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The Archives of Internal Medicine recently published an article discussing the Study of Neurontin: Titrate to Effect, Profile of Safety (STEPS) Trial and the possibility of it being a seeding trial. Although I had never heard this term before, the definition reveals nothing surprising about drug companies: They target physicians in hopes of making more money. 

Seeding is a term defined as "Clinical trials, deceptively portrayed as patient studies which are used to promote drugs recently approved or under review by the FDA by encouraging prescribers to use these medication under the guise of participating as an investigator in a clinical trial". What the drug companies (in this case Parke-Davis, a subsidiary of Pfizer Inc who as a matter of fact payed 2.3 billion in "misbranding" Bextra) do is essentially reach out to most primary care physicians the majority of which have little experience as investigators in clinical trials, and ask them to be a part of a study. Each physician is assigned a small number of patients (less than 10), which is unusual for clinical trials due to the sheer increase in logistical problems this creates such as ensuring physicians follow proper protocol. These studies are usually phase IV trials or trials that occur just before the FDA approves the medication and their purpose is to familiarize physicians with the medications in hopes that the positive outcome their patients have will increase prescribing rates for that drug which of course leads to more money. 

The STEPS trial was presented as a study to determine the best dosing strategy (tapering up) for patients with epilepsy  who were candidates for gabapentin therapy. In the case of STEPS trial, drug reps encouraged physicians to schedule "shadow days" in which the majority of the patients seen were prospective patients (in this case epileptic patients) and the drug reps would see these patients and encourage them to enroll for the study. Physicians would also get rewards for different milestones completed, for example: free lunch for the first 3 patients enrolled and free dinner for 7 patients enrolled. If physicians did not follow the right dosing protocol on a participant, they were excluded from the trial. The interesting thing about that is the company did not provide strict dosing guidelines as to when to step up therapy. Now why would a company go through all this and not have protocols in place so they could acquire as many results as possible? I can't answer it either. What makes this even more astonishing to me was the the drug reps would often complete the data forms that would be used as results for the trial. 

Not to steal Pfizer's thunder but Merck has also been accused of performing seeding trials. Published in 2003, the ADVANTAGE trial claimed to assess the difference in GI tolerability between Vioxx (rofecoxib) and naproxen, when in fact it was to increase Vioxx revenue power by reaching out to physicians. This study was conceived, performed, and written by Merck's marketing division and the research department was completely uninvolved. As a matter of fact the head of the research department at the time was quoted as saying "small marketing studies are intellectually redundant and are extremely dangerous...". The study was setup very similarly to the STEPS trial: they reached out to PCPs to be investigators who had about 9 pts each and studied them for 3 months starting 2 months before the drug was approved by the FDA. 

The evidence of how blatantly obvious that this was a seeding trial in almost nauseating. The ADVANTAGE trial won the "Best Physician Program Award" (an award given by Merck execs) and an internal memo from some higher-ups said:The objectives were to provide a product trial among a key physician group to accelerate uptake of VIOXX as the second entrant in a highly competitive new class and gather data important to this customer group", the customer group being physicians.  The most obvious evidence is presented in a memo sent by a marketing division employee who wrote to her colleagues "It may be a seeding study, but let's not call it that in our internal documents". It's like their writing this post for me. 

The biggest ethical problem here is when the drug companies reach out to these physicians, they withhold the information that this is a marketing scheme, not a clinical research trials. This also occurs with patients in terms of informed consent. Informed consent is mis-represented when speaking of seeding trials because often times physicians, patients, IRBs nor the FDA are not told the truth about the intent of these trials (marketing goals) which raises the question: Is it true informed consent? The answer seems obviously "NO". When the physicians and patients begin the trial, they believe they are testing new clinical use or a new dosing regimen etc for this drug when in fact this is not the main concern for the drug companies and often the physicians are the target consumer, not the patients themselves.  Although this is not made clear to physicians or patients, internal company documents help reveal the intentions of these trials. 

Though seeding trials are not illegal they are highly unethical and all Clinicians should be aware of the main characteristics which include low physician-participant ratio (Less than 10), high number of inexperienced physicians, poor quality assurance measures (drug reps filling out data forms). Being aware of some of these characteristics will help ensure that only quality, meaningful studies will be executed in the future. 

If you made it this far, please provide feedback. I'm new at this but would like to keep going and want to get better....but be gentle :)