The Good Steward of Science

Mikkael Sekeres, MD, MS
Director of the Leukemia Program at the Cleveland Clinic in Cleveland, Ohio

I have participated in a number of clinical trials and database projects with pharmaceutical companies and, as a result, have been an author on a few abstracts and manuscripts with industry as a partner.

Truth be told, much of this research has been extremely rewarding, intellectually stimulating, and – most importantly – has advanced care for my patients. Academic-industry partnerships have become almost-requisite for drug development and for providing an adequate portfolio of trials for people with devastating hematologic conditions who need better therapies. The notion that we can make these advances based solely on in-house, bench-to-bedside approaches is aspirational, logistically impractical, and, consequently, has become largely effete.

This much, I suspect, industry and I can agree on.

When it comes to publishing results of trials, our motivations for doing so may diverge. Though pharmaceutical companies mandate separation between their medical affairs and sales divisions, in practice, they can influence each other. I don’t care one whiff how a scientific publication influences units of drugs sold or supports off-label medication use. My medical affairs collaborators or in-house writers who hold stock in the company may not be so cavalier – even if subconsciously.

Several years ago, I was approached by a pharmaceutical company who knew of my interests in myeloid malignancies and working with big datasets. Their marketing team had accumulated a lot of information about U.S. physician practice patterns specific to patients with these conditions. They wondered if I would be interested in exploring their data and developing some research questions.

I nearly fell over myself replying in the affirmative. At the time, little was known about the epidemiology and “real-world” treatment of patients with chronic myeloid malignancies.

We quickly put into place the appropriate confidential disclosure agreement, and before long I was working with the company’s statistician on a near-daily basis. She was surprised when I asked to review the actual SAS (statistical) outputs from her analyses, but hey, some of us like to spend our weekends watching the Pittsburgh Steelers annihilate the Cleveland Browns in football, while others like to pore over 2×2 tables of numbers displayed in inelegant fonts.

Which is not something I would ever admit on a first date. Or on a second date. Or, really, within the first five years of marriage.

I put together an abstract, and after it went through approximately 37 layers of approval within the company (this is hyperbole; it was closer to 35 layers of approval) submitted it for consideration for that year’s ASH annual meeting. I was thrilled to learn that it was accepted as a poster presentation and stood by the poster summarizing our research in the first week of that December.

In early September, after submitting the abstract, and while the data and their interpretation were still fresh in my mind, I wrote a draft of the manuscript and sent it to the company’s statistician and their medical writer to review. Within 24 hours, I received a reply, saying:

“Wow, you put this together quickly! [Read: We weren’t quite ready for that.] A job in medical writing is available for you anytime you fancy a career change! [Read: We have in-house writers who could have written it for you, so stick to being a doctor.] I am working to figure out how quickly we can do this, taking into account internal resources and review times. [Read: I’m going to have to run this up the flagpole and see if we can allow a renegade researcher to determine how to present these data.]” I think I even saw some of the sender’s sweat running in rivulets down my computer monitor.

“Oh, I was just so excited about the findings, I couldn’t help myself!” I answered, only a little tongue-in-cheek. “I don’t think it would take too much to finish and submit it to a journal.”

The reply back was more formal. “Unfortunately, I don’t think we are going to be able to get the manuscript submitted by December. A January/February submission time is more realistic.”

Over the next few months, comments from employees of the company about the manuscript trickled in. One deleted a sentence from the discussion section in which I referenced a policy decision restricting use of a drug the company manufactured. I put it back in. Another asked for more analyses supporting use of another drug the company manufactured. I ignored it.

Conference calls were requested. I participated. Further manuscript edits and suggestions came. I maintained my equipoise. In all, the paper went through 12 iterations. This is not hyperbole; Manuscript.v.12 was the document name of the final version submitted to a journal. When it was accepted, I could proudly hold it up as a successful collaboration with industry that was balanced in its reporting and discussion of results.

But it took a heck of a lot of mettle to get there.

Spin can be subtle, but influential. How many times have we read introduction sections to early-phase study publications that provide low estimates of response rates to established therapies, setting the reader up to be impressed with the moderate response rate observed with the drug being studied? Or that claim an “unmet medical need” for a drug, when really the only unmet need is for the drug to find an indication in which it works marginally?

Manuscripts declare drugs “promising” with response rates of less than 15 percent, or state a drug has “acceptable toxicity” even though the rates of significant adverse events or early deaths may eclipse that response rate. Discussion sections may take a detour to discuss other drugs manufactured by the same company that sponsored the trial. Conclusion sections suggest that a particular intervention represents a new “standard of care” for the disease in question, when “standards” should be declared only by the hematology/oncology community as a whole.

To avoid this spin, ideally, as clinical investigators, we should all write the first draft of any manuscript. Recognizing other demands on our time, and that not all clinical investigators deliver manuscripts efficiently (and thus can unwittingly hold important findings captive, which may delay translation to clinical practice), we need to be rigorous stewards of the balanced presentation and publication of trial results.

Especially when delivered by emissaries who are employed by the company that stands to benefit from those findings.

Words matter. We owe it to the scientific community, and to our patients, to make sure those words are ours.