The clinical trial process is what every drug or medical device goes through before it comes to market. And it's difficult for the public to understand for many reasons, including proprietary claims on information, complicated scientific jargon, bureaucracy, and good, old-fashioned corruption. We asked Molly Maloof, a doctor and a medical technology consultant, to help us uncover some hidden truths and understand some common misconceptions about clinical trials.
1. Many Clinical Trials Don't Report Their Results
You can look up the status and conclusions of clinical trials online. There are pointers on the site for looking up different studies, and interpreting their results. This is not as helpful as you might think for the simple reason that many of the institutions conducting studies do not report their results. Lack of reporting has been a problem in the past. If a drug or device failed to provide the desired results in one study, the study will be scrapped and another study initiated. Do one hundred thousand repetitions of a group of ten coin flips and pure coincidence will get you a run of ten heads or ten tails. Likewise, if you test a drug many times, coincidence will make one study indicate the drug has an effect, or has a strong effect instead of a weak one. To combat the problem of companies publishing carefully-selected studies, mandatory reporting standards have been instituted. But so many studies are conducted that tracking results is a complicated affair, and companies can get away with simply going quiet.
There are trends as to which studies pull a fade instead of publishing conclusions. Studies in later phases of drug testing are more likely to post results, probably because if a drug gets to Phase IV of a clinical trial, it is almost certainly having some positive effect. (Read here about all the phases of the clinical trial, and what each tests for.) Contrary to what cynics might expect, it's not the big drug companies quietly burying results. Industry-funded studies were more likely to report than studies funded by other sources.
2. Mandatory Reporting Standards Aren't Always Mandatory
There are exceptions to the mandatory reporting strictures. There are extensions and exemptions. How does one get an extension or an exemption? Write in and make a good case for it. In many ways, this is understandable. There are so many different details that can play a factor in clinical trials that listing permissible reasons for exemptions would be exhausting, ridiculous, and still leave studies with understandably unpublishable results high and dry. But leaving too much up to interpretation also has its drawbacks.
People who work at the FDA and the NIH have also worked in the drug industry, and some will work in the industry again. That means that they will get requests for exemptions from people who were their colleagues, or from people who they would like to be their colleagues. So while it is possible to get an exemption, or at least a years-long extension, for legitimate reasons, it's nearly impossible to quality-check the process.
3. The People A Drug is Tested On Might Not Be the People Who Will Use It
There are good reasons for using only certain people for drug testing. As with any other kind of test, keeping variables down to a minimum simplifies the process, especially in the early stages. If someone has a health problem after taking the drug, it's better to have a good indication that it was the drug causing the problem, not something that pops up due to age or unrelated illness. Occasionally, though, limiting the testing pool to get the best outcomes negates the purpose of testing. Women are often left out of trials because of worries about hormonal fluctuations interacting with the workings of the drug. People with minor unrelated illnesses are left out, but will still be among those taking the drug when it passes the clinical testing phase.
And then there clinical trials that are outsourced to other countries. It can be cheaper to test drugs abroad, and people in other countries might be more willing to take drugs – especially drugs for a condition that is already treatable with existing drugs in the manufacturer's home country. There's nothing necessarily wrong with this, but it means that the drugs may be tested using only specific ethnic groups, as well as under specific social and physical conditions that might not be present in the group it will be primarily used to treat.
What's more, trials don't always report the fact that they test using just a subset of people. So a sedentary elderly woman with a minor health problem extraneous to the one she's taking the drugs for will have no idea she's taking a drug that was tested only on twenty-five-year-old active and healthy men. This doesn't invalidate clinical testing, but it does represent a problematic compromise. Minimizing variables is a good strategy for understanding the workings of a drug, but can lead to disappointing results when that drug is used on a wider population, where variation is the norm.
4. Some Medical Technology Isn't Really Tested at All
With the explosion of medical technology and apps, we're seeing a lot of tech that's meant to monitor people's health. Some tech doesn't qualify as medical. Something that's not much more complex than a pedometer combined with a electronic way of tracking food intake couldn't really be called medical technology. Then there's the stuff that straddles the line. For example, there's Beddit, a device and app that monitors you while you sleep and tells you how to "sleep better." It can keep track of your heart rate and your snoring patterns, but can it really tell you how well you sleep?
Whether it can or not, it hasn't gone through a really rigorous testing progress. Clinical polysomnography — the measure of how well you're sleeping — involves an electroencephalogram, a blood oxygen saturation study, and tracking of eye movements. This isn't to say that Beddit is useless. It just exists, along with a lot of medical technology, in the gray area between useful toys and actual scientific devices. Although this technology may be tested, it isn't the kind of testing that actual medical instruments, or drugs, are subjected to. Also, because they're not selling official medical technology, tech companies in this space aren't subject to the same privacy laws that official medical institutions are. While there's nothing intentionally nefarious going on, it's important to realize that there is an entire semi-medical industry that exists outside the guidelines of actual medicine.
5. Clinical Trials Are Being Outsourced
For a long time there was a set mode of testing for clinical trials. It went sort of like this: "Drug X is meant to do Y. We're going to test X to see whether it does Y." Generally the tests were done by the researchers, or at least the institutions, that developed the drug. Now the process is being streamlined, and it's being done so by contract research organizations.
This is affecting how the tests are done. Instead of one unified test (Can X do Y?), there is a sort of branching tree of test possibilities (Can X do Y? If not, can X do Z or Q?). It's called adaptive design, and it's slowly catching on. Depending on how the drug does at different points, the test is adjusted. The simplest adjustment is an early end to the trial. Obviously, any study would stop if the drug were seen to be actively harmful, but adaptive design allows for a stop if, in later phases, the drug isn't getting the desired results.
If the drug isn't performing as well as hoped, there is also the option to adjust the dose, or adjust the group of people who are taking the drug. If a pain relief drug isn't working for people who are in a lot of pain, perhaps it will work on people who are only in mild pain, or in pain due to one particular cause. Maybe it will work by tripling the dose or changing the timing of the dose. Instead of confirming or discrediting one use for the drug, studies are becoming a kind of guided exploration of what the drug can do. There are pros and cons to the idea. Although adaptive design could conceivably prop up weak drugs, it can also streamline a needlessly bulky process, and allow researchers to focus in on the specific uses of new drugs instead of guessing at their best applications.
6. Private Industry Funds the Vast Majority of Drug Trials, and This Affects Ethics
Since the 1980s, there's been a huge shift in the funding of clinical trials. Government cut spending, and industry increased it. These days between 80 and 90 percent of trials are funded by private industry. Even the best companies exist to make a profit, and the best way to do that is to get their drug to market as soon as possible. Ethical issues arise when the business of drug development conflicts with distribution of the drugs by health care providers who lack sufficient information regarding the drug's risks.
A good example of this is OxyContin. Oxycodone hydrochloride, the generic name for the drug, is fantastic way to deal with chronic pain. Unlike many other pain medications, it doesn't have a threshold beyond which it stops being effective. A handful of aspirin won't take away more pain than a regular dose of aspirin, but oxycodone hydrochloride will relieve greater and greater pain as the dose increases. It's also an effective time-release drug, meaning that people who use it properly feel no pain for about twelve hours. Anyone who is in constant pain has their life immeasurably improved by it.
But because its time-release mechanism can be bypassed, and because its effects increase as more and more is ingested, it can be incredibly addictive. Abuse of the drug skyrocketed as both patients and recreational drug users got hooked. This was a case not of an evil drug company attempting to sell strychnine as cold medicine, nor of incompetent doctors handing out useless or harmful pills. The problem was that the drug was effective, but inherently addictive, and doctors needed to be trained how to deal with that.
Unfortunately, neither doctors inside nor outside drug companies had the power to make that happen. Outside the drug industry, only part of medical training deals with the complications of pain management — an effective pill is often considered management, and addiction is irrelevant. The problem is that requiring doctors to be trained in recognizing the signs of addiction before prescribing the drug would mean throwing additional resources at a drug that already works exactly as it was meant to work. A new kind of drug doesn't just treat a medical issue, it changes the medical environment, and it's nobody's "job" to deal with that. At least, that's how it seems from the perspective of industry.
7. Most Doctors Don't Fully Understand Clinical Trials
About 10 percent of doctors sign patients up for 80 percent of clinical trials. There's a huge gap between that 10 percent and the rest. Many clinicians don't know how to get their patients into trials, and more importantly they don't know how to interpret the results of a clinical trial. There's a divide between the community of physicians that regularly work with trials and the community that regularly works with patients, not because either is incompetent but because research is a legitimate area of specialization. Maloof, who consulted on this article, works in medical technology. A big part of her job is translating between the researchers who specialize in medical technology, and the clinicians who work with patients. And medical technology research grows more complicated by the day.
As does cancer research. Cancer research has moved from scalpels to radiation to drugs to genetics. If a tumor has one genetic marker, a certain drug can be prescribed. If it has another genetic marker, a different drug is prescribed. And the different treatment regimens are constantly being updated. Even if all cutting edge research were covered by medical schools, it would be superseded by other research a few years into a new doctor's career.
So while there will probably always be room for improvement on how trials are conducted and reported, a more pressing area of reform may be in how the products of these trials move from the research world to the world of medicine. Who has the responsibility to educate doctors on all the effects, including social effects, of a new drug? Who is responsible for follow-up studies when an entirely new mode of treatment becomes part of society? Who bridges the gaps between the research world, and the practical world of medicine? The drug companies? The hospitals? Governmental regulation? These are questions that need to be answered, and soon.
Top Image: Matthew Bowden
Syringe Images: Armin Kübelbeck
Scale Pharmacy Image: German Federal Archives
[Via BMJ, GPO, Outsourcing Pharma.]