Given the deadliness of the Ebola virus, should experimental treatments include a control group? Accepting what the article claims about the extremely limited amount of the treatment available, having a control group sounds ethical. In the case of a deadly disease with large amounts of experimental treatments available, the question would be more difficult.

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The WHO has given an ethical green light [3] to the use of these experimental therapies, with the caveat that “there is a moral obligation to collect and share all data generated, including from treatments provided for ‘compassionate use’ (access to an unapproved drug outside of a clinical trial).” They mention a number of ethical issues, but leave out the one that troubles me. The unethical behavior here, which was just given a green light by the WHO, is not doing an experiment, but doing an experiment without using a control group. There should be no compassionate use exceptions. Everybody who wants these treatments should have to enter a randomized trial to have a chance of getting them.

Five patients have received the ZMapp serum so far. Two US missionaries recovered, a Spanish priest died, and reports are not yet in for two Liberian doctors. Unfortunately, the supply is now exhausted, and we must wait until more is manufactured. Another experimental treatment, TKM-Ebola, also now has a green light for use in patients [4]. I don’t know how many people we can treat with the quantity of TKM-Ebola available today. I hope it is many more than the five we could treat with ZMapp.

At least five patients have received a potentially effective treatment, but nobody has yet been assigned to a control group. This is the ethical travesty, and it needs to stop.

With 1013/1848 = 55% of reported Ebola patients dying during this outbreak, you may think that we don’t need a control group. Surely we will notice if the death rate goes down from there [5]. But this is not as easy as you might think. Some of those infected patients haven’t died yet, but will die later, so the true death rate is likely a little higher than 55%. And neither the typically more privileged patients who receive the therapies, nor the care they receive during their treatment are likely to be representative of the average Ebola patient suffering and perhaps dying at home in their village.

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[magical thyme]

1. I see some misconceptions in the article

"To find out whether a treatment will work on real patients in clinics, there is only one way to do it: we need to test it on real patients in clinics."

Wrong. In the field, levels and quality of care vary from clinic to clinic. Without large quantities of the drug given to large numbers of patients across multiple clinics, those variations will not be leveled out.


"Everybody who wants these treatments should have to enter a randomized trial to have a chance of getting them."

There are good reasons for making the drug available first to the doctors and nurses. It's called a shortage of doctors and nurses available to treat the patients. Save their lives and they will be at least for a while immune to Ebola and able to save additional lives. So when you save an Ebola doctor's life, you are saving multiple lives. More bang for the buck.

Second, the doctors and nurses recognize their symptoms and start treatment immediately. That increases the chances of the drug working, compared to somebody who waited until they were in the hemmorhagic stage before showing up at a clinic. It also provides a more consistent time frame for comparing results.

The US should have led the way by tossing a coin to see which of the two American patients got ZMapp and which got a placebo. And then it should have given its second dose to Africa on the condition that it be randomly distributed to one out of two preselected patients in the same manner. This would have been the ethical thing to do.

Given the very small quantities of the drug available, there will not be any statistically valid data obtained at this point. You need a minimum of 60 data points, and ideally thousands, to get statistically useful data. The lare difference in the age of the 2 patients, for example, make a potentially significant difference in the outcome.

If ten patients had been rigorously randomized such that only five of them received the scarce ZMapp treatments and the other five got a placebo, and if ZMapp really were a miracle drug reducing the death rate from 60% to 0%, then there is a 69% probability that we would have been able to conclude in a “statistically significant” fashion, from that tiny but well designed trial, that the drug works

No. You need at least 60 data points to obtain statistically significant data. At least that's what it was when I took pre-med statistics 5 years ago. That means at least 60 patients getting the identical care from the same starting point. And age impacts recovery from any illness, period.

In the meantime, with the very small number of doses available, real information can be obtained on dosing and real information can be obtained on efficacy if other aspects of care are consistent.

Until there are thousands of doses available, I believe it should be reserved for the doctors and nurses, both African and non-African, taking on the risk of treating the Ebola patients.

[Thor_MN]

2. "nobody has yet been assigned to a control group."

With something as lethal as ebola, is injecting people with saline and lying to them that it is an experimental treatment, worthwhile or ethical?

"We would like you to receive this useless injection in order to dot "i"s and cross "t"s. You are likely going to die, but we will have controlled data."

[bananas]

4. They have an extremely limited supply and can't give it to more than a few people anyway

In similar circumstances, drawing straws is usually the most ethical approach.

People in control groups aren't lied to - both the drug and non-drug patients are told beforehand they won't know which group they'll be assigned to, and neither will their doctors.

[Thor_MN]

5. Those getting a placebo are being lied to. Hiding behind randomized chance does not change it.

I understand very well how control groups work. I understand the very low quantities of treatment available.

In a male pattern baldness study, the need for a control group is obvious and warranted. In the case of ebola, however, is it ethical to give a person false hope that the MIGHT be getting a real treatment? They already face around a 50-50 chance of dying. Does the false hope given to the placebo group have ANY value? Does it serve a purpose?

[HuckleB]

6. +1,000,000 ... 000

[bananas]

3. Here's the direct link

http://scientiasalon.wordpress.com/2014/08/14/on-the-science-and-ethics-of-ebola-treatments/

[politicat]

7. I design experimental protocols for work in humans. Randomizing would be unethical now.

This is a disease with a 60% mortality rate. We have extremely limited resources to fight it, and the most limited resource are the human doctors, nurses and health workers.

We don't randomize humans in life or death situations. This is why end-stage cancer patients are allowed highly experimental treatments without control groups and why MRSA patients sometimes get new antibiotics that aren't through trials yet. Statistics are the means for building the control group afterwards.

If I suggested to my board that we give placebos or just didn't bother to treat half of our extremely depressed, suicidal patients, I'm pretty sure I'd be up for an ethics investigation.

This is the same "logic" that lead to the Tuskeegee syphilis experiments.