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

Transcription

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

2 Medical Device Prosecutions: A comparison of the Bard and Serono Cases Michael Loucks First Assistant U.S. Attorney District of Massachusetts Michael Loucks, First Assistant U.S. Attorney; the opinions expressed essed are personal and not those of the

3 Off Label Promotion Physician prescription of a product off- label is lawful Drug/Device company must obtain FDA approval to sell drug/device (approval depends on classification): Must demonstrate drug/device is safe and effective for intended use Drug/device must contain labeling reflecting, among other things, conditions of use

4 Labeling Is Critical Prior to approval, FDA reviews Proposed labeling: what mfgr is claiming to the intended user Specifics about risks and benefits; Results of animal, pre-clinical and clinical trials Evidence regarding safety and efficacy. 21 CFR (d).

5 Intended Use: 21 CFR The intent is determined by such persons' expressions or may be shown by the circumstances surrounding the distribution of the article. This objective intent may, for example, be shown by labeling claims, advertising matter, or oral or written statements by such persons or their representatives. It may be shown by the circumstances that the article is, with the knowledge of such persons or their representatives, offered and used for a purpose for which it is neither labeled nor advertised.

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

7 Post Approval Claims Claims in promotional labeling or advertising must be consistent with approved labeling. 21 CFR 202.1(e)(4). Issues Issues arise regarding: dissemination of reprints of articles Continuing medical education programs Sales and marketing brochures, statements

8 Factors relevant to prosecution What is the total marketplace for the approved uses? Is the company targeting doctors who do not treat persons with the intended medical issues? Does it have sales budgets for non-approved uses? Are employees paid bonuses for sales for non- approved uses? Did company seek FDA approval for other uses and not get it?

9 Relevant Factors Did the company choose not to seek FDA approval? Why not? To protect a future drug from generic competition? No data to demonstrate product is safe and effective? If company is using literature to support unapproved uses, does it claim the product is safe and effective for those uses? Does it employ consultants to push off label? Does it incent customers to prescribe off label?

10 C.R. Bard, Inc. Violations of the Food, Drug and Cosmetic Act in the distribution of adulterated heart catheters Several different Class III devices One device suffered a failure as a result of a use that was off-label Company made changes in devices after approval, without seeking new approvals from the FDA

11 C.R. Bard, Inc. Restriction in labeling: affected use Bard was marketplace leader (55% + ) Following the rules = loss of sales Marketing pamphlets, handouts, sales rep statements: all pushed off-label use Sales force, while aware of the label, not told the reason for restriction Doctors followed promotion, used device off-label

12 C.R. Bard, Inc. Criminal conduct: Company charged October 1993; pled guilty and was sentenced, April 1994, fined $30,500,000, which was then the highest criminal fine ever imposed in an FDCA case Two month, highly publicized jury trial of employees in Boston Federal Court, summer 1995

13 Serono Laboratories, Inc. Criminal conduct: Violations of the Food Drug and Cosmetic Act in the distribution of a drug, serostim, and a medical device, a bio-impedance impedance analysis machine Local headquarters in Boston, some criminal activities took place in Boston throughout late 1990s

14 Serono Conspired with a device maker to craft software to increase the number of patients diagnosed as suffering from the approved indication for Serostim Software never demonstrated as safe and effective to, and never approved by, the FDA Sales reps had device, performed tests directly on patients in doctor s s offices Device manufacturer, its president pled guilty during negotiations with Serono

15 Serono Conspired to offer kickbacks to physicians to prescribe Serostim All-expenses expenses-paid paid trip to Cannes France Sales managers given a target $$ goal of prescriptions to hit in short period Doctors told that if they prescribed certain number of scripts, they would get the trip One sales manager who participated has pled guilty; charges pending on others

16 Bard The 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.

17 Bard First 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.

18 Bard ISSUE: 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.

19 Bard The 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 his boss

20 Bard The 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."

21 Bard [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?

22 Serono Confronted with a rapidly diminishing market, Serono Labs 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.

23 Serono 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 Serostim should be prescribed and reimbursed.

24 Serono The "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 extracellular water. Depletion of LBM results in muscle weakness, organ failure, and death.

25 Serono 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."

26 Serono The 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, Serono Labs 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.

27 Serono Serono 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.

28 Serono Serono 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.

29 Serono The 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 Serostim prescriptions. 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.

30 Serono 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.

31 Pharmaceutical Industry Cases $885 million,, $290 million criminal, TAP $704 million, $136 million criminal, Serono $600 million, $200 million criminal, Abbott $430 million, $240 million criminal, Warner Lambert $355 million,, $63.9 million criminal, Astra Zeneca $344.5 million, $52.5 million criminal, Schering $257 million,, $6 million criminal, Bayer $150 million,, GlaxoSmithKline $137.5 million, Caremark RX $87.6 million,, GlaxoSmithKline $50 million, $30 million criminal, Genentech $49 million,, Pfizer $18.5 million, Dey Laboratories $14 million, Bayer Total paid/pending since 10/2001: $4,082,100,000 Criminal Fines paid/pending: $1,012,460,000