Via email from Adriane Fugh-Berman, selected abstracts for talks to be given at the third annual PharmedOut conference June14-15 at Georgetown University. Please see my previous post for more information.
Regulating Medical Devices: A Historical Perspective
Suzanne Junod, PhD, FDA
In drafting what would become the 1976 Medical Device Amendment, framers of the legislation sought to avoid some of the perceived shortcomings in the Kefauver Harris Drug Amendments which had been enacted after the thalidomide disaster in 1962. In particular, they wanted to minimize adverse effects on an industry characterized by change and innovation. At that time, however, there was no formal field of biomedical engineering while entrepreneurial zeal had begun to create indisputable regulatory issues. Two of FDA’s first device “hires,” in fact, were a pair of engineers from NASA who concluded after a week on the job that conditions in the biomedical industry at that time were “appalling” and that standard engineering practices including back up systems, redundancies, and performance standards were simply non-existent. Their insights, along with some early lessons learned “the hard way,” helped determine the unique ways in which FDA came to perceive its role in regulating medical devices, ways which differed markedly from those adopted for the regulation of new drugs.
Direct-to-consumer advertising of prescription drugs: educating the public to misuse medicines
Barbara Mintzes, PhD, Therapeutics Initiative, British Columbia
Direct-to-consumer advertising of prescription medicines (DTCA) is arguably the most intensive “educational” campaign the US public receives on health issues. On average, Americans spend over 100 times as long watching TV ads about medicines as seeing a doctor each year. These ads include powerful messages about how to recognize and treat everyday and serious health problems, thresholds for care, the role and value of medicines, and expected health effects. Because the aim is to sell a medicine, this “education of a special kind” consistently supports overuse of medicines. I will use examples of recent DTCA campaigns to illustrate the gulf between the scientific evidence on treatment effects, appropriate use, and advertising messages.
Cardiovascular Devices: The Role of Evidence in the FDA Approval Process
Rita Redberg, MD, Archives of Internal Medicine and UC San Francisco
There has been a rapid increase in complexity and use of medical devices, and many of them are cardiovascular. While some of these are life-saving, some are not, and even more have unknown clinical benefit. The current state of the quality of evidence prior to FDA approval of high-risk devices, with some examples and suggestions on how to improve this process so that patients could be more assured of benefits outweighing harms will be discussed.
Left To Our Own Devices: A Surgeon’s Perspective
Amy Friedman MD, SUNY Upstate Medical University
A practical overview of the extent to which the typical clinician comprehends the regulatory pathway for medical devices will be presented. The extent to which clinicians are (or are not) familiar with the specific level of scientific data review that the medical devices they use in patients have undergone prior to gaining FDA clearance for human use will be illustrated. Two specific examples of medical devices that have been associated with significant patient harm, but were not previously recognized to be of concern will be used to illustrate the context of unknown patient safety and risk in the clinical arena.
Radiation From Medical Imaging: A Hidden Epidemic
Rebecca Smith-Bindman, MD, UC San Francisco
Many clinicians are unaware of the amount of radiation delivered from CT scans and other medical imaging techniques and extant data regarding increased risk of cancer from radiation exposure. This presentation will cover the long-term risks of radiation from medical imaging, legislative and quality improvement efforts around CT imaging, and present a framework for reducing inappropriate imaging.
The Failure of the DePuy ASR Hip Prosthesis: Implications for device safety initiatives
John Restaino, DPM, JD, MPH, University of South Carolina School of Pharmacy
The use of metal-on-metal bearings in total hip replacements has seen a sharp decline after a decade-long increase in their use, due to the recall of DePuy’s ASR prosthesis and the growing realization that metal-on-metal prostheses are associated not only with a high failure rates but also elevated systemic cobalt and chromium levels. In the U.S., the ASR XL total hip replacement passed through the FDA’s 510(k) clearance process via the “substantial equivalence” route wherein companies need only to show that their product is similar to a ‘predicate’ device already on the market. In 2007 the Australian National Joint Replacement Registry reported that the ASR required revisions at a rate five times the expected rate at two years. Following years of denial by DePuy that ASR implants were failing, ASR hip prostheses were recalled from the U.S. market on August 24, 2010.
The Supreme Court Strikes Back: IMS v. Sorrell – a Constitutional Right to Track Prescription Data?
Sean Flynn, JD, American University Washington College of Law
The Supreme Court ruled in IMS v. Sorrell that Vermont’s law restricting the use of prescription data to target pharmaceutical detailing to doctors violated the First Amendment of the Constitution. How broad is the right recognized? What room is left for states to control commercial access to confidential medical data for marketing purposes?
Julie Taitsman MD JD, Health and Human Services Ofﬁce of the Inspector General
The Office of Inspector General for the U.S. Department of Health and Human Services (OIG) provides oversight for the Medicare and Medicaid programs. This presentation will offer an overview of OIG efforts, via audits, evaluations, inspections, and enforcement actions, to combat unnecessary or harmful medical care.
Exploiting Homeless Mentally Ill Patients in Drug Safety Trials
Carl Elliott, MD, PhD, University of Minnesota Center for Bioethics, author of White Coat, Black Hat
For years pharmaceutical companies have paid marginalized populations to test the safety of new drugs. In recent years, however, specialized psychiatric trial sites have begun recruiting mentally patients from homeless shelters, boarding houses and recovery facilities. These subjects are often paid to test the safety of new drugs in Phase I trials, raising new ethical questions about exploitation of vulnerable populations.
PharmedOut, a Georgetown University Medical Center-based pharmaceutical marketing research project, hosts its third annual conference focusing on the misinformation and patient harm that can occur from pharmaceutical and medical device marketing.
- Rita Redberg M.D., M.Sc., Archives of Internal Medicine Editor-in-Chief; professor of medicine, University of California, San Francisco
- Carl Elliott M.D. Ph.D., author, White Coat, Black Hat; professor, University of Minnesota’s Center for Bioethics
- Kay Dickersin Ph.D., director, Center for Clinical Trials, Johns Hopkins Center for Global Health
- Julie Taitsman M.D., J.D., chief medical officer, Office of the Inspector General, U.S. Department of Health and Human Services
- Sharon Treat J.D., executive director, National Legislative Association on Prescription Drug Prices
- Joel Lexchin M.D., professor, York University
- Donald Light Ph.D., professor, University of Medicine and Dentistry of New Jersey
For more information and to register, visit the PharmedOut conference page.
WHEN: Thursday, June 14 and Friday, June 15, 2012, 8:00 a.m. to 5:30 p.m. ET.
Thursday morning: Marketing of antipsychotic medications and other drugs
Thursday afternoon: Potential health risks of CT scans and other medical devices
Friday morning: Legislative and regulatory updates and solutions
Friday afternoon: Informing and protecting patients: The role of industry, media, and payers
WHERE: Lohrfink Auditorium in the Hariri Building, Georgetown University, 37th and O Streets, N.W., Washington, D.C., 20057.
In the May 2012 issue of The Scientist, Data Diving: What lies untapped beneath the surface of published clinical trial analyses could rock the world of independent review. Discusses the problem of missing data and how it affects the reliability of systematic reviews.
On the Scientific American website, a guest post by cardiologist and researcher Jalees Rehman, Open Science and Access to Medical Research. Rehman discusses the special challenges of sharing clinical research, including the need to maintain patient confidentiality and the need for independent institutions to interpret the data in an unbiased manner so that vulnerable patients are not misled or given false hope.
In the November 21, 2011 issue of the Medical Journal of Australia, Time to mandate data release and independent audits for all clinical trials, by Ian Haines and George Gabor Miklos. Here are the last two paragraphs:
Medical journals and their editors have a choice — to be viewed as “an extension of the marketing arm of pharmaceutical companies,” or to be beacons of transparent data processes that inform clinicians, improve patient treatment, and provide high standards on which governments, health care providers and patients can have confidence.
Medical journals should demonstrate strong leadership by mandating open access to detailed clinical trial protocols and de-identified raw study data. They should insist on independent audits of data, concomitant publication of an “accompanying abstract,” and lodgement of the data in independent databases; these three actions should be a precondition for publication. (citations omitted)
Finally, in Science Translational Medicine, Learning from Hackers: Open-Source Clinical Trials, by Adam Dunn, Richard Day, Kenneth Mandl and Enrico Coiera. Behind a paywall, but here’s a news article in Australian Life Scientist and a post on Dunn’s blog.
The Patient-Centered Outcomes Research Institute’s mission is to fund health research that offers patients and caregivers the information they need to make medical decisions. The PCORI Board of Governors has adopted the following working definition of “patient-centered outcomes research.”
Patient-Centered Outcomes Research (PCOR) helps people and their caregivers communicate and make informed health care decisions, allowing their voices to be heard in assessing the value of health care options. This research answers patient-centered questions such as:
- “Given my personal characteristics, conditions and preferences, what should I expect will happen to me?”
- “What are my options and what are the potential benefits and harms of those options?”
- “What can I do to improve the outcomes that are most important to me?”
- “How can clinicians and the care delivery systems they work in help me make the best decisions about my health and healthcare?”
To answer these questions, PCOR:
- Assesses the benefits and harms of preventive, diagnostic, therapeutic, palliative, or health delivery system interventions to inform decision making, highlighting comparisons and outcomes that matter to people;
- Is inclusive of an individual’s preferences, autonomy and needs, focusing on outcomes that people notice and care about such as survival, function, symptoms, and health related quality of life;
- Incorporates a wide variety of settings and diversity of participants to address individual differences and barriers to implementation and dissemination; and
- Investigates (or may investigate) optimizing outcomes while addressing burden to individuals, availability of services, technology, and personnel, and other stakeholder perspectives.
Listen to this inspirational speech by PCORI Board of Governors member Harlan Krumholz, at the PCORI National Patient and Stakeholder Dialogue, February 27, 2012:
I’m taking the liberty of posting the entire text of this memo from the Harvard Faculty Advisory Council. The suggested actions are particularly delightful. H/T @PLoS.
To: Faculty Members in all Schools, Faculties, and Units
From: The Faculty Advisory Council
Date: April 17, 2012
RE: Periodical Subscriptions
We write to communicate an untenable situation facing the Harvard Library. Many large journal publishers have made the scholarly communication environment fiscally unsustainable and academically restrictive. This situation is exacerbated by efforts of certain publishers (called “providers”) to acquire, bundle, and increase the pricing on journals.
Harvard’s annual cost for journals from these providers now approaches $3.75M. In 2010, the comparable amount accounted for more than 20% of all periodical subscription costs and just under 10% of all collection costs for everything the Library acquires. Some journals cost as much as $40,000 per year, others in the tens of thousands. Prices for online content from two providers have increased by about 145% over the past six years, which far exceeds not only the consumer price index, but also the higher education and the library price indices. These journals therefore claim an ever-increasing share of our overall collection budget. Even though scholarly output continues to grow and publishing can be expensive, profit margins of 35% and more suggest that the prices we must pay do not solely result from an increasing supply of new articles.
The Library has never received anything close to full reimbursement for these expenditures from overhead collected by the University on grant and research funds.
The Faculty Advisory Council to the Library, representing university faculty in all schools and in consultation with the Harvard Library leadership, reached this conclusion: major periodical subscriptions, especially to electronic journals published by historically key providers, cannot be sustained: continuing these subscriptions on their current footing is financially untenable. Doing so would seriously erode collection efforts in many other areas, already compromised.
It is untenable for contracts with at least two major providers to continue on the basis identical with past agreements. Costs are now prohibitive. Moreover, some providers bundle many journals as one subscription, with major, high-use journals bundled in with journals consulted far less frequently. Since the Library now must change its subscriptions and since faculty and graduate students are chief users, please consider the following options open to faculty and students (F) and the Library (L), state other options you think viable, and communicate your views:
1. Make sure that all of your own papers are accessible by submitting them to DASH in accordance with the faculty-initiated open-access policies (F).
2. Consider submitting articles to open-access journals, or to ones that have reasonable, sustainable subscription costs; move prestige to open access (F).
3. If on the editorial board of a journal involved, determine if it can be published as open access material, or independently from publishers that practice pricing described above. If not, consider resigning (F).
4. Contact professional organizations to raise these issues (F).
5. Encourage professional associations to take control of scholarly literature in their field or shift the management of their e-journals to library-friendly organizations (F).
6. Encourage colleagues to consider and to discuss these or other options (F).
7. Sign contracts that unbundle subscriptions and concentrate on higher-use journals (L).
8. Move journals to a sustainable pay per use system, (L).
9. Insist on subscription contracts in which the terms can be made public (L).
Danil Makarov and colleagues have an interesting paper in the April 2012 issue of Health Affairs entitled “Appropriate And Inappropriate Imaging Rates for Prostate Cancer Go Hand In Hand By Region, As If Set By Thermostat.” Using data from the SEER-Medicare database, the researchers examined regional differences in imaging for prostate cancer patients. The SEER program of the National Cancer Institute collects information about cancer site, stage, and histology for cancer patients from sixteen geographic regions. For cancer patients who are included in the SEER database and are covered by Medicare, information is available on Medicare claims for health care services. The sample consisted of 48,148 prostate cancer patients aged 66-85 who were diagnosed with prostate cancer in 2004 or 2005.
The patients were divided into low- and high-risk groups. According to the 2002 guidelines of the National Comprehensive Cancer Network, which were in effect at the time, high-risk patients should receive imaging such as bone scans, MRIs and CT scans under certain circumstances. In low-risk patients, all imaging was considered inappropriate except CT scans for planning purposes in patients undergoing external beam radiation therapy.
The researchers found that overall rates of imaging varied among the different SEER regions. Imaging appropriateness was not uniformly worse in regions with high rates of overall imaging. Rather, regions with high overall imaging rates had higher rates of inappropriate imaging and higher rates of appropriate imaging. Men with high-risk prostate cancer were more likely to receive appropriate imaging if they lived in areas with higher rates of inappropriate imaging. The authors call this the “thermostat model” of health care utilization. Dividing the regions into quartiles according to rates of inappropriate imaging of low-risk men, in quartile 4 (highest rate of inappropriate imaging), the odds ratio for men with high-risk prostate cancer receiving appropriate imaging was 1.75, with odds ratios in the next two quartiles being 1.48 and 1.04.
The authors state that their analysis suggests that
efforts to lower inappropriate use of imaging may simultaneously lower appropriate use of imaging because the two appear to be coupled. Therefore, policy measures aimed simply at limiting inappropriate imaging in regions with high resource use could have the unintended consequence of decreasing imaging for those patients for whom such care is indicated.
Policies will need to be multifaceted to break down the thermostat-like relationship between inappropriate and appropriate health care use. Accountable care organizations will need clearly defined quality metrics for a broad range of conditions. They will also need well-designed systems to ensure that the right patients are getting the right tests and procedures — and that costs are not contained at the expense of quality. Cost-control policies must selectively educate providers to change their behavior and reduce the use of unnecessary care, while still ensuring appropriate care. Such efforts could take on many forms: profiling physicians who inappropriately overuse resources, linking payment to appropriate utilization criteria, or providing rewards and incentives to physicians and organizations that optimize resource use.
Danil V. Makarov, Rani Desai, James B. Yu, Richa Sharma, Nitya Abraham, Peter C. Albertson, Harlan M. Krumholz, David F. Penson, Cary P. Gross. Appropriate And Inappropriate Imaging Rates For Prostate Cancer Go Hand In Hand By Region, As If Set By Thermostat. Health Affairs 31:4 (2012).
Addendum 4/23/2012: see also Jeff Levin-Scherz’s post on his Managing Healthcare Costs blog.
Qnexa, a combination of phentermine and topiramate, is a proposed anti-obesity medication. Although clinical trials demonstrate that Qnexa can lead to an approximately 10% weight loss, an FDA advisory committee recommended against approval in 2010 because of safety concerns (an increased risk of cleft lip and palette and increased heart rate, which could increase the cardiovascular risk). On February 22, 2012, an FDA advisory committee voted 20-2 in favor of approval, based on an additional submission by the sponsor, Vivus Inc.
In a commentary in Annals of Internal Medicine, Michael Lauer of the National Heart, Lung, and Blood Institute explains why he voted against recommending approval. Briefly, he discusses how the small pre-approval trials conducted by the sponsor, and the small number (12) of major cardiovascular events that occurred during those trials, give us insufficient information to determine whether Qnexa increases the risk of cardiovascular events. Qnexa is thus like a used car that could be either a “lemon” or a “peach.” In addition, based on prior experiences with obesity medications that were withdrawn from the market due to cardiovascular effects, we have reason to be concerned about an obesity medication that increases heart rate (consider the case of Meridia, previously discussed on this blog here and here). Finally, the sponsor’s argument that certain improved biomarkers, such as blood pressure and high-sensitivity C-reactive protein, outweigh any effect of the increased heart rate, fails to assuage his concerns given the failure of surrogates in the past. He states that “We cannot assume that just because a drug reduces weight and improves some biomarkers that it will be safe, let alone beneficial.” I completely agree. Here is his conclusion, but his commentary is open access, so I urge you to read it in full:
So what to do? We can resolve the information asymmetry by insisting on a large-scale, preapproval cardiovascular outcomes trial of Qnexa. It would be too risky to rely on postapproval surveillance or to hope that a rigorous trial could be conducted in a timely manner. If Qnexa prevents cardiovascular events, or at least doesn’t increase the risk for them, in a preapproval trial, then we will all know that we have the peach we’ve been waiting for.
See my previous post on the need for data sharing. For the past three years, a group of researchers has been trying to gather all of the clinical trial data for the anti-influenza drug Tamiflu (oseltamivir), without success. As a result there is continuing uncertainty about the benefits — and harms — of the drug. They tell their story in a New York Times op-ed and an article in PLoS Medicine. Here is the summary from the PLoS Medicine article:
- Systematic reviews of published randomized clinical trials (RCTs) are considered the gold standard source of synthesized evidence for interventions, but their conclusions are vulnerable to distortion when trial sponsors have strong interests that might benefit from suppressing or promoting selected data.
- More reliable evidence synthesis would result from systematic reviewing of clinical study reports—standardized documents representing the most complete record of the planning, execution, and results of clinical trials, which are submitted by industry to government drug regulators.
- Unfortunately, industry and regulators have historically treated clinical study reports as confidential documents, impeding additional scrutiny by independent researchers.
- We propose clinical study reports become available to such scrutiny, and describe one manufacturer’s unconvincing reasons for refusing to provide us access to full clinical study reports. We challenge industry to either provide open access to clinical study reports or publically defend their current position of RCT data secrecy.
Also in PLoS Medicine, a response by a group of European drug regulators. The regulators agree that that data secrecy is no longer acceptable but list some reasons for caution.
Peter Doshi and Tom Jefferson, “Drug Data Shouldn’t Be Secret,” New York Times, April 10, 2012.
Doshi P, Jefferson T, Del Mar C (2012) The Imperative to Share Clinical Study Reports: Recommendations from the Tamiflu Experience. PLoS Med 9(4): e1001201. doi:10.1371/journal.pmed.1001201
Eichler H-G, Abadie E, Breckenridge A, Leufkens H, Rasi G (2012) Open Clinical Trial Data for All? A View from Regulators. PLoS Med 9(4): e1001202. doi:10.1371/journal.pmed.1001202
Here is a summary from Pharmalot.
In the USA at least, the data legally belong to trialists on the grounds that it requires work to create knowledge from data. But science, particularly medical science, is essentially an enterprise conducted for moral reasons. We need to do not just what is legal but what is right. As such, we must take into account the probable wishes of the patients who give us their blood, fill in our questionnaires and die on our trials. It is difficult to believe that any patient on my trial, who completed complex questionnaires so diligently over such a long period of time, would really have wanted me to keep the data for myself rather than share it with others for the benefit of medical science in general. Vickers AJ. Whose data set is it anyway? Sharing raw data from randomized trials. Trials. 2006;7:15.
Every day, patients and their caregivers are faced with difficult decisions about treatment. They turn to physicians and other healthcare professionals to interpret the medical evidence and assist them in making individualized decisions. Unfortunately, we are learning that what is published in the medical literature represents only a portion of the evidence that is relevant to the risks and benefits of available treatments. In a profession that seeks to rely on evidence, it is ironic that we tolerate a system that enables evidence to be outside of public view. Krumholz HM. Open Science and Data Sharing in Clinical Research: Basing Informed Decisions on the Totality of the Evidence. Circulation: Cardiovascular Quality and Outcomes. 2012;5: 141-142
We are all patients, and will all face questions about what medical treatments to pursue. Some questions are trivial and unimportant, others can mean the difference between life and death. We rely on evidence-based medicine to give us reliable information about the risks and benefits associated with medical interventions, but a disturbing amount of evidence indicates that the medical literature is not always reliable. Many clinical trials are not published within a reasonable time after completion or are never published at all. Missing data leads to systematic reviews that are based on only a portion of the trials that were conducted, which can affect the results in unknown and unpredictable ways. Missing data may in some cases hold important information about risk, as in the case of Vioxx (rofecoxib). Merck had data several years before Vioxx was withdrawn from the market that showed the drug increased the risk of heart attacks, but most of the data was unpublished and out of public view. In other cases, clinical trials are published but the data are reported in a misleading and biased way, as when a negative trial is presented so as to appear positive, or analyses showing harm are omitted.
What is to be done? What can we do to make evidence-based medicine more evidence-based? Four commentaries in the March 2012 issue of Circulation: Cardiovascular Quality and Outcomes discuss how making clinical research data available outside individual drug and device companies or research groups could greatly add to the depth and reliability of our knowledge. Currently, with certain exceptions, access to most clinical trial data is restricted to the investigators or the funders. Harlan Krumholz, in an editor’s perspective, outlines the key concepts:
Now is the time to bring data sharing and open science into the mainstream of clinical research, particularly with respect to trials that contain information about the risks and benefits of treatments in current use. This could be accomplished through the following steps:
Post, in the public domain, the study protocol for each published trial. The protocol should be comprehensive and include policies and procedures relevant to actions taken in the trial.
Develop mechanisms for those who own trial data to share their raw data and individual patient data.
Encourage industry to commit to place all its clinical research data relevant to approved products in the public domain. This action would acknowledge that the privilege of selling products is accompanied by a responsibility to share all the clinical research data relevant to the products’ benefits and harms.
Develop a culture within academics that values data sharing and open science. After a period in which the original investigators can complete their funded studies, the data should be de-identified and made available for investigators globally.
Identify, within all systematic reviews, trials that are not published, using sources such as clinicaltrials.gov and regulatory postings to determine what is missing.
It must be acknowledged that there are many obstacles — political, cultural, financial — to accomplishing these goals. Some of these obstacles are discussed in the other three commentaries, which are open access and which I urge you to read:
Spertus, JA. The Double-Edged Sword of Open Access to Research Data. Circulation: Cardiovascular Quality and Outcomes. 2012;5;143-144.
Ross JS, Lehman R, Gross CP. The Importance of Clinical Trial Data Sharing: Toward More Open Science. Circulation: Cardiovascular Quality and Outcomes. 2012;5;238-240.
Gotzsche PC. Strengthening and Opening Up Health Research by Sharing Our Raw Data. Circulation: Cardiovascular Quality and Outcomes. 2012;5;236-237.
Whatever the difficulties, the current situation is clearly intolerable. Patients deserve reliable information on the risks and benefits of medical treatments and the subjects of clinical trials deserve that their contributions be fully used to benefit other patients.
As discussed by Larry Husten on CardioBrief, a 2011 review article in Korean Circulation Journal appears to plagiarize from a 2009 article that was published in Journal of the American College of Cardiology. I spent several hours comparing the two articles, and found that several paragraphs in the KCJ article consisted primarily of paraphrasing, without attribution, of text from the JACC article. In addition, the majority of references in the KCJ article and two of the figures are the same as in the JACC article, and several of the headings are the same or very similar. The KCJ article does not cite the JACC article at all.
The JACC article is by Franz Messerli and Gurusher Panjrath. The KCJ article is by Chang Gyu Park and Ju Young Lee.
Moreover, Figure 4 in the KCJ article appears to have been copied from figure 1 in the 2009 revised European Guidelines on Hypertension Management, although the figure instead references a 2006 study by Messerli and colleagues that was published in the Annals of Internal Medicine.
See Larry’s post on CardioBrief for more details.
Update: Larry reports that the editor of KCJ contacted him to say that the article is now being investigated by the publishing committee of the Korean Society of Cardiology and that an additional investigation has been requested from the Ethics Commission of the Korean Association of Medical Journal Editors.