Fractures of Bones and the Costs of Competent Research

Professor Gordon Guyatt, MD, MSc, FRCP, OC is a Distinguished University Professor in the Department of Health Research Methods, Evidence and Impact and Medicine at McMaster University. He is a Fellow of the Canadian Academy of Health Sciences.

The British Medical Journal or BMJ had a list of 117 nominees in 2010 for the Lifetime Achievement Award. Guyatt was short-listed and came in second-place in the end. He earned the title of an Officer of the Order of Canada based on contributions from evidence-based medicine and its teaching.

He was elected a Fellow of the Royal Society of Canada in 2012 and a Member of the Canadian Medical Hall of Fame in 2015. He lectured on public vs. private healthcare funding in March of 2017, which seemed a valuable conversation to publish in order to have this in the internet’s digital repository with one of Canada’s foremost academics.

For those with an interest in standardized metrics or academic rankings, he is the 14th most cited academic in the world in terms of H-Index at 240 and has a total citation count of more than 247,000. That is, he probably has among the highest H-Indexes, of any Canadian academic living or dead.

Scott Douglas Jacobsen: So, you’ve also done some work with regards to fractures of bones. Now, it is not necessarily your main stream of research. We were talking off tape about two particular narratives.

One with regards to the pluses and minuses of a big nail and a small nail with the regards to the tibia. Another with regards to an ultrasound device. You noted the devices have a less strict qualification system to get them certified than do pharmaceuticals or drugs.

Distinguished Professor Gordon Guyatt: Yes! It is dramatic. The standards to get a drug on the market are moderately high. They are not as tough as they used to be, and that is an area of controversy, but they are still substantially more stringent than devices.

Devices can get out there much easier than you can drugs. The review process and the barriers you have to jump over are much less with devices than drugs.

Jacobsen: That also leads to of question that is a preface to all of this. Why did the strictures for pharmaceuticals go down? Why are devices less strict than pharmaceuticals in general?

Guyatt: In terms of the first question, there is a controversy, so there is a trade-off. So, some people would say, “Let’s get new drugs out to people, where previously it took too long.” We had these drugs that are beneficial.

There are all these obstructions and the poor patients are suffering because the drugs are not coming out soon enough. On the other hand, there is another argument that it is not infrequent that drugs come out. We find out bad things about them later; that even apparent benefits do not benefit people. So, on the one hand, good drugs get out, and do not make people wait.

On the other hand, be appropriately cautious, make sure that people are benefiting, and make sure and be more careful about the potential adverse effects, that is the argument back and forth. I am not sure that there is any definitive right or wrong.

But there are many of us who have concerns about the pharmaceutical industry and the way the pharmaceutical industry operates. We are on the side of, “Come on. Wait. Do not do it too soon. Make sure it is right, and better too. There are lots of good drugs on the market now.”

“Unless, something is a real breakthrough. Wait to make sure that it is a breakthrough,” it is more of an small incremental game. Let’s test it before it gets out. So, that is the tension as far as that is concerned.

Jacobsen: To the second question, it had to do with devices having much lower standards.

Guyatt: It is a historical accident. So, way back in the early 60s, what changed the landscape with respect to drugs was thalidomide, it was given to women to prevent the nausea of pregnancy. It ameliorated the problem.

However, it caused these horrible limb abnormalities in the kids. People said, “Oh! You’ve got to do things differently here. This is bad news.” So, it changed the environment as far as drugs. Where I suppose, there haven’t been any particular catastrophes in terms of devices.

They are seen as potentially less dangerous and the culture of tough regulation has never grown up.

Jacobsen: Now with regards to fractures of bones, what is the background with regards to doing some side research with Jason W. Busse regarding?

Guyatt: First, there is Mohit Bhandari. So, Mohit Bhandari is an orthopaedic surgeon who came to me when he was still in his training as an ambitious young guy. He came to me wanting to train in research methods, which is what I train people in. He said, “I’d like to do a big orthopaedic trial.”

So, I said, “I tell you what. Here is the trial you want to do,” and it was this trial of when people fractured their tibia. You need to put a nail in to hold the pieces of the tibia together again properly.

There are two ways of putting the nail in. You put in a little nail that maintains the blood supply in the bone marrow. Or you put in a big nail that requires reaming out the bone marrow and the little nail has the advantage of maintaining the blood supply, which is promoting healing.

The big nail has the advantage of the structural bed being a better structure. So, Mohit said, “It is a real controversy whether we should be using these big nails or small nails. We should sort that out.”

So, I said, “Okay, tell you what, tell me who the leading guy in North America is in this field. Let’s see if he would be interested in heading up a trial where we do this.”

So, we got in touch with him. He is in the States. Let’s talk to him. So, we talked to him. We said, “We are want to do clinical trials. Would you be interested in leading the trial because we need some established authority to lead to trial?” So, he said, “Sure.”

So, he helped us gain access to leading orthopaedic colleagues.” Eventually, we got the trial funded in part in Canada and in the States. Mohit led the trial. By the time the trial was finished, he was on faculty as an investigator and ended up leading the trial to completion and getting the appropriate credit as the leader of the trial.

So, we enrolled over twelve hundred patients, which was a big trial at the time. It was one of the biggest in orthopaedic trauma that had previously been done. It found out that, overall, it did not make much difference whether you used a big nail or the small nail, but possibly a small nail was better in the more severe fractures.

The big nail was better in the less severe fractures and ended up as one of the first big major orthopaedic trauma trials.

Jacobsen: Why the small nail for big fractures and the big nail for the small fractures?

Guyatt: The theory: surgeons before they started had this suspicion. They said, “In the cases of the more serious fractures, the maintaining of the blood supply may be more important. In the less serious fractures, the maintaining of the blood supply is not as important.”

That was the rationale beforehand. They had the idea. So, it became more credible because they had the idea in advance when we found that the small nail seemed to be better in the more serious fractures. The big nail in the less serious.

It made us more inclined to believe that because that was the hypothesis that the surgeons stated and they had some biology for it before the trial started.

Jacobsen: with regards to the last part of the research which regards to fracture bones at least that we have talked about on tape one of them has to do with an ultrasound device.

Guyatt: Okay! So, story, there is so a guy named Jason W. Busse. Another guy who did a Ph.D. with me. By training, he is a chiropractor, but he got interested in research. He came to work with us. He was also working closely with Mohit.

So, the opportunity came along; I am sure through Mohit. I do not remember the details. It was with a company that makes an ultrasound device, which was reportedly enhancing the healing of fractures and in keeping with the lower standards of evidence for our devices.

This device has been licensed for use on the basis of some evidence – not convincing, not strong. These are not high quality studies. It is based on the enhanced radial x-ray healing of fractures and the company then said, “We think our device is great. Let’s get some randomized trials strong and randomised trial evidence about the effect of the device.”

So, we arranged. We made a deal with the company. Jason W. Busse was leading the trial. He set up a randomized trial of this ultrasound device. We got some funding from the industry. We got some funding from the Canadian Institute of Health Research. So, off we go, we are doing our trial, early on when we were doing the trial.

Jason did a systematic review of all the evidence that was available thus far. The evidence said, “We are not so sure of this radiological healing. There is no evidence at all that anybody functionally benefits from this. Because if your x-ray looks better, and if you cannot walk sooner or have less pain or something like this, who cares if the x-ray looks better?”

We published this in the British Medical Journal (BMJ), this review. The company was not thrilled. In fact, Jason was the first author of this. The company told Mohit, “We want nothing more to do with Jason, get rid of this Jason. He has stabbed us in the back.”

However, Jason was the principal investigator in the study. We were not going to Jettison Jason. So, although, the company did not want in on meetings and so on. Anyway Jason continued to lead the trial. So, usually with these studies, we are committed to go to the end to get as definitive an answer as possible.

We do not go looking at the data partway. However, the company had access to the data part way. They looked at the data. They find nothing good is happening. They say, “Let’s stop the trial.”

So, we fought with them. We managed to continue longer than we would otherwise. However, eventually, they stopped the trial, but not before we would have enrolled 500 patients. That was enough to get a reasonable conclusion.

Then we did not get the complete follow up. Some because they stopped it, but not bad. So, the trial is finished. No benefit whatsoever either on fracture healing or on function in the patients. One of the issues was there was only about 70% or 80% compliance with the device not bad.

What about in terms of what you would expect out in the real world anyway, they obviously did not get the result. So, the first thing, they made all sorts of arguments about how we should present the results.

Either the results said that this compliance was so low, it is not a problem or there is a subgroup that benefits. Anyway, we went through a prolonged discussion about that. We said, “No, sorry, there are not any subgroups who benefit from this device as far as we can tell. It does not do any good.”

So, they tried. They delayed us. They threatened us all with a couple of years between when we would have had to publish and when we published. Because of all their obstruction and so on. Then, of course, they fund going to meetings and say, “Do not pay any attention to this trial and so on.”

But eventually, we published that in the British Medical Journal. In addition, we have another initiative that tries to get ground-breaking evidence that might be practiced, changing out to clinicians as soon as possible.

Then we published one of these rapid recommendations about do not use this ultrasound along with the trial. So, that was an adventure.

Jacobsen: Thanks for the opportunity, anytime.

Guyatt: A pleasure.

We conducted an extensive interview for In-Sight: Independent Interview-Based Journal before: here, here, here, here, here, and here. We have other interviews in Canadian Atheist (here and here), Canadian Science (here), Canadian Students for Sensible Drug Policy, Conatus News, Humanist Voices, News Intervention (here and here), and The Good Men Project (here, here, here, here, here, here, here, here, here, here, and here).

Photo by Owen Beard on Unsplash