One of the reasons non-scientists see science as at all valuable is that scientific research may result in useful medical treatments. And one of the aspects of science that seems elusive to non-scientists is just how long it can take scientific research to bring those useful medical treatments about.
In the 5 September 2008 issue of Science, Despina G. Contopoulos-Ioannidis, George A. Alexiou, Theodore C. Gouvias, and John P. A. Ioannidis [1] present research that examines just how long it has taken to get from initial discoveries to medical interventions.
Contopoulos-Ioannidis et al. identified articles that reported research showing a medical intervention to be effective in clinical trials and that were highly cited in the scientific literature (receiving more than 1000 citations each in 1990-2004). These articles represent an endpoint of a sort, the culmination of many preliminary research studies in clinical trials. However, of the highly-cited studies reporting positive outcomes in clinical trials, not all were replicated or even unchallenged by the end of 2006. Some were contradicted by subsequent studies. Others were
found to have had initially stronger effects … when larger or better controlled subsequent studies were performed (1298)
The researchers then combed the literature to trace backward from these articles to their antecedents. In particular, for each of the highly cited articles in the study, they determined
the year when the earliest journal publication on preparation, isolation, or synthesis appeared or the earliest patent was awarded (whichever occurred first). (1298)
The time interval between the first report on preparation, isolation, or synthesis (or the earliest patent) and the highly cited articles reporting successful clinical interventions — between the report of findings with clinical potential and the determination via clinical trials that that promise is realized in a treatment — is the “translational lag”. (There is, of course, another lag that’s harder to quantify this way — that between the initial findings in the research lab and the publication of those findings.)
Contopoulos-Ioannidis et al. found that the median translational lag for the highly cited articled in their study was 24 years. That’s a long time. Moreover, they noted that the translational lag
was longer on average (median 44 versus 17 years) for those interventions that were fully or partially “refuted” (contradicted or having initially stronger effects) than for nonrefuted ones (replicated or remaining unchallenged) (1298)
This is an interesting difference. My first thoughts were that perhaps the longer translational lag represented scientific tenacity in the face of a potentially useful intervention. Alternatively, maybe scientists got to the findings that stood up faster owing to a better sense of what was likely to work; perhaps this sense prompted them to pursue their research with more vigor, getting it translated to clinical studies more efficiently.
But I suspect I shouldn’t be trying to interpret the results in quite this way.
I was imagining two promising preliminary findings (call them X and Y) reported in the same year, then trying to imagine why X, translated to clinical trials more quickly, would also be more likely to stand the test of time than Y, which is translated to clinical trials more slowly. But this research works backwards from the highly cited successful clinical trials to the initially promising preliminary results. In other words, the clinical trial that is the descendant of Y (which ends up weakened or partially refuted) is working from a promising preliminary finding that has been kicking along for much, much longer. Why Y takes so long to be pursued may well be connected to the amount of promise researchers judge it to have.
As the authors put it:
claims for large benefits from old interventions require extra caution as they are likely to be exaggerated. (1298)
In light of this quantification of the lag in translating early research findings to medical interventions, what lessons should scientists draw? First, they ought to recognize what kind of time is required to realize the potential of promising findings. Contopoulos-Ioannidis et al. write:
As scientists, we should convey to our funders and the public the immense difficulty of the scientific discovery process. Successful translation is demanding and takes a lot of effort and time even under the best circumstances; making unrealistic promises for quick discoveries and cures may damage the credibility of science in the eyes of the public. (1299)
Of course, looking at research strategies and practices that can make translation more efficient would also help.
The authors also recommend appropriate skepticism about promising interventions “hiding in plain sight”:
Translational efforts for common diseases should focus more on novel agents and new cutting-edge technologies; for these ailments, it is unlikely that genuine major benefits from interventions already known for a long time have gone unnoticed. (1299)
This is not to say that old interventions couldn’t work, simply that they generally haven’t resulted in clinically proven interventions described in highly cited scientific papers.
It seems like this last issue might be relevant to the discussion of autism and attempts to treat it going on in the ScienceBlogs Book Club right now.
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[1] Despina G. Contopoulos-Ioannidis, George A. Alexiou, Theodore C. Gouvias, and John P. A. Ioannidis, “Life Cycle of Translational Research for Medical Interventions,” Science (5 September 2008) Vol. 321, no. 5894, 1298 – 1299.
I think that basing the “translational lag” on time since first synthesis/isolation or patent can be misleading. Drug companies frequently develop the synthetic methods for a whole family of related compounds simultaneously. They are then put through some basic animal and antimicrobial screens for pharmacologic activity and toxicity (and this information is seldom published on unpromising analogs), and only the most promising compounds receive further study immediately. The others are put on the shelf until a new possible use is found or a new screening technique is developed (or until process patents on more successful compounds are about to expire), when they are dragged out for further evaluation.
It would be interesting to go back over the data in this study to see how many of those “older” compounds had analogs that came to market much earlier.
I think a more realistic “translational lag” would be from the date of publication of the earliest animal or antimicrobial data.
As you can probably guess from the published lags, original synthesis patents are seldom still in force by the time a product reaches the marketing stage. The patents still in force at that time are the process patents for the mass production and formulation of the compound into a finished product.
I wonder how unique to medicine this really is; I suspect the “translational lag” in medicine is only focused on because of the sense of urgency in the field, not because it is special.
It would be interesting to compare with some other fields. How long, for instance, between the discovery of a new type of compound for storing electrical charge and the production start of a new type of battery (lithium-ion to take one). If you compare to the time between the discovery of some interesting new result in computer science or mathematics and the time when it ends up as part of real-world computer software, you can get a sense of how much of the lag time is procedural – safety issues, production methods – and how much is intrinsic to the process of science.
In response to Janne’s speculations, “translational lag” in technology areas is highly variable. The lithium-ion battery had quite a long lag, due to problems in development of appropriate cathode and anode materials, and very largely due to safety issues — so 21 years from the first proposal (1970) to first commercial product (1991).
On the other hand, where safety and materials problems are minimal, the lag can be very short. The first patent for a transistor was filed in June 1948. By 1950 a transistor was commercially available from Raytheon for radio hobbyists, although it was handmade and very expensive. In 1952 the patents were licensed to several manufacturers, and within months Western Electric, Raytheon, GE, and RCA were in commercial production. Bell Telephone had transistors in commercial operation in the first long distance direct-dialing network by October 1952, and the first retail transistorized product (a hearing aid) was on the market in March of 1953. Source: http://transistorhistory.50webs.com/xstrhist.html
With the exception of medical devices, non-drug technology does not face anywhere near the time and financial constraints imposed by the FDA’s New Drug Application process.