ClinicalTrials.gov, a great resource for patients, is being abused to market bad medicine

This wasn't supposed to happen.

Since 1997, the National Institutes of Health has maintained a database of clinical trials, ClinicalTrials.gov, that lists trials under way in the U.S. and throughout the world. It's an invaluable resource, providing a single source for patients trying to find where to get the newest experimental treatments, and for doctors and scientists looking to enroll patients in their trials.

In recent years, companies offering questionable stem cell therapies got the bright idea that they could describe their treatments as clinical trials, register them on ClinicalTrials.gov, and thereby get some free advertising. Most stem cell treatments are not FDA-approved, and many have little or no data supporting their effectiveness, but clinics can still register their "trials" on the NIH site, making it appear that they are supported and endorsed by the government. A new study by Leigh Turner, published this week in Regenerative Medicine, reveals the growing extent of this problem.

What's especially worrisome is that some stem-cell treatment clinics charge patients very high fees to participate in their "trials." Some patients (perhaps most) don't know that legitimate clinical trials virtually never charge fees.

Consider this example, reported last July by Emily Bazar at Kaiser Health News: California resident Linda Smith has knee osteoarthritis, and was looking for treatments that could restore her knees to health without surgery. She found a stem cell trial at ClinicalTrials.gov that was run by StemGenex, a clinic in La Jolla. The clinic promised it could inject stem cells into her knees to replace lost cartilage. When she inquired about signing onto the trial, Smith was shocked to learn that StemGenex wanted a $14,000 fee for her to participate.

StemGenex claimed that “The actual treatment is not part of the study protocol”: you pay for the treatment, they explained, and the study is merely a followup to see how you did afterwards.

What nonsense. I checked the StemGenex site today (a year after the quotes above), and they proudly boast that they are registered on ClinicalTrials.gov, and that

"Stem cell therapy for Osteoarthritis is being studied for efficacy in improving the complications in patients through the use of their own stem cells."

Hmm. This sure sounds like the study is about the treatment. StemGenex's site strongly suggests that their therapy works wonders:

"The goal of each stem cell treatment is to inject the stem cells into the joint to create cartilage (chondryte cells)."

Sounds good, right? If only it were true.

I've got bad knees myself, so I've been following the research on stem cell treatments for cartilage replacement for years. I would love to be able to get a simple injection that could repair my damaged cartilage. Alas, though, no one has yet developed an effective stem cell treatment for bad knees, although it is plausible, and legitimate trials are under way right now (here's one).

Unfortunately, the lack of evidence hasn't stopped clinics from offering stem cell injections right now, accompanied by all sorts of promises that are not backed by science. It's not just knee injections, either: this past March, Sharon Begley at STAT reported on three women who were blinded by stem cell therapy injected into their eyes.

Most patients think, mistakenly, that if a clinic offers stem cell therapy, it must have been approved by the FDA. That's not true–clinics offering these therapies don't have FDA approval, and they argue that they don't need it (which might be correct, but that's a topic for another day).

Patients also assume that trials listed on ClincialTrials.gov must have been approved by some government agency, but that's not true either. The site is a clearinghouse that uses the honor system, nothing more, to ensure that trials listed there are legitimate. If you read their Disclaimer (but who does?), you find that studies listed on the site are not necessarily funded by NIH or approved by the FDA.

Turner's study found 7 trials that openly state they charge patients to participate. At least they're honest about it. Turner found many more (including several run by StemGenex) that appear to charge patients despite not explaining their policy on ClinicalTrials.gov. For example, a stem cell trial by Cell Surgical Network plans to enroll 3000 patients and will charge each of them $6000 or more to participate. As Turner writes

"Cell Surgical Network uses its registered ClinicalTrials.gov study as a powerful marketing device. Press releases and the websites of the clinics that are part of this network emphasize that the study is registered on ClinicalTrials.gov."

NIH needs to start policing this site before the situation gets worse. Coincidentally, I know just where they can find the resources to do it. NIH just announced that it's about to start regulating all sorts of basic science studies as clinical trials, a move that will cause a "massive amount of dysfunction and paperwork," according to one MIT scientist. Rather than over-regulating basic science, NIH should devote those same resources to cleaning up and then continuously monitoring the ClinicalTrials.gov database.

What these stem cell clinics are doing is not a clinical trial, and advertising their services through ClinicalTrials.gov is reprehensible. For now, if a doctor or clinic tries to charge you to participate in a clinical trial, your best course may be to find another trial–and another doctor.

Do hyaluronic acid injections help knee pain? Don't waste your money.

As spring turns into summer, we spend more time outdoors, exercising, gardening, or just walking around. And for many people, more exercise means knee pain. Count me among the afflicted.

Several people, including my orthopedic specialist, have suggested that I try injections of hyaluronic acid to treat my knee pain. Many people swear by it, and even though I looked into this two years ago (and rejected it as ineffective), I thought I would look again. Perhaps the evidence had changed.

It hadn't.

Superficially, these injections sound reasonable. Hyaluronic acid is already inside your knee and helps to lubricate and cushion the joint. Adding more lubricant seems like a good idea; after all, it works for cars, bicycles, door hinges, or any other creaky joint.

But not for knees. Just recently, Anne Rutjes, Peter Jüni and their colleagues published a very large review of the evidence on knee injections. They looked at 89 trials involving over 12,000 adults and found that in the trials that were properly controlled (blinded), hyaluronic acid injections had either no effect or a “clinically irrelevant effect”; that is, too small a difference to matter to the patient. (They also found five unpublished trials that showed no effect at all; this is a good example of the so-called “file drawer effect”, where studies that don’t have the desired outcome are stashed away in a drawer and never published.)

Rutjes and colleagues also pointed out that there’s a real risk of harm when you inject something deep into the knee joint. To quote their summary for patients (published along with the article),

“Viscosupplementation [injection of hyaluronic acid] may provide little if no pain relief or function improvement in patients with knee osteoarthritis. It also seems to increase the risk for adverse events."

If you don’t believe Rutjes, perhaps you’ll believe the American Academy of Orthopaedic Surgeons (AAOS), who reviewed a large body of evidence and wrote: 

“We cannot recommend using hyaluronic acid for patients with symptomatic osteoarthritis of the knee. Strength of recommendation: Strong.”

After looking at numerous studies, the AAOS concluded that there was no clinically meaningful benefit from these injections. This document is their official recommendation for physicians.

I was disturbed, though, to find that the AAOS information for patients directly contradicts their own recommendations to clinicians, and suggests that knee injections might work. On their patient-oriented web page, they offer the wishy-washy comment that “hyaluronic acid does seem to have anti-inflammatory and pain-relieving properties … [that] may last for several months,” though “not all patients will have relief of pain.”

What the heck? Are they orthopedists trying to hide the truth from their patients? Why would they do that?

I checked to see if the AAOS patient information was merely out of date, but no, it was reviewed in 2014, and the clinical recommendations appeared in 2013. I have to assume that the authors of the patient information page are not the same doctors who established the official recommendations for clinicians–but it seems unlikely that they are ignorant of their own organizations official guidelines. So why don’t they warn patients that hyaluronic acid injections don’t work? Is it because hyaluronic acid treatments are a significant money-maker for some orthopedists? 

I can hear the response from some doctors already: "In my experience," they say, "this works for some patients." Sorry, but one doctor's experience (or "clinical judgment", as some call it) doesn't trump science. That's why we do experiments, to determine whether or not our subjective impression is correct. In this case, the science is clear.

Incidentally, the Mayo Clinic also fails on this topic. Their site states that hyaluronic acid 

“can be injected into your knee to improve mobility and ease pain. Relief may last as long as six months to a year.” 

They cite no evidence to back this up. Patients looking at either the Mayo site or the AAOS site will be misled into thinking that these injections might be worth a try.

WebMD does a much better job, writing that 

“one study published in Rheumatology found that hyaluronan was no better at reducing joint pain than a placebo injection of salt water. An analysis of seven different studies published in the Journal of Family Practice did not recommend the treatment, since the benefits–if it had any at all–were so slight.”

Note that unlike the Mayo Clinic page,  the WebMD page mentions specific studies and names the journals.

So what does work for knee pain? Physical therapy and exercise to strengthen the muscles around the knee is still the best course, according to the AAOS's clinical guide. Weight loss also helps, by reducing the load on the knee. The only medical intervention that helps is an NSAID pain reliever such as ibuprofen. (See my 2013 article for other treatments that don’t work, including acupuncture (not even close) and glucosamine-condroitin supplements).

As for me, I bought a knee brace even though the AAOS says it doesn’t help. But it feels like it’s helping, and it was cheap. And my knee is definitely feeling better. Why not take advantage of a placebo effect once in a while?

What Works for Knee Pain? Good Medicine, Bad Medicine, and Wasted Money

Knee pain is a very common problem, affecting young and old alike.  Among athletes, knees take a beating, particularly in sports that involve running and twisting.  Among older people, the cartilage that provides a cushion in our knees often just wears out, producing chronic stiffness and pain.

I've had knee problems myself, so I was interested to see an article posted on CNN, with content from Harvard Medical School called "Alternative Treatments for Knee Pain."  Would it describe "alternative" medicine, as in "complementary and alternative medicine," or would it present real medicine for knee pain?

A little of both, as it turns out.  But it does more: it inadvertently illustrates one of the major flaws with the U.S. health system.  We don't discriminate between effective and ineffective treatments, and some doctors seem content to let patients try anything, regardless of efficacy or cost.

The article describes several treatments for knee pain, and for each one it turns to Eric Berkson, M.D., for an opinion on how well the treatment works.  Berkson is an orthopaedic surgeon at Massachusetts General Hospital and an Instructor in Orthopaedic Surgery at Harvard Medical School.

Despite these excellent credentials, Dr. Berkson doesn't seem to have a firm command of science-based medicine. The article starts out strong, recommending the most effective therapies, but then wanders into unproven therapies, and concludes with Berkson making an unscientific recommendation for the most wildly ineffective treatment of all: acupuncture.  Let's look quickly at each "alternative."

The most effective treatments, according to Dr. Berkson, are physical therapy and weight loss.  Berkson is on solid scientific ground here: physical therapy strengthens the muscles around the knee, relieving some stress on the joint, and weight loss does the same thing by reducing the load directly.  If you stopped reading at this point, you'd be in great shape.

Next is a discussion of chondroitin and glucosamine, two very popular supplements that are often used to treat joint pain.  After many years of competing claims about these supplements, NIH conducted a large, $12.5 million study called GAIT to test whether these supplements worked for knee pain. The researchers looked at glucosamine and chondroitin separately and together, and compared them to a standard pain reliever (celecoxib, brand name Celebrex®, an NSAID) and to a placebo.

The conclusion: celecoxib worked, but the supplements did not.  In a small subset of patients with moderate to severe pain, there was a hint of a benefit for glucosamine-condroitin, but it wasn't significant.  For patients with mild pain, though, only celecoxib was better than a placebo.

Despite this large and compelling study, Berkson says

"there's a lot of evidence that they [glucosamine and chondroitin] work, but only in a certain percentage of patients." 

Perhaps he's referring to patients with moderate to severe pain from the GAIT study, but the article doesn't explain if that's what he means.  And then Berkson recommends them anyway, saying "there's little downside to trying the supplements."  Especially if it makes the patient think the doctor is helping.

The article then describes three different treatments that involve injections of various substances into the knee.  To keep this brief, I'll just consider the first: viscosupplementation, a fancy name which means that hyaluronic acid is injected into the knee. It's supposed to help lubricate the joint, which sounds plausible: after all, we lubricate machines to keep them running smoothly.  Shouldn't some "grease" help our knees?

For hyalonuric acid, the answer is simply no.  A large review just last year, involving over 12,000 patients (Rutjes et al. 2012) shows that hyaluronic acid has little or no benefit, and possibly causes harm.  Their conclusion:

"In patients with knee osteoarthritis, viscosupplementation is associated with a small and clinically irrelevant benefit and an increased risk for serious adverse events."

Berkson's own colleagues, the American Academy of Orthopaedic Surgeons, just issued a 1200-page report on treatments for knee osteoarthritis, and they found strong evidence against the use of hyalonuric acid.  To be specific, the AAOS says "We cannot recommend using hyaluronic acid for patients with osteoarthritis of the knee."  They label this a "strong" recommendation.

Despite the the advice of his own professional organization, Dr. Berkson says

"I have some patients who think [hyalonuric acid is] a miracle drug that keeps their symptoms at bay.  Given that the risks of injection are very low, it makes sense to try it if insurance will pay."

Oh my.  Here we have a medical expert recommending an expensive treatment - he estimates the cost is about $1500 - despite the evidence, apparently because he has patients who think it works.  Paying for expensive, ineffective procedures is a poor way to treat patients and a great way to run up costs.

(Aside: I might seem to be picking on Dr. Berkson here, but I think his responses are probably typical of many practicing doctors.  Not to excuse him, but it's easy to follow your instincts and to rely on anecdotes from patients.)

After briefly discussing two other injection therapies, the CNN/Harvard article addresses one last alternative: acupuncture.  It quotes Berkson again, this time saying:

"Acupuncture works in some patients, although I don't think science knows exactly why it works. It's worth trying if other things aren't working for you."

Despite Dr. Berkson's comment, the science doesn't support him.  Acupuncture for knee pain, and for other pain, simply doesn't work.  (See this article for a lengthy discussion, with citations.)  Just to pretend for a second: in order for acupuncture to work, there would have to be lines of force (called "meridians") through which a mystical, apparently unmeasurable life force ("qi") flows, and furthermore you'd have to be able to manipulate this life force by plunging needles into the skin.  There is no support whatsoever for these ideas in human biology and physiology.

The American Academy of Orthopaedic Surgeon's report addresses acupuncture too, stating that "We cannot recommend using acupuncture in patients with symptomatic osteoarthritis of the knee."

Dr. Berkson's recommendation is akin to a shrug: while admitting that he doesn't know why it might work, he just says to give it a try.  His own professional organization, after an extensive review of the scientific evidence, disagrees.

The CNN Health article, with "content provided by the faculty of the Harvard Medical School," demonstrates in a microcosm how health care dollars are wasted in the U.S.  First it recommends the most effective and least expensive treatments: weight loss and exercise.  Both of these involve lifestyle changes that are difficult for many people.  The article then suggests alternative treatments for knee pain that include:

1. Glucosamine and chondroitin supplements - ineffective but cheap. 
2. Knee injections of hyalonuric acid - ineffective and very expensive.
3. Acupuncture - ineffective, wildly implausible, and sort of cheap.

Despite the evidence against them, the doctor quoted throughout the article recommends trying all three, especially if (as is common) the patient doesn't have to pay the bills.

Science only supports three treatments for knee pain, as physician Harriet Hall summarized in her recent blog post: exercise, weight loss, and NSAIDs.  The "alternatives" described by CNN, no matter how appealing they sound, are a waste of time and money.