Dr. Drug Rep

[Guest guest]

November 25, 2007Dr. Drug RepBy DANIEL CARLATI. Faculty DevelopmentOn a blustery fall New England day in 2001, a friendly representativefrom Wyeth Pharmaceuticals came into my office in Newburyport, Mass.,and made me an offer I found hard to refuse. He asked me if I'd liketo give talks to other doctors about using Effexor XR for treatingdepression. He told me that I would go around to doctors' officesduring lunchtime and talk about some of the features of Effexor. Itwould be pretty easy. Wyeth would provide a set of slides and even payfor me to attend a speaker's training session, and he quickly floatedsome numbers. I would be paid $500 for one-hour "Lunch and Learn"talks at local doctors' offices, or $750 if I had to drive an hour. Iwould be flown to New York for a "faculty-development program," whereI would be pampered in a Midtown hotel for two nights and would bepaid an additional "honorarium."I thought about his proposition. I had a busy private practice inpsychiatry, specializing in psychopharmacology. I was quite familiarwith Effexor, since I had read recent studies showing that it might beslightly more effective than S.S.R.I.'s, the most commonly prescribedantidepressants: the Prozacs, Paxils and Zolofts of the world.S.S.R.I. stands for selective serotonin reuptake inhibitor, referringto the fact that these drugs increase levels of the neurotransmitterserotonin, a chemical in the brain involved in regulating moods.Effexor, on the other hand, was being marketed as a dual reuptakeinhibitor, meaning that it increases both serotonin andnorepinephrine, another neurotransmitter. The theory promoted by Wyethwas that two neurotransmitters are better than one, and that Effexorwas more powerful and effective than S.S.R.I.'s.I had already prescribed Effexor to several patients, and it seemed towork as well as the S.S.R.I.'s. If I gave talks to primary-caredoctors about Effexor, I reasoned, I would be doing nothing unethical.It was a perfectly effective treatment option, with some data tosuggest advantages over its competitors. The Wyeth rep was simplysuggesting that I discuss some of the data with other doctors. Sure,Wyeth would benefit, but so would other doctors, who would become moreeducated about a good medication.A few weeks later, my wife and I walked through the luxurious lobby ofthe Millennium Hotel in Midtown Manhattan. At the reception desk, whenI gave my name, the attendant keyed it into the computer and said,with a dazzling smile: "Hello, Dr. Carlat, I see that you are with theWyeth conference. Here are your materials."She handed me a folder containing the schedule of talks, an invitationto various dinners and receptions and two tickets to a Broadwaymusical. "Enjoy your stay, doctor." I had no doubt that I would,though I felt a gnawing at the edge of my conscience. This seemed likea lot of money to lavish on me just so that I could provide someeducation to primary-care doctors in a small town north of Boston.The next morning, the conference began. There were a hundred or soother psychiatrists from different parts of the U.S. I recognized acouple of the attendees, including an acquaintance I hadn't seen in awhile. I'd heard that he moved to another state and was making abundle of money, but nobody seemed to know exactly how.I joined him at his table and asked him what he had been up to. Hesaid he had a busy private practice and had given a lot of talks forWarner-Lambert, a company that had since been acquired by Pfizer. Histalks were on Neurontin, a drug that was approved for epilepsy butthat my friend had found helpful for bipolar disorder in his practice.(In 2004, Warner-Lambert pleaded guilty to illegally marketingNeurontin for unapproved uses. It is illegal for companies to paydoctors to promote so-called off-label uses.)I knew about Neurontin and had prescribed it occasionally for bipolardisorder in my practice, though I had never found it very helpful. Arecent study found that it worked no better than a placebo for thiscondition. I asked him if he really thought Neurontin worked forbipolar, and he said that he felt it was "great for some patients" andthat he used it "all the time." Given my clinical experiences with thedrug, I wondered whether his positive opinion had been influenced bythe money he was paid to give talks.But I put those questions aside as we gulped down our coffees and tookseats in a large lecture room. On the agenda were talks from some ofthe most esteemed academics in the field, authors of hundreds ofarticles in the major psychiatric journals. They included MichaelThase, of the University of Pittsburgh and the researcher whosingle-handedly put Effexor on the map with a meta-analysis, andNorman Sussman, a professor of psychiatry at New York University, whowas master of ceremonies.Thase strode to the lectern first in order to describe hisgroundbreaking work synthesizing data from more than 2,000 patientswho had been enrolled in studies comparing Effexor with S.S.R.I.'s. Atthis time, with his Effexor study a topic of conversation in themental-health world, Thase was one of the most well known and wellrespected psychiatrists in the United States. He cut a captivatingfigure onstage: tall and slim, dynamic, incredibly articulate and amaster of the research craft.He began by reviewing the results of the meta-analysis that had thepsychiatric world abuzz. After carefully pooling and processing datafrom eight separate clinical trials, Thase published a trulysignificant finding: Effexor caused a 45 percent remission rate inpatients in contrast to the S.S.R.I. rate of 35 percent and theplacebo rate of 25 percent. It was the first time one antidepressantwas shown to be more effective than any other. Previously,psychiatrists chose antidepressants based on a combination ofguesswork, gut feeling and tailoring a drug's side effects to apatient's symptom profile. If Effexor was truly more effective thanS.S.R.I.'s, it would amount to a revolution in psychiatric practiceand a potential windfall for Wyeth.One impressive aspect of Thase's presentation was that he was notcontent to rest on his laurels; rather he raised a series of potentialcriticisms of his results and then rebutted them convincingly. Forexample, skeptics had pointed out that Thase was a paid consultant toWyeth and that both of his co-authors were employees of the company.Thase responded that he had requested and had received all of thecompany's data and had not cherry-picked from those studies mostfavorable for Effexor. This was a significant point, because companiessometimes withhold negative data from publication in medical journals.For example, in 2004, GlaxoSmithKline was sued by Eliot Spitzer, whowas then the New York attorney general, for suppressing data hintingthat Paxil causes suicidal thoughts in children. The company settledthe case and agreed to make clinical-trial results public.Another objection was that while the study was billed as comparingEffexor with S.S.R.I.'s in general, in fact most of the data comparedEffexor with one specific S.S.R.I.: Prozac. Perhaps Effexor was,indeed, more effective than Prozac; this did not necessarily mean thatit was more effective than the other S.S.R.I.'s in common use. ButThase announced that since the original study, he had analyzed data onPaxil and other meds and also found differences in remission rates.For his study, Thase chose what was at that time an unusual measure ofantidepressant improvement: "remission," rather than the more standardmeasure, "response." In clinical antidepressant trials, a "response"is defined as a 50 percent improvement in depressive symptoms, asmeasured by the Hamilton depression scale. Thus, if a patient enters astudy scoring a 24 on the Hamilton (which would be a moderate degreeof depression), he or she would have "responded" if the final score,after treatment, was 12 or less.Remission, on the other hand, is defined as "complete" recovery. Whileyou might think that a patient would have to score a 0 on the Hamiltonto be in remission, in fact very few people score that low, no matterhow deliriously happy they are. Instead, researchers come up withvarious cutoff scores for remission. Thase chose a cutoff score of 7or below.In his study, he emphasized the remission rates and not the responserates. As I listened to his presentation, I wondered why. Was itbecause he felt that remission was the only really meaningful outcomeby which to compare drugs? Or was it because using remission madeEffexor look more impressive than response did? Thase indirectlyaddressed this issue in his paper by pointing out that even whenremission was defined in different ways, with different cutoff points,Effexor beat the S.S.R.I.'s every time. That struck me as a prettyconvincing endorsement of Wyeth's antidepressant.The next speaker, Norm Sussman, took the baton from Thase and exploredthe concept of remission in more detail. Sussman's job was tosystematically go through the officially sanctioned "slide deck" —slides provided to us by Wyeth, which we were expected to use duringour own presentations.If Thase was the riveting academic, Sussman was the engaging populist,translating some of the drier research concepts into terms that ourprimary-care-physician audiences would understand. Sussman exhorted usnot to be satisfied with response and encouraged us to set the barhigher. "Is the patient doing everything they were doing before theygot depressed?" he asked. "Are they doing it even better? That'sremission." To further persuade us, he highlighted a slide showingthat patients who made it all the way to remission are less likely torelapse to another depressive episode than patients who merelyresponded. And for all its methodological limitations, it was a slidethat I would become well acquainted with, as I would use it over andover again in my own talks.When it came to side effects, Effexor's greatest liability was that itcould cause hypertension, a side effect not shared by S.S.R.I.'s.Sussman showed us some data from the clinical trials, indicating thatat lower doses, about 3 percent of patients taking Effexor hadhypertension as compared with about 2 percent of patients assigned toa placebo. There was only a 1 percent difference between Effexor andplacebo, he commented, and pointed out that treating high bloodpressure might be a small price to pay for relief from depression.It was an accurate reading of the data, and I remember finding it aconvincing defense of Effexor's safety. As I look back at my notesnow, however, I notice that another way of describing the same numberswould have been to say that Effexor leads to a 50 percent greater rateof hypertension than a placebo. Framed this way, Effexor looks morehazardous.And so it went for the rest of the afternoon.Was I swallowing the message whole? Certainly not. I knew that thiswas hardly impartial medical education, and that we were being fed amarketing line. But when you are treated like the anointed, wined anddined in Manhattan and placed among the leaders of the field, youinevitably put some of your critical faculties on hold. I was trulyimpressed with Effexor's remission numbers, and like any physician, Iwas hopeful that something new and different had been introduced to myquiver of therapeutic options.At the end of the last lecture, we were all handed envelopes as weleft the conference room. Inside were checks for $750. It was time toenjoy ourselves in the city.II. The Art and Science of DetailingPharmaceutical "detailing" is the term used to describe those salesvisits in which drug reps go to doctors' offices to describe thebenefits of a specific drug. Once I returned to my Newburyport officefrom New York, a couple of voice-mail messages from local Wyeth repswere already waiting for me, inviting me to give some presentations atlocal doctors' offices. I was about to begin my speaking — anddetailing — career in earnest.How many doctors speak for drug companies? We don't know for sure, butone recent study indicates that at least 25 percent of all doctors inthe United States receive drug money for lecturing to physicians orfor helping to market drugs in other ways. This meant that I was aboutto join some 200,000 American physicians who are being paid bycompanies to promote their drugs. I felt quite flattered to have beenrecruited, and I assumed that the rep had picked me because of somespecial personal or professional quality.The first talk I gave brought me back to earth rather quickly. Idistinctly remember the awkwardness of walking into my first waitingroom. The receptionist slid the glass partition open and asked if Ihad an appointment."Actually, I'm here to meet with the doctor.""Oh, O.K. And is that a scheduled appointment?""I'm here to give a talk."A light went on. "Oh, are you part of the drug lunch?"Regardless of how I preferred to think of myself (an educator, apsychiatrist, a consultant), I was now classified as one facet of alunch helping to pitch a drug, a convincing sidekick to help the salesrep. Eventually, with an internal wince, I began to introduce myselfas "Dr. Carlat, here for the Wyeth lunch."The drug rep who arranged the lunch was always there, usually anattractive, vivacious woman with platters of gourmet sandwiches intow. Hungry doctors and their staff of nurses and receptionists wouldfilter into the lunch room, grateful for free food.Once there was a critical mass (and crucially, once the M.D.'sarrived), I was given the go-ahead by the Wyeth reps to start. I doveinto my talk, going through a handout that I created, based on theofficial slide deck. I discussed the importance of remission, thebasics of the Thase study showing the advantage of Effexor, how todose the drug, the side effects, and I added a quick review of theother common antidepressants.While I still had some doubts, I continued to be impressed by the 10percent advantage in remission rates that Effexor held overS.S.R.I.'s; that advantage seemed significant enough to overcomeEffexor's more prominent side effects. Yes, I was highlightingEffexor's selling points and playing down its disadvantages, and Iknew it. But was my salesmanship going to bring harm to anybody? Itseemed unlikely. The worst case was that Effexor was no more effectivethan anything else; it certainly was no less effective.During my first few talks, I worried a lot about my performance. Was Itoo boring? Did the doctors see me as sleazy? Did the Wyeth reps findme sufficiently persuasive? But the day after my talks, I would get acall or an e-mail message from the rep saying that I did a great job,that the doctor was impressed and that they wanted to use me more.Indeed, I started receiving more and more invitations from other reps,and I soon had talks scheduled every week. I learned later that Wyethand other companies have speaker-evaluation systems. After my talks,the reps would fill out a questionnaire rating my performance, whichquickly became available to other Wyeth reps throughout the area.As the reps became comfortable with me, they began to see me more as asales colleague. I received faxes before talks preparing me forparticular doctors. One note informed me that the physician we'd bevisiting that day was a "decile 6 doctor and is not prescribing anyEffexor XR, so please tailor accordingly. There is also one more docin the practice that we are not familiar with." The term "decile 6" isdrug-rep jargon for a doctor who prescribes a lot of medications. Thehigher the "decile" (in a range from 1 to 10), the higher theprescription volume, and the more potentially lucrative that doctorcould be for the company.A note from another rep reminded me of a scene from "Mission:Impossible.Dr. Carlat: Our main target, Dr. , is an internist. Hespreads his usage among three antidepressants, Celexa, Zoloft andPaxil, at about 25-30 percent each. He is currently using about 6percent Effexor XR. Our access is very challenging with lunches sixmonths out." This doctor's schedule of lunches was filled with repsfrom other companies; it would be vital to make our sales visitcount.+Naïve as I was, I found myself astonished at the level of detail thatdrug companies were able to acquire about doctors' prescribing habits.I asked my reps about it; they told me that they received printoutstracking local doctors' prescriptions every week. The process iscalled "prescription data-mining," in which specializedpharmacy-information companies (like IMS Health and Verispan) buyprescription data from local pharmacies, repackage it, then sell it topharmaceutical companies. This information is then passed on to thedrug reps, who use it to tailor their drug-detailing strategies. Thismay include deciding which physicians to aim for, as my Wyeth repsdid, but it can help sales in other ways. For example, Shahram Ahari,a former drug rep for Eli Lilly (the maker of Prozac) who is now aresearcher at the University of California at San Francisco's Schoolof Pharmacy, said in an article in The Washington Post that as a drugrep he would use this data to find out which doctors were prescribingProzac's competitors, like Effexor. Then he would play up specificfeatures of Prozac that contrasted favorably with the other drug, likethe ease with which patients can get off Prozac, as compared with thehard time they can have withdrawing from Effexor.The American Medical Association is also a key player in prescriptiondata-mining. Pharmacies typically will not release doctors' names tothe data-mining companies, but they will release their DrugEnforcement Agency numbers. The A.M.A. licenses its file of U.S.physicians, allowing the data-mining companies to match up D.E.A.numbers to specific physicians. The A.M.A. makes millions ininformation-leasing money.Once drug companies have identified the doctors, they must woo them.In the April 2007 issue of the journal PLoS Medicine, Dr. AdrianeFugh-Berman of Georgetown teamed up with Ahari (the former drug rep)to describe the myriad techniques drug reps use to establishrelationships with physicians, including inviting them to a speaker'smeeting. These can serve to cement a positive a relationship betweenthe rep and the doctor. This relationship is crucial, they say, since"drug reps increase drug sales by influencing physicians, and they doso with finely titrated doses of friendship."III. Uncomfortable MomentsI gave many talks over the ensuing several months, and I graduallybecame more comfortable with the process. Each setting was somewhatdifferent. Sometimes I spoke to a crowded conference room with severalphysicians, nurses and other clinical staff. Other times, I sat at asmall lunch table with only one other physician (plus the rep), havingwhat amounted to a conversation about treating depression. My basicEffexor spiel was similar in the various settings, with the focus onremission and the Thase data.Meanwhile, I was keeping up with new developments in the researchliterature related to Effexor, and not all of the news was positive.For example, as more data came out comparing Effexor with S.S.R.I.'sother than Prozac, the Effexor remission advantage became slimmer —more like 5 percent instead of the originally reported 10 percent.Statistically, this 5 percent advantage meant that only one out of 20patients would potentially do better on Effexor than S.S.R.I.'s — muchless compelling than the earlier proportion of one out of 10.I also became aware of other critiques of the original Thasemeta-analysis. For example, some patients enrolled in the originalEffexor studies took S.S.R.I.'s in the past and presumably had notresponded well. This meant that the study population may have beenenriched with patients who were treatment-resistant to S.S.R.I.'s,giving Effexor an inherent advantage.I didn't mention any of this in my talks, partly because none of ithad been included in official company slides, and partly because I wasconcerned that the reps wouldn't invite me to give talks if I divulgedany negative information. But I was beginning to struggle with theethics of my silence.One of my most uncomfortable moments came when I gave a presentationto a large group of psychiatrists. I was in the midst of wrapping upmy talk with some information about Effexor and blood pressure.Referring to a large study paid for by Wyeth, I reported that patientsare liable to develop hypertension only if they are taking Effexor atdoses higher than 300 milligrams per day."Really?" one psychiatrist in the room said. "I've seen hypertensionat lower doses in my patients.""I suppose it can happen, but it's rare at doses that are commonlyused for depression."He looked at me, frowned and shook his head. "That hasn't been my experience."I reached into my folder where I kept some of the key Effexor studiesin case such questions arose.According to this study of 3,744 patients, the rate of high bloodpressure was 2.2 percent in the placebo group, and 2.9 percent in thegroup of patients who had taken daily doses of Effexor no larger than300 milligrams. Patients taking more than 300 milligrams had a 9percent risk of hypertension. As I went through the numbers with thedoctor, however, I felt unsettled. I started talking faster, a suresign of nervousness for me.Driving home, I went back over the talk in my mind. I knew I had notlied — I had reported the data exactly as they were reported in thepaper. But still, I had spun the results of the study in the mostpositive way possible, and I had not talked about the limitations ofthe data. I had not, for example, mentioned that if you focusedspecifically on patients taking between 200 and 300 milligrams perday, a commonly prescribed dosage range, you found a 3.7 percentincidence of hypertension. While this was not a statisticallysignificant higher rate than the placebo, it still hinted that suchmoderate doses could, indeed, cause hypertension. Nor had I mentionedthe fact that since the data were derived from placebo-controlledclinical trials, the patients were probably not representative of thepatients seen in most real practices. Patients who are very old or whohave significant medical problems are excluded from such studies. Butreal-world patients may well be at higher risk to develop hypertensionon Effexor. +I realized that in my canned talks, I was blithely minimizing thehypertension risks, conveniently overlooking the fact thathypertension is a dangerous condition and not one to be trifled with.Why, I began to wonder, would anyone prescribe an antidepressant thatcould cause hypertension when there were many other alternatives? Andwhy wasn't I asking this obvious question out loud during my talks?I felt rattled. That psychiatrist's frown stayed with me — a mixtureof skepticism and contempt. I wondered if he saw me for what I fearedI had become — a drug rep with an M.D. I began to think that the moneywas affecting my critical judgement. I was willing to dance around thetruth in order to make the drug reps happy. Receiving $750 checks forchatting with some doctors during a lunch break was such easy moneythat it left me giddy. Like an addiction, it was very hard to give up.There was another problem: one of Effexor's side effects. Patients whostopped the medication were calling their doctors and reportingsymptoms like severe dizziness and lightheadedness, bizarreelectric-shock sensations in their heads, insomnia, sadness andtearfulness. Some patients thought they were having strokes or nervousbreakdowns and were showing up in emergency rooms. Gradually, however,it became clear that these were "withdrawal" symptoms. These wereparticularly common problems with Effexor because it has a shorthalf-life, a measure of the time it takes the body to metabolize halfof the total amount of a drug in the bloodstream. Paxil, another shorthalf-life antidepressant, caused similar problems.At the Wyeth meeting in New York, these withdrawal effects werementioned in passing, though we were assured that Effexor withdrawalsymptoms were uncommon and could usually be avoided by tapering downthe dose very slowly. But in my practice, that strategy often did notwork, and patients were having a very hard time coming off Effexor inorder to start a trial of a different antidepressant.I wrestled with how to handle this issue in my Effexor talks, since Ibelieved it was a significant disadvantage of the drug. Psychiatristsfrequently have to switch medications because of side effects or lackof effectiveness, and anticipating this potential need to changemedications plays into our initial choice of a drug. Knowing thatEffexor was hard to give up made me think twice about prescribing itin the first place.During my talks, I found myself playing both sides of the issue,making sure to mention that withdrawal symptoms could be severe butassuring doctors that they could "usually" be avoided. Was I lying?Not really, since there were no solid published data, and indeed somepatients had little problem coming off Effexor. But was I tweaking andpruning the truth in order to stay positive about the product?Definitely. And how did I rationalize this? I convinced myself that Ihad told "most" of the truth and that the potential negativeconsequences of this small truth "gap" were too trivial to worryabout.As the months went on, I developed more and more reservations aboutrecommending that Effexor be used as a "first line" drug before tryingthe S.S.R.I.'s. Not only were the newer comparative data lessimpressive, but the studies were short-term, lasting only 6 to 12weeks. It seemed entirely possible that if the clinical trials hadbeen longer — say, six months — S.S.R.I.'s would have caught up withEffexor. Effexor was turning out to be an antidepressant that mighthave a very slight effectiveness advantage over S.S.R.I.'s but thatcaused high blood pressure and had prolonged withdrawal symptoms.At my next Lunch and Learn, I mentioned toward the end of mypresentation that data in support of Effexor were mainly short-term,and that there was a possibility that S.S.R.I.'s were just aseffective. I felt reckless, but I left the office with a restoredsense of integrity.Several days later, I was visited by the same district manager whofirst offered me the speaking job. Pleasant as always, he said: "Myreps told me that you weren't as enthusiastic about our product atyour last talk. I told them that even Dr. Carlat can't hit a home runevery time. Have you been sick?"At that moment, I decided my career as an industry-sponsored speakerwas over. The manager's message couldn't be clearer: I was being paidto enthusiastically endorse their drug. Once I stopped doing that, Iwas of little value to them, no matter how much "medical education" Iprovided.IV. Life After Drug MoneyA year after starting my educational talks for drug companies (I hadalso given two talks for Forest Pharmaceuticals, pushing theantidepressant Lexapro), I quit. I had made about $30,000 insupplemental income from these talks, a significant addition to the$140,000 or so I made from my private practice. Now I publish amedical-education newsletter for psychiatrists that is not financed bythe pharmaceutical industry and that tries to critically assess drugresearch and marketing claims. I still see patients, and I stillprescribe Effexor. I don't prescribe it as frequently as I used to,but I have seen many patients turn their lives around because theyresponded to this drug and to nothing else. +In 2002, the drug industry's trade group adopted voluntary guidelineslimiting some of the more lavish benefits to doctors. While theguidelines still allow all-expenses-paid trips for physicians toattend meetings at fancy hotels, they no longer pay for spouses toattend the dinners or hand out tickets to musicals. In an e-mailmessage, a Wyeth spokesman wrote that Wyeth employees must follow thatcode and "our own Wyeth policies, which, in some cases, exceed" thetrade group's code.Looking back on the year I spent speaking for Wyeth, I've asked myselfif my work as a company speaker led me to do bad things. Did Icontribute to faulty medical decision making? Did my advice leaddoctors to make inappropriate drug choices, and did their patientssuffer needlessly?Maybe. I'm sure I persuaded many physicians to prescribe Effexor,potentially contributing to blood-pressure problems and withdrawalsymptoms. On the other hand, it's possible that some of those patientsmight have gained more relief from their depression and anxiety thanthey would have if they had been started on an S.S.R.I. Not likely,but possible.I still allow drug reps to visit my office and give me their pitches.While these visits are short on useful medical information, they doallow me to keep up with trends in drug marketing. Recently, a repfrom Bristol-Myers Squibb came into my office and invited me to adinner program on the antipsychotic Abilify."I think it will be a great program, Dr. Carlat," he said. "Would youlike to come?" I glanced at the invitation. I recognized the name ofthe speaker, a prominent and widely published psychiatrist flown infrom another state. The restaurant was one of the finest in town.I was tempted. The wine, the great food, the proximity to a famousresearcher — why not rejoin that inner circle of the select for anevening? But then I flashed to a memory of myself five years earlier,standing at a lectern and clearing my throat at the beginning of adrug-company presentation. I vividly remembered my sensations — thecareful monitoring of what I would say, the calculations of how frankI should be."No," I said, as I handed the rep back the invitation. "I don't thinkI can make it. But thanks anyway."Daniel Carlat is an assistant clinical professor of psychiatry atTufts University School of Medicine and the publisher of The CarlatPsychiatry Report.Copyright 2007 The New York Times Company