Ebola shows we learned too little from AIDS

The largest Ebola outbreak ravages out of control in Africa as WHO considers declaring a public health emergency on suspicion of the disease reaching Saudi Arabia.

Ebola is a health and humanitarian disaster, and a serious infectious disease threat, but a separate WHO action shows systematic weaknesses in how new drugs are researched, developed, approved, and delivered to patients. On August 6, WHO announced an ethics panel to decide if and how to use experimental therapies for Ebola.

If this all sounds a bit familiar, it should. In the depths of the AIDS crisis, patients clamored for access to new drugs with unknown risks. There were no protocols in place. Haphazard experimentation on patients is illegal as well as unethical. But people were dying. Patient advocates created the political will to overcome these obstacles, and let patients choose risks using the meager information available. The result: many, many lives saved.

What did we learn from the AIDS crisis about how to better manage medical research? Approximately nothing. AIDS remains an exception in healthcare research, in every sense of the word. For example, NIH-funded AIDS research still has separate deadlines and mostly separate review from all other medical research. In our thinking, we've quarantined the whole AIDS crisis itself, as an event. Sure, we rethought what "patient" and "clinical trial" meant for AIDS because we had to. But we're not going to let that infect our thinking in other areas of medicine.

Ebola has no cure or effective treatment. Our response to Ebola is essentially medieval, because we have nothing better. Vaccines and drugs have not been developed, because most people who get Ebola are poor. Clearly, the economic costs of Ebola outbreaks would justify significant development costs. The costs of fighting just this one outbreak will be in the hundreds of millions of dollars, and I suspect the total economic losses will be in the billions. So even though the people who get Ebola don't have much money, it still makes economic sense to prevent Ebola outbreaks. Why then don't we?

There is an experimental drug, ZMapp, that has been manufactured in very small quantities. It has been tried on two Ebola patients. Controversially, those patients were both white health workers. Some in Africa now demand that wider access to ZMapp be provided, or at least considered. If this sounds like AIDS all over again, well, it's not much different.

Getting an approved drug to market is expensive, perhaps a billion dollars, depending on how you count. (There are many ways to count, but they all lead to very large numbers.) A poorly-managed trial could prevent a drug from ever being approved. That means never helping many people, and not incidentally never making back money invested in development. So drug companies are nervous about offering unapproved drugs to desperate people, for both ethical and financial reasons.

Why is ZMapp in short supply? Is it hard to make? Yes and no. ZMapp is a combination of three antibodies extracted from transgenic tobacco plants. Tobacco plants grow as fast as tobacco plants want to grow, so while manufacturing of ZMapp is ultimately scalable, the lag to get more drug is real: somebody literally has to plant tobacco plants in a greenhouse and wait for them to grow.

Other, faster manufacturing platforms could be considered, but ZMapp's manufacturer has disincentives to do this: to get a drug approved by the FDA (or elsewhere in the world) only trials using material from the exact manufacturing process used for the production drug can be used to support approval. This is for good reason, of course, particularly for a biotech drug like ZMapp. For biotech drugs produced in yeast, even changing the size of the incubation chamber can change the impurities that must be filtered out of the final drug.

But these are some of the reasons that stack up a billion dollars in front of getting a new drug approved. The AIDS crisis showed us we need to change our thinking. We changed our thinking. Then, when the AIDS crisis abated, we changed our thinking right back. This Ebola outbreak and the resulting humanitarian, moral, and ethical crises show that we learned little from the AIDS outbreak.

We have to drive the cost of drug development back down, and get drugs into the hands of patients sooner. That means that patients will get drugs with safety profiles that are less well understood. This means that we will have accept that some of these drugs will have side effects, and some people will be hurt or killed by those side effects. We can work towards drugs with better side effect profiles, and in fact drugs like ZMapp will mostly be quite safe. Mostly. But not always. So only patients who face serious risks in the absence of treatment should be offered these therapies, and they should be fully informed of the risks.

This is not an abstraction for me. Someone close to me participated in several clinical trials to combat an extremely dangerous disease that ultimately killed them. One of those trials was for an antibody therapy. Overall, experimental drugs made a horrible and lethal disease manageable and survivable. At least for a while. But the disease ultimately proved fatal, and in this case a bad reaction to antibody therapy probably hastened the end. What I learned is that this is hard in the abstract, but at the individual level, it's even harder, because you really don't know what's going to happen.

The changes I outline here, which encompasses ideas of both adaptive and pragmatic clinical trials, integrate clinical trials into clinical practice. This happens in two ways. First, clinical trials themselves are designed to answer questions about clinical practice and real benefit to patients, and adapt to meet patient needs as they progress. Second, drugs are approved, sooner, but approval is contingent on continuing investigation of how patients react to the drug.

This results in a faster drug development cycle, benefitting patients sooner and cutting the cost of drug development, encouraging more drugs to be developed. But, initial patient populations are smaller, have clearer risk/benefit relative to taking the drug, and are more carefully monitored. So, side-effects are more likely to be found earlier, when fewer patients have taken the drug.

A perfect world? Hardly. But a better world, with safer, more effective drugs that are cheaper and more widely available. The drug industry is complicated enough that even this massive change would not solve all of it's problems. But it would make a great difference.

(For more information from people who've thought about this stuff a lot more than I have, google "pragmatic trial" and "adaptive trial".)

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