ZOSTAVAX VACCINE: Unpacking the Data from Merck & Co. Clinical Trials

ZOSTAVAX VACCINE:

Unpacking the Data from Merck & Co. Clinical Trials

October 11, 2018

 

 

 

 

 

 

 

 

 

 

The following information and conclusions are based on opinions formed after a review of relevant facts and data by John Ray, Senior Consultant, Mass Tort Nexus

Background

Herpes zoster (shingles) is a symptom of the varicella-zoster virus, the same virus that causes chickenpox. Individuals experiencing active herpes zoster infections often report debilitating pain and blistering skin rashes typically located on the face and torso. The varicella-zoster virus (chickenpox) can remain dormant in the body indefinitely and may emerge decades later as herpes zoster (shingles). Not all persons who have the varicella-zoster virus will develop herpes zoster, and it is impossible to predict who will and who won’t.

American pharmaceutical giant, Merck & Co. (Merck), released its Zostavax vaccine to the market in 2006. In its marketing campaign, Merck claims that “you have a 1 in 3 chance of contracting shingles,” and that the Zostavax vaccine reduces the occurrence of zoster by “51% overall in subjects aged 60 years or older.” The FDA approved the Zostavax vaccine prior to its market release.

Summary of Findings

  1. At a minimum, valid clinical trial results are based on two conditions: (1) trial participants must be diagnostically homogeneous (i.e., they share the same medical diagnosis); and, (2) the number of trial participants must be statistically significant (i.e., results may be reliably extrapolated to a larger group).
  2. Results from the Zostavax clinical trials conducted by Merck are arguably invalid because the trial participants were neither diagnostically homogeneous or comprised a statistically significant number.
  3. Because the risk of developing herpes zoster is higher for those that received the Zostavax vaccine than those who didn’t, Merck’s public marketing campaign of the Zostavax vaccine misled consumers, at best, and caused significant harm, at worst.

 Methodology Flaws in the Zostavax Clinical Trials

Diagnostically Homogeneous Trial Participants

Generally, clinical trials are intended to observe occurrences and outcomes from product administration with trial participants that share a medical diagnosis (i.e., diagnostically homogenous). For example, a clinical trial involving a drug to treat type 2 diabetes would only enroll individuals diagnosed with type 2 diabetes. Once a diagnostically homogenous group is identified and recruited for a clinical trial, an equal proportion of the group will be administered the drug being studied while the remainder will be administered either a placebo or another drug intended to treat the same disease or condition in trials testing one drug against another.

Zostavax vaccine clinical trials conducted by Merck differed significantly from normal clinical trial methodology in that Zostavax is not intended to treat an existing diagnosed disease or condition but rather is intended to prevent herpes zoster, a symptom of the varicella-zoster virus. If trial participants did not share a diagnosis of an existing disease or condition and could not reliably predict the future onset of a herpes zoster condition, trial participants were not—and could not be—diagnostically homogeneous. Therefore, conclusions reached by Merck from the Zostavax clinical trials are arguably invalid.

Statistically Significant Number of Trial Participants

After clinical trial observations are recorded, the results are extrapolated to represent predictable outcomes in a larger population. Extrapolations from statistically significant numbers are never as reliable as data collected from a larger, real-world population. Significant real-world data (e.g., data collected from Medicare, countries with national health care systems and/or unbiased third-party authorities) existed prior to the Zostavax trials regarding occurrence rates of herpes zoster by age group.

Numerous authorities and governments had already established that the probability of contracting herpes zoster during a lifetime was between 30 and 33%. Given the fact that a “risk without vaccination rate” was generated using far more reliable methods, there was no reason for Merck to include a placebo group in their trials when real-world data existed relevant to the unvaccinated.

In addition, Merck disqualified participants with compromised immune function from the Zostavax clinical trials. Immuno-compromised individuals are significantly more likely to develop herpes zoster. The 30 – 33% lifetime occurrence rate established by trusted sources from real-world data included persons with compromised immune function. As a result, the real-world data must be considered more accurate than the Zostavax trial data relevant to the placebo group.

The following chart shows the broad results of the first Zostavax trial conducted by Merck. Merck claims that for subjects 60 years of age or older there is a 51% reduction of risk. These results are misleading because they average occurrence rates of persons 80 years of age and older (who are significantly more likely to develop herpes zoster based on real-world data) with occurrence rates from age groups that are significantly less likely to develop herpes zoster. These statistics were used by Merck to obtain licensure for Zostavax from the FDA.

[Merck’s Zostavax link: https://www.merckvaccines.com/Products/Zostavax/efficacy/]

Methodology Flaws in the Zostavax Clinical Trials

Diagnostically Homogeneous Trial Participants

Generally, clinical trials are intended to observe occurrences and outcomes from product administration with trial participants that share a medical diagnosis (i.e., diagnostically homogenous). For example, a clinical trial involving a drug to treat type 2 diabetes would only enroll individuals diagnosed with type 2 diabetes. Once a diagnostically homogenous group is identified and recruited for a clinical trial, an equal proportion of the group will be administered the drug being studied while the remainder will be administered either a placebo or another drug intended to treat the same disease or condition in trials testing one drug against another.

Zostavax vaccine clinical trials conducted by Merck differed significantly from normal clinical trial methodology in that Zostavax is not intended to treat an existing diagnosed disease or condition but rather is intended to prevent herpes zoster, a symptom of the varicella-zoster virus. If trial participants did not share a diagnosis of an existing disease or condition and could not reliably predict the future onset of a herpes zoster condition, trial participants were not—and could not be—diagnostically homogeneous. Therefore, conclusions reached by Merck from the Zostavax clinical trials are arguably invalid.

Statistically Significant Number of Trial Participants

After clinical trial observations are recorded, the results are extrapolated to represent predictable outcomes in a larger population. Extrapolations from statistically significant numbers are never as reliable as data collected from a larger, real-world population. Significant real-world data (e.g., data collected from Medicare, countries with national health care systems and/or unbiased third-party authorities) existed prior to the Zostavax trials regarding occurrence rates of herpes zoster by age group.

Numerous authorities and governments had already established that the probability of contracting herpes zoster during a lifetime was between 30 and 33%. Given the fact that a “risk without vaccination rate” was generated using far more reliable methods, there was no reason for Merck to include a placebo group in their trials when real-world data existed relevant to the unvaccinated.

In addition, Merck disqualified participants with compromised immune function from the Zostavax clinical trials. Immuno-compromised individuals are significantly more likely to develop herpes zoster. The 30 – 33% lifetime occurrence rate established by trusted sources from real-world data included persons with compromised immune function. As a result, the real-world data must be considered more accurate than the Zostavax trial data relevant to the placebo group.

The following chart shows the broad results of the first Zostavax trial conducted by Merck. Merck claims that for subjects 60 years of age or older there is a 51% reduction of risk. These results are misleading because they average occurrence rates of persons 80 years of age and older (who are significantly more likely to develop herpes zoster based on real-world data) with occurrence rates from age groups that are significantly less likely to develop herpes zoster. These statistics were used by Merck to obtain licensure for Zostavax from the FDA.

[Merck’s Zostavax link: https://www.merckvaccines.com/Products/Zostavax/efficacy/]

Merck’s Misleading Marketing Scheme

 

 

 

 

 

Merck used the blanket statement, “You have a 1 in 3 chance of contracting shingles,” in their fear-based advertising campaigns for Zostavax. If we ignore the placebo trial group data in favor of the more reliable real-world data which tells us that 33% of individuals will experience herpes zoster during their lifetime leaving 67% that will not, we can conclude the following:

Age Group 60-69

Merck claimed a Zostavax efficacy rate of 64%. When this rate is compared to the real-world data rate, we can conclude that administration of the Zostavax vaccine increased the risk of experiencing herpes zoster by 3% for this group. Those who do not receive the Zostavax vaccine have a 67% chance of never manifesting herpes zoster symptoms while those that do receive the vaccine have a 64% chance of never contracting Herpes Zoster.

Age Group 70-79

Merck claimed a Zostavax efficacy rate of 41%. When this rate is compared to the real-world data rate, we can conclude that administration of the Zostavax vaccine increased the risk of developing herpes zoster by 26% for this group. Those who do not receive Zostavax have a 67% chance of never manifesting herpes zoster symptoms while those that receive the vaccine have a 41% chance of never contracting Herpes Zoster.

 Age Group > 80

Merck claimed a Zostavax efficacy rate of 18%. When this rate is compared to the real-world data rate, we can conclude that administration of Zostavax increased the risk of developing herpes zoster by 49% for this group. Those who do not receive Zostavax have a 67% chance of never manifesting herpes zoster symptoms while those that receive the vaccine have an 18% chance of never contracting Herpes Zoster.

The blended rate (all age groups in the study combined) of 51% efficacy claimed by Merck compared with occurrence rates from real-world data, leads us to conclude that for all intended users, the risk of developing herpes zoster after vaccination with Zostavax is greater than prior to vaccination. Real-world data demonstrates that the relative risk of contracting herpes zoster post-vaccination is 49% while those who are not vaccinated face a 33% risk.

The following graph shows herpes zoster occurrence rates by age group. A comparison of Zostavax trial data to real-world occurrence rates supports another conclusion—the age groups most at risk for developing herpes zoster (and most in need of an effective vaccine) had the least probability of protection from administration of the Zostavax vaccine and were arguably at the highest risk for developing Zostavax as a result of receiving the vaccine.

The foregoing is an observation of statistics and data related to Zostavax. The method by which Merck used and manipulated this data in misleading marketing and advertising is covered in other sections of the material.

The conclusions contained herein are based on opinions formed by the author after a review of the relevant data. We acknowledge that others could draw differing conclusions and opinions based on the same observations.

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FDA Statement March 15, 2019 Re: “Efforts to evaluate materials in medical devices to address potential safety questions”  

 

Statement from FDA Commissioner Scott Gottlieb, M.D. and Jeff Shuren, M.D., Director of the Center for Devices and Radiological Health, on efforts to evaluate materials in medical devices to address potential safety questions

For Immediate Release

March 15, 2019

FDA Statement

We’re in an unprecedented era of innovation in medical devices with advances in materials science that have led to technological breakthroughs such as the 3D printing of medical devices, continuous glucose monitoring patches for diabetes and miniaturized brain implants to treat epilepsy and Parkinson’s disease. Helping to ensure patients have access to safe medical devices that improve function and overall quality of life is a crucial part of the mission of the U.S. Food and Drug Administration. Our regulatory framework is designed to ensure that benefits patients receive from these devices are weighed against probable risks.

The vast majority of patients implanted with medical devices have no adverse reactions. The device works and performs as expected to treat medical conditions or help patients better manage their health. However, a growing body of evidence suggests that a small number of patients may have biological responses to certain types of materials in implantable or insertable devices. For example, they develop inflammatory reactions and tissue changes causing pain and other symptoms that may interfere with their quality of life.

Materials used in today’s medical devices vary as widely as the devices themselves—whether the material is metal, plastic, silicone, an animal-derived product or some combination of these. Because, in the case of implantable or insertable devices, these materials come into contact with tissue or other parts of the body for sometimes extended periods of time, we do a careful evaluation during our premarket review to determine if there is a potential adverse biological response resulting from contact of the device’s component materials with the body and whether the associated risks are unacceptable.

Specifically, we review information about the materials used in the composition of the device and require companies to include a biocompatibility evaluation or risk analysis, as well as clinical studies, when appropriate. In 2016, we finalized updated guidance for industry laying out what we look for in biocompatibility evaluations in order to ensure device manufacturers have adequately assessed the potential of their device to cause adverse biological responses in patients. By clarifying expectations for all devices requiring premarket submissions, we are helping to ensure that manufacturers are providing evidence that demonstrates that any risk to patient health or safety has been adequately evaluated prior to marketing.

These steps help to address any risks that may be posed by, for example, the potential presence of harmful chemicals or materials that might trigger allergic or other adverse reactions in some individuals. While such testing generally has been a reliable predictor of a material’s safety, we also recognize the importance of advancing the science we rely on to evaluate device materials and patient risk factors both before and after devices enter the market to assure we optimally reduce risks to patients and maximize benefits. Once a device is on the market we have a number of tools in place to monitor a device’s benefit-risk profile as it is used in a real-world setting. In cases where new information about safety or effectiveness becomes available, we can and have taken action to inform patients and health care providers about new risks or safety considerations and how to mitigate those risks. These actions include working with companies to recall and correct issues that arise postmarket, issuing safety communications or other updates for health care providers or patients about safe use of devices, requiring boxed warnings or contraindications be added to labeling, requiring postmarket studies, and up-classifying devices to allow us to regulate them more stringently, as we did with metal-on-metal total hip replacement devices. We are also working to fully implement the National Evaluation System for health Technology (NEST) that will link and synthesize data from different sources including clinical registries, electronic health records and medical billing claims; this will help improve the quality of real-world evidence that will empower the FDA to more quickly identify, communicate and act on new or increased medical device safety concerns.

Our understanding of medical technologies evolves over time. As we learn more about long-term effects of materials and as materials science advances and new innovations become a reality, it’s imperative our regulation of devices evolves along with these advances to ensure patients are protected.

Prior to, and as part of, our April 2018 Medical Device Safety Action Plan, the FDA has been carefully evaluating the body of evidence on this issue. This includes current published studies, and information submitted to us as reports in our public adverse events database or through data from postmarket studies that we required manufacturers to conduct. We also have our own team of FDA scientists and engineers conducting research to better understand device materials in our Center for Devices and Radiological Health’s (CDRH) Office of Science and Engineering Laboratories (OSEL).

Based on our evaluation and discussions with experts elsewhere in the government and academia, we believe the current evidence, although limited, suggests some individuals may be predisposed to develop an immune/inflammatory reaction when exposed to select materials.

The symptoms some patients experience may be limited to the region where the device is implanted or may be more generalized. Symptoms include but are not limited to fatigue, rash, joint and muscle pain or weakness. Although uncommon and varied, these symptoms may share common underlying immune/inflammatory pathways and mimic more well-established inflammatory conditions.

In the small subsets of patients who have reported these symptoms, the symptoms may not develop for several years following implantation. As a result, they may not be detected even in larger and longer clinical studies. To date, these symptoms have not been reported with most materials used in medical devices, including most metals. Moreover, when reported, they have tended to be limited to small subsets of patients.

As an example, some patients, mostly with a history of pre-existing allergies, may develop allergic skin lesions with certain device use. This risk is usually identified by patch testing for potential device material-related allergens. However, not all device-related reactions are allergic in nature. Therefore, the utility of skin patch testing is limited.

Enhancing our collective understanding of materials science could lead to identifying materials that may cause an exaggerated response in sensitive individuals and advance the development of safer materials. Development of new tests to identify at-risk patients would help ensure they do not receive implantable devices that contain the material to which they are sensitive, therefore further enhancing patient safety and advance a precision medicine approach to the selection of device interventions.

It’s clear more work needs to be done.

To this end, we’re undertaking a broad effort to engage the public, scientists and industry stakeholders to gather information and help us determine the current state of the science, critical gaps in the existing science that need to be addressed, what approaches should be considered to further our understanding of medical device materials and improve the safety of devices for patients.

Breast implants

Breast implants have a silicone outer shell, with either a textured or non-textured surface, and are filled with silicone gel or saline. The FDA has regularly communicated about risks associated with breast implants, such as capsular contracture, implant rupture and breast implant-associated anaplastic large cell lymphoma (BIA-ALCL). More confirmed cases of BIA-ALCL have been reported in patients with textured surface implants than in patients with smooth-surface breast implants. We’ve also heard from patients who are concerned that their implants may be connected to other health conditions that could be associated with their immune system’s response to these devices, resulting in symptoms like chronic fatigue, cognitive issues and muscle pain. While the FDA doesn’t have definitive evidence suggesting breast implants are associated with these conditions, we’re looking to gain a fuller understanding of this issue to communicate risk, minimize harm and help in the treatment of affected patients. This topic will be discussed at our upcoming two-day public meeting of the General and Plastic Surgery Devices Panel on March 25 and 26 and will be informed by our ongoing assessment of the long-term health effects of various materials.

In addition, we’ve been coordinating on two different breast implant registries to learn more about how these devices perform and interact with the body’s tissues at the cellular and organ levels. For instance, we worked with the American Society of Plastic Surgeons/the Plastic Surgery Foundation to develop the Patient Registry and Outcomes for Breast Implants and Anaplastic Large Cell Lymphoma Etiology and Epidemiology (PROFILE). This registry collects real-world data regarding patients who have a confirmed diagnosis of BIA-ALCL. The data collected from this registry as well as from medical device reports submitted to the FDA, medical literature and meetings with patient advocates have contributed to our understanding of BIA-ALCL and our communication updates to the public regarding BIA-ALCL. Additionally, we’re working with multiple stakeholders to advance the development of the National Breast Implant Registry (NBIR) to provide a platform for evaluating real world data on the safety and performance of breast implants. This will help us better evaluate data from providers regarding their patients with breast implants.

We’ll continue to report on significant findings as new information and analyses become available and if any of these findings prompt the agency to issue new recommendations or policies to mitigate risks.

Metals in devices

Metal device implants have been used in patients for more than a century, beginning with bone- stabilizing plates to heal fractures and advancing to state-of-the-art stents, prostheses and implantable defibrillators. Many implants are meant to remain in a patient’s body for years or even a lifetime. During this time, we know that tiny amounts of metals may be gradually released into the bloodstream and surrounding tissues.

The FDA regularly conducts thorough reviews of the latest scientific evidence. We continue to find that most patients experience no adverse health effects from these metals interacting either locally where the devices are implanted or systemically throughout the body. However, after carefully reviewing the current scientific literature, reports in our public adverse event database as well as findings from post-approval and postmarket surveillance studies, we believe there’s a need to evaluate through a comprehensive process concerns that were brought to light with particular devices, such as metal-on-metal total hip replacement devices and the permanent birth control implant Essure, a coiled wire that’s composed of multiple metals, including nitinol (a nickel and titanium alloy) and stainless steel, and is inserted into a woman’s fallopian tubes.

Nitinol in devices

Last December, we announced a revised protocol for the postmarket surveillance study of the Essure device to, in part, better understand how the materials in the device interact with the body’s immune system. The FDA worked with Bayer, the manufacturer of the device, to make sure the company implemented several approved modifications to the study that we believe will strengthen the evidence collected.

First and foremost, women in the study will be followed for five years, rather than the three years that were initially required. This extension will provide us with longer-term information on adverse risks of the device, including issues that may lead women to have the device removed. We also required additional blood testing of patients enrolled in follow-up visits during the study to learn more about patients’ levels of certain inflammatory markers that can be indicators of increased inflammation. This could help us better evaluate potential immune reactions to the device and define whether these findings are associated with symptoms that patients have reported in relation to Essure. These reported symptoms include persistent pain and hypersensitivity reactions, headaches, fatigue and cognitive difficulties.

The use of nitinol in other devices has increased—particularly for cardiovascular stents, guidewires and other devices used in minimally-invasive medical procedures. This owes to the metal’s properties. Nitinol is flexible and bendable with the ability to spring back, like a Slinky, into its original shape.

Many of the symptoms reported by some patients who had Essure implanted have not been reported by patients who had other nitinol-containing devices implanted, which could be related to the location of the implants. The particular site in the body where a device is placed may contribute to the potential for the device to cause an immune/inflammatory reaction. In the next few months, we’re planning to publish draft guidance on the use of nitinol in medical devices. This new guidance will include recommendations from the FDA on what manufacturers should include in their premarket submission of a device containing nitinol, including technical testing recommendations, labeling and information on how the device is manufactured and other factors that could affect the breakdown of the material in the body.

Metal-on-metal total hip replacement devices

Three years ago, the FDA strengthened the regulation of metal-on-metal total hip replacement devices requiring that manufacturers submit premarket approval applications to keep their devices on the market. That decision was based on significant safety concerns associated with adverse biological reactions to the metal wear particles and ions generated by the metal ball rubbing the metal socket joint during everyday use. These metal particles were found to have the potential to cause damage to the surrounding bones and soft tissues (including muscle) in some patients leading to pain, device failure and the need for repeat surgery to replace the implant. Some patients also developed severe systemic conditions, including damage to their heart, kidneys and thyroid, from the metal ions entering their bloodstream and reaching distant organs.

There are currently no FDA-approved metal-on-metal total hip replacement devices marketed for use in the U.S. However, many patients still have these devices implanted in their body, and the FDA felt it was imperative that manufacturers continue to meet their obligations for completing their postmarket surveillance studies. Today, we’re sharing interim results from these studies. The results show significantly higher blood levels of metal ions (cobalt and chromium) in patients with metal-on-metal hip implants compared to those without metal implants. While that’s not unanticipated, the data also suggest that the standard blood level threshold measurement of 7.0 parts per billion (micrograms/liter) or higher for metal ions, is not optimal to determine if an implant is functioning safely. Some patients in the postmarket surveillance studies had levels higher than this with no adverse medical complications, while others had severe symptoms with lower ion levels in their blood. This suggests that there are additional factors, besides metal ion levels, that affect which patients experience adverse events from metal-on-metal total hip replacement devices.

In addition to the clinical evaluations, the postmarket surveillance studies included a detailed analysis of more than 2,000 devices from patients who elected to have their implants removed. On average, patients who had their devices removed had higher metal ion levels compared to other patients in the postmarket surveillance studies who didn’t. Also, the wear between the metal ball and metal socket was found to be higher than what was expected based on testing performed on the devices before they were allowed on the market. When considering all devices that were explanted, it appears that certain factors, including those related to the design or surgical placement of the device, may be associated with a higher wearing down of the device and elevated metal ion levels.

Based on these findings, the FDA is working with standards development organizations (such as the American Society for Testing and Materials) to develop new standards to improve how metal-on-metal total hip replacement devices are evaluated and identify additional testing protocols for new metal-on-metal devices that are submitted to the FDA for review.

Advisory panel meeting

To help us gain a broader understanding of nitinol and other metals in devices, we’re announcing today that we plan to hold an advisory committee meeting this fall to discuss metal implants and the potential risk for certain patients to have “hypersensitivity” or exaggerated immune and inflammatory reactions to these metals. We’ve been exploring the link between immune and inflammatory markers and symptoms such as pain, headaches and fatigue in patients who have these devices implanted. This advisory committee meeting is part of our ongoing effort to advance the evaluation of materials used in implantable devices.

The panel meeting will engage experts in the field to provide input on what relevant scientific information the FDA should solicit from manufacturers to be considered in both premarket review and postmarket surveillance. Importantly, we’d like to determine how to identify patients who might be at increased risk of having a hypersensitivity response before they receive a metal implant, so they can consider those risks along with the device’s benefits. An additional purpose of the meeting will be to identify gaps in current scientific knowledge to determine what studies are essential to further expand our understanding of this important public health issue, including to what extent immune/inflammatory responses to certain metals contribute to device-related adverse events and steps we can take to mitigate potential risks.

Prior to this meeting, the FDA will release a peer-reviewed white paper that summarizes the current scientific knowledge regarding different aspects of metal implants, including how the structure and function of these devices are impacted by the body’s tissues, muscles and blood supply and how the metal components dissolve and interact with immune cells.

These efforts are just a few aspects of our ongoing evaluation of the effects of materials in at-risk patients. Our goal in taking these steps is to ensure that the benefits of devices made of metal materials continue to outweigh their risks. For the vast majority of patients this is the case and will remain the case as we go through these steps. However, for certain small subsets of patients who exhibit sensitivities to select materials, we must determine what additional actions we should take to make sure they are protected and understand the unique risks they may encounter.

Animal materials in devices

We’re also making efforts to improve the safety of devices made from animal-derived materials such as additives used on device coatings or heart valves made from pig tissue. We know that animal-derived materials may provide benefits over metal or synthetic materials because they can more closely match the biophysical properties of tissues within the human body. But these materials may carry a risk of transmitting infectious disease when improperly collected, stored, or manufactured. Specifically, animal tissues can contain infectious agents known as prions, which cause neurodegenerative disorders such as Bovine Spongiform Encephalopathy (BSE) or Mad Cow Disease. Yesterday, we issued final guidance on Medical Devices Containing Materials Derived from Animal Sources to provide recommendations to device manufacturers for how to minimize the potential risk of transmitting these rare but serious infectious diseases while still providing patients access to beneficial devices made from animal-derived materials.

Research efforts to better understand innovative materials

We’re also beginning to see manufacturers incorporate new types of materials in devices. CDRH’s OSEL has been conducting a wide array of research studies to learn more about the new advances in device materials. For example, our scientists are looking to better understand and characterize an innovative form of carbon called graphene, which has enormous applications in biotechnology and device development because it is lightweight, flexible, a superb conductor of electricity and is many times stronger than steel.

In anticipation of new device applications for, say, graphene-containing drug delivery systems or ultrasensitive biosensors that can be used with diagnostic tests, our scientists are working quickly to characterize and learn more about graphene’s chemical properties—both in terms of how durable it will be in medical devices and how it will interact with the body’s tissues and immune system.

OSEL has also worked on understanding how nanoparticles—tiny particles composed of just a few atoms—in medical devices interact with the immune system and whether they’re causing any toxic effects in the body. While these advances are promising, OSEL researchers are working to ensure that the benefits of the new material outweigh any risks that may come from these particles interacting with human cells.

Next steps

Modernizing the regulatory framework pertaining to the FDA’s review of medical device materials requires a multi-step approach. We’ll gather input from patients, device manufacturers, researchers and physicians to learn more about their concerns and ideas for how the FDA should proceed. Any new initiatives we implement must be rooted in putting patient safety first and based on sound science.

More closely evaluating the potential for certain materials to cause immune/inflammatory reactions in a small number of patients may improve our understanding of materials, help uncover ways to identify patients predisposed to these reactions and improve the overall safety and performance of medical devices. This is part of our continuing effort to advance opportunities for enabling modern materials to improve the performance of medical devices while also advancing our assurance of safety for these products. We look forward to providing updates about our progress and ongoing research. We believe our continuing efforts will ultimately provide patients and doctors with better access to more effective and safer medical devices.

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Bayer AG Completes Monsanto Purchase – What’s Next On Litigation Docket?

Bayer now faces Roundup MDL 2741 along with Xarelto MDL 2592 and more than 30,000 plaintiffs

By Mark A. York (March 7, 2019)

 

 

 

 

 

(MASS TORT NEXUS MEDIA) The integration of Monsanto into the Bayer AG Group was completed as of August 2018, which by chance coincided with the $289 million jury verdict against Monsanto on August 10, 2018 in a California trial over its Roundup “glyphosate” weed killer. The state court jury found that Monsanto’s Roundup was the cause of plaintiff R Johnson’s fatal diagnosis of non-hodgkins lymphoma.

As part of the deal completion, there were numerous requirements set by the US Department of Justice including the divestment by Bayer of certain Crop Science businesses to BASF Corp., which had sales volumes of around 2.2 billion euros. Bayer already became the sole owner of Monsanto Company on June 7, 2018, by becoming the sole Monsanto stock shareholder, resulting in Bayer assuming additional liabilities related to Monsanto’s Roundup litigation dockets across the United States.

The acquisition of Monsanto creates a market leading worldwide agriculture company, with Bayer assuming a much more direct access route to the highly coveted US farm and crop markets.

As part of the Bayer acquisition, they have inherited the Monsanto docket of Roundup litigation pending state and federal dockets across the USA. There is a current Monsanto Roundup trial underway in the US District Court in San Francisco that started February 25, 2019 in front of Judge Vince Chhabria, in the first Monsanto Roundup MDL 2740 bellwether trial. See Mass Tort Nexus Roundup Briefcase ROUNDUP-MONSANTO-(GLYPHOSATE)-MDL-2741-(USDC-ND-California).

Glyphosate, the active ingredient in Roundup, has been under scrutiny for years including when in 2015, the International Agency for Research on Cancer (IARC), which is part of the World Health Organization, identified the ingredient as a “probable carcinogen.” Monsanto has adamantly denied those claims. Bayer now faces a flurry of back to back trial is state and federal courtrooms with the first trial having just started.

Monsanto Roundup Trial Schedule 2019-2020

02/25/2019  – Federal Court – Hardeman (underway)
03/18/2019  – CA JCCP – Pilliod (2 plaintiffs)
04/01/2019  – St. Louis City Court – Hall
04/22/2019  – St. Louis County Court – Gordon
05/25/2019  – Federal Court – Stevick or Gebeyehou
09/09/2019  – St. Louis County Court – 4 plaintiffs
01/21/2020  – St. Louis City Court – 10 plaintiffs
03/23/2020  – St. Louis City Court

The German parent entity Bayer AG, has started aggressively divesting assets including their animal products division, cutting consumer marketing group costs, closing several US manufacturing locations to the tune of more than $3 billion. Where Bayer decides to put the recently acquired cash remains to be seen, since they are also facing more than 20,000 lawsuits in the Xarelto MDL 2592 litigation.

See Mass Tort Nexus Briefcase Re: XARELTO-(rivaroxaban)-MDL-2592-USDC-ED-Louisiana

MONSANTO ROUNDUP “GLYPHOSATE” MDL 2741

Bayer AG’s chief executive officer Werner Baumann, said this week the company might consider settling lawsuits over Monsanto’s glyphosate-containing weed-killers depending on how high court costs rise, but stressed it remained focused on defending the combined company against claims they cause cancer.

“If we can settle nuisances at some point where the defense costs in preparing cases are higher than potential settlement amounts, we will of course consider it from an economic standpoint,” CEO Werner Baumann told reporters when asked whether there was any scenario in which Bayer would consider settlement.

Baumann expressed confidence that Bayer could handle the litigation, and cited its “inexpensive” $12 million settlement of 4,000 lawsuits over its contraceptive Mirena device. Bayer also won five of six trials over its best-selling bloodthinner Xarelto, over which it faces 24,000 U.S. lawsuits. The sixth jury found in favor of a plaintiff, but a judge later overturned the decision.

“Due to our exposure as a pharmaceutical company, we have the experience to defend those (glyphosate) cases,” he said, also adding “the jury pool likely has grown more hostile” due to negative media coverage following the Johnson verdict.

Baumann said the company’s legal strategy had been revised following the integration of Bayer and Monsanto in mid-August. He declined to provide details, but recent court filings reveal some of the steps the company has taken.

Bayer recently added the attorneys from law firm Arnold & Portner, who won the Xarelto cases for the company to its glyphosate defense team.

As for the glyphosate verdict in California state court on August 10, 2018, Bayer believes that the jury’s decision is at odds with the weight of scientific evidence, decades of real world experience and the conclusions of regulators around the world that all confirm glyphosate is safe and does not cause non-Hodgkin’s lymphoma. The National Institutes of Health (NIH) recently reaffirmed glyphosate does not cause cancer. The U.S. Environmental Protection Agency (EPA), the European Food Safety Authority (EFSA), the European Chemicals Agency (ECHA) and other regulators around the world have also concluded that glyphosate can be used safely.

CEO Baumann had invited German media to visit Bayer’s new operations in the former research and development facilities of Monsanto in St. Louis, Missouri, when he made the statements on Monsanto litigation and bringing in the Bayer legal philosophy to support the ever-growing Roundup litigation in dockets across the country.

LITIGATION IMPACT ON BAYER EARNINGS

Shares in Bayer have lost 25 percent in value since Aug. 10, when a San Francisco jury awarded $289 million to Dewayne Johnson on grounds Monsanto failed to warn the school groundskeeper and other consumers of the cancer risks posed by glyphosate-based RoundUp and Ranger Pro.

Johnson has terminal non-Hodgkin’s lymphoma that he alleges was caused by the herbicides. The jury’s verdict is just the first step in this case, and it remains subject to post-trial motions in the trial court and to an appeal, as announced by Monsanto. As this case proceeds, Bayer believes courts ultimately will find that Monsanto and glyphosate were not responsible for Mr. Johnson’s illness.

Bayer denies that glyphosate causes cancer and says decades of scientific studies and real-world use have shown the chemical to be safe for human use.

The number of glyphosate cases that Bayer faces across the United States has jumped to more than 11,000, prompting concerns among investors about the impact of litigation costs on Bayer’s bottom line.

More recently, Bayer AG’s defense of Monsanto and its weed killer has taken a big hit after a major academic journal said Monsanto has improperly influenced study results related to a connection between cancer and glyphosate. . The journal, Critical Reviews in Toxicology a major toxicology peer review group that analyzes health risks of chemicals, now supports plaintiffs contentions that Monsanto ghost-wrote safety reviews into Roundup and its primary ingredient glyphosate and links to cancer.

Critical Review in Toxicology Issues Correction of Glyphosate-Monsanto “Roundup Study”

Sept. 27, 2018 – The academic journal Critical Reviews in Toxicology issued corrections yesterday for articles that were published in a 2016 supplemental issue dedicated to reviewing the safety of glyphosate, the active ingredient in Monsanto’s Roundup weed killer.

The corrections indicate that Monsanto did not fully disclose its involvement in the five articles published under the title, “An Independent Review of the Carcinogenic Potential of Glyphosate,” which concluded that glyphosate was not likely carcinogenic to humans. The review was written by expert panels overseen by Intertek, a consulting firm hired by Monsanto.

Critical Reviews in Toxicology’s publisher, Taylor & Francis, issued a rare “Expression of Concern” because the review authors failed to provide “an adequate explanation as to why the necessary level of transparency was not met on first submission.”

The journal’s correction bolsters what Roundup cancer attorneys have been saying for years: rather than informing consumers and the public about the link between Roundup and non-Hodgkin lymphoma, Monsanto ghostwrote science and engaged in deceptive PR campaigns to create the impression that its blockbuster Roundup herbicide is safe.

The law firm of Baum, Hedlund, Aristei & Goldman, which represents nearly 1,000 plaintiffs in Roundup cancer lawsuits, issued the following statement on the journal corrections:

“This decision confirms, as we have long contended based on the documentary evidence, that Monsanto made substantial contributions to these manuscripts. However, while some of Monsanto’s involvement in these publications has been acknowledged in the corrections, the investigation by Taylor & Francis fell far short of revealing the extent to which Monsanto violated scientific standards and ethics in this “independent” review.”

The corrections, incorporating apologies from several authors for their declaration failures, are a step in the right direction but do not go far enough to address what we know to be true based on the evidence.

For example:

  • Another correction states that Monsanto scientist William Heydens “pointed out some typographical errors.” Based on the documents we have, Heydens was far more involved in drafting, editing and organizing the reviews than the correction indicates. In an email correspondence with Dr. Ashley Roberts of Intertek, Heydens admits to writing “a draft introduction chapter” for the series of reviews, then asks Roberts “who should be the ultimate author” of the introduction chapter he ghostwrote. Dr. Heydens’ full involvement in these reviews remains uncorrected despite the fact that many of his edits and revisions can be found in the published final manuscript.
  • The reviews were conceived as part of a company plan to discredit IARC well before the agency came to its conclusion that glyphosate is a probable human carcinogen. One of the plan’s stated goals was to “orchestrate outcry with IARC decision, ”while another plan made clear that the company sought a “WHO Retraction” and made it a priority to “invalidate relevance of IARC.” A Monsanto “Post-IARC Meeting” details several scientists that Monsanto pegged as potential authors. The meeting presentation also asks the question, “How much writing can be done by Monsanto scientists to help keep costs down?” In an email under the subject “Post-IARC Activities to Support Glyphosate,” Monsanto executive Michael Koch wrote that the review on animal data cited by IARC should be “initiated by MON as ghost writers,” and “this would be more powerful if authored by non-Monsanto scientists (e.g., Kirkland, Kier, Williams, Greim and maybe Keith Solomon.)
  • The authors of these papers cited previous reviews that were ghostwritten by Monsanto. In an email discussing the plan for the review papers, Heydens wrote, “An option would be to add Greim and Kier or Kirkland to have their names on the publication, but we would be keeping the cost down by us doing the writing and they would just edit & sign their names so to speak. Recall that is how we handled Williams, Kroes & Munro, 2000.”

While we are pleased that the journal will take steps to correct some of the falsehoods in the original declaration of interest and acknowledgment, and we commend the authors who apologized for their violation of disclosure requirements, the scientific integrity of this “review” was compromised the day it was published and, therefore, a complete disclosure of Monsanto’s involvement, ghostwriting and payments to the experts undermining any assertions of their independence is necessary.

Our release of the Monsanto Papers and their part in the recent Monsanto verdict clearly put pressure on these authors to take at least these steps toward correcting the misleading impression that their reviews were free of Monsanto involvement and direction. It is a shame that Monsanto and now Bayer refuse to apologize for their role in this affair. We will continue to put pressure on Monsanto and Bayer to vindicate the rights of our clients.

Allegations of Ghostwriting Central to $289.2 Million Monsanto Roundup Verdict

Monsanto has long maintained that the 2016 glyphosate review in Critical Reviews in Toxicology was independent, and the original Declaration of Interest underscored the company’s claim:

“The Expert Panelists were engaged by, and acted as consultants to, Intertek, and were not directly contacted by the Monsanto Company. Funding for this evaluation was provided to Intertek by the Monsanto Company which is a primary producer of glyphosate and products containing this active ingredient. Neither any Monsanto company employees nor any attorneys reviewed any of the Expert Panel’s manuscripts prior to submission to the journal.”

But according to internal company documents obtained during the discovery phase of the Monsanto Roundup litigation, it is evident that “An Independent Review of the Carcinogenic Potential of Glyphosate” was anything but independent.

Allegations of ghostwriting scientific literature on glyphosate and Roundup were presented in the first Monsanto Roundup lawsuit to proceed to trial. The suit, filed by former California groundskeeper, Dewayne “Lee” Johnson, culminated in a $289.2 million verdict last month against Monsanto.

Internal company documents that are now part of the Monsanto Papers show that Monsanto scientist and executive William Heydens did not just review the glyphosate review; Heydens actually drafted and edited the work without disclosing his or his company’s involvement.

In an email communication between Heydens and Dr. Ashley Roberts, Heydens wrote:

“OK, I have gone through the entire document and indicated what I think should stay, what can go, and in a couple spots I did a little editing. I took a crack at adding a little text: on page 10 to address John’s comments about toxicologists’ use of Hill’s criteria…”

Heydens also argued with one of the paper’s authors, Dr. John Acquavella, about statements he wanted to include about IARC. In the comments of a draft of the paper, Acquavella deemed the statements “inflammatory” and “not necessary,” to which Heydens said, “I would ignore John’s comment.”

During a deposition, Heydens admitted that draft manuscripts of the glyphosate review were sent to him, and that he read “parts of them” before the paper was published. When asked whether or not he made dozens of edits to the manuscript, Heydens said, “I don’t recall.”

“Although I’m glad the journal is now on record finding that they were misled when publishing these articles, a retraction is more than warranted for this situation,” said Nathan Donley, a senior scientist at the Center for Biological Diversity. Donley was one of four scientists to send a letter to the editors of Critical Reviews in Toxicology last year asking for a retraction.

“Furthermore, the journal appears to be allowing the phrase ‘an independent review’ to remain in the title of the issue. There is nothing independent about this review by any stretch of the imagination.”

Reviews Updated with New Acknowledgments and Declaration of Interest Sections

Several of the authors issued apologies in the updated Declaration of Interest sections of three of the five review papers, including:

  • Keith R. Solomon (has worked as consultant for Monsanto)
  • David Brusick (has worked as consultant for Monsanto)
  • Marilyn Aardema
  • Larry Kier (has worked as consultant for Monsanto)
  • David Kirkland (has worked as consultant for Monsanto)
  • Gary Williams (has worked as consultant for Monsanto)
  • John Acquavella (former Monsanto employee, has worked as consultant for Monsanto)
  • David Garabrant
  • Gary Marsh
  • Tom Sorahan (former Monsanto employee, has worked as consultant for Monsanto)
  • Douglas L. Weed (has worked as consultant for Monsanto)

2003 De Roos Pesticide Non-Hodgkin’s Lymphoma Study

In this study, researchers analyzed data that was originally gathered by the National Cancer Institute (NCI) in the 1980s. As part of its investigation into the association between pesticide exposure and non-Hodgkin’s lymphoma in men, the NCI conducted three case control studies; one in Nebraska, one in Iowa and Minnesota, and one in Kansas. In case control studies, individuals with a disease, the cases, are compared to subjects without the disease, the controls. The goal is to determine if the cases were exposed to certain substances much more frequently than the controls. Researchers can use the data to estimate how much exposure to the substance increases the risk of acquiring the disease.

De Roos and his group, which included a number of scientists who had been involved in the three original studies, wanted to explore the effect of exposure to multiple pesticides (the pesticide group includes insecticides and herbicides like Roundup) on NHL risk. The researchers analyzed data from 870 cases and 2,569 controls. Men in both groups were interviewed about their exposure to agricultural pesticides and other risk factors for NHL. Forty-seven insecticides and herbicides were examined.

De Roos reported that nine pesticides, including glyphosate, were associated with increased incidence of non-Hodgkin’s lymphoma. It is significant that only nine of the 47 pesticides were linked to NHL. This, says De Roos, suggests that the findings for these pesticides were not simply the result of recall bias (inaccuracies in the recall of the subjects interviewed) or bias related to the selection of the 47 pesticides analyzed in the study. In other words, the association of these nine pesticides with NHL did not just happen by chance or because of a fault with the way the study was conducted. The high toxicity of these pesticides can be seen in the fact that four of them (fonofos, chlordane, dieldrin and copper acetoarsenite) have since been banned in the United States. A fifth, diazinon, used to be a popular insecticide, but can no longer be purchased by consumers due its health risks to humans, particularly children. Yet another (atrazine) was banned in the European Union. This is the exclusive “club” of which glyphosate was discovered to be a member.

When De Roos restricted her analysis to just these nine “potentially carcinogenic” pesticides, she discovered a significant trend. The more of these pesticides a subject used, the more the NHL incidence increased. Subjects who used five or more of the nine pesticides were “twice as likely to be NHL cases than controls.” It turned out that glyphosate was a special ingredient in this “stew” of highly toxic pesticides. When De Roos removed it and repeated the analysis with just eight pesticides, the trend towards increasing NHL incidence when an increased number of pesticides was used disappeared.

De Roos makes an important point at the conclusion of this study. For regulatory purposes, government agencies necessarily focus on pesticides individually. But risks to the public are often amplified by exposure to multiple pesticides. Protecting public health must involve an assessment of pesticides not just individually, but as they are used in possible combination with other pesticides.

Summary Information

Title
Integrative assessment of multiple pesticides as risk factors for non-Hodgkin’s lymphoma among men

Authors
A J De Roos1, S H Zahm1, K P Cantor1, D D Weisenburger2, F F Holmes3, L F Burmeister4, A Blair1

  1. Division of Cancer Epidemiology and Genetics, National Cancer Institute, USA
  2. University of Nebraska Medical Center, Omaha, NE, USA
  3. Kansas University Medical Center, Kansas City, KS, USA
  4. University of Iowa College of Medicine, Iowa City, IA, USA

Journal
Occupational and Environmental Medicine and Chemical Toxicology; 60 (9), September 2003

HOW MONSANTO MANIPULATED THE SYSTEM

Newly-released emails written by executives at Monsanto Co. show that Monsanto employees ghostwrote articles for independent scientists. Leading up to a regulatory hearing on the safety of glyphosate, Monsanto employees were looking for scientific studies showing that Roundup is safe.

Monsanto executive William “Bill” Heydens, Regulatory Product Safety Assessment Lead, instructed his staff to ghostwrite portions of a scientific article, planning to have scientists “just sign their names” to the study.

“Monsanto tells us that Roundup is safe because scientists say it is safe.  But apparently scientists sign their names, while Monsanto signs the checks,” says Kara Cook-Schultz, Toxics Director at U.S. PIRG. “This calls into question multiple studies written, or possibly ghostwritten, by agricultural scientists.”

Click here to see the actual unsealed documents with Heyden’s brazen ghost-writing plan.

 

Also included in the email chain is evidence showing that Monsanto regularly works together with other international chemical companies—such as Syngenta and Dow—to publish scientific papers. Christophe Gustin, Monsanto’s Crop Protection Regulatory Affairs Lead at Monsanto Europe, asked for Syngenta and Dow’s sign-off prior to hiring a scientist to publish the results of internal, unpublished studies on Roundup.

Court records show that Monsanto was tipped off by the US EPA, of a determination  by the International Agency for Research on Cancer, part of the World Health Organization, that glyphosate was a probable carcinogen. The WHO cited direct research linking glyphosate to non-Hodgkin’s lymphoma. The unreleased study results and findings were illegally handed over to Monsanto by US EPA deputy division director Jess Rowland as soon as it came across his desk. That led the company to prepare a public relations assault on the finding well in advance of its publication. Monsanto executives, in their internal email traffic, also said Mr. Rowland had promised to beat back an effort by the Department of Health and Human Services to conduct its own review.

People should know that there are superb scientists in the world who would disagree with Monsanto and some of the regulatory agencies’ evaluations, and even E.P.A. has disagreement within the agency

People should know that there are superb scientists in the world who would disagree with Monsanto and some of the regulatory agencies’ evaluations, and even E.P.A. has disagreement within the agency.

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