Category Archives: drug safety

2013 Gina Kolata article on PKSK9 inhibitors was inaccurate

2013 front page New York Times article by Gina Kolata on PCSK9 inhibitors was inaccurate. Here is Kolata’ lede:

She was a 32-year-old aerobics instructor from a Dallas suburb — healthy, college educated, with two young children. Nothing out of the ordinary, except one thing.    

Her cholesterol was astoundingly low. Her low-density lipoprotein, or LDL, the form that promotes heart disease, was 14, a level unheard-of in healthy adults, whose normal level is over 100.

The reason was a rare gene mutation she had inherited from both her mother and her father. Only one other person, a young, healthy Zimbabwean woman whose LDL cholesterol was 15, has ever been found with the same double dose of the mutation.           

Here is an excerpt from the FDA clinical review of Sanofi/Regeneron’s PCSK9 inhibitor alirocumab:

We are aware of three cases of individuals homozygous (or compound heterozygous) for loss-of-function PCSK9 alleles with very low LDL-C concentrations that have been reported in the literature:

1.  a 21-year-old African woman with an LDL-C of 15 mg/dL; no further information about this patient was provided, except that she was identified for genotyping at a postnatal clinic,

2.  a 32-year-old African American woman with an LDL-C of 14 mg/dL; she is an apparently healthy, normotensive, fertile, college-educated individual with normal liver and renal function tests, and

3.  a 49-year-old French white man who was found to have extremely low LDL-C (7 mg/dL) on admission for rapid-onset of an insulin-requiring diabetes mellitus of unknown etiology; LDL-C not during acute illness was reported to be 16 mg/dL. This patient was shown to have moderate liver steatosis on abdominal ultrasound with normal hepatic enzymes and liver function tests. He had no reported history of diarrhea, eye, or neurological abnormalities related to any vitamin deficiency. His mother was deceased at age 66 from dementia, whereas his father was healthy at age 79. His grandparents died at the ages of 79, 87, 91, and 94 years.

At this time there are too few cases to provide conclusive data about loss-of-function PCSK9 polymorphisms and the risk of human disease, although given the association of statins with diabetes risk, the development of diabetes in the 49-year-old man discussed above is of interest. (See Dr. Roberts’ safety review for further discussion of alirocumab and glycemic parameters).

The third case is the one missed by Kolata. It was published in Arteriosclerosis, Thrombosis, and Vascular Biology, an American Heart Association journal, in 2009, and could have been found with a PubMed search. The case is interesting in that it conflicts with one of the oft-repeated but inaccurate narratives with respect to PCSK9 inhibitors, the idea that all known persons with extremely low LDL due to having two PCSK9 loss-of-function mutations are completely healthy. I agree with the FDA reviewer that there are too few such cases to provide conclusive data about loss-of-function PCSK9 polymorphisms that result in extremely low LDL levels and the risk of disease. (The issue of whether alirocumab increases blood glucose and the risk of developing diabetes is also discussed extensively in the review, with the reviewer concluding that the evidence is inconclusive at this point.)

Do PCSK9 inhibitors affect diabetes risk?

Two PCSK9 inhibitors, evolocumab and alirocumab, are under consideration at the FDA and will be the subject of advisory committee meetings on June 9 and 10. Evolocumab and alirocumab are monoclonal antibodies that inhibit proprotein convertase subtilisin/kexin type 9 (PCSK9), an enzyme that plays a role in regulating levels of LDL cholesterol by binding to LDL receptors and promoting their degradation; the resulting reduction in LDL receptors reduces the liver’s ability to remove circulating LDL. PCSK9 inhibitors prevent PCSK9 from degrading LDL receptors; the increased LDL receptor density results in increased clearance of LDL from the bloodstream. The expectation is that lower LDL levels in patients who receive PCSK9 inhibitors will result in a reduction in cardiovascular events and this strategy is currently being tested in large outcomes trials, which will be completed in a few years. Until those trials are completed, the safety and efficacy of these drugs will not be known.

One of the unknowns with PCSK9 inhibitors is their effect (if any) on blood glucose levels and the development of new-onset diabetes. Statins are known to increase the risk of new-onset diabetes by about 9% overall, with increased risk from intensive vs. moderate intensity statin therapy. One reason to wonder whether PCSK9 inhibitors might have a similar effect is that both statins and PCSK9 inhibitors, though having different mechanisms of action, both involve the removal of LDL through upregulation of LDL receptors. The reason statins increase blood glucose is unknown, but recently it has been suggested that that the LDL receptor might be involved, with greater LDL receptor activity correlating with a higher risk of diabetes. A recent study showed that patients with familial hypercholesterolemia (FH) in the Dutch FH registry have a lower prevalence of type 2 diabetes as compared to their unaffected relatives. FH is a genetic disease in which the LDL receptor function is reduced, leading to higher serum levels of LDL cholesterol. In addition, the study found a dose-response relationship, with more severe FH mutations linked to lower risk of diabetes as compared to less severe mutations. In other words, the study showed an association between less functional LDL receptors and a lower prevalence of type 2 diabetes. In an editorial, David Preiss and Naveed Sattar note that the study suggests that “the expression and function of LDL receptors may be important for glucose homeostasis” and that the advent of PCSK9 inhibitors provides an opportunity to further examine a possible link between LDL receptor expression and glycemia and diabetes risk.

I’ve looked at some of the published data on PCSK9 inhibitors and blood glucose and diabetes risk. With respect to alirocumab, I abstracted a subset of the data in an abstract presented at the March 2015 American College of Cardiology conference.

As you can see, the data show small numerical increases in new-onset diabetes and worsening of preexisting diabetes, as well as larger increases in fasting glucose and hemoglobin A1c over the course of a year in patients on alirocumab as compared to patients on placebo (all patients were also on a statin). With respect to evolocumab, I found the following data:

1. A 52-week placebo-controlled trial of evolocumab in patients with hyperlipidemia published in the New England Journal of Medicine in 2014 found the mean change from baseline for fasting glucose at week 52 was 1.3 mg per deciliter for evolocumab and 0.4 mg per deciliter for placebo. The mean change from baseline for HbA1c at week 52 was 0.02% for evolocumab and 0.00% for placebo (table 3 and supplementary table S3).

1. The Osler trials recently published in the New England Journal of Medicine showed that 1.1% of the patients who received evolocumab developed diabetes, as compared to 0.7% of the patients in the standard of care group.

What do all these small differences add up to? It’s not possible to say yet, but I assume someone will do a meta-analysis at some point, and there may be some discussion of this issue in the FDA review of these agents, which will be posted prior to advisory committee meetings.

I should note that even if PCSK9 inhibitors do increase blood glucose and the risk of developing diabetes, they would still be very worthwhile for patients who are at significant risk of heart attack and stroke, if they are shown to be effective and have acceptable safety.

BMJ: Clinical trial data for all drugs in current use must be available for independent scrutiny

In an impassioned editorial, BMJ editor Fiona Godlee calls on the pharmaceutical industry to release clinical trial data on all approved drugs, and on medical journals to publish industry-funded trials only when there is a commitment to make patient-level data available on reasonable request.  She states that the BMJ will require this commitment for all clinical trials of drugs and devices, whether industry-funded or not, beginning in January 2013.  In addition, BMJ is publishing online all correspondence between Roche and the Cochrane Collaboration researchers regarding the oseltamivir (Tamiflu) data.  More on the battle for Tamiflu data here.

Addendum 11/2/2012:  read Pharmalot’s coverage here.

BMJ editor: Open letter to Roche about oseltamivir trial data


Roche promised in 2009 to release full reports from clinical trials of oseltamivir in response to an investigation by the BMJ and the Cochrane Collaboration.  In this open letter to John Bell, regius professor of medicine at Oxford University and a Roche board member, the BMJ’s editor in chief further urges the company to disclose the full data.

Read the full letter here.

Background here.

Johns Hopkins to launch Center for Drug Safety and Effectiveness

Johns Hopkins is launching a new Center for Drug Safety and Effectiveness.  Via G. Caleb

On Wednesday, October 24, we will launch the Johns Hopkins Center for Drug Safety and Effectiveness, a collaborative effort of the Bloomberg School of Public Health and Johns Hopkins Medicine.  The Center will fulfill its mission by supporting individuals engaged in research, training, clinical programs and public service to optimize the safe and effective use of prescription medicines in the United States and around the world.
We are delighted that Dr. Mark McClellan will deliver the inaugural lecture for the Center on October 24 at 4:00 PM, with a reception to follow.

Compare and contrast: two review articles on ezetimibe

For the past several years I have been following the ezetimibe controversy (see these posts on Gooznews and this blog here, here, here, here, here, here, here, here, here, here, here, here, here, here, and here).  In my view, we continue to lack evidence of ezetimibe’s clinical benefit, or even safety, 10 years after FDA approval.

I have a Google Scholar Alert for ezetimibe, so often links to articles on ezetimibe arrive in my email inbox.  Recently, two review articles on ezetimibe were published that were a study in contrasts.  The first, by Sheila Doggrell, takes a skeptical view toward ezetimibe and reaches the following conclusion:

The comparison of clinical trials with simvastatin and ezetimibe alone and together has clearly shown that simvastatin decreases LDL-cholesterol and this is associated with improved clinical outcomes. Also, ezetimibe alone or in the presence of simvastatin lowers LDL-cholesterol. However, ezetimibe alone or in the presence of simvastatin has not been shown to have any irrefutable beneficial effects on clinical outcomes. Thus, until/unless the use of ezetimibe is clearly shown to improve clinical outcomes, its use should be largely restricted to clinical trials investigating clinical outcomes, and ezetimibe should not be used routinely in everyday practice.

The second, by Binh An Phan, Thomas Dayspring and Peter Toth, takes a much more optimistic view:

In the current treatment of cardiovascular disease, many subjects fail to reach LDL-C targets or remain at high risk for CHD events despite optimal statin and medical therapy. Ezetimibe inhibits intestinal cholesterol absorption and is effective in lowering cholesterol as monotherapy or in combination with statins in several populations, including those with FH, sitosterolemia, and insulin resistance. Significant controversy has been generated regarding the clinical effectiveness of ezetimibe, particularly after the publication of ENHANCE and ARBITER-6 despite both trials having significant methodological flaws that limited their ability to evaluate the benefit of ezetimibe. Growing data suggest that ezetimibe in combination with statin has a positive effect on the progression of atherosclerosis and reduces cardiovascular events in subjects at risk for CHD, including those with chronic kidney disease. Results from IMPROVE-IT are forthcoming and may help to guide better the use of ezetimibe in very high-risk CHD populations. Until that time and based upon the current available data, ezetimibe should remain a viable adjunct to statin therapy in the treatment of hypercholesterolemia.

Dr. Phan and colleagues find reasons to dismiss the negative results of ENHANCE and ARBITER 6-HALTS as due to “methodological flaws” and use copious amounts of hand-waving to find support for ezetimibe in the SEAS and SHARP trials, even though those trials compared the combination of simvastatin and ezetimibe with placebo and thus can tell us nothing about what, if anything, ezetimibe added to those results.  Could the differing views of Doggrell and Phan et al. have anything to do with the fact that Dr. Doggrell declares no conflicts of interest relating to ezetimibe, while Phan, Dayspring and Toth declare the following conflicts:

Binh An Phan is a speaker for Abbott. Thomas Dayspring consults for Abbott, GSK, Health Diagnostic Labs, Kowa Company, Eli Lilly, Merck, Genentech, The Roche Group, Genzyme, and Omthera. He is on the Lecture Bureau for Abbott, GSK, Health Diagnostic Labs, Kowa, Eli Lilly, LipoScience, Merck. Peter P Toth is a speaker for Abbott, AstraZeneca, Amylin, Boehringer-Ingelheim, GSK, Kowa, Merck and consults for Abbott, Aegerion, AstraZeneca, Atherotech, Genzyme, Genentech, Kowa, and Merck.

It is not too surprising that authors who are consultants and on the speaker’s bureau for Merck would take a favorable view of ezetimibe.  What is surprising is that anyone would take their word for it.


Doggrell SA. The ezetimibe controversy — can this be resolved by comparing the clinical trials with simvastatin and ezetimibe alone and together? Expert Opin. Pharmacother. (2012) 13(10):1469-1480.

Phan BAP, et al. Ezetimibe therapy:  mechanism of action and clinical update. Vascular Health and Risk Management 2012:8:415-427.

Addendum, May 5, 2015:  Unfortunately, the GoozNews blog is no longer up on the web.

More information on the PharmedOut conference

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?

Federal Litigation
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.

Lauer: is Qnexa a lemon or a peach?

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.

More on the need for data sharing — the Tamiflu example

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.

Chantix meta-analysis

Because I was on vacation when the latest Chantix (varenicline) news broke, I’m a week late in posting on it. Last Monday, a meta-analysis was published online in the Canadian Medical Association Journal. The meta-analysis, which combined 14 Chantix clinical trials involving 8216 partcipants, showed a 72% increased risk of ischemic or arrhythmic adverse cardiovascular events. Moreover, all except one trial involving approximately 700 participants excluded patients with a history of cardiovascular disease, indicating that Chantix may have heart risks even for people without a history of heart trouble. The meta-analysis follows last month’s FDA warning that Chantix may raise the risk of cardiovascular events in persons with a history of cardiovascular disease.

A number of people have raised safety concerns with Chantix since it was approved in 2006, including John Spangler and Curt Furberg of Wake Forest University School of Medicine (see background here, here and here), both of whom were co-authors on the meta-analysis. In 2008, researchers at the Institute for Safe Medication Practices issued a report showing a high rate of serious adverse events associated with the drug. In response to the ISMP report, the Federal Aviation Administration said it would no longer permit pilots or air traffic controllers to use Chantix, and the Federal Motor Carrier Safety Administration advised medical examiners to not qualify anyone currently using Chantix for a commercial motor vehicle license. The Chantix label includes a warning that Chantix may impair driving ability. The label also contains a boxed warning relating to Chantix’s psychiatric risks. Last year, a study published in The Annals of Pharmacotherapy found that Chantix was associated with violent or aggressive thoughts and acts. A study in PLoS One found that Chantix was associated with acts of violence toward others.

In my opinion, smokers should rely on other methods to stop smoking, such as nicotine replacement therapy, bupropion or counseling, rather than using Chantix.


Get every new post delivered to your Inbox.

Join 3,047 other followers