(Mass Tort Nexus Media) Bayer and Johnson & Johnson both issued press releases on March 25th indicating to the public, as well as stockholders and analysts, that the companies had reached a settlement to resolve approximately 25,000 claims related to Xarelto. This announcement was arguably highly misleading, in that the agreement reached has not actually resulted in the settlement of a single Xarelto lawsuit (to the best of our knowledge) and certainly not 25,000 cases.
At the time of press release, in which Bayer and Johnson & Johnson led the public and the market to believe they had resolved (settled) 25,000 pending Xarelto lawsuits, the overwhelming majority of firms representing those 25,000 clients had yet to receive significant details related to the proposed settlement, and of course had yet to present any offer to their individual clients, who would have to accept any offer made before a case could actually be settled.
Law Firms attending the Mass Torts Made Perfect conference in Las Vegas last week received more details related to the defendants proposed settlement and the reaction was not positive.
Large Scale Rejection of Proposed Settlement?
Mass Tort Nexus has spoken with a great a number of firms who were in attendance at MTMP, as well as numerous others since that time, and the clear indication that we have received would lead us to the conclusion that it is highly unlikely that the defendants proposed settlement will be accepted by enough firms (or rather their clients), to make going forward with the current proposed settlement anything other than a waste of time.
Law Firms that have been in contact with Mass Tort Nexus have indicated that they will fulfill their duty to present any offer made by defendants for their cases to the individual clients; however, they will not likely recommend that clients accept the offers made under the proposed settlement scheme. Many of the firms made colorful comments that we will not publish; however, there was a common theme among the comments:
“I would feel like I was selling out my clients if I recommend they accept the current offer the defendants have made.”
Others went as far as to say:
“I think it would be malpractice to recommend that clients accept the final amounts likely to be offered in this settlement scheme”
Dilemma for Bayer and Johnson & Johnson
The premature and arguably misleading public announcement, which would likely be considered official stock holder guidance, may create additional problems for the corporations already plagued by legal woes, which pose risks to their respective stock prices and stock holder value. If the proposed Xarelto settlement does fall through, as it appears will likely be the case, the companies will be faced with having to walk back previous positive news “We have resolved the risk associated with the Xarelto litigation” to “not only have we not resolved the risk associated with the Xarelto litigation, but that risk may now be more significant than it was before we proposed a settlement, and many plaintiffs firms see it as more of an insult than an offer.”
If the proposed settlement was even close to something plaintiffs might except in significant numbers, Bayer and J&J might have been in a position to “tweak the settlement” and avoid having to deliver bad news to their stockholders and the public. Unfortunately for Bayer and J&J, the proposed settlement seems to be so far from “acceptable” that their only option may be to scrap the current proposed settlement and come back with another proposal, that will not be received with such strong resistance. If the two corporate giants have any hope of salvaging their messaging to the market, they will need to act quickly.
Proposed Settlement Appears to be a “Non-Starter”
For now, it appears that there is no amount of lipstick that would make the proposed Xarelto settlement scheme attractive. Most of the firms Mass Tort Nexus has spoken to have indicated that the defendants offer is not even a starting point.
MTN will provide more information in future articles about the proposed settlement, as well as the reasons a large number of firms do not feel the settlement is fair and just to their clients. At this point in time; however, it seems likely that the proposed Xarelto settlement is:
[4-9-2019] The U.S. Food and Drug Administration (FDA) has received reports of serious harm in patients who are physically dependent on opioid pain medicines suddenly having these medicines discontinued or the dose rapidly decreased. These include serious withdrawal symptoms, uncontrolled pain, psychological distress, and suicide.
While we continue to track this safety concern as part of our ongoing monitoring of risks associated with opioid pain medicines, we are requiring changes to the prescribing information for these medicines that are intended for use in the outpatient setting. These changes will provide expanded guidance to health care professionals on how to safely decrease the dose in patients who are physically dependent on opioid pain medicines when the dose is to be decreased or the medicine is to be discontinued.
Rapid discontinuation can result in uncontrolled pain or withdrawal symptoms. In turn, these symptoms can lead patients to seek other sources of opioid pain medicines, which may be confused with drug-seeking for abuse. Patients may attempt to treat their pain or withdrawal symptoms with illicit opioids, such as heroin, and other substances.
Opioids are a class of powerful prescription medicines that are used to manage pain when other treatments and medicines cannot be taken or are not able to provide enough pain relief. They have serious risks, including abuse, addiction, overdose, and death. Examples of common opioids include codeine, fentanyl, hydrocodone, hydromorphone, morphine, oxycodone, and oxymorphone.
Health care professionals should not abruptly discontinue opioids in a patient who is physically dependent. When you and your patient have agreed to taper the dose of opioid analgesic, consider a variety of factors, including the dose of the drug, the duration of treatment, the type of pain being treated, and the physical and psychological attributes of the patient. No standard opioid tapering schedule exists that is suitable for all patients. Create a patient-specific plan to gradually taper the dose of the opioid and ensure ongoing monitoring and support, as needed, to avoid serious withdrawal symptoms, worsening of the patient’s pain, or psychological distress (For tapering and additional recommendations, see Additional Information for Health Care Professionals).
Patients taking opioid pain medicines long-term should not suddenly stop taking your medicine without first discussing with your health care professional a plan for how to slowly decrease the dose of the opioid and continue to manage your pain. Even when the opioid dose is decreased gradually, you may experience symptoms of withdrawal (See Additional Information for Patients). Contact your health care professional if you experience increased pain, withdrawal symptoms, changes in your mood, or thoughts of suicide.
We are continuing to monitor this safety concern and will update the public if we have new information. Because we are constantly monitoring the safety of opioid pain medicines, we are also including new prescribing information on other side effects including central sleep apnea and drug interactions. We are also updating information on proper storage and disposal of these medicines that is currently available on our Disposal of Unused Medicines webpage.
To help FDA track safety issues with medicines, we urge patients and health care professionals to report side effects involving opioids or other medicines to the FDA MedWatch program, using the information in the “Contact FDA” box at the bottom of the page.
“Fentanyl Spray Federal Criminal Trial” Now In US District Court of Massachusetts Jury Deliberations
By Mark A. York (April 8, 2019)
December 2016 saw Insys Therpaeutics Founder John Kapoor, CEO Michael Babich and five other senior executives indicted on criminal charges for paying kickbacks and bribes to medical professionals and committing fraud against insurance companies across the country for offering a highly addictive Fentanyl prescription product “Subsys” to the masses. The Insys boardroom was indicted in the US District Court of Massachusetts, where the entire team has engaged a stable of top national law firms to defend the indictments. The “Subsys” sales teams were charged in federal indictments across the country, including Arkansas, Connecticut, Alaska and New York and the indictments will only increase as these cases proceed and “cooperating witnesses” decide that prison isn’t an option.
To compound further harsh scrutiny for Insys, it’s new CEO Saeed Motahari, moved over from Purdue Pharmaceuticals, the Oxycontin maker, who’s also a major target of criminal and civil investigations across the country by various agencies. Purdue is being investigated for false marketing, off-label use and ignoring Oxycontin’s highly addictive dangers for years, while bringing in literally billions of dollars in profits.
PRIOR DOCTOR INDICTMENTS
Doctors who’ve written massive numbers of Subsys prescription, under the “fee to speak” program have been indicted and they include pain clinics, medical centers and other healthcare facilities who now face federal criminal charges for fraudulent prescription writing, submitting false claims to insurance companies and numerous other federal charges and all face a minimum of 20 to 50 years in federal prison. Two of the busiest “Subsys” prescription writers in the country were Alabama doctors, John Couch and Xiulu Ruan, who earned over $40 million from Insys, and were charged with running a pill mill between 2013 and 2015, have been convicted and sentenced to 20 years each in federal prison.
The top “Subsys” prescriber of all, Dr. Gavin Awerbach, of Saginaw, MI pled guilty to defrauding Medicare and Blue Cross out of $3.1 million in improper Subsys prescriptions, his criminal sentence is pending. To show the far reach of Insys and its corporate plans to saturate the US market with opioids, in Anchorage, Alaska Dr. Mahmood Ahmad, was charged with a massive Subsys prescribing operation, which he denies, but immediately surrendered his Alaska medical license which caused the revocation of his license Arkansas.
THE OFF LABEL CAMPAIGN
The only people who are supposed to be taking Subsys are adult cancer patients, according to the FDA “Subsys” approval files, anything other than that is an “off label” indication. Now you can take a drug to treat something off label if you want to, but you have to get your doctor to get pass a prior authorization.
Anthem alleges that Insys has an entire unit to get around this requirement — it’s titled the “reimbursement unit.” Investigative journalists exposed this fraud initially as far back as 2015 on behalf of the Southern Investigative Reporting Foundation, see Insys Therapeutics “Subsys” Off Label Rx Fraud.
The Reimbursement Unit claim was basically the company’s fraudulent prescription approval factory, which helped participating doctors process claims (the doctors had so many they couldn’t handle them all). The unit falsified records to show patients had cancer and called insurers, pretending to be patients or other medical professionals, to facilitate approval of payment for off-label treatment.
This is the Unit’s script for obtaining off-label approval (taken from the Anthem suit):
The script read: “The physician is aware that the medication is intended for the management of breakthrough pain in cancer patients. The physician is treating the patient for their pain (or breakthrough pain, whichever is applicable).” The script deliberately omitted the word “cancer as applied to the patient treatment under discussion.”
Prosecutors also said that two former Insys employees who were first charged in 2016 in connection with the scheme, Jonathan Roper and Fernando Serrano, had secretly pleaded guilty and become cooperating witnesses. The five doctors were arrested last Friday morning and face charges including that they violated the federal anti-kickback law and conspired to commit fraud.
INSYS RX ABUSES WERE BLATANT
The case is the latest in a series of medical practitioners and former Insys executives and employees facing criminal charges related to Subsys, the company’s potentially addictive fentanyl-based spray.
Federal prosecutors in Boston are moving forward aggressively against the seven former Insys executives and managers as well billionaire founder John Kapoor, all accused of actively designing and participating in the scheme to bribe doctors to prescribe Subsys and to defraud insurers into paying for it. Insys has said it may need to pay at least $150 million towards part of a settlement with the U.S. Justice Department as well as numerous other state investigations around the country, not to mention the civil complaints filed against the company in the Opiate Prescription MDL 2804, see OPIOID-CRISIS-BRIEFCASE-INCLUDING-MDL-2804-OPIATE-PRESCRIPTION-LITIGATION, where the Insys sales and marketing tactics are listed as prime examples of boardroom designed “profits over patients” policies are cited.
Insys is joined in the massive Federal Opioid MDL 2804, by other Big Pharma defendants including Purdue Pharmaceuticals, Endo Health, J&J’s Janssen Pharmaceutical and other opioid manufacturers who were allowed to place profits over patients for more than 15 years, while earning billions in profits.
UNETHICAL SALES TACTICS
According to the most recent and prior doctor indictments, the physicians have participated in Insys’ speaker programs, which were in reality social gatherings at high-end restaurants. They earned kickbacks ranging from $68,000 and $308,000 and were among the top 20 prescribers of Subsys nationwide at some point during the marketing campaign. A few doctors indicted as far back as late 2016 have already been sentenced to federal prison terms up to 20 years and forfeit of millions of dollars in assets. The Insys marketing tactics included trips with doctors to strip clubs with Insys sales managers; and often with Insys executives, where they covered lap dances and drinks which on one trip ran up a tab of over $4,100 which was apparently enough to convince physicians to write massive numbers of off-label fentanyl prescriptions.
The Criminal Trial Status
A cooperating witness testified by calling the payments bribes, a former vice president of Insys Therapeutics stood by a giant spreadsheet in court Tuesday and described how the drug company funneled phony “speaking fees” to doctors in exchange for prescribing its highly addictive opioid painkiller.
Alec Burlakoff, who has pleaded guilty to racketeering charges and is testifying in US District Court in Boston against Insys founder John N. Kapoor and four former colleagues, said Kapoor encouraged the program in late 2012 to spur doctors to prescribe Subsys, an under-the-tongue fentanyl spray.
But Kapoor insisted that each practitioner generate at least twice as much revenue for Insys by writing Subsys prescriptions than he or she received from the company.
Burlakoff stood next to an enlarged spreadsheet that executives prepared in December 2012. One column showed what each “speaker” received every time he or she supposedly met with other doctors to promote Subsys. The amounts ranged from $1,000 to $1,600 to $2,400 depending on whether Insys designated them local, regional, or national experts.
In truth, he said, the designation “national expert” was ludicrous and some doctors had only sordid reputations for running “pill mills.”
Another column showed how many prescriptions the practitioners wrote for Subsys, while another displayed how many they wrote for competing fentanyl products.
Assistant US Attorney Fred Wyshak Jr. asked Burlakoff what another column listing sums of money represented.
“That’s the amount of money we paid in bribes to date,” said Burlakoff, the former vice president of sales, prompting one of the defense lawyers for the five defendants to object.
Kapoor and four other former executives of the Chandler, Ariz.-based company are on trial for allegedly conspiring to violate the federal criminal Racketeer Influenced and Corrupt Organizations Act, or RICO, by paying bribes and kickbacks to practitioners. Prosecutors typically use RICO to go after alleged mobsters.
It is the first criminal trial of pharmaceutical executives who marketed an opioid painkiller since the nation’s deadly opioid epidemic began.
Burlakoff, whom jurors first saw last month dressed as a bottle of Subsys spray in a jaw-dropping in-house rap video, said that at least one executive strenuously objected to the company tracking how many Subsys prescriptions participants in the speakers program wrote.
Matthew Napoletano, Insys’s former head of marketing, who has already testified under immunity for the government, rose from his chair at a meeting with Kapoor, Burlakoff, and other executives, Burlakoff said. Napoletano said such a spreadsheet could be viewed as evidence of a crime.
But the company went forward with the payment program.
The payments were hardly the only way Insys prodded doctors to write Subsys prescriptions, Burlakoff said. Leaders of the sales team, including Joseph Rowan, a former regional sales director who is among the defendants, would buy coolers full of steaks for doctors, according to Burlakoff.
In other cases, he said, Insys executives would put staffers in the offices of big Subsys prescribers on the payroll of the drug company; those staffers were often spending considerable time on the phone with insurers trying to get them to approve Subsys prescriptions, and “now doctors would no longer be complaining” about the expense of paying those employees to do that.
Burlakoff, who became vice president of sales in 2012 after spending years at Cephalon, Eli Lilly and Company, and other drug makers, said Insys didn’t only provide incentives to physicians; the company also gave incentives to members of the sales team.
Sales representatives at Insys, he said, had a starting salary of $40,000 a year, less than half of what such employees typically made at other drug companies. But they received an extraordinary commission of 10 percent on the sales they made each quarter, and it wasn’t capped.
Several sales representatives, he said, made $110,000 in a quarter based just on the commission.
As part of the boardroom strategy to get doctors to prescribe Subsys, Insys spent millions paying them off through a fraudulent “speakers program” meant to educate medical professionals about the drug. The speaking engagements were a veiled attempt to cover-up the direct payment to doctors for writing prescriptions, the more prescriptions you wrote, the higher your “speaking fees” increased. There are e-mails, texts and other Insys communications from all levels of company personnel stating “if they not writing prescription, they’re off the speaking program”, this policy resulted in one Alabama sales rep being paid over $700 thousand in Subsys based Rx commissions for one year, while her base salary was $40 thousand.
SALES REP NATALIE REED PERHAC
In the plea, Perhacs admitted that she was hired to be the personal sales representative for one of Insys’s most important prescribers, Dr. Xiulu Ruan. Ruan is one of two Alabama doctors who picked up over $115,000 in speaker fees from 2012 to 2015, and earned in excess of $40 million in related medical earnings during the same period. Earlier this year they were sentenced to 20 years in jail each for running a “pill mill” and helping Insys sales rep Natalie Reed Perhacs sell Subsys, for which she was paid in excess of $700 thousand in commissions, see Perhac Guilty Plea in Alabama Federal Court.
Perhac Plea Excerpts:
Admision No. 78: . Perhacs admitted that her primary responsibility at Insys was to increase the volume of Subsys® prescribed by Dr. Ruan, and his partner Dr. John Patrick Couch. This… was accomplished by (1) handling prior authorizations for their patients who had been prescribed Subsys®; (2) identifying patients who had been at the same strength of Subsys® for several months and recommending that Dr. Ruan or Dr. Couch increase the patients’ prescription strength; and (3) setting up and attending paid speaker programs.
Admission No. 79:. Ms. Perhac admitted that because of her involvement in the prior authorization process, she knew that the vast majority of Dr. Ruan and Dr. Couch’s patients did not have breakthrough cancer pain.
As you can see by the Perhac admissions, numbers 78 and 79, which reflect the vast number of charges lodged against her, the federal government is cracking down on everyone involved with the “Subsys” fraud. According to confidential sources, the recent June 2017 FDA “Opioid Crisis” Conference and related strategic review of the opioid crisis, will result in many more indictments and charges against drug makers and the medical providers who’ve helped facilitate the opioid epidemic that is currently in place across the United States.
How the results of the trail against the Insys Therapeutics boardroom plays out in the overall “Opioid Crisis” battle remains to be seen. There is always the question of why the Sackler family (Purdue Pharma) and the billions they’ve earned off improper marketing of Oxycontin and their scorched earth sales tactics, have not resulted in criminal indictments yet? Perhaps the Sackler family habit of donating billions to charities and having hospital wings named in their honor was a very strategic and forward looking business model that is now paying great dividends.
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
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 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.
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.
Statement from FDA Commissioner Scott Gottlieb, M.D., on new steps to strengthen the long-term safety oversight of the Essure device following discontinuation of its U.S. sales
For Immediate Release
December 20, 2018
When new safety concerns arise for particular devices, we’re committed to taking action to develop post-market information that can help patients and providers make more informed decisions and also support regulatory actions that reduce any potential risks to patients. We’ve taken a series of such steps with respect to Essure, a permanent birth control device. The product has been the focus of several important FDA safety actions. We’re announcing some additional steps today to make sure the FDA continues to evaluate the product’s long-term safety profile past its scheduled discontinuation from the U.S. market following a series of earlier regulatory actions that we took apply significant new requirements on its use. This includes the agency’s decision to take the step of making Essure a restricted device.
In July, citing the declining annual number of implantations, the manufacturer of the device, Bayer, announced that Essure will no longer be sold or distributed in the U.S. after Dec. 31, 2018. At that time, I stressed that, even when Essure is no longer sold, the FDA would remain vigilant in its oversight of the device. This includes requiring that Bayer complete the postmarket surveillance study that we ordered in February 2016. I also affirmed that we’d continue to actively communicate with patients and physicians as new information about the device becomes available or as the FDA takes additional regulatory steps.
Today, I’m providing an update on new steps to revise and strengthen the manufacturer’s postmarket study, to make sure we continue to collect long-term safety information following the discontinuation of the product to better evaluate the safety profile of the device when used in the real world.
First and foremost, women in the study will be followed for five years, rather than the three years that was initially required. This significant extension follows the FDA’s request that the company go beyond the three-year period provided for by law. 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.
Second, we’re requiring 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 whether these findings are associated with symptoms that patients have reported related to Essure.
The FDA is also requiring Bayer to continue to enroll patients who might still opt to receive Essure in advance of its full discontinuation from the U.S. market, and to continue to submit more frequent reports to the FDA on the study’s progress and results. Since FDA’s 2016 decision to order Bayer to conduct the postmarket study and then to add a boxed warning and Patient Decision Checklist to the labeling, sales of Essure declined by 70 percent. Earlier this year, the FDA decided to restrict the sale and distribution of the device to only health care providers and facilities that provide information to patients about the risks and benefits of this device and that give patients the opportunity to sign an acknowledgement of understanding before implantation. In view of this decline in sales and the manufacturer’s decision to discontinue sales and distribution at the end of this year, we recognize that Bayer is having challenges reaching the study’s initial sample size that relied on enrolling patients who were newly implanted with Essure until May 2020. We believe that this new, revised study plan will help provide more long-term information regarding complications that may be experienced by patients who have Essure, despite reduced enrollment.
For the past several years, the FDA has been monitoring the progress of an Essure post-approval study that was mandated to gather long-term data on pregnancies occurring in patients who may have received a transvaginal ultrasound in order to confirm that Essure was properly placed in a woman’s fallopian tubes and could be relied upon to prevent pregnancy. The FDA’s Center for Devices and Radiological Health conducted an analysis of an ongoing post-approval study data to gain a fuller understanding of device removals over time; they also completed their extensive evaluation into a significant collection of medical device reports submitted in 2017 and the first half of 2018 that mentioned issues involving potential device removal to learn more about why women were choosing to have the device removed, which usually requires a surgical procedure. CDRH also spent the past several months actively evaluating more than 15,000 medical device reports submitted to FDA in 2017 through June 2018 on the Essure device. (The majority of these reports referenced an instance in which the device was removed from a patient, and most came from cases that were made available by plaintiff attorneys as part of litigation against the manufacturer Bayer.) CDRH is providing some important new information about the removals of the Essure device learned from this analysis on our website.
Based on this information, the FDA instructed Bayer to extend the postmarket surveillance study from three years to five years to capture longer term information about device removals. We believe it’s important to continue closely monitoring device removals in the postmarket surveillance study to gain greater knowledge of this issue.
Following Essure’s removal from the market, the FDA is committed to continuing to monitor women who have the device implanted. In addition to the post-market surveillance study, the agency will continue its efforts to monitor Essure’s safety and effectiveness since its approval in 2002 by reviewing the medical literature, clinical trial information, post-approval study data and medical device reports submitted to the agency. This follows previous actions the FDA has taken, including requiring Bayer to add a boxed warning to the labeling of Essure and issue a Patient Decision Checklist to help women considering Essure to be fully informed about potential risks and the sales restriction that FDA placed on the product.
I personally had the opportunity to meet with women who have been adversely affected by Essure to listen and learn about their concerns. Some of the women I spoke with developed significant medical problems that they ascribe to their use of the product. We remain committed to these women and to improving how we monitor the safety of medical devices, including those related to women’s health.
We’re also advancing new ways to solidify our monitoring systems to achieve our new goal to consistently be the first among the world’s regulatory agencies to identify and act upon safety signals related to medical devices.
As we announced when we issued our Medical Device Safety Action Plan in April, we’re working to implement an active surveillance system to help us detect device safety signals faster, including for devices related to women’s health. We’re implementing active surveillance capabilities as part of our National Evaluation System of health Technology, which will leverage a wide range of data systems that could provide real-time information on device safety signals from electronic health information, such as registries and electronic medical records. We’re also continuing our ongoing efforts to strengthen our Coordinated Registry Networks (CRN), which link different real-world data sources to generate clinical evidence about medical devices used by patients.
We’re especially focused on addressing clinical questions for device therapies that address conditions that are unique to women, such as treatment of uterine fibroids, pelvic floor disorders, female sterilization (including the Essure device) and long-acting reversible contraception. To advance these goals, the FDA partnered with the American College of Obstetricians and Gynecologists, the American Urogynecologic Society, the National Library of Medicine and others on this effort, which is known as the Women’s Health Technologies CRN, or WHT-CRN. Once fully implemented, the WHT-CRN can be used to answer crucial questions on medical devices for women’s health to help supplement the evidence we’re gathering from postmarket studies and medical device reports. It could also help us detect safety issues with medical devices faster, enabling us to take actions — like the implementation of special controls — sooner.
We believe women who’ve been using Essure successfully to prevent pregnancy can and should continue to do so. Women who suspect the device may be related to symptoms they are experiencing, such as persistent pain, should talk to their doctor on what steps may be appropriate. Device removal has its own risks. Patients should discuss the benefits and risks of any procedure with their health care providers before deciding on the best option for them. The FDA will continue to collect and review reports of adverse events associated with device removal and is committed to continuing to provide updates on our evaluation of this data as the information is collected and we develop new findings about the device.
The U.S. Food and Drug Administration (FDA) inspected your drug manufacturing facility, Zhejiang Huahai Pharmaceutical Co., Ltd., located at Coastal Industrial Zone, Chuannan No. 1 Branch No. 9, Donghai Fifth Avenue, Linhai, Taizhou Zhejiang, from July 23 to August 3, 2018.
This warning letter summarizes significant deviations from current good manufacturing practice (CGMP) for active pharmaceutical ingredients (API).
Because your methods, facilities, or controls for manufacturing, processing, packing, or holding do not conform to CGMP, your API are adulterated within the meaning of section 501(a)(2)(B) of the Federal Food, Drug, and Cosmetic Act (FD&C Act), 21 U.S.C. 351(a)(2)(B).
We reviewed your August 26, 2018, response in detail and acknowledge receipt of your subsequent correspondence.
During our inspection, our investigators observed specific deviations including, but not limited to, the following.
Failure of your quality unit to ensure that quality-related complaints are investigated and resolved.
Your firm received a complaint from a customer on June 6, 2018, after an unknown peak was detected during residual solvents testing for valsartan API manufactured at your facility. The unknown peak was identified as the probable human carcinogen N-nitrosodimethylamine (NDMA). Your investigation (DCE-18001) determined that the presence of NDMA was caused by the convergence of three process-related factors, one factor being the use of the solvent (b)(4)). Your investigation concluded that only one valsartan manufacturing process (referred to as the (b)(4) process in your investigation) was impacted by the presence of NDMA.
However, FDA analyses of samples of your API, and finished drug product manufactured with your API, identified NDMA in multiple batches manufactured with a different process, namely the (b)(4) process, which did not use the solvent (b)(4). These data demonstrate that your investigation was inadequate and failed to resolve the control and presence of NDMA in valsartan API distributed to customers. Your investigation also failed:
To include other factors that may have contributed to the presence of NDMA. For example, your investigation lacked a comprehensive evaluation of all raw materials used during manufacturing, including (b)(4).
To assess factors that could put your API at risk for NDMA cross-contamination, including batch blending, solvent recovery and re-use, shared production lines, and cleaning procedures.
To evaluate the potential for other mutagenic impurities to form in your products.
Our investigators also noted other examples of your firm’s inadequate investigation of unknown peaks observed in chromatograms. For example, valsartan intermediates (b)(4) and (b)(4) failed testing for an unknown impurity (specification ≤ (b)(4)%) with results of (b)(4)% for both batches. Your action plan indicated that the impurity would be identified as part of the investigation; however, you failed to do this. In addition, no root cause was determined for the presence of the unknown impurity. You stated that you reprocessed the batches and released them for further production.
Your response states that NDMA was difficult to detect. However, if you had investigated further, you may have found indicators in your residual solvent chromatograms alerting you to the presence of NDMA. For example, you told our investigators you were aware of a peak that eluted after the (b)(4) peak in valsartan API residual solvent chromatograms where the presence of NDMA was suspected to elute. At the time of testing, you considered this unidentified peak to be noise and investigated no further. Additionally, residual solvent chromatograms for valsartan API validation batches manufactured using your (b)(4) process, with (b)(4) in 2012 ((b)(4), and (b)(4)) show at least one unidentified peak eluting after the (b)(4) peak in the area where the presence of NDMA was suspected to elute.
Your response also states that you were not the only firm to identify NDMA in valsartan API. In your case, FDA analyses of samples identified amounts of NDMA in valsartan API manufactured at your firm that were significantly higher than the NDMA levels in valsartan API manufactured by other firms. FDA has grave concerns about the potential presence of mutagenic impurities in all intermediates and API manufactured at your facility, both because of the data indicating the presence of impurities in API manufactured by multiple processes, and because of the significant inadequacies in your investigation.
In response to this letter:
Submit risk assessments for all APIs and intermediates manufactured at your facility for the potential presence of mutagenic impurities.
Provide an update on investigations and CAPA plans initiated to address the presence of NDMA and other potential mutagenic impurities in all APIs manufactured at your firm.
Provide a thorough, independent assessment of your overall system for investigating deviations, discrepancies, out-of-specification (OOS) results, complaints, and other failures. In addition, provide a retrospective review of all distributed batches within expiry to determine if your firm released batches that did not conform to established specifications or appropriate manufacturing standards.
Provide test results for all (b)(4)and intermediates for the presence of NDMA, N-Nitrosodiethylamine (NDEA), and other potentially mutagenic impurities.
Your firm received a customer complaint on September 13, 2016, concerning (b)(4) API batches ((b)(4) and (b)(4)) that exceeded the specification for (b)(4) (≤ (b)(4)ppm). (b)(4) has been classified as a probable human carcinogen. Your customer’s test results conflicted with your (b)(4) test results, which showed the two batches meeting the specification upon release. Your complaint investigation (CC-16008) identified no clear laboratory error, and no anomalies were detected during the production of the batches. Your investigation failed to evaluate other (b)(4) API batches to determine if the presence of excess (b)(4) was an adverse trend. For example, (b)(4)batches (b)(4), and (b)(4) were OOS for (b)(4) because of production errors; however, they were not discussed in your complaint investigation.
Your response states that (b)(4) API batches (b)(4) and (b)(4) were returned, reprocessed, and released to customers in non-U.S. markets.
Your response also states that in August 2017 you implemented a new (b)(4) test method that uses a (b)(4) LC-MS/MS method, to replace the (b)(4) LC-MS method that was prone to erroneous OOS results. You failed to verify the reliability of the (b)(4) results for all (b)(4) API batches (including (b)(4) batch (b)(4)) originally released using your (b)(4) LC-MS method, which you indicated was inferior to your updated method.
In response to this letter, provide:
A risk assessment for all (b)(4) API batches manufactured within expiry.
A revised complaint handling procedure and details of any further controls your facility has implemented to ensure that all complaints are adequately documented and thoroughly investigated.
Procedures for accepting and reprocessing returned drugs.
Results of (b)(4) testing of all (b)(4)API batches released to the U.S. market using your updated (b)(4) LC-MS/MS (b)(4) test method.
Failure to evaluate the potential effect that changes in the manufacturing process may have on the quality of your API.
In November 2011 you approved a valsartan API process change (PCRC – 11025) that included the use of the solvent (b)(4). Your intention was to improve the manufacturing process, increase product yield, and lower production costs. However, you failed to adequately assess the potential formation of mutagenic impurities when you implemented the new process. Specifically, you did not consider the potential for mutagenic or other toxic impurities to form from (b)(4) degradants, including the primary (b)(4) degradant, (b)(4). According to your ongoing investigation, (b)(4) is required for the probable human carcinogen NDMA to form during the valsartan API manufacturing process. NDMA was identified in valsartan API manufactured at your facility.
You also failed to evaluate the need for additional analytical methods to ensure that unanticipated impurities were appropriately detected and controlled in your valsartan API before you approved the process change. You are responsible for developing and using suitable methods to detect impurities when developing, and making changes to, your manufacturing processes. If new or higher levels of impurities are detected, you should fully evaluate the impurities and take action to ensure the drug is safe for patients.
Your response states that predicting NDMA formation during the valsartan manufacturing process required an extra dimension over current industry practice, and that that your process development study was adequate. We disagree. We remind you that common industry practice may not always be consistent with CGMP requirements and that you are responsible for the quality of drugs you produce.
Your response does not describe sufficient corrective actions to ensure that your firm has adequate change management procedures in place: (1) to thoroughly evaluate your API manufacturing processes, including changes to those processes; and (2) to detect any unsafe impurities, including potentially mutagenic impurities. For FDA’s current thinking on control of potentially mutagenic impurities, see FDA’s guidance document M7(R1) Assessment and Control of DNA Reactive (Mutagenic) Impurities in Pharmaceuticals To Limit Potential Carcinogenic Risk for approaches that FDA considers appropriate for evaluating mutagenic impurities, at https://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM347725.pdf.
In response to this letter, provide:
Detailed revised change management procedures describing how your firm will assess and control all impurities, including mutagenic impurities, in API and intermediates manufactured at your facility.
Detailed procedures describing how your firm establishes impurity profiles for products manufactured at your firm. These procedures should contain instructions for comparing at appropriate intervals against the impurity profile in the regulatory submission, or for comparing against historical data, to detect changes to the API resulting from modifications in raw materials, equipment operating parameters, or the production process.
A retrospective analysis of other API and intermediates manufactured at your firm to determine if they were adequately evaluated for anticipated and unanticipated impurities, including potentially mutagenic impurities.
CGMP Consultant Recommended
Based upon the nature of the deviations we identified at your firm, we strongly recommend engaging a consultant qualified to evaluate your operations and assist your firm in meeting CGMP requirements. Your use of a consultant does not relieve your firm’s obligation to comply with CGMP. Your firm’s executive management remains responsible for fully resolving all deficiencies and ensuring ongoing CGMP compliance.
FDA considers the expectations outlined in ICH Q7 in determining whether API are manufactured in conformance with CGMP. See FDA’s guidance document Q7 Good Manufacturing Practice Guidance for Active Pharmaceutical Ingredients for guidance regarding CGMP for the manufacture of API, at https://www.fda.gov/downloads/Drugs/…/Guidances/ucm073497.pdf.
Deviations cited in this letter are not intended as an all-inclusive list. You are responsible for investigating these deviations, for determining the causes, for preventing their recurrence, and for preventing other deviations.
If you are considering an action that is likely to lead to a disruption in the supply of drugs produced at your facility, FDA requests that you contact CDER’s Drug Shortages Staff immediately, at email@example.com, so that FDA can work with you on the most effective way to bring your operations into compliance with the law. Contacting the Drug Shortages Staff also allows you to meet any obligations you may have to report discontinuances or interruptions in your drug manufacture under 21 U.S.C. 356C(b) and allows FDA to consider, as soon as possible, what actions, if any, may be needed to avoid shortages and protect the health of patients who depend on your products.
FDA placed your firm on Import Alert 66-40 on September 28, 2018.
Until you correct all deviations completely and we confirm your compliance with CGMP, FDA may withhold approval of any new applications or supplements listing your firm as a drug manufacturer.
Failure to correct these deviations may also result in FDA continuing to refuse admission of articles manufactured at Zhejiang Huahai Pharmaceutical Co., Ltd., located at Coastal Industrial Zone, Chuannan No. 1 Branch No. 9, Donghai Fifth Avenue, Linhai, Taizhou Zhejiang, into the United States under section 801(a)(3) of the FD&C Act, 21 U.S.C. 381(a)(3). Under the same authority, articles may be subject to refusal of admission, in that the methods and controls used in their manufacture do not appear to conform to CGMP within the meaning of section 501(a)(2)(B) of the FD&C Act, 21 U.S.C. 351(a)(2)(B).
After you receive this letter, respond to this office in writing within 15 working days. Specify what you have done since our inspection to correct your deviations and to prevent their recurrence. If you cannot complete corrective actions within 15 working days, state your reasons for delay and your schedule for completion.
WHY THE MOTTO OF “PROFITS BEFORE PATIENTS” IS STILL THE BANNER:
HERE’S A FULL REPORT
By Mark A. York (November 26, 2018)
(MASS TORT NEXUS MEDIA) For years, medical device companies have stated that the products they are developing and placing into the marketplace are safe and helping patients in the USA and worldwide. That is often not the case and people around the world are suffering.
Medical device makers and compensated doctors have touted FDA approved implants and other devices as the surgical cure for millions of patients suffering from a wide range of pain disorders, making them one of the fastest-growing products in the $400 billion medical device industry. Companies and doctors aggressively push them as a safe antidote to the deadly opioid crisis in the U.S. and as a treatment for an aging population in need of chronic pain relief and many other afflictions.
Manufacturer headlines like these instill consumer confidence that medical devices are safe and effective. After all, they have the FDA’s stamp of approval, right? NO!
The reality is, the FDA seldom requires rigorous evidence that a device works well–and safely–before allowing it onto the market. Medical devices are the diverse array of non-drug products used to diagnosis and treat medical conditions, from bandages to MRI scanners to smartphone apps to artificial hips.
This low standard of evidence applies to even the highest risk devices such as those that are implanted in a person’s body. Surgical mesh, pacemakers and gastric weight loss balloons are just a few examples of devices that have had serious safety problems.
Devices are subject to weaker standards than drugs because they’re regulated under a different law. The Medical Device Amendments of 1976 was intended to encourage innovation while allowing for a range of review standards based on risk, according to legal expert Richard A. Merrill. An array of corporate lobbying has since prompted Congress to ease regulations and make it easier for devices to get the FDA’s approval.
In 2011, an Institute of Medicine panel recommended that the “flawed” system be replaced, because it does not actually establish safety and effectiveness. At the time the FDA said it disagreed with the group’s recommendations.
Defective devices cleared through this system have included hip replacements that failed prematurely, surgical mesh linked to pain and bleeding and a surgical instrument that inadvertently spread uterine cancer.
When makers of medical devices learn that one of their products has malfunctioned in a way that could kill or seriously injure people, they are required to file a report with the Food and Drug Administration (FDA). The reports are meant to alert regulators that patients may be in danger.
However, in the future, under a deal the FDA has negotiated with industry lobbyists, manufacturers could generally wait three months before reporting malfunctions, and they could report malfunctions in “summary” form, according to an FDA document.
This 2017 deal apparently means that the government and the public could receive less detailed and less timely warnings.
Jim Taft listened intently as his pain management doctor described a medical device that could change his life, it wouldn’t fix the nerve damage in his mangled right arm, but a spinal-cord stimulator would cloak his pain, making him “good as new.”
Taft’s stimulator failed soon after it was surgically implanted. After an operation to repair it, he said the device shocked him so many times that he couldn’t sleep and even fell down a flight of stairs. Today, the 45-year-old Taft is virtually paralyzed.
“I thought I would have a wonderful life,” Taft said. “But look at me.” Taft is just one of the thousands of patients who have been injured by an implanted medical device, almost always by a device that was made in the USA.
A recent global investigation has found that hundreds of thousands of unsafe medical devices have been implanted in patients around the world and device failures are considered very normal.
A recent worldwide investigation was carried out by the International Consortium of Investigative Journalists (ICIJ) in coordination with the British Medical Journal and various media outlets including the Guardian newspaper and BBC Panorama.
The probe found that pacemakers, artificial knees, hips and rods to support the spinal cord are among the faulty devices that were implanted in patients and that failed. These unsafe medical devices have resulted in thousands of injuries and deaths and quite often patients are forced to undergo removal or revision surgeries.
The investigation found that many of the unsafe medical devices did not complete patient trials before their commercial launch, adding that some of the pacemakers were implanted when the manufacturers were aware of the problems, while some devices were approved on the basis of a regulatory nod secured in other countries.
Poor regulations across countries, lenient testing standards and lack of clarity allowed these faulty medical devices to reach the market.
In the UK alone, the regulators received 62,000 “adverse incident” reports associated with medical devices between 2015 and 2018. About 1,004 of such cases even resulted in the death of patients.
In the USA, the Food and Drug Administration (FDA) has been notified of 5.4 million ‘adverse events’ over the last ten years. Faulty devices were linked to approximately 1.7 million injuries and 83,000 deaths.
Even though these medical devices are made in the USA, the U.S. Food and Drug Administration had not, and still has not, deemed them good enough for Americans. The FDA has permitted sales overseas of unproven devices and products via an obscure FDA provision in which products are registered as an “export only” device, requiring far less FDA scrutiny than for devices that are sold domestically.
An example is PyroTITAN, by Intergra LifeSciences of New Jersey, among the biggest medical device companies in the world and maker of more than a dozen export-only devices with troubled track records identified as “export only” which is a U.S.-made implant for losing weight that instead led to numerous emergency surgeries, stents that could cut into arteries and heart valves sold in Spain and Italy that, according to the FDA, caused severe infections and may have caused a five-year-old child to die. These items were found by analyzing and comparing databases in 10 countries, and a lack of international standards for identifying devices means it is difficult to know how many other troubled devices exist.
For U.S. companies, exporting medical devices is big business, valued last year at more than $41 billion. Currently about 4,600 devices are registered with the FDA as “export only” devices. Several executives for medical device makers said registering the devices is faster, less expensive and has involved less oversight than getting them approved for sale inside the U.S. The troubled devices identified by NBC News have been sold around the world. The destinations range from the Netherlands to Namibia, Chile to Canada, Japan to Germany.
Recently, NBC probed export-only devices as part of the same global project organized by the International Consortium of Investigative Journalists, a news organization notable for its work on the Panama Papers, to examine the medical device industry. More than 250 reporters in 36 countries worked on stories that began publishing Sunday.
Worldwide US Device Exports are Often Substandard
Zimmer Biomet is one of the big medical device companies named in the investigation. The company has previously had to discontinue sales of a metal-on-metal hip implant system which was cause to flesh-rotting via metallosis poisoning. The company seems to have maintained the tried and true Big Pharma mantra of “we do what the FDA requires, therefor we are excluded from accepting responsibility for defective medical products” which is often pushed as a coverall statement by medical device makers when they are under scrutiny.
“We adhere to strict regulatory standard, and work closely with the FDA and all applicable regulatory agencies in each of our regions as part of our commitment to operating a first-rate quality management system across our global manufacturing network.
Abbott has also come under scrutiny for its Nanostim pacemaker, which has received complaints about implant battery failures and parts of the device falling off inside patients. The company released the following statement: “In accordance with the European CE Mark approval process, the Nanostim leadless pacing system was approved based on strong performance and safety data.”
Medical device companies and doctors tout spinal-cord stimulators to treat patients suffering from a wide range of pain disorders. But an investigation by AP found the devices rank third in injury reports to the FDA in 10 years.
But the stimulators — devices that use electrical currents to block pain signals before they reach the brain — are more dangerous than many patients know, an Associated Press investigation found. They account for the third-highest number of medical device injury reports to the U.S. Food and Drug Administration, with more than 80,000 incidents flagged since 2008.
Patients report that they have been shocked or burned or have suffered spinal-cord nerve damage ranging from muscle weakness to paraplegia, FDA data shows. Among the 4,000 types of devices tracked by the FDA, only metal hip replacements and insulin pumps have logged more injury reports.
The FDA data contains more than 500 reports of people with spinal-cord stimulators who died but details are scant, making it difficult to determine if the deaths were related to the stimulator or implant surgery.
An animated look at the spinal cord stimulator, its benefits and potential problems. (AP Animation/Peter Hamlin)
Medical device manufacturers insist spinal-cord stimulators are safe — some 60,000 are implanted annually — and doctors who specialize in these surgeries say they have helped reduce pain for many of their patients.
Most of these devices have been approved by the FDA with little clinical testing and the agency’s data shows that spinal-cord stimulators have a disproportionately higher number of injuries compared to hip implants, which are far more plentiful.
The AP reported on spinal stimulators as part of a year long joint investigation of the global medical devices industry that included NBC, the International Consortium of Investigative Journalists and more than 50 other media partners around the world. Reporters collected and analyzed millions of medical records, recall notices and other product safety warnings, in addition to interviewing doctors, patients, researchers and company whistleblowers.
The media partners found that, across all types of medical devices, more than 1.7 million injuries and nearly 83,000 deaths were reported to the FDA over the last decade.
The investigation also found that the FDA — considered by other countries to be the gold standard in medical device oversight — puts people at risk by pushing devices through an abbreviated approval process, then responds slowly when it comes to forcing companies to correct sometimes life-threatening products.
Devices are rarely pulled from the market, even when major problems emerge, and the FDA does not disclose how many devices are implanted in the U.S. each year — critical information that could be used to calculate success and failure rates.
The FDA acknowledges its data has limitations, including mistakes, omissions and under-reporting that can make it difficult to determine whether a device directly caused an injury or death, but it rejects any suggestion of failed oversight.
“There are over 190,000 different devices on the U.S. market. We approve or clear about a dozen new or modified devices every single business day,” Dr. Jeffrey Shuren, the FDA’s medical device director said at an industry conference in May. “The few devices that get attention at any time in the press is fewer than the devices we may put on the market in a single business day. That to me doesn’t say that the system is failing. It’s remarkable that the system is working as it does.”
In response to reporters’ questions, the FDA said last week that it was taking new action to create “a more robust medical device safety net for patients through better data.” ″Unfortunately, the FDA cannot always know the full extent of the benefits and risks of a device before it reaches the market,” the agency said. In the last 50 years, the medical device industry has revolutionized treatment for some of the deadliest scourges of modern medicine, introducing devices to treat or diagnose heart disease, cancer and diabetes.
Medical device companies have “invested countless resources — both capital and human — in developing leading-edge compliance programs,” said Janet Trunzo, head of technology and regulatory affairs for AdvaMed, the industry’s main trade association.
At the same time, medical device makers also have spent billions to try to influence regulators, hospitals and doctors.
In the United States, where drug and device manufacturers are required to disclose payments to physicians, the 10 largest medical device companies paid nearly $600 million to doctors or their hospitals last year to cover consulting fees, research, travel and entertainment expenses, according to an AP and ICIJ analysis of data from the Centers for Medicare & Medicaid Services. This figure doesn’t include payments from device manufacturers like Johnson & Johnson and Allergan, which also sell other products.
On top of that, lobbying records show that the top four spinal-cord stimulator manufacturers have spent more than $22 million combined since 2017 to try to influence legislation benefiting their overall business, which includes other medical devices.
Some companies have been fined for bribing physicians, illegally promoting products for unapproved uses and paying for studies that proclaim the safety and effectiveness of their products, according to the joint investigation.
In a 2016 case, Olympus Corp. of the Americas, the largest U.S. distributor of endoscopes and related medical equipment, agreed to pay $623.2 million “to resolve criminal charges and civil claims relating to a scheme to pay kickbacks to doctors and hospitals,” according to the U.S. Justice Department. Olympus said that it “agreed to make various improvements to its compliance program.”
In a case the previous year involving spinal-cord stimulators, Medtronic,Inc. agreed to pay $2.8 million to settle Justice Department claims that the company had harmed patients and defrauded federal health care programs by providing physicians “powerful” financial inducements that turned them into “salesmen” for costly procedures. Medtronic denied wrongdoing. “As a matter of policy, Medtronic does not comment on specific litigation,” the company said in a statement. “We do stand behind the safety and efficacy of our Spinal Cord Stimulators and the strong benefits this technology provides to patients, many of whom have tried all other therapy options to no benefit.”
Some doctors enthusiastically promote spinal-cord stimulators without disclosing to patients they’ve received money from medical device manufacturers. Some experts say doctors are not legally required to disclose such payments, but they have an ethical obligation to do so. Sometimes the money goes to the doctors’ hospitals, and not directly to them.
As for Taft, he said he just wanted to get better, but he has lost hope. “This is my death sentence,” Taft said, stretched out beneath his bed’s wooden headboard on which he’s carved the words “death row.”
“I’ll die here,” he said.
Why Hasn’t The FDA Learned From Past Failures?
A generation ago, tens of thousands of women were injured by the Dalkon Shield, an intrauterine device that caused life-threatening infections. Consumer advocates demanded testing and pre-market approval of medical devices to prevent deaths and injuries associated with defective products.
So in 1976, Congress passed the Medical Device Amendment, a law meant to assure Americans that devices recommended by their doctors would do good and not harm.
“Until today, the American consumer could not be sure that a medical device used by his physician, his hospital or himself was as safe and effective as it could or should be,” President Gerald Ford said when he signed the bill into law.
Charged with carrying out the law, the FDA created three classes of medical devices. High-risk products like spinal-cord stimulators are designated to be held to the most rigorous clinical testing standards. But the vast majority of devices go through a less stringent review process that provides an easy path to market for devices deemed “substantially equivalent” to products already approved for use.
As designed by Congress, that process should have been phased out. Instead, it became the standard path to market for thousands of devices, including hip replacements implanted in tens of thousands of patients that would later be recalled because metal shavings from the devices made some people sick.
The AP found that the FDA has allowed some spinal-cord stimulators to reach the market without new clinical studies, approving them largely based on results from studies of earlier spinal stimulators.
Spinal stimulators are complex devices that send electrical currents through wires placed along the spine, using a battery implanted under the skin. An external remote controls the device.
The four biggest makers of spinal-cord stimulators are Boston Scientific Corp., based in Marlborough, Massachusetts; Medtronic, with headquarters in Ireland and the U.S.; Nevro, in Redwood City, California; and Illinois-based Abbott, which entered the market after its $23.6 billion purchase of St. Jude Medical, Inc.
St. Jude’s application to go to market with its first spinal stimulator contained no original patient data and was based on clinical results from other studies, while Boston Scientific’s application for its Precision spinal-cord stimulator was based largely on older data, though it did include a small, original study of 26 patients who were tracked for as little as two weeks.
Once approved, medical device companies can use countless supplementary requests to alter their products, even when the changes are substantial.
For example, there have been only six new spinal-cord stimulator devices approved since 1984, with 835 supplemental changes to those devices given the go-ahead through the middle of this year, the AP found. Medtronic alone has been granted 394 supplemental changes to its stimulator since 1984, covering everything from altering the sterilization process to updating the design.
“It’s kind of the story of FDA’s regulation of devices, where they’re just putting stuff on the market,” said Diana Zuckerman, president of the National Center for Health Research, who has studied medical devices for nearly 30 years.
Medical device manufacturers have cited multiple industry-funded studies showing the effectiveness of spinal-cord stimulation in the treatment of chronic pain. Experts say treatment is considered successful if pain is reduced by at least half, but not every patient experiences that much pain reduction.
A 2016 study looking at different stimulation systems found “significant evidence” that they were “a safe, clinical and cost-effective treatment for many chronic pain conditions.”
But Zuckerman noted that the more extensive studies came after the devices were being widely used on people. “These patients are guinea pigs,” she said.
FDA said in a statement that it approves, clears or grants marketing authorization to an average of 12 devices per business day and its decisions are “based on valid scientific evidence” that the devices are safe and effective.
Dr. Walter J. Koroshetz, director at the neurological disorders and stroke division at the National Institutes of Health, said trials for medical devices like spinal-cord stimulators are generally small and industry-sponsored, with a “substantial” placebo effect.
“I don’t know of anyone who is happy with spinal-cord technology as it stands,” Koroshetz said. “I think everybody thinks it can be better.”
Every time Jim Taft walked into his pain management doctor’s office, he would glance at the brochures touting spinal-cord stimulators — the ones with pictures of people swimming, biking and fishing.
Inside the exam room, Taft said, his doctor told him the device had been successful for his other patients and would improve his quality of life.
On lifetime worker’s compensation after his right arm was crushed as he was hauling materials for an architectural engineering company, Taft had been seeing the doctor for five years before he decided to get a stimulator in 2014. What finally swayed him, he said, was the doctor’s plan to wean him off painkillers.
Taft said his pain management doctor praised the technology, saying stimulators had improved the quality of life for his patients. But four years later, Taft is unable to walk more than a few steps.
Taft is one of 40 patients interviewed by the AP who said they had problems with spinal-cord stimulators. The AP found them through online forums for people with medical devices. Twenty-eight of them said their spinal-cord stimulators not only failed to alleviate pain but left them worse off than before their surgeries.
Zuckerman, who has worked at the U.S. Department of Health and Human Services and as a senior policy adviser to then-first lady Hillary Rodham Clinton, said no doctor wants to think they’re harming patients.
“But there’s a tremendous financial incentive to downplay, ignore or forget bad patient experiences and just focus on how happy patients are,” she said.
More than half the patients interviewed by the AP said they felt pressured to get stimulators because they feared their doctors would cut off their pain medications — the only thing helping them.
Stimulators are considered a treatment of “last resort” by insurance companies, as well as Medicare and Medicaid. That means doctors must follow a protocol before insurance will pay for the device and implantation.
Physicians must show that conservative treatments failed to help, and patients also undergo psychological assessments to evaluate the likelihood of success. They then typically undergo a trial period lasting three days to a week with thin electrodes inserted under the skin. If patients say they got relief from the external transmitter sending electrical pulses to the contacts near their spines, they have surgery to implant a permanent stimulator.
Taft said his three-day trial helped reduce his pain so, a few days before his surgery, he began preparing for a new life. He ordered lumber to refurbish a patio and deck for his wife, Renee, as thanks for her years of support.
In April 2014, Boston Scientific’s Precision stimulator was implanted in Taft by Jason Highsmith, a Charleston, South Carolina, neurosurgeon who has received $181,000 from the company over the past five years in the form of consulting fees and payments for travel and entertainment. A Boston Scientific sales representative was in the operating room — a common practice, the AP found.
Highsmith would not comment on the payments. Other doctors have defended the practice, saying they do important work that helps the companies — and ultimately patients — and deserve to be compensated for their time.
From the time Taft was cut open and the device placed inside his body, he had nothing but problems, according to hundreds of pages of medical records reviewed by the AP. The device began randomly shocking him, and the battery burned his skin.
Taft and his wife complained repeatedly, but said his doctors and a Boston Scientific representative told them that spinal-cord stimulators don’t cause the kind of problems he had.
That runs counter to Boston Scientific’s own literature, which acknowledges that spinal stimulators and the procedures to implant them carry risks, such as the leads moving, overstimulation, paralysis and infections.
That also is not reflected in the AP’s analysis of FDA injury reports, which found shocking and burning had been reported for all major models of spinal-cord stimulators. For Boston Scientific devices, infection was the most common complaint over the past decade, mentioned in more than 4,000 injury reports.
In response to questions, the company called infection “unfortunately a risk in any surgical procedure” that the company works hard to avoid. It added that the FDA’s data “shouldn’t be interpreted as a causal sign of a challenge with our device. In fact, many examples of reportable infections include those that were caused by the surgical procedure or post-operative care.”
“In our internal quality assessments, over 95 percent of the injury reports were temporary or reversible in nature,” the company added.
Taft said had he known the devices hurt so many people, he would have reconsidered getting one. A Boston Scientific sales representative tried reprogramming the device, he said, but nothing worked.
“I told them that it feels like the lead is moving up and down my spine,” Taft said. “They said, ‘It can’t move.’” But in July 2014, X-rays revealed the lead indeed had moved — two inches on one side.
Highsmith told the AP the electrode broke from “vigorous activity,” though Taft said that would not have been possible due to his condition. Taft said he was in such bad shape after his surgery that he was never able to redo the patio and deck for his wife or do anything else vigorous.
That October, Highsmith said, he operated on Taft to install a new lead, tested the battery and reinserted it.
Still, Taft’s medical records show that he continued to report numbness, tingling and pain. During a January 2015 appointment, a physician assistant wrote that the device “seemed to make his pain worse.”
The stimulator was surgically removed in August 2015. The following June, Taft got a second opinion from a clinic that specializes in spinal injuries, which said he had “significant axial and low back pain due to implantation and explantation” of the stimulator.
Highsmith said other doctors have documented severe arthritis in Taft and that, while he has not examined Taft in more than three years, it’s “likely his current condition is the result of disease progression and other factors.”
He did not answer questions about whether he informed Taft of the risks associated with stimulators.
The doctor said the overwhelming majority of his spinal-cord stimulator patients gain significant pain relief.
“Unfortunately, in spite of the major medical breakthroughs with devices like these, some patients still suffer from intractable pain,” he said.
Renee Taft, a paralegal, reached out to Boston Scientific in 2017, but said the company refused to help because her husband’s stimulator had been removed and blamed Taft for his problems, also saying he had engaged in “rigorous physical activity” after surgery.
In the letter from the company’s legal department, Boston Scientific also noted that federal law shielded manufacturers from personal liability claims involving medical devices approved by the FDA.
In response to questions from investigators, Boston Scientific again blamed Taft’s “activity level” but didn’t elaborate. The company also said other factors could contribute to his problems such as “hyperalgesia, a phenomenon associated with long-term opioid use which results in patients becoming increasingly sensitive to some stimuli.”
Since 2005, there have been 50 recalls involving spinal stimulators, averaging about four per year in the last five years. Roughly half the recalls involved stimulators made by Medtronic, the world’s largest device manufacturer, though none warned of a risk of serious injury or death.
The experience of nearly all the 40 patients interviewed by the AP reflected one common fact. Their pain was reduced during the trial but returned once their stimulators were implanted.
Experts say the answer may be a placebo effect created when expectations are built up during the trial that only the stimulator can offer relief from pain, exacerbated by patients not wanting to disappoint family members, who often have been serving as their caregivers.
“If patients know this is a last resort, a last hope, of course they will respond well,” said Dr. Michael Gofeld, a Toronto-based anesthesiologist and pain management specialist who has studied and implanted spinal-cord stimulators in both the U.S. and Canada.
By the time the trial ends, the patient is “flying high, the endorphin levels are high,” Gofeld said.
Manufacturer representatives are heavily involved during the entire process. Along with often being in the operating room during surgery in case the physician has questions, they meet with patients to program the devices in the weeks following surgery.
Most of the patients interviewed by the AP said the adjustments to their devices were performed by sales representatives, often with no doctor or nurse present. That includes one patient who was billed for programming as if the doctor was in the room, though he was not.
“People who are selling the device should not be in charge of maintenance,” Gofeld said. “It’s totally unethical.”
In a 2015 Texas case, a former Medtronic sales representative filed suit contending she was fired after complaining that the company trained employees to program neurostimulators without physicians present. She also claimed that a Medtronic supervisor snatched surgical gloves away from her when she refused to bandage a patient during a procedure, pushed her aside and then cleaned and dressed the patient’s wound. Medtronic denied the allegations, and the case was settled on undisclosed terms.
In the Justice Department case involving Medtronic, a salesman who said he earned as much as $600,000 a year selling spinal-cord stimulators claimed sales representatives encouraged physicians to perform unnecessary procedures that drove up the costs for Medicare and other federal health programs.
“While there have been a few instances where individuals or affiliates did not comply with Medtronic’s policies, we acted to remedy the situation in each case once discovered and to correct any misconduct,” the company said.
Gofeld said he believes stimulators do work, but that many of the problems usually arise when doctors don’t choose appropriate candidates. And he thinks the stimulators are used too often in the U.S.
Nevro, one of the four big manufacturers, has cited estimates that there are as many as 4,400 facilities in the U.S where spinal-stimulation devices are implanted by a variety of physicians, including neurosurgeons, psychiatrists and pain specialists.
It’s a lucrative business . Analysts say stimulators and the surgery to implant them costs between $32,000 and $50,000, with the device itself constituting $20,000 to $25,000 of that amount. If surgery is performed in a hospital, the patient usually stays overnight, and the hospital charges a facility fee for obtaining the device. Costs are typically covered by insurance.
The AP found that doctors can make more money if they perform the surgery at physician-owned outpatient surgery centers, since the doctor buys the device, marks it up and adds on the facility fee.
In Canada, where Gofeld now works, he said the surgeries are done only by those who specialize in the procedures. He said spinal-cord stimulators should be used when pain starts and not after failed back surgeries.
“By then,” he said, “it’s too late.”
When Surgeries Never Stop
While manufacturers and top FDA officials tout stimulators as a weapon in the battle against opioids, neurosurgeons like Steven Falowski are the front-line evangelists.
“Chronic pain is one of the largest health-care burdens we have in the U.S. It’s more than heart disease, cancer and diabetes combined,” Falowski said in an interview. If they’re used early enough for pain, they can prevent people from going on opium-based pain killers, said Falowski, who speaks at neuromodulation conferences and teaches other doctors how to implant stimulators.
Since 2013, device manufacturers have paid Falowski — or St. Luke’s University Health Network in Fountain Hill, Pennsylvania, where he works — nearly $863,000, including $611,000 from St. Jude or its new parent company, Abbott, according to the Centers for Medicare and Medicaid Services database. The payments range from consulting fees to travel and entertainment expenses.
Falowski said he has conducted research and done other work for manufacturers, adding, “The contracts with industry are with my hospital and not with me.”
St. Luke’s told the AP that it keeps the majority of the payments from device makers, but that Falowski “may receive a portion of these payments through his annual compensation.” AP’s analysis showed Abbott products were more likely than other major models to include reports of a hot or burning sensation near the site of the battery, with about 5,600 injury reports since 2008 referring to the words “heat” or “burn.”
Abbott said that many of the “adverse events” reports in the FDA’s data stemmed from a device that was voluntarily recalled in 2011. The company added that feeling a temperature increase at the implant site “is often a reality for rechargeable spinal-cord stimulation systems,” which is why the company is now concentrating on devices that do not need to be recharged.
Falowski said doctors do important work for medical device companies, and he has been involved in device development, education, clinical trials and research.
“You’re trying to help patients and you realize as a physician by yourself you’re not going to generate $200 million to make the next best implant for a patient and it’s going to take a company to do that,” he said. “So I think the important part in that relationship is transparency and disclosures.”
Experts interviewed by the AP said doctors are not legally required to tell their patients about financial relationships with medical device manufacturers, but that it would be the right thing to do.
“The patient should be fully informed before consenting to a procedure,” said Genevieve P. Kanter, an assistant professor at the University of Pennsylvania who specializes in internal medicine, medical ethics and health policy.
Abbott Issues Warning After Surgeries For Thousands of Patients
In October 2016, Abbott notified physicians and patients that a subset of ICD and cardiac resynchronization therapy defibrillator (CRT-D) devices manufactured between January 2010 and May 2015 could potentially experience premature battery depletion due to short circuits from lithium clusters.
The potential for premature battery depletion in the affected devices is low. The new Battery Performance Alert can be used as a tool to further assist in identifying the potential for these devices to experience premature battery depletion.
It’s a voluntary recall, so patients are being told to consult with their doctors before coming in for the procedure — which thankfully consists of a simple 3-minute wireless firmware update (using a wand, according to the pamphlet) instead of anything invasive.
The FDA-approved firmware update actually includes a pair of important-sounding fixes. In addition to some enhanced security, the update also comes with a way to detect if a device’s battery drains abnormally quickly and alert the patient.
The FDA and Abbott say they haven’t had issues with any of the 50,000 firmware updates they’ve installed on devices like this so far.
Based on historical results as well as litigation related to adverse events with medical device FDA approvals and disclosures by device makers, it would seem that the reality of the dangers related to this device and thousands of other FDA approved devices, we may never know the truth on how dangerous these products really are.
(Images and text excerpts have been taken from NBC News and Associated Press media releases)
Xarelto Study Red Flags Ignored: Why were medical research professionals ignored when red flags were raised over the viability of the Xarelto Rocket AF and Einstein DVT study results? Now the clinical trials for both are considered flawed, and the two most recent studies, the “Commander HF” and“Mariner,” failed to produce clear evidence that Xarelto is able to reduce the rate of blood clots in certain high-risk patients or after an acute decline in their condition.
By Mark A. York (October 23, 2018)
(MASS TORT NEXUS MEDIA) Xarelto (rivaroxaban) is a prescription blood thinner created by Bayer and Janssen Pharmaceuticals that was approved by the Food and Drug Administration (FDA) in 2011. This drug is an anticoagulant for preventing blood from clotting, often used to treat deep vein thrombosis, atrial fibrillation, pulmonary embolism, stroke, and other conditions.
More than one study has shown Xarelto can cause a higher rate of internal bleeding, than other anticoagulant drugs and until very recently, there was no available “antidote” for stopping internal bleeding in patients taking Xarelto. With warfarin, vitamin K has been shown to stop bleeding but there is no vitamin K “parallel” for people taking Xarelto. For Xarelto, it can take 24 hours for a dose to get out of the body. That means that if internal bleeding starts, the patient may simply have to wait it out and hope it stops on its own.
What The Medical Studies Say About Xarelto?
The FDA has received thousands of adverse event reports regarding Xarelto and medical studies have examined the safety of this drug:
New England Journal of Medicine (2011): Published the ROCKET-AF study, which compared Xarelto to Warfarin in patients suffering from atrial fibrillation. This was the biggest clinical trial of this medication and it compared the effects of Xarelto to the effects of a similar drug known as Warfarin in over 14,000 patients. The study concluded that “there was not significant between-group difference in the risk of major bleeding.”
Archives of Internal Medicine (2012): The study discussed the risk of uncontrollable bleeding outweighing the benefits for several different blood thinners including Xarelto. The researchers in this study found that there was a tripled risk of bleeding among the patients, who were given the drug, and no improvement in overall survival rates.
Institute for Safe Medication Practices (2012): Issued a report based on FDA data from the first quarter of 2012. During this period, the FDA received 356 adverse event reports of Xarelto side effects including “serious, disabling, or fatal injury.” Additionally, 158 reports indicated blood clots were the serious side effect.
Medscape (2013): Xarelto is associated with a higher risk of bleeding in certain patients. It caused a nearly 3-fold increase of the risk of bleeding in “acutely ill patients” and 4-fold increased risk of major bleeding in patients that had “Acute Coronary Syndrome” (ACS).
Drug Makers Failed To Disclose Faulty Device In Xarelto Trials
Rivaroxaban and the ROCKET AF trial issue chronicles: A closer look at benefit risk profile of the drug.
Study Analysis: There has been a lot of hue and cry over the recent question raised about the ROCKET AF trial for rivaroxaban which was the only trial used by the company for drug approval from USFDA. This is indeed a very important concern as it directly impacts the well-being of the patients who are at the receiving end of this very highly prescribed anticoagulant drug in 2014. The main concern with this whole confusion surrounding the ROCKET AF trial is that the device used for measuring the INR in trial arm of warfarin patient was faulty and gave lower INR values than it should have, leading to over dosing of warfarin and thereby increasing bleeding problems with the same, compared to the trial arm of rivaroxaban. However, there has been a reanalysis done by the ROCKET AF researchers, which again reinforced the prior result database of the trial and which was accepted by FDA as well. In the reanalysis, the US FDA clearly mentioned that the effect of the faulty device results in causing bleeding episodes, both minor and major, was minimal.
However, following this reanalysis, not everyone who raised the question in the first place was convinced and there was a demand that the data of the complete ROCKET AF trial should be made public for everyone to assess and understand the risks. But since the trial was done and results released before the principles on responsible clinical trial data sharing came into effect, the parent pharmaceutical company for rivaroxaban refused to share the patient level details, citing concerns on privacy and transparency policy .
In spite of everything said and written for and against this issue, a simple question arises, regarding the amount of belief, honesty and hard work that goes without questioning when you bring a new chemical entity to the research stage, get it approved and then bring it to market. For this to happen, there have to be maintained a very fine balance between pharmaceutical companies, drug regulatory authorities and marketing people. In this case, after initial suspicions, the drug regulatory authorities have cleared and supported the approval of rivaroxaban after reanalysis and that should have a say, in case we want to continue trust with this process of drug entry into the market.
Rivaroxaban has shown its efficacy and safety both in patients who required adequate anticoagulation e.g. those who had atrial fibrillation and underwent cardioversion. There are few other trials where rivaroxaban has performed better or equally good than warfarin in terms of both efficacy and safety . These results lead us to believe that all was not wrong with the ROCKET AF trial results. All these, combined with personal experiences of those physicians who had been using the drug rivaroxaban for the last couple of years with a hugely favorable result clearly imply that the drug rivaroxaban is holding its side strongly in the midst of all the controversies surrounding its approval and efficacy and it is here to stay. Adding a last word to all this discussion is that rivaroxaban will always hold an upper hand compared to warfarin when prescribed because of its very favorable and easy to use once daily dosing. We cannot discard all the positive reports and positive experiences associated with this drug, based on real time data, only because of the question raised by some, and considering the fact that the question had been satisficatorily answered with a re analysis with no change in the result.
What Did Or Didn’t The FDA Do About Xarelto?
In July, 2011, the U.S Food and Drug Administration (FDA) initially approved the medicine for sale on the market for a limited group of people. This included people who had knee or hip replacement surgery because they were considered to be at a higher risk of blood clotting. Read the FDA News Release here.
In November, 2011, Xarelto was approved for a larger group of people, including people with an abnormal heart rhythm, and was used to prevent stroke. Read further.
In June, 2012, an FDA advisory panel voted against approving this medicine for the treatment of acute coronary syndrome.
In November, 2012, Xarelto was later approved for general treatment of deep vein thrombosis (DVT) and pulmonary embolism (PE) after a fast track regulatory review by the FDA. Read more.
October 22, 2014, the FDA issued a recall for approximately 13,500 bottles of Xarelto after receiving a customer complaint about contamination in a sales sample.
January 12, 2015 – An antidote may have been discovered by Portola Pharmaceuticals for Xarelto. A late-stage clinical trial of the intravenous medication, andexanet alfa, met its goal of “immediately and significantly” reversing Xarelto.
The approval history for Xarelto was actually pretty controversial. FDA reviewers originally said that they recommended against approval, then there was an FDA advisory committee (independent group of key opinion leaders) and they voted in favor, so the FDA approved the drug. Their concern was with how the Phase III trials were run and whether Xarelto had really proved its efficacy. The tests compared patients on warfarin to patients on Xarelto, but the patients on the warfarin run had poor TTR. That means the patients weren’t well controlled on warfarin to begin with, which skews the data in favor of Xarelto.
During the approval process, Xarelto actually wanted a superiority label, which would say that the drug was better than warfarin and other blood thinners. Because of the concerns with the Phase III data, the FDA only gave them a non-inferior label, which says they’re essentially the same in terms of effectiveness.
The INRatio device was the subject of two FDA warning letters about inaccurate readings just as the trial was starting in 2005 and 2006. In 2014, the device was recalled. The use of the INRatio device may have skewed the results with inaccurate readings, making Xarelto look better in comparison with warfarin.
In a 2017 annual report issued by the Institute for Safe Medication Practices (ISMP), it was stated that oral anticoagulant drugs, including Xarelto (rivaroxaban), showed “unacceptably high risks,” according to two government data sources, the FAERS adverse events reports for 2016 and a new systematic study by the Centers for Disease Control and Prevention (CDC).
Overall, the CDC found in its systematic study that the FDA’s FAERS voluntary reporting underestimates anticoagulant drug-related injuries. The CDC discovered that approximately 228,600 emergency department visits occur each year due to the use of blood thinner drugs, including Xarelto, which is 10 times more than the FAERS total number of voluntary reports.
Xarelto Clinical Trial Red Flags
Controversy Surrounding ROCKET-AF: A Call for Transparency, But Should We Be Changing Practice?
Prior to the emergence of novel oral anticoagulants (NOACS), nearly all patients were prescribed vitamin K antagonists for thromboembolic prophylaxis in non-valvular atrial fibrillation (AF). Rivaroxaban (Xarelto, Bayer/Johnson & Johnson), an oral factor Xa inhibitor, is now one of the most frequently prescribed NOACs used for this indication.1,2
ROCKET-AF (Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared with Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation), published in the New England Journal of Medicine in 2011, demonstrated the non-inferiority of rivaroxaban compared with warfarin for the primary prevention of stroke or systemic embolism in patients with AF. This double-blinded randomised trial, which included 14,264 patients across 45 countries, also showed no significant difference in the risk of major bleeding between these two groups.3
Rivaroxaban use in AF has become widespread since the publication of this trial and US Food and Drug Administration (FDA) approval. Two additional Factor Xa inhibitors, apixaban and edoxaban, have also been evaluated in similar randomised trials and have demonstrated non-inferiority to warfarin for stroke or systemic embolism prophylaxis in patients with non-valvular AF with no significant difference in major bleeding.4,5
In recent months, the results of ROCKET-AF have come into question after the FDA issued a recall notice for the device used to obtain International Normalised Ratio (INR) measurements in the warfarin control group. The FDA found that lower INR values were seen with the ‘point-of-care’ INRatio Monitor System (Alere) compared with a plasma-based laboratory in patients with certain medical conditions.2 These conditions included abnormal haemoglobin levels, abnormal bleeding and abnormal fibrinogen levels.6Since the FDA recall of this device, there has been widespread concern that falsely low INR readings in ROCKET-AF may have led to warfarin overdosing. Inappropriately high warfarin dosing could have increased bleeding rates in the control group and therefore made the rivaroxaban arm appear falsely favourable.7 This point-of-care device recall also highlighted a lack of transparency of the specifics of devices used in large clinical trials.
In response, the authors from ROCKET-AF released a correspondence in February 2016, citing the FDA recall. They also provided a post hoc analysis of patients who may have been affected by the recall. They found that major bleeding was greater in patients with conditions affected by the recall, but, reassuringly, the bleeding risk was greater in those who were on rivaroxaban and not warfarin.6
Despite this post hoc analysis, concern has arisen regarding the generalisability of ROCKET-AF given the faulty point-of-care INR readings. There has been a call for complete transparency of the data from this trial and a better explanation of the mechanism of the incorrect INR measurements.7
Once published, the data supporting an FDA-approved treatment should be available for independent analysis. One issue is that rivaroxaban was approved in the US prior to 1 January 2014, before a new transparency policy on clinical trial data sharing was approved by the European Federation of Pharmaceutical Industries and Associations (EFPIA) and the Pharmaceutical Research and Manufacturers of America (PhRMA).2 Drug companies are refusing to share any data on pharmaceuticals approved before 2014.
A device malfunction in a large clinical trial also should raise concern, especially when that trial has altered clinical practice for millions of patients. On review of Patel et al’s correspondence regarding the point-of-care malfunction, there is inadequate explanation of the mechanism of these faulty readings. Why are they only seen only in patients with abnormal haemoglobin and fibrinogen levels? How inaccurate could the readings be – within 0.1 or 1.0 of a gold standard value? Most alarming is the revelation that the manufacturer had evidence of faulty readings in similar models dating back to 2002.2
Despite legitimate concerns regarding the absence of data transparency and the faulty point-of-care device, rivaroxaban need not be removed from clinical practice for AF patients. In ROCKET-AF, the drug demonstrated non-inferiority to warfarin in preventing thromboembolic events. In addition, data has shown that patients potentially affected by the faulty point-of-care device actually bled more on rivaroxaban than warfarin.6 Therefore, the original risk–benefit ratio presented in ROCKET-AF remains true.
There are other, albeit smaller, randomised trials with shorter follow-up times that compare rivaroxaban and warfarin for thromboembolic prophylaxis.8,9 For example, Cappato et al in 2014, randomised 1,504 patients to show that oral rivaroxaban was non-inferior to warfarin in preventing a composite endpoint of stroke, transient ischaemic attack, peripheral embolism, myocardial infarction and cardiovascular death in patients with AF undergoing cardioversion. Major bleeding rates in the rivaroxaban and warfarin arms were similar (0.6 % versus 0.8 % respectively).8
The prospective observational trial XANTUS (Xarelto for Prevention of Stroke in Patients with Atrial Fibrillation) followed 6.784 patients on rivaroxaban for AF during a mean time of 329 days at 311 different hospitals. Major bleeding occurred in 128 patients (2.1 events/100 patient years) and 43 patients (0.7 events/100 patient years) suffered a stroke. These numbers are more reassuring than those seen in ROCKET-AF, though the patient population had a lower risk profile, with an average CHADS2 score of 2.0 compared with 3.5 in ROCKET-AF.10
To further mitigate concern regarding inaccuracies of bleeding rates in the ROCKET-AF control group, it is helpful to compare bleeding rates in the warfarin arms of the other major NOAC trials. The RE-LY (Randomised Evaluation of Long-Term Anticoagulation Therapy) trial, had a warfarin-arm major bleeding rate of 3.4%/year.11 The ARISTOTLE (Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation) trial, had a warfarin-arm major bleeding rate of 3.1%/year.4 The ENGAGE AF-TIMI 48 (Effective Anticoagulation with Factor Xa Next Generation in Atrial Fibrillation-Thrombolysis in Myocardial Infarction 48) trial, had a warfarin-arm major bleeding rate of 3.4 %/year.5The warfarin arm of ROCKET-AF had a 3.4 %/year major bleeding rate, comparable to the other studies. Furthermore, the ROCKET-AF patients are known to be at higher risk for stroke and bleeding; their average CHADS2 score was highest among these studies (3.5 compared with 2.1–2.8).3 In addition, ROCKET-AF had a very high percentage of patients with a HAS-BLED score ≥3 (62 %) compared with the other studies (23 % in ARISTOTLE and 51 % in ENGAGE AF-TIMI 48).12–14
Several large randomised trials have compared the safety and efficacy of rivaroxaban versus warfarin for venous thromboembolic disease. The warfarin arm of the EINSTEIN-PE trial (Oral Direct Factor Xa Inhibitor Rivaroxaban in Patients with Acute Symptomatic Pulmonary Embolism), which randomised patients with pulmonary embolism to warfarin or rivaroxaban, had a major bleeding rate of 2.2 %. The bleeding rate was lower in the rivaroxaban arm (1.1 %) and notably patients received a higher loading dose of rivaroxaban for the first 3 weeks (15 mg twice daily) compared with the daily 20 mg daily in ROCKET-AF.15
The recent uncertainties surrounding ROCKET-AF demonstrate the need for widespread data transparency for major trials with the capability of so greatly affecting patients’ lives. These are complicated issues both for the companies’ manufacturing products and the clinical trial organisations who carry out these studies and analyse the data. Ultimately the goal of full transparency to allow increased confidence in trial results should be sought. In this instance there is no compelling evidence of imminent danger of excessive bleeding with rivaroxaban. We should take notice of the recent findings, but there is no need to change practice.
What Are Xarelto Side Effects?
The most dangerous Xarelto side effect is uncontrollable bleeding. Blood thinning drugs have also been associated with bleeding complications. Other side effects include:
For Information on Xarelto and other mass torts see:
Michael Brady Lunch will speak on the Xarelto litigation as well as the status of Pradaxa litigation and related issues at the upcoming Mass Tort Nexus “CLE Immersion Course”
November 9 -12, 2018 at The Riverside Hotel in Fort Lauderdale , FL.
Kubitza D, Becka M, Wensing G, et al. Safety, pharmacodynamics, and pharmacokinetics of BAY 59-7939 – an oral, direct Factor Xa inhibitor – after multiple dosing in healthy male subjects. Eur J Clin Pharmacol. 2005;61:873–80. PMID: 16328318. [PubMed]
Cohen D. Rivaroxaban: can we trust the evidence? BMJ. 2016;352:i575. DOI: 10.1136/bmj.i575; PMID: 26843102. [PubMed]
Patel MR, Mahaffey KW, Garg J, et al. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N Engl J Med. 2011;365:883–91. DOI: 10.1056/NEJMoa1009638; PMID: 21830957. [PubMed]
Granger CB, Alexander JH, McMurray JJ, et al. Apixaban versus warfarin in patients with atrial fibrillation. N Engl J Med. 2011;365:981–92. DOI: 10.1056/NEJMoa1107039; PMID: 21870978.[PubMed]
Giugliano RP, Ruff CT, Braunwald E, et al. Edoxaban versus warfarin in patients with atrial fibrillation. N Engl J Med. 2013;369:2093–104. DOI: 10.1056/NEJMoa1310907; PMID: 24251359. [PubMed]
Patel MR, Hellkamp AS, Fox KA, et al. Point-of-care warfarin monitoring in the ROCKET AF Trial. N Engl J Med. 2016;374:785–8. DOI: 10.1056/NEJMc1515842; PMID: 26839968. [PubMed]
Mandrola J. Rivaroxaban: It’s not time to cut the rope, yet. Medscape. 9 February 2016. Available at: www.medscape.com/viewarticle/858648. (accessed 6 May 2016.
Cappato R, Ezekowitz MD, Klein AL, et al. Rivaroxaban vs. vitamin K antagonists for cardioversion in atrial fibrillation. Eur Heart J. 2014;35:3346–55. DOI: 10.1093/eurheartj/ehu367; PMID: 25182247.[PubMed]
Cappato R, Marchlinski FE, Hohnloser SH, et al. Uninterrupted rivaroxaban vs. uninterrupted vitamin K antagonists for catheter ablation in non-valvular atrial fibrillation. Eur Heart J. 2015;36:1805–11. DOI: 10.1093/eurheartj/ehv177; PMID: 25975659. [PMC free article] [PubMed]
Camm AJ, Amarenco P, Haas S, et al. XANTUS: a real-world, prospective, observational study of patients treated with rivaroxaban for stroke prevention in atrial fibrillation. Eur Heart J. 2016;37:1145–53.DOI: 10.1093/eurheartj/ehv466; PMID: 26330425. [PMC free article] [PubMed]
Connolly SJ, Ezekowitz MD, Yusuf S, et al. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med. 2009;361:1139–51. DOI: 10.1056/NEJMoa0905561; PMID: 19717844.[PubMed]
Sherwood MW, Nessel CC, Hellkamp AS, et al. Gastrointestinal bleeding in patients with atrial fibrillation treated With rivaroxaban or warfarin: ROCKET AF trial. J Am Coll Cardiol. 2015;66:2271–81.DOI: 10.1016/j.jacc.2015.09.024; PMID: 26610874. [PubMed]
Lopes RD, Al-Khatib SM, Wallentin L, et al. Efficacy and safety of apixaban compared with warfarin according to patient risk of stroke and of bleeding in atrial fibrillation: a secondary analysis of a randomised controlled trial. Lancet. 2012;380:1749–58. DOI: 10.1016/S0140-6736(12)60986-6; PMID: 23036896. [PubMed]
Eisen A, Giugliano RP, Ruff CT, et al. Edoxaban vs warfarin in patients with nonvalvular atrial fibrillation in the US Food and Drug Administration approval population: An analysis from the Effective Anticoagulation with Factor Xa Next Generation in Atrial Fibrillation-Thrombolysis in Myocardial Infarction 48 (ENGAGE AF-TIMI 48) trial. Am Heart J. 2016;172:144–51. DOI: 10.1016/j.ahj.2015.11.004; PMID: 26856226. [PubMed]
EINSTEIN-PE Investigators, Buller HR, Prins MH, et al. Oral rivaroxaban for the treatment of symptomatic pulmonary embolism. N Engl J Med. 2012;366:1287–97. DOI: 10.1056/ NEJMoa1113572. PMID: 22449293. [PubMed]
(MASS TORT NEXUS MEDIA) In 2017 and continuing into 2018, Big Pharma has been fighting major legal battles related to off-label marketing of drugs for unintended uses. They also engaged in a parallel strategy, where they were influencing the FDA and other policy making agencies behind the scenes in Washington DC. Big Pharma was paying millions to lobbyists, making campaign donations and generally buying influence as they always have. It was a foregone conclusion that with the Trump administration view of , “no regulatory oversight required” that there would be some loosening of the FDA regulatory shackles.
Big Pharma was getting ready for freedom to sell, sell, sell their drugs in any way they could, including off-label marketing of the drugs for unintended use purposes. A corporate policy, that’s technically illegal, yet results in billions of dollars in profits every years for Big Pharma. Then the FDA rolled out an unexpected new proposed rule, in March 2017 cracking down on “off-label’ marketing of drugs. This new rule change wasn’t in Big Pharma’s bests interests, sending the drug industry into a furious lobbying scramble. Bring in the Trump camp and on January 12, 2018 Big Pharma and the army of lobbyists and elected officials that were recruited, seem to have succeeded in stopping the FDA rules change that would have tightened up “off label” marketing of drugs.
This seems to be further evidence of the Trump administration permitting private corporations to control what goes on behind the scenes in federal regulatory agencies these days. The same loosening of enforcement rules has been seen in the EPA as well as in Dept. of Energy oversight enforcement authority. Whatever else you might think about the ramped up Trump vs. Obama administration mindset, this rule delay is an example of the new FDA leadership doing what is in the best interests of those they are supposed to be regulating, the drug makers, and not in the interests of the US consumers.
To put this into perspective, consider the current “Opioid Crisis” gripping the entire country, where “off-label” marketing of opiates for the last 20 years by drug makers, has resulted in thousands of deaths each year, unknown financial losses and the related social impact felt in every state across the country. Another result is the Opiate Prescription Litigation MDL 2804, (see OPIOID CRISIS BRIEFCASE: MDL 2804 OPIATE PRESCRIPTION LITIGATION) where litigation started when hundreds of counties, states and cities and other entities impacted by the catastrophic expense related to combatting the opiate healthcare crisis fought back. The various parties have filed lawsuits against opioid drug makers and distributors, demanding repayment of the billions of dollars spent on addressing the massive costs related to opioid abuse, primarily due to opioid based prescription drugs flooding the country.
When the Obama administration ended on January 9, 2017, the FDA issued a Final Rule on “Clarification of When Products Made or Derived from Tobacco are Regulated as Drugs, Devices, or Combination Products; Amendments to Regulations Regarding ‘Intended Uses.’” That “clarification” was meant to enable additional enforcement and control over drug makers rampant “off -label” marketing of drugs for purposes that were never FDA approved. This was an attempt by the FDA to have the ability to punish off-label promotions, where previously the process was a two-step regulatory review, whereby off-label promotions are said to prove an indicated use not included in the label and, thus, not accompanied by adequate directions for use – making the product misbranded. These regulations have been around since the 1950s, but a recent series of court decisions invoking the First Amendment called into question the FDA’s interpretation of “intended use” and its efforts to shut down truthful medical-science communications about potential benefits from off-label use.
In a 2015 proposed rule, the FDA referred to striking the language from regulations permitting the FDA to consider a manufacturer’s mere knowledge of actual use as evidence of intended use, which would have further enabled Big Pharma drug marketing abuses to go unchecked. But then, the FDA’s January 9, 2017 proposal reversed course, stating that retained knowledge of off-label use as evidence of intended use, clarified that any relevant source of evidence, whether circumstantial or direct could demonstrate intended use, and ultimately invoked the dreaded “totality of the evidence” standard. This would have enable the FDA to begin oversight and enforcement of practices such as the blatant and wide open “off-label” marketing of opioid prescription drugs that started in the mid-1990’s and never stopped.
Instead of putting a check on Big Pharma abuses, we have the Trump administration placing a hold on new regulations, and delaying the “intended use” regulation change to March 19, 2018, so that comments could be received and considered, and thereby enabling the Big Pharma “lobby machine” to become fully engaged across all DC circles, ensuring that the FDA changes are effectively put to rest.
The bottom line is that the FDA is now proposing to “delay until further notice” the portions of the final rule amending the FDA’s existing regulations on “off-label” drug use, when describing the types of evidence that may be considered in determining a medical product’s intended uses. The FDA will receive comments on this proposal through February 5, 2018.
Here is the official FDA publication of January 16, 2018:
Global health care giant Johnson & Johnson (J&J) and its subsidiaries will pay more than $2.2 billion to resolve criminal and civil liability arising from allegations relating to the prescription drugs Risperdal, Invega and Natrecor, including promotion for uses not approved as safe and effective by the Food and Drug Administration (FDA) and payment of kickbacks to physicians and to the nation’s largest long-term care pharmacy provider. The global resolution is one of the largest health care fraud settlements in U.S. history, including criminal fines and forfeiture totaling $485 million and civil settlements with the federal government and states totaling $1.72 billion.
“The conduct at issue in this case jeopardized the health and safety of patients and damaged the public trust,” stated Eric Holder, then US Attorney General, “This multibillion-dollar resolution demonstrates the Justice Department’s firm commitment to preventing and combating all forms of health care fraud. And it proves our determination to hold accountable any corporation that breaks the law and enriches its bottom line at the expense of the American people” he added.
The resolution includes criminal fines and forfeiture for violations of the law and civil settlements based on the False Claims Act arising out of multiple investigations of the company and its subsidiaries.
“When companies put profit over patients’ health and misuse taxpayer dollars, we demand accountability,” said Associate Attorney General Tony West. “In addition to significant monetary sanctions, we will ensure that non-monetary measures are in place to facilitate change in corporate behavior and help ensure the playing field is level for all market participants.”
The Federal Food, Drug, and Cosmetic Act (FDCA) protects the health and safety of the public by ensuring, among other things, that drugs intended for use in humans are safe and effective for their intended uses and that the labeling of such drugs bear true, complete and accurate information. Under the FDCA, a pharmaceutical company must specify the intended uses of a drug in its new drug application to the FDA. Before approval, the FDA must determine that the drug is safe and effective for those specified uses. Once the drug is approved, if the company intends a different use and then introduces the drug into interstate commerce for that new, unapproved use, the drug becomes misbranded. The unapproved use is also known as an “off-label” use because it is not included in the drug’s FDA-approved labeling.
“When pharmaceutical companies interfere with the FDA’s mission of ensuring that drugs are safe and effective for the American public, they undermine the doctor-patient relationship and put the health and safety of patients at risk,” said Director of the FDA’s Office of Criminal Investigations John Roth. “Today’s settlement demonstrates the government’s continued focus on pharmaceutical companies that put profits ahead of the public’s health. The FDA will continue to devote resources to criminal investigations targeting pharmaceutical companies that disregard the drug approval process and recklessly promote drugs for uses that have not been proven to be safe and effective.”
J&J RISPERDAL MARKETING ABUSE
In a related civil complaint filed today in the Eastern District of Pennsylvania, the United States alleges that Janssen marketed Risperdal to control the behaviors and conduct of the nation’s most vulnerable patients: elderly nursing home residents, children and individuals with mental disabilities. The government alleges that J&J and Janssen caused false claims to be submitted to federal health care programs by promoting Risperdal for off-label uses that federal health care programs did not cover, making false and misleading statements about the safety and efficacy of Risperdal and paying kickbacks to physicians to prescribe Risperdal.
“J&J’s promotion of Risperdal for unapproved uses threatened the most vulnerable populations of our society – children, the elderly and those with developmental disabilities,” said U.S. Attorney for the Eastern District of Pennsylvania Zane Memeger. “This historic settlement sends the message that drug manufacturers who place profits over patient care will face severe criminal and civil penalties.”
In its complaint, the government alleges that the FDA repeatedly advised Janssen that marketing Risperdal as safe and effective for the elderly would be “misleading.” The FDA cautioned Janssen that behavioral disturbances in elderly dementia patients were not necessarily manifestations of psychotic disorders and might even be “appropriate responses to the deplorable conditions under which some demented patients are housed, thus raising an ethical question regarding the use of an antipsychotic medication for inappropriate behavioral control.”
The complaint further alleges that J&J and Janssen were aware that Risperdal posed serious health risks for the elderly, including an increased risk of strokes, but that the companies downplayed these risks. For example, when a J&J study of Risperdal showed a significant risk of strokes and other adverse events in elderly dementia patients, the complaint alleges that Janssen combined the study data with other studies to make it appear that there was a lower overall risk of adverse events. A year after J&J had received the results of a second study confirming the increased safety risk for elderly patients taking Risperdal, but had not published the data, one physician who worked on the study cautioned Janssen that “[a]t this point, so long after [the study] has been completed … we must be concerned that this gives the strong appearance that Janssen is purposely withholding the findings.”
The complaint also alleges that Janssen knew that patients taking Risperdal had an increased risk of developing diabetes, but nonetheless promoted Risperdal as “uncompromised by safety concerns (does not cause diabetes).” When Janssen received the initial results of studies indicating that Risperdal posed the same diabetes risk as other antipsychotics, the complaint alleges that the company retained outside consultants to re-analyze the study results and ultimately published articles stating that Risperdal was actually associated with a lower risk of developing diabetes.
The complaint alleges that, despite the FDA warnings and increased health risks, from 1999 through 2005, Janssen aggressively marketed Risperdal to control behavioral disturbances in dementia patients through an “ElderCare sales force” designed to target nursing homes and doctors who treated the elderly. In business plans, Janssen’s goal was to “[m]aximize and grow RISPERDAL’s market leadership in geriatrics and long term care.” The company touted Risperdal as having “proven efficacy” and “an excellent safety and tolerability profile” in geriatric patients.
In addition to promoting Risperdal for elderly dementia patients, from 1999 through 2005, Janssen allegedly promoted the antipsychotic drug for use in children and individuals with mental disabilities. The complaint alleges that J&J and Janssen knew that Risperdal posed certain health risks to children, including the risk of elevated levels of prolactin, a hormone that can stimulate breast development and milk production. Nonetheless, one of Janssen’s Key Base Business Goals was to grow and protect the drug’s market share with child/adolescent patients. Janssen instructed its sales representatives to call on child psychiatrists, as well as mental health facilities that primarily treated children, and to market Risperdal as safe and effective for symptoms of various childhood disorders, such as attention deficit hyperactivity disorder, oppositional defiant disorder, obsessive-compulsive disorder and autism. Until late 2006, Risperdal was not approved for use in children for any purpose, and the FDA repeatedly warned the company against promoting it for use in children.
The government’s complaint also contains allegations that Janssen paid speaker fees to doctors to influence them to write prescriptions for Risperdal. Sales representatives allegedly told these doctors that if they wanted to receive payments for speaking, they needed to increase their Risperdal prescriptions.
In addition to allegations relating to Risperdal, today’s settlement also resolves allegations relating to Invega, a newer antipsychotic drug also sold by Janssen. Although Invega was approved only for the treatment of schizophrenia and schizoaffective disorder, the government alleges that, from 2006 through 2009, J&J and Janssen marketed the drug for off-label indications and made false and misleading statements about its safety and efficacy.
As part of the global resolution, J&J and Janssen have agreed to pay a total of $1.391 billion to resolve the false claims allegedly resulting from their off-label marketing and kickbacks for Risperdal and Invega. This total includes $1.273 billion to be paid as part of the resolution announced today, as well as $118 million that J&J and Janssen paid to the state of Texas in March 2012 to resolve similar allegations relating to Risperdal. Because Medicaid is a joint federal-state program, J&J’s conduct caused losses to both the federal and state governments. The additional payment made by J&J as part of today’s settlement will be shared between the federal and state governments, with the federal government recovering $749 million, and the states recovering $524 million. The federal government and Texas each received $59 million from the Texas settlement.
NURSING HOME PATIENT ABUSES BY J&J
The civil settlement also resolves allegations that, in furtherance of their efforts to target elderly dementia patients in nursing homes, J&J and Janssen paid kickbacks to Omnicare Inc., the nation’s largest pharmacy specializing in dispensing drugs to nursing home patients. In a complaint filed in the District of Massachusetts in January 2010, the United States alleged that J&J paid millions of dollars in kickbacks to Omnicare under the guise of market share rebate payments, data-purchase agreements, “grants” and “educational funding.” These kickbacks were intended to induce Omnicare and its hundreds of consultant pharmacists to engage in “active intervention programs” to promote the use of Risperdal and other J&J drugs in nursing homes. Omnicare’s consultant pharmacists regularly reviewed nursing home patients’ medical charts and made recommendations to physicians on what drugs should be prescribed for those patients. Although consultant pharmacists purported to provide “independent” recommendations based on their clinical judgment, J&J viewed the pharmacists as an “extension of [J&J’s] sales force.”
J&J and Janssen have agreed to pay $149 million to resolve the government’s contention that these kickbacks caused Omnicare to submit false claims to federal health care programs. The federal share of this settlement is $132 million, and the five participating states’ total share is $17 million. In 2009, Omnicare paid $98 million to resolve its civil liability for claims that it accepted kickbacks from J&J and Janssen, along with certain other conduct.
“Consultant pharmacists can play an important role in protecting nursing home residents from the use of antipsychotic drugs as chemical restraints,” said U.S. Attorney for the District of Massachusetts Carmen Ortiz. “This settlement is a reminder that the recommendations of consultant pharmacists should be based on their independent clinical judgment and should not be the product of money paid by drug companies.”
OFF-LABEL USE OF HEART DRUG NATRECOR
The civil settlement announced today also resolves allegations that J&J and another of its subsidiaries, Scios Inc., caused false and fraudulent claims to be submitted to federal health care programs for the heart failure drug Natrecor. In August 2001, the FDA approved Natrecor to treat patients with acutely decompensated congestive heart failure who have shortness of breath at rest or with minimal activity. This approval was based on a study involving hospitalized patients experiencing severe heart failure who received infusions of Natrecor over an average 36-hour period.
In a civil complaint filed in 2009 in the Northern District of California, the government alleged that, shortly after Natrecor was approved, Scios launched an aggressive campaign to market the drug for scheduled, serial outpatient infusions for patients with less severe heart failure – a use not included in the FDA-approved label and not covered by federal health care programs. These infusions generally involved visits to an outpatient clinic or doctor’s office for four- to six-hour infusions one or two times per week for several weeks or months.
The government’s complaint alleged that Scios had no sound scientific evidence supporting the medical necessity of these outpatient infusions and misleadingly used a small pilot study to encourage the serial outpatient use of the drug. Among other things, Scios sponsored an extensive speaker program through which doctors were paid to tout the purported benefits of serial outpatient use of Natrecor. Scios also urged doctors and hospitals to set up outpatient clinics specifically to administer the serial outpatient infusions, in some cases providing funds to defray the costs of setting up the clinics, and supplied providers with extensive resources and support for billing Medicare for the outpatient infusions.
As part of today’s resolution, J&J and Scios have agreed to pay the federal government $184 million to resolve their civil liability for the alleged false claims to federal health care programs resulting from their off-label marketing of Natrecor. In October 2011, Scios pleaded guilty to a misdemeanor FDCA violation and paid a criminal fine of $85 million for introducing Natrecor into interstate commerce for an off-label use.
“This case is an example of a drug company encouraging doctors to use a drug in a way that was unsupported by valid scientific evidence,” said First Assistant U.S. Attorney for the Northern District of California Brian Stretch. “We are committed to ensuring that federal health care programs do not pay for such inappropriate uses, and that pharmaceutical companies market their drugs only for uses that have been proven safe and effective.”
Non-Monetary Provisions of the Global Resolution and Corporate Integrity Agreement
In addition to the criminal and civil resolutions, J&J executed a five-year Corporate Integrity Agreement (CIA) with the Department of Health and Human Services Office of Inspector General (HHS-OIG). The CIA includes provisions requiring J&J to implement major changes to the way its pharmaceutical affiliates do business. Among other things, the CIA requires J&J to change its executive compensation program to permit the company to recoup annual bonuses and other long-term incentives from covered executives if they, or their subordinates, engage in significant misconduct. J&J may recoup monies from executives who are current employees and from those who have left the company. The CIA also requires J&J’s pharmaceutical businesses to implement and maintain transparency regarding their research practices, publication policies and payments to physicians. On an annual basis, management employees, including senior executives and certain members of J&J’s independent board of directors, must certify compliance with provisions of the CIA. J&J must submit detailed annual reports to HHS-OIG about its compliance program and its business operations.
“OIG will work aggressively with our law enforcement partners to hold companies accountable for marketing and promotion that violate laws intended to protect the public,” said Inspector General of the U.S. Department of Health and Human Services Daniel R. Levinson. “Our compliance agreement with Johnson & Johnson increases individual accountability for board members, sales representatives, company executives and management. The agreement also contains strong monitoring and reporting provisions to help ensure that the public is protected from future unlawful and potentially harmful off-label marketing.”
FEDERAL AND STATE JOINT CRIMINAL INVESTIGATIONS
This resolution marks the culmination of an extensive, coordinated investigation by federal and state law enforcement partners that is the hallmark of the Health Care Fraud Prevention and Enforcement Action Team (HEAT) initiative, which fosters government collaborations to fight fraud. Announced in May 2009 by Attorney General Eric Holder and Health and Human Services Secretary Kathleen Sebelius, the HEAT initiative has focused efforts to reduce and prevent Medicare and Medicaid financial fraud through enhanced cooperation.
The criminal cases against Janssen and Scios were handled by the U.S. Attorney’s Offices for the Eastern District of Pennsylvania and the Northern District of California and the Civil Division’s Consumer Protection Branch. The civil settlements were handled by the U.S. Attorney’s Offices for the Eastern District of Pennsylvania, the Northern District of California and the District of Massachusetts and the Civil Division’s Commercial Litigation Branch. Assistance was provided by the HHS Office of Counsel to the Inspector General, Office of the General Counsel-CMS Division, the FDA’s Office of Chief Counsel and the National Association of Medicaid Fraud Control Units.
This matter was investigated by HHS-OIG, the Department of Defense’s Defense Criminal Investigative Service, the FDA’s Office of Criminal Investigations, the Office of Personnel Management’s Office of Inspector General, the Department of Veterans Affairs, the Department of Labor, TRICARE Program Integrity, the U.S. Postal Inspection Service’s Office of the Inspector General and the FBI.
One of the most powerful tools in the fight against Medicare and Medicaid financial fraud is the False Claims Act. Since January 2009, the Justice Department has recovered a total of more than $16.7 billion through False Claims Act cases, with more than $11.9 billion of that amount recovered in cases involving fraud against federal health care programs.
The department enforces the FDCA by prosecuting those who illegally distribute unapproved, misbranded and adulterated drugs and medical devices in violation of the Act. Since 2009, fines, penalties and forfeitures that have been imposed in connection with such FDCA violations have totaled more than $6 billion.
The civil settlements described above resolve multiple lawsuits filed under the qui tam, or whistleblower, provisions of the False Claims Act, which allow private citizens to bring civil actions on behalf of the government and to share in any recovery. From the federal government’s share of the civil settlements announced today, the whistleblowers in the Eastern District of Pennsylvania will receive $112 million, the whistleblowers in the District of Massachusetts will receive $27.7 million and the whistleblower in the Northern District of California will receive $28 million. Except to the extent that J&J subsidiaries have pleaded guilty or agreed to plead guilty to the criminal charges discussed above, the claims settled by the civil settlements are allegations only, and there has been no determination of liability
With the Trump Administration still claiming that no regulatory oversight is needed to monitor the US drug industry, that they can self-regulate, it appears that there will be no letup in the rampant “off-label: and unintended use marketing of pharmaceutical drugs in the United States. The one way that Big Pharma is held accountable is in the courtroom, although financial damages and penalties against the drug companies amounting to billions of dollars each year being awarded by juries, wont change FDA policy, it does provide a small amount of official recognition that there are ongoing abuses by the pharmaceutical industry in the USA.
(MASS TORT NEXUS MEDIA) It’s been called the most perilous drug crisis ever in the United States, the epicenter of the opioid epidemic, overdose deaths have quadrupled since 1999, killing more than 100 people every day. Pharmaceutical opiate pain relief is an essential clinical tool, but with physicians writing over 240 million opioid prescriptions to Americans every year, the potential for catastrophe is enormous. Now it seems to be coming into realization that the opioid crisis is here and the damage is catastrophic, gauged against the devastating impact on families and communities across the United States. How can we get the message out that addiction is now recognized as a medical, not a criminal problem, and new treatments are on the horizon. How do we protect the population from misusing opioids? An Opioid Crisis Summit featuring national leaders who are involved in the day to day efforts to fight this opiate crisis on all levels, including Ohio Lieutenant Governor Mary Taylor, Dr. Rahul Gupta, West Virginia Director of Public Health and others who are involved in providing real time solutions to the opiate epidemic as well as treating physicians and legal professionals who are active in offering solutions.
The Definitive Opioid Crisis Summit For All of America:
In the late 1990s, pharmaceutical companies reassured the medical community that patients would not become addicted to prescription opioid pain relievers, and healthcare providers began to prescribe them at greater rates. This subsequently led to widespread diversion and misuse of these medications before it became clear that these medications could indeed be highly addictive. Opioid overdose rates began to increase. In 2015, more than 33,000 Americans died as a result of an opioid overdose, including prescription opioids, heroin, and illicitly manufactured fentanyl, a powerful synthetic opioid.1That same year, an estimated 2 million people in the United States suffered from substance use disorders related to prescription opioid pain relievers, and 591,000 suffered from a heroin use disorder (not mutually exclusive).
What do we know about the opioid crisis?
Roughly 21 to 29 percent of patients prescribed opioids for chronic pain misuse them.
Between 8 and 12 percent develop an opioid use disorder.
An estimated 4 to 6 percent who misuse prescription opioids transition to heroin.
About 80 percent of people who use heroin first misused prescription opioids.
Opioid overdoses increased 30 percent from July 2016 through September 2017 in 52 areas in 45 states.
The Midwestern region saw opioid overdoses increase 70 percent from July 2016 through September 2017.
Opioid overdoses in large cities increase by 54 percent in 16 states.
Quarterly rate of suspected opioid overdose, by US region
Source: Centers for Disease Control and Prevention.
This issue has become a public health crisis with devastating consequences including increases in opioid misuse and related overdoses, as well as the rising incidence of neonatal abstinence syndrome due to opioid use and misuse during pregnancy. The increase in injection drug use has also contributed to the spread of infectious diseases including HIV and hepatitis C. As seen throughout the history of medicine, science can be an important part of the solution in resolving such a public health crisis.
The Opioid Crisis Summit Agenda
An unprecedented group of elected officials, political and medical experts, and academic leaders from around the country are set to examine the crisis and offer insight and solutions.
On July 21-22, 2018, the definitive Opioid Crisis Summit presented by Mass Tort Nexus will convene a symposium to present a firsthand account as to the depth and severity of the crisis. The research team at Mass Tort Nexus has brought together influential speakers including the Lieutenant Governor of Ohio, Mary Taylor; State Attorney for Palm Beach County Florida, Dave Aronberg, Esq.; Director of Public Health, State of West Virginia, Rahul Gupta, MD; Executive Director, Novus Medical Detox Centers, Kent Runyon; The Amy Winehouse Project Addiction Recovery Center, Susan Anderson and Blades Williamson; Opioid Crisis Advocate, Stephen Gelfand, MD and Opioid Crisis Expert, John Ray. These speakers are coming together to give our attendees a firsthand look at just how dramatic the impact of the opioid crisis is within our communities.
Summit attendees including attorneys, elected officials and healthcare officials will be giving specific information regarding the legal aspects of the Opioid Crisis as well. This relates to the Opiate Prescription MDL 2804, where hundreds of counties, states and cities across the country have filed lawsuits against the opiate pharmaceutical industry as a whole. This includes key MDL 2804 leadership counsel who will discuss signing of both entity and individual cases, regarding case criteria, damage models and estimated timeframes for settlement. See MDL 2804 Opiate Prescription Litigation US District Court of Ohio, for the National Prescription Opiate Litigation docket information.
This level of professional expertise and real time awareness of the issues regarding the opioid crisis in the United States has never been assembled on a scale such as this and if you are wanting to get the most critical and complete information, please contact someone at Mass Tort Nexus before all seats are taken.