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30 posts from May 2012

May 31, 2012

Pharmaceutical Companies Adopt 10 Recommendations for Clinical Trial Transparency

Clinical trial transparency
A recent article from amednews noted how “Eight leading pharmaceutical companies have approved 10 recommendations aimed at improving transparency to address what they call a “credibility gap” that faces industry-funded clinical research.”

“Some observers, including some journal editors and academic reviewers, maintain a persistent negative view of industry-sponsored studies,” said an article in May’s Mayo Clinic Proceedings, co-written by 11 drug industry representatives and medical journal editors.  The 10 recommendations include:

  • Ensure that clinical studies and publications address clinically important questions.
  • Make public all results, including negative or unfavorable ones, in a timely fashion while avoiding redundancy.
  • Improve understanding and disclosure of authors’ potential conflicts of interest.
  • Educate authors on how to develop quality manuscripts and meet journal expectations.
  • Improve disclosure of authorship contributions and writing assistance and continue education on best publication practices to end ghostwriting and guest authorship.
  • Report adverse event data more transparently and in a more clinically meaningful manner.
  • Provide access to more complete protocol information.
  • Transparently report statistical methods used in analysis.
  • Ensure that authors can access complete study data, that they know how to do so, and that they can attest to this.
  • Support the sharing of prior reviews from other journals.

The recommendations grew out of a 2010 meeting of 23 medical journal editors and industry representatives as part of the Medical Publishing Insights and Practices Initiative, founded in 2008 by drugmakers and the International Society for Medical Publication Professionals.

Merck is one of the eight companies participating in the initiative, along with Amgen, AstraZeneca, Bristol-Myers Squibb, GlaxoSmithKline, Johnson & Johnson, Pfizer and Takeda. Editors at 65 biomedical journals worldwide also have taken part in the initiative.  Editors from The Lancet, the Journal of Clinical Oncology and Annals of Internal Medicine co-wrote the Mayo Clinic Proceedings article.

“Private industry has been hurt by some bad apples,” said Maja Zecevic, PhD, who co-wrote the Mayo Clinic Proceedings article and is North American senior editor at The Lancet. “We want to avoid bad things happening by being transparent from the start, instead of going back at the end when the publication is out and the drug is out.”

Zecevic said she believes drugmakers involved in the initiative will follow through on the recommendations and have a strong financial incentive to improve how their clinical research is perceived. Longtime industry critics questioned the companies’ commitment.

“The [recommendations] all seem fine,” said Jerome P. Kassirer, MD, former editor-in-chief of The New England Journal of Medicine and author of the 2004 book On the Take: How Medicine’s Complicity with Big Business Can Endanger Your Health. “The question is whether the pharmaceutical companies will practice what they preach. They don’t always do this, as is evident from the multiple multimillion-dollar suits we hear about, year after year.”

The pledge toward greater transparency should be applauded, said Howard Bauchner, MD, editor-in-chief of The Journal of the American Medical Association. Dr. Bauchner was invited to a 2011 initiative meeting but declined to attend, as he was still settling into his position at JAMA. He said he is open to working with industry to improve the quality of trial-results reporting.

The Mayo Clinic Proceedings article criticizes as unfair a JAMA editorial policy adopted in 2005 that requires independent analysis of industry-sponsored trial data by an academic statistician before publishing results. Dr. Bauchner said he will address that and several other journal policies in an editorial to be published in the next few months. He said JAMA gives all submissions a fair shake, no matter who supported the study.

“Our standards for reviewing papers are identical, regardless of who the funder is,” Dr. Bauchner said. “We work very hard with authors, regardless of the funder, to ensure that reporting of clinical trials is accurate and valid.”

Study Shows Restricting Sales Reps Access May Be Dangerous to Your Health

No Sales Reps 2
Over the last decade or so, we have seen a tremendous amount of attention surrounding the use and influence of pharmaceutical representatives who “detail” physicians and other health care professionals about new treatments and products.  A recent study published in the Journal of Clinical Hypertension  shows that practitioners who restrict access to sales reps are quicker to adopt new therapies but also slower to adjust to negative news about a drug on the market.

The article was co-authored by George Chressanthis, PhD, a former employee of AstraZeneca Pharmaceuticals LP (AZ), who was project director of this research while employed there.  Chressanthis is a professor at Temple University, Fox School of Business.  The research was supported by AZ through an independent academic research program for public dissemination.  The other authors include Michael Seiders, a former employee of AZ effective February 1, 2012; Pratap Khedkar, Nitin Jain, and Prashant Poddar, who all acted as compensated project consultants from ZS Associates to help complete this research.

Executive Summary

Medical practices were divided into four categories based on the degree of sales representative access to clinicians: very low, low, medium, and high from a database compiled by ZS Associates called AccessMonitor (Evanston, IL) used extensively by many pharmaceutical companies.  Clinical decisions of 58,647 to 72,114 physicians were statistically analyzed using prescription data from IMS Health in three critical areas: an innovative drug for type 2 diabetes (sitagliptin), an older diabetes drug with a new Food and Drug Administration (FDA)–required black box warning for cardiovascular safety (rosiglitazone), and a combination lipid therapy that had reported negative outcomes in a clinical trial (simvastatin+ezetimbe).

No previous study has used measurements of sales representative access limits at the physician level with actual prescription behavior and analyzed on a scale large enough to measure the effect of access limits on physician clinical prescription decisions to new medical information.  Specifically, this research analyzed whether physicians in more access-limited offices respond to different types of new medical information by changing their product prescription market share in a smaller and longer fashion than counterparts in more open-access offices, while controlling for other factors that affect their decision.

For the uptake of the new diabetes agent, the authors found that physicians with very low access to representatives had the lowest adoption of this new therapy and took 1.4 and 4.6 times longer to adopt than physicians in the low- and medium-access restriction categories, respectively. In responding to the black box warning for rosiglitazone, the authors found that physicians with very low access were 4.0 times slower to reduce their use of this treatment than those with low access.

Likewise, there was significantly less response in terms of changing prescribing to the negative news with the lipid therapy for physicians in more access-restricted offices. Overall, cardiologists were the most responsive to information changes relative to primary care physicians.  These findings emphasize that limiting access to pharmaceutical representatives can have the unintended effect of reducing appropriate responses to negative information about drugs just as much as responses to positive information about innovative drugs.

The study recognized how “physicians make multiple complex clinical decisions daily for their patients where medical information is costly and time consuming to acquire.”  Accordingly, “optimal health decisions for patients are the result of physicians weighing the value and relevance of medical and marketing information from a variety of channels on top of their own training and experiential knowledge.”  

The authors concluded that, limits placed on the flow of relevant medical information from any channel “will affect physician decision-making, unless that physician can easily replace that lost information through another channel.  Drug sales representatives provide timely and convenient regulated clinical information used by physicians, nurses, and office staff.”


Pharmaceutical sales representative access to physicians has been getting increasingly difficult.  Sales representatives have been the main channel for transmitting marketing information through “detailing” to physicians for the past 50 years, accounting for 60% of all sales and marketing expenditures.  Currently, all marketing information by sales representatives to physicians are regulated and enforced by FDA under the newly named Office of Prescription Drug Promotion to ensure that all information delivered is consistent with FDA-approved product labeling.

In 2010, about 11% of American physicians have “severe” or “no-see” (meaning sales representatives cannot see physicians in their office) pharmaceutical representative access limits and up to another 34% have some restrictions.  Significant geographic variation in access limits exist around the United States.

There has been progressive tightening of access-limit policies resulting in an increase in physicians having severe or no-see ratings over the past few years.  These increasing access limits and outright bans of contacts with industry representatives have occurred as more academic articles, policies at medical schools, and physician anti-detailing campaigns call for such restrictions.  Legal arguments have advocated limiting First Amendment protections of pharmaceutical commercial speech to physicians and banning the selling of physician prescription information.  

Challenging this research are arguments that limiting commercial speech and more tightly regulating academic-industry research relationships will do more harm than good. Empirical evidence exists showing that sales and marketing are associated with an increase in the adoption of new clinical evidence that is beneficial to patients.  The industry has argued against sales force access limits and revised its code of conduct to correct for past abuses and to prevent future infractions. (i.e. PhRMA, AdvaMed Codes).

The US Supreme Court recently ruled 6–3 a Vermont law as unconstitutionally restricting the distribution of prescriber information to pharmaceutical companies and sales representatives as a way to limit detailing to physicians.  The Court majority opinion also noted: “If pharmaceutical marketing affects treatment decisions, it does so because doctors find it persuasive.… Indeed the record demonstrates that some Vermont doctors view targeted detailing based on prescriber-identifying information as “very helpful” because it allows detailers to shape their messages to each doctor’s practice.”  

Study Design

The key question analyzed was: Did physician access limits restrict the flow of new medical information enough to affect both the speed and extent of physician clinical decisions as measured by their prescribing decisions?

The study looked at physician prescription data applying previous literature on the analysis of medical information markets to three recent and well-known product cases. The authors estimated individual physician clinical responses, measured by prescription extent and speed of product prescription share changes, to positive and negative new medical information in three medical events:

  1. Launch in October 2006 of sitagliptin, a first-in-class selective dipeptidyl peptidase-4 inhibitor drug and recognized new product to treat type 2 diabetes;
  2. The release of the Effect of Combination Ezetimibe and High-Dose Simvastatin vs. Simvastatin Alone on the Atherosclerotic Process in Subjects with Heterozygous Familial Hypercholesterolemia (ENHANCE) negative clinical trial outcome results in January 2008 involving the combination drug simvastatin/ezetimbe, used to lower low-density lipoprotein cholesterol; and
  3. The effect of a critical New England Journal of Medicine (NEJM) study published in May 2007 on rosiglitazone, used to treat type 2 diabetes, and subsequent FDA-imposed black-box warning in August 2007, due to a higher risk of heart failure in patients taking the drug.

These product cases were selected based on these factors: (1) events came after the development of physician-level access limit measurements, (2) events represented new medical information to the market that could affect physician clinical prescription decisions, (3) events represented negative and positive new medical information to determine whether physician clinical prescription decisions varied by type of new information, (4) availability of other physician-level measures consistent with the medical market literature needed for proper model estimation of access limit effects, and (5) product cases dealt with important and costly chronic conditions.

The study analyzed major new medical information events were to determine their affect on physician clinical prescription decisions such as a new product launch, new drug clinical trial information, or FDA announcements such as a black-box warning.  Positive and negative news items were selected and statistically tested to determine whether physician clinical prescription responses varied by type of new medical information.  The study used IMS Health data analyzing actual dispensed prescriptions to determine what physicians actually did in response to varying access limits.

Physician clinical prescription decisions were measured on their extent and speed of product prescription market share adoption vs decline relative to variations in access limits.  Analysis was done to control for physician and nonphysician factors that affected the variation of access limits.  For example, physicians who are high-volume prescribers are the focus of many sales representative efforts, creating greater congestion in these offices while affecting physician time with patients.  A possible response by physicians would be to erect greater access limits to counter congestion costs and protect their time devoted to patient care.

Access challenges are most severe in New England, the Upper Midwest, parts of the Mountain West, and the West Coast.  The rest of the country has relatively greater access, although pockets of severe access limits exist.  A comparison of earlier AccessMonitor MSA access maps to S1 2011 reveals a significant growth in access limits, as measured by the proportion of high-access prescribers falling from approximately 74% in S1 2008 to about 55% in S1 2011. 

Significant access variation exists among physician specialties, with nephrology (68%), oncology (57%), and cardiology (54%) being the most limited, and urology (21%), OB/GYN (21%), and allergy (28%) being the least limited, when adding up the percentage of severe and moderate-access limit data (noted in parentheses).

All the empirical results showed increasing sales representative access limits significantly affected physician responses to new medical and marketing information consistent with expectations. All the variables and model fit in each case were highly significant .

Results for the sitagliptin new-product launch case revealed adoption_extent prescribing market share change for the very low-access physicians had a long-likelihood estimate 3.7 times greater than the low access category.  Physicians in very low-access offices had the smallest adoption of sitagliptin, followed by physicians in low-access offices, relative to high-access physicians.  The interaction of physician specialty and access limits (specialty*access) showed that effects from access limits were less on knowledgeable specialists such as cardiologists (CARDs) and diabetologists (DIAs), and endocrinologists (ENDOs) relative to primary care physicians (PCPs).

CARDs and DIAs/ENDOs in very low and low-access offices had greater adoption (positive coefficients) of the sitagliptin than PCPs. Physicians with high-market volume of new prescriptions (Volume) had lower sitagliptin adoption than low-volume physicians compared with the medium-volume category. Physicians facing very low-managed care control had lower adoption_extent than physicians in low to very high control. Physician-specialty CARDs and DIA/ENDOs had larger adoption than PCPs. Larger group practice size and higher age of physician since graduation had a depressing effect on adoption_extent. Greater adoption was shown by physicians in rural areas relative to urban MSAs.

Key findings in the sitagliptin case showed physicians in very low-access offices took 1.4 and 4.6 times longer to adopt than physicians in the low- and medium-access categories, respectively. CARDs, DIA/ENDOs, and IMs took less time to adopt relative to PCPs as did physicians in the high-volume category. Physicians facing very low to high managed care control took less time to adopt than those in the very high category.

Results for the simvastatin/ezetimbe clinical trial case revealed similar effects to sitagliptin for the results from access, volume, physician specialty, interaction effects of specialty*access, age, group practice size, and rural location. Physicians facing medium to low managed care control generated greater product declines than physicians facing high and very high control. Smaller product market share declines occurred with older physicians and those in larger group practices.

Results for the rosiglitazone NEJM/black-box warning case revealed physicians in low-access offices had a lower decline than physicians in the other categories. CARDs and IMs showed larger share declines while DIA/ENDOs revealed smaller declines relative to PCPs. The effects of the interaction terms specialty*access showed CARDs and DIA/ENDOs in very low offices having higher switching changes than PCPs. Physicians with high-market volume, in larger-group practices, and in rural areas were associated with smaller declines, while older physicians experienced larger share declines.

Key findings in the rosiglitazone case showed physicians in very low-access offices with a speed change four times longer than physicians in low-access offices. CARDs took less time, but DIA/ENDOs and IMs took longer to switch than PCPs. Physicians facing very low to high managed care control took more time to switch relative to those in the very high control category, although statistical significance was weaker.

Factors with the greatest relative contribution in explaining adoption_extent changes were physician volume (31.8% to 48.2%), managed care (19.3% to 24.4%), specialty (17.1% to 22.0%), and access plus the interaction of specialty*access (16.0% to 0.5%). Access plus specialty*access restriction effects mattered more for the new product sitagliptin case (16.0%) than the negative information cases of simvastatin/ezetimbe (5.0%) and rosiglitazone (1.9%) in the adoption_extent models.

Access Limits and Clinical Practice

This study estimated the effects of increasing sales representative access limits to physicians on their response to new medical information.  Physicians in more access-limited offices adopted the first-in-class new drug much less and at a slower speed than their counterpart physicians in more open-access offices.  Sales representatives had greater effects on physicians during the drug launch case where they represent a key source of new medical information. Regarding negative medical news cases, physicians derive this information from other sources such as medical journals and conferences, clinical practice, FDA announcements, and discussions with colleagues.

The more informed physicians as inferred by specialty adopted sitagliptin in greater amounts and at a faster rate than PCPs. Increasing sales representative access limits restrict the flow of medical and marketing information needed by physicians to make better-informed clinical prescription decisions for their patients.

Access limits were statistically significant in affecting the speed of physician response in the new-product launch and NEJM/FDA black-box warning cases but not in the negative clinical trial information case. The effects of increasing access limits worked to interact with physician specialty, with specialists such as CARDs and DIA/ENDOs being less affected compared with PCPs. This suggests that PCPs relied more heavily on sales representatives as a source for new medical information than specialists in treating patients. This result has significant clinical implications given that PCPs represent the first line of medical treatment for patients in our health care system.

Conclusion, Future Research

The authors asserted that, “More needs to be understood regarding the potential unintended effects of sales representative access limits to physicians, the consequences these limits can have on physician clinical decisions, and patient health. Policies that promote physician ignorance of new medical information resulting from access limits runs counter to protecting patient health.”  This study, however, did not have measures of patient health.

Nevertheless, results for the negative news cases provide potential insights. PCPs in restricted-access environments had slower and lower prescription product share reductions than counterparts in more open access offices. This means patients of these physicians were put through greater potential risks that were less prevalent for patients being treated by more open-access limit physicians. The intuitive insights from the negative news cases deserve further investigation.

Pharmaceutical companies are increasingly using digital technologies to connect with physicians as a consequence of factors such as changes in ways physicians are accessing medical information, cost pressures of maintaining large sales forces, and increasing access limits.  As a result, the authors recommended analysis into the long-term clinical and patient health effects of policies that ban sales representatives from hospitals and medical schools as the training grounds for future physicians

Lastly, a more complete evaluation is needed on overall health care costs and benefits of increasing physician access limits vs granting more open access. Further analysis may show increasing access limits resulting in additional patient health care costs. This may be outweighed by the costs of allowing greater access to physicians. These costs include greater congestion and disruption of physician and office practices that work against protecting patient health, encouraging greater branded drug use when appropriate lower-cost generic drugs are available for patients, and spending on sales and marketing activities that could be better spent elsewhere to drive higher benefits to patients.

The authors also note that more study is needed to determine whether the effects found here for diabetes and lipid drugs are extended to other drug classes and specialties.

May 30, 2012

AAMC: CME Aligning and Educating for Quality

CME Course 12

In a recent article published by the American Association of Medical Colleges (AAMC), two authors challenged traditional continuing medical education (CME) notions in favor of a new program: Aligning and Educating for Quality (ae4Q), which recently entered its second phase after a successful pilot. 

Launched in January 2011, ae4Q is designed to help medical schools and teaching hospitals align their clinical quality improvement with their CME programs and activities.  The goal is to go beyond simply issuing certificates of attendance to physicians and instead move toward helping them demonstrably improve their performance.  The programs assess clinical data to identify practice gaps and then develop a CME activity with that information.  When the educational intervention is complete, physician performance is measured again to determine if it has improved.


In the past, physicians have experienced CME as “knowledge transfer,” and traditional CME has avoided an “integrative approach.  “Most of today’s practicing physicians experience CME as knowledge transfer.  “But by and large, CME remains rooted in an older tradition.”  An instructor delivers a lecture and answers a few questions, ending with the assumption that he has transferred his knowledge, to the betterment of his colleagues.”

“If you’re just sitting in a room for an hour and listening to a lecture while you plan your dinner in your head, you haven’t been engaged,” said Dave Davis, M.D., senior director of continuing education and performance improvement at the AAMC.  Davis and his colleague Nancy Davis, Ph.D., AAMC director of practice-based learning and improvement, are challenging traditional notions of CME through the ae4Q. 

 “I never thought it would be 2012, and we would still be delivering CME in the traditional lecture format,” said Chuck Kilo, M.D., chief medical officer at Oregon Health Sciences University. “There hasn’t been a whole lot of activity to move away from traditional lectures in which someone talks to you.”

Additionally, ae4Q goes beyond education by encouraging CME planners to collaborate with their quality improvement colleagues to tackle specific patient-centered quality goals.  “This is a very big deal,” said Susan Pingelton, M.D., associate dean of CME at the University of Kansas Medical Center.  “Institutions have their silos, and the continuing education silo is in one part of the medical center, while the quality improvement department is housed in its own silo in the hospital. In the past, these two entities never talked, never crossed.”

Success stories

At the University of Kansas Hospital, an ae4Q pilot site, hospital leaders are breaking those silos and using ae4Q to improve care for patients by educating physicians and other providers on best practices for specific conditions.  The incidence of venous thromboembolism (VTE) was unacceptably high. Pulmonary embolism, the chief complication of VTE, is the biggest cause of preventable death in today’s hospitals, and leaders at the institution knew they could do better.  In an attempt to lower its rate of VTE, the University of Kansas School of Medicine’s CME department joined forces with the hospital’s quality improvement department to develop a multidisciplinary team of doctors, nurses, pharmacists, and educators to study the problem and determine why some patients were not getting necessary preventive care.  The group examined 300 cases and identified the causes it believed led to the complication.

With that information in hand, the team developed an education plan centered on identifying risk factors for VTE and diagnosing and treating the condition.  Small-group sessions complemented didactic learning, and physicians carried “badge buddies,” which listed the risk factors for VTE. Nurses were trained to work with physicians to prevent and detect VTE, and pharmacists assisted physicians by risk-assessing admitted patients. The hospital even posted an educational video on YouTube.

Did it work? “Between January 2011 and November 2011, our incidence of VTE fell by 35 percent,” Pingelton said.

Other medical schools and teaching hospitals also have experienced success with ae4Q. Physicians at the University of Iowa Hospitals and Clinics were ordering too much blood, setting up the potential for unnecessary or overtransfusions.  The CME department at University of Iowa Carver College of Medicine began working with the chief quality officer at the University of Iowa Hospitals and Clinics to study blood utilization.  A steering committee and four task forces studied the problem and developed the educational intervention.  The chief quality officer subsequently presented relevant data to physicians at rounds and case presentations in the specialties that would most impact patients.  The ensuing change was notable.  Between October and December last year, utilization of red blood cells in the hospital decreased by 17 percent, and single-unit orders decreased from 63 percent to 13 percent.

“The real value of ae4Q goes way beyond an individual project,” said Susan Zollo, M.A., director of CME at Iowa’s medical school.  “It has to do with an institutional mindset that acknowledges and continually reinforces the relationship between patient care, patient outcomes, and education—how we make sure that what is actually happening in the patient care setting is informing our educational process.”

What’s next?

Ae4Q’s ultimate aim of quality improvement is supported by a companion pilot program, Teaching for Quality (Te4Q), part of the AAMC’s Best Practices for Better Care initiative. Launched last January, Te4Q seeks to further integrate quality improvement and patient safety into medical education curricula by establishing interdisciplinary teaching resources and faculty development opportunities for teachers.

“Te4Q is a faculty development initiative to help cultivate teaching skills, specifically around quality and patient safety,” Nancy Davis explained.  A steering committee drawn from medical schools and teaching hospitals around the country is developing teaching tools that ultimately will be available to the academic medicine community.


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