Michael Loucks, First Assistant U.S. Attorney; the ... · Michael Loucks, First Assistant U.S. Attorney; the opinions expressed are personal and not those of the Department of Justice.

Michael Loucks, First Assistant U.S. Attorney; the opinions exprMichael Loucks, First Assistant U.S. Attorney; the opinions expressed are personal and not those of essed are personal and not those of the Department of Justice.the Department of Justice.

Michael Loucks, First Assistant U.S. Attorney; the opinions exprMichael Loucks, First Assistant U.S. Attorney; the opinions expressed are personal and not those of essed are personal and not those of the Department of Justice.the Department of Justice.

Medical Device Medical Device Prosecutions:Prosecutions:

A comparison of the A comparison of the Bard and Bard and SeronoSerono CasesCases

Michael Loucks Michael Loucks First Assistant U.S. First Assistant U.S.

Attorney Attorney District of MassachusettsDistrict of Massachusetts

Michael Loucks, First Assistant U.S. Attorney; the opinions exprMichael Loucks, First Assistant U.S. Attorney; the opinions expressed are personal and not those of the essed are personal and not those of the Department of Justice.Department of Justice.

Off Label PromotionOff Label Promotion

Physician prescription of a product offPhysician prescription of a product off--label is lawfullabel is lawfulDrug/Device company must obtain FDA Drug/Device company must obtain FDA approval to sell drug/device (approval approval to sell drug/device (approval depends on classification):depends on classification):

Must demonstrate drug/device is safe and Must demonstrate drug/device is safe and effective for intended useeffective for intended useDrug/device must contain labeling reflecting, Drug/device must contain labeling reflecting, among other things, conditions of useamong other things, conditions of use


Labeling Is CriticalLabeling Is Critical

Prior to approval, FDA reviewsPrior to approval, FDA reviewsProposed labeling: what Proposed labeling: what mfgrmfgr is claiming to is claiming to the intended userthe intended userSpecifics about risks and benefits; Specifics about risks and benefits; Results of animal, preResults of animal, pre--clinical and clinical clinical and clinical trials trials Evidence regarding safety and efficacy. 21 Evidence regarding safety and efficacy. 21 CFR 201.100(d).CFR 201.100(d).


Intended Use: Intended Use: 21 CFR 201.12821 CFR 201.128

The intent is determined by such persons' The intent is determined by such persons' expressions or may be shown by the circumstances expressions or may be shown by the circumstances surrounding the distribution of the article. This surrounding the distribution of the article. This objective intent may, for example, be shown by objective intent may, for example, be shown by labeling claims, advertising matter, or oral or written labeling claims, advertising matter, or oral or written statements by such persons or their representatives. statements by such persons or their representatives. It may be shown by the circumstances that the It may be shown by the circumstances that the article is, with the knowledge of such persons or article is, with the knowledge of such persons or their representatives, offered and used for a purpose their representatives, offered and used for a purpose for which it is neither labeled nor advertised.for which it is neither labeled nor advertised.


Intended UseIntended UseBut if a manufacturer knows, or has But if a manufacturer knows, or has knowledge of facts that would give him notice knowledge of facts that would give him notice that a device introduced into interstate that a device introduced into interstate commerce by him is to be used for conditions, commerce by him is to be used for conditions, purposes, or uses other than the ones for which purposes, or uses other than the ones for which he offers it, he is required to provide adequate he offers it, he is required to provide adequate labeling for such a device which accords with labeling for such a device which accords with such other uses to which the article is to be such other uses to which the article is to be put.put.


Post ApprovalPost ApprovalClaims in promotional Claims in promotional ““labelinglabeling”” or or advertising must be consistent with advertising must be consistent with approved labeling. 21 CFR 202.1(e)(4).approved labeling. 21 CFR 202.1(e)(4).Issues arise regarding:Issues arise regarding:

dissemination of reprints of articles dissemination of reprints of articles Continuing medical education programsContinuing medical education programsSales and marketing brochures, statementsSales and marketing brochures, statements


Factors relevant to prosecutionFactors relevant to prosecution

What is the total marketplace for the approved What is the total marketplace for the approved uses?uses?Is the company targeting doctors who do Is the company targeting doctors who do notnottreat persons with the intended medical issues?treat persons with the intended medical issues?

Does it have sales budgets for nonDoes it have sales budgets for non--approved uses?approved uses?Are employees paid bonuses for sales for nonAre employees paid bonuses for sales for non--approved uses?approved uses?

Did company seek FDA approval for other uses Did company seek FDA approval for other uses and not get it?and not get it?


Relevant FactorsRelevant FactorsDid the company choose not to seek FDA Did the company choose not to seek FDA approval? Why not?approval? Why not?

To protect a future drug from generic competition?To protect a future drug from generic competition?No data to demonstrate product is safe and No data to demonstrate product is safe and effective?effective?

If company is using literature to support If company is using literature to support unapproved uses, does it claim the product is unapproved uses, does it claim the product is safe and effective for those uses?safe and effective for those uses?Does it employ consultants to push off label?Does it employ consultants to push off label?Does it Does it incentincent customers to prescribe off label?customers to prescribe off label?


C.R. Bard, Inc.C.R. Bard, Inc.

Violations of the Food, Drug and Cosmetic Violations of the Food, Drug and Cosmetic Act in the distribution of adulterated heart Act in the distribution of adulterated heart catheterscatheters

Several different Class III devicesSeveral different Class III devicesOne device suffered a failure as a result of a One device suffered a failure as a result of a use that was offuse that was off--label label Company made changes in devices after Company made changes in devices after approval, without seeking new approvals from approval, without seeking new approvals from the FDAthe FDA


C.R. Bard, Inc. C.R. Bard, Inc.

Restriction in labeling: affected useRestriction in labeling: affected useBard was marketplace leader (55% + )Bard was marketplace leader (55% + )Following the rules = loss of salesFollowing the rules = loss of salesMarketing pamphlets, handouts, sales rep Marketing pamphlets, handouts, sales rep statements: all pushed offstatements: all pushed off--label uselabel useSales force, while aware of the label, not Sales force, while aware of the label, not told the reason for restriction told the reason for restriction Doctors followed promotion, used device Doctors followed promotion, used device offoff--labellabel


C.R. Bard, Inc.C.R. Bard, Inc.

Criminal conduct: 1987Criminal conduct: 1987--19901990Company charged October 1993; pled guilty Company charged October 1993; pled guilty and was sentenced, April 1994, fined and was sentenced, April 1994, fined $30,500,000, which was then the highest $30,500,000, which was then the highest criminal fine ever imposed in an FDCA casecriminal fine ever imposed in an FDCA caseTwo month, highly publicized jury trial of Two month, highly publicized jury trial of employees in Boston Federal Court, summer employees in Boston Federal Court, summer 19951995


SeronoSerono Laboratories, Inc.Laboratories, Inc.

Criminal conduct: 1996Criminal conduct: 1996--20022002Violations of the Food Drug and Cosmetic Violations of the Food Drug and Cosmetic Act in the distribution of a drug, Act in the distribution of a drug, serostimserostim, , and a medical device, a bioand a medical device, a bio--impedance impedance analysis machineanalysis machineLocal headquarters in Boston, some Local headquarters in Boston, some criminal activities took place in Boston criminal activities took place in Boston throughout late 1990sthroughout late 1990s


SeronoSeronoConspired with a device maker to craft Conspired with a device maker to craft software to increase the number of patients software to increase the number of patients diagnosed as suffering from the approved diagnosed as suffering from the approved indication for indication for SerostimSerostim

Software never demonstrated as safe and effective Software never demonstrated as safe and effective to, and never approved by, the FDAto, and never approved by, the FDASales reps had device, performed tests directly on Sales reps had device, performed tests directly on patients in doctorpatients in doctor’’s officess officesDevice manufacturer, its president pled guilty during Device manufacturer, its president pled guilty during negotiations with negotiations with SeronoSerono


SeronoSerono

Conspired to offer kickbacks to physicians to Conspired to offer kickbacks to physicians to prescribe prescribe SerostimSerostim

AllAll--expensesexpenses--paid trip to Cannes France paid trip to Cannes France Sales managers given a target $$ goal of Sales managers given a target $$ goal of prescriptions to hit in short periodprescriptions to hit in short periodDoctors told that if they prescribed certain number Doctors told that if they prescribed certain number of scripts, they would get the trip of scripts, they would get the trip

One sales manager who participated has pled One sales manager who participated has pled guilty; charges pending on othersguilty; charges pending on others


BardBardThe labelling provided to the FDA stated "Warning: Do Not Turn the Probe II device more than one rotation (360 degrees) in the same direction."

In fact, physicians were routinely being told by USCI personnel in the human clinicals that the device could be rotated 15 times.


BardBardFirst Objective: to verify that the Probe B design may be freely rotated and/or define when rotation compromises performance.

Dr. King was anxious to use the redesigned probe in this case and checked with me several times to be sure... we could turn it ten revolutions in one direction.


BardBardISSUE: We have recently had several Probe failures involving the loss of the spring tip (New Probe) and/or loss of the entire neck extension (2 Regular probes).

Physicians have been told "You can twist this thing 15 times and nothing will happen."

We need to consider the risks, engineering evaluations, market release and training issues before this product hits the market.


BardBardThe issue that we have been struggling with is how to remain committed to that precept [quality product] when we face the daily struggle of meeting sales objectives in a highly competitive environment. I agree that we have slipped. I concur that several of the decisions including the Mini, 3 Lumen and Probe were weighted too heavily with commercial interest.

Memo by President of the catheter division to Memo by President of the catheter division to his boss his boss


BardBardThe USCI culture was "not keeping corporate in New Jersey totally informed about what was going on.""Cutting corners became a way of life. That became a way of life. Or, we'll do the testing on human beings. None of us in this room would want to be the person tested on. We cut corners which were bad. We knew things were happening and we didn't tell corporate."


BardBard[W]e never give our people enough time to accomplish their jobs but rather rush the program to the next step before it is ready. .. We feel enormous pressure from upper management and marketing to continue despite the unsolved technical issue. .. We chose not to address these design flaws but rather to begin production and fix these things on the way. We now find ourselves in the most uncomfortable position of trying to decide what to sell without adequate tests in place to identify the quality of our results. ... Test protocol: how was this missed? Were we so with the program that we failed to anticipate that something could go wrong? Does asking tough questions or making waves put one in the political shithouse?


SeronoSeronoConfronted with a rapidly diminishing market, SeronoLabs and others embarked on a campaign to "redefine" AIDS wasting immediately following the launch of Serostim.

The company sought to expand the definition of AIDS wasting to encompass newly emerging symptoms exhibited by AIDS patients and promoted Serostim to treat these symptoms, even though the FDA had not evaluated or approved the safety and efficacy of the drug to treat them.


SeronoSerono

Despite knowing that the devices lacked FDA approval, Serono Labs promoted the use of BIA technology to physicians, patients, state Medicaid agencies and other third-party payors as an appropriate tool for determining whether Serostimshould be prescribed and reimbursed.


SeronoSeronoThe "clinical pharmacology" section of the product label described the disease state as follows:

AIDS-associated wasting is a metabolic disorder characterized by abnormalities of intermediary metabolism resulting in weight loss, inappropriate depletion of lean body mass (LBM), and paradoxical preservation of body fat. LBM includes primarily skeletal muscle, organ tissue, blood and blood constituents, and both intracellular and extracellularwater. Depletion of LBM results in muscle weakness, organ failure, and death.


SeronoSerono

The label further described the studies Serono Labs had performed on the drug and made it clear that the trial showing Serostim to be effective had been performed on patients with "AIDS wasting" who had "unintentional weight loss of at least 10% or weighed less than 90% of the lower limit of ideal body weight."


SeronoSeronoThe FDA objected to Serono Labs’s request that the confirmatory study lower the 10% weight loss figure as the benchmark of AIDS wasting; in response, SeronoLabs agreed to continue to use the 10% weight loss criterion. Serono Labs also raised with FDA the possibility of measuring changes in “body cell mass,” or “BCM,”instead of “lean body mass,” or “LBM,” in the study. Following objections by FDA to measuring changes in BCM rather than LBM during the Phase IV confirmatory trial, Serono Labs dropped the proposal to measure BCM and agreed to continue to measure changes in LBM in the confirmatory trial.


SeronoSeronoSerono Labs launched a campaign to "redefine AIDS wasting" in order to create a market for Serostim by expanding the disease state for which Serostim could be prescribed as a treatment. The sales force made sales presentations and disseminated literature stating that wasting was being "masked" by weight gain in the post-HAART era and that patients were still experiencing AIDS wasting following the advent of HAART, despite an absence of weight loss.


SeronoSeronoSerono Labs claimed it was not possible to tell whether patients were wasting simply by looking at them. According to Serono Labs, even if patients were not losing weight - and had actually gained weight - there could be no certainty that they were free from the wasting syndrome. According to Serono Labs, given current technology, BCM could only be measured by performing BIA tests in tandem with certain software. Serono Labs’s central marketing tool became the BIA test.


SeronoSeronoThe company’s sales force aggressively sought out opportunities to market Serostim directly to AIDS patients by performing BIA tests on them whenever possible. Clinical consultants were required to report - and were even rated on - their "BIA hit rate," i.e., the number of BIAs performed that resulted in Serostimprescriptions. To meet sales goals, clinical consultants devised methods of manipulating the test results by changing the patient's height, weight, and the numerical "resistance" and "reactance" readings generated by the BIA itself, so that the test showed patients to be wasting who, in fact, were not.


SeronoSerono

One regional sales director urged her sales force to say that the patients could be "rotting inside," likening the inability to readily detect wasting in the post-HAART era to the difficulty of distinguishing between a low-fat and regular-fat muffin.


Pharmaceutical Industry CasesPharmaceutical Industry Cases$885 million$885 million, $290 million criminal, TAP, $290 million criminal, TAP$704 million, $704 million, $136 million criminal, $136 million criminal, SeronoSerono$600 million, $600 million, $200 million criminal, Abbott $200 million criminal, Abbott $430 million, $430 million, $240 million criminal, Warner Lambert$240 million criminal, Warner Lambert$355 million$355 million, $63.9 million criminal, , $63.9 million criminal, AstraAstra ZenecaZeneca$344.5 million, $344.5 million, $52.5 million criminal, Schering $52.5 million criminal, Schering $257 million$257 million, $6 million criminal, Bayer, $6 million criminal, Bayer$150 million$150 million, GlaxoSmithKline, GlaxoSmithKline$137.5 million, $137.5 million, Caremark RXCaremark RX$87.6 million$87.6 million, GlaxoSmithKline, GlaxoSmithKline$50 million, $50 million, $30 million criminal, $30 million criminal, GenentechGenentech$49 million$49 million, Pfizer, Pfizer$18.5 million, $18.5 million, DeyDey LaboratoriesLaboratories$14 million, $14 million, BayerBayer

Total paid/pending since 10/2001: $4,082,100,000Criminal Fines paid/pending: $1,012,460,000

Michael Loucks, First Assistant U.S. Attorney; the ... · Michael Loucks, First Assistant U.S. Attorney; the opinions expressed are personal and not those of the Department of Justice.

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