Astra Zeneca Seroquel Settlement and Corporate Integrity Agreement

Under the Food, Drug and Cosmetic Act, a company must specify the intended uses of a product in its new drug application to the Food and Drug Administration (FDA).  Before a drug is approved the FDA must determine that the drug is safe and effective for the use proposed by the company, and once approved, the drug may not be marketed or promoted for off-label uses. 

Although doctors are permitted to prescribe any approved drug for off-label uses, it is illegal for drug makers to promote medications for any purpose not specifically approved by the F.D.A.

The FDA originally approved Seroquel in September 1997 for the treatment of manifestations of psychotic disorders.  In September 2000, FDA proposed narrowing the approval for Seroquel to the short term treatment of schizophrenia only.  In January 2004, the FDA approved Seroquel for short term treatment of acute manic episodes associated with bipolar disorder (bipolar mania).  In October 2006, the FDA approved Seroquel for bipolar depression.

During this time frame, an AstraZeneca employee (who just happens to also been the key witness in the Eli Lilly settlement) brought certain conduct to the attention of the government in 2004 and 2006, in which two separate qui tam actions were filed under the False Claims Act statutes in the U.S. District Court for the Eastern District of Pennsylvania. One of the investigations related to physicians who had participated in clinical trials. The other inquiry involved sales staff. Last October, the company reached an agreement in principle, and the final Settlement Agreement was reached and released this week. Within the agreement, the United States contended that AstraZeneca:

–   Promoted the unapproved uses by improperly, and unduly influencing the content of, and speakers, in company-sponsored continuing medical education (CME) programs;    

–   Engaged doctors to give promotional speaker programs on unapproved uses for Seroquel and to conduct studies on unapproved uses of Seroquel;   

–   Recruited doctors to serve as authors of articles that were ghostwritten by medical literature companies and about studies the doctors in question did not conduct;

–   Used those studies and articles as the basis for promotional messages about unapproved uses of Seroquel; and    

–   Violated the federal Anti-Kickback Statute by offering and paying illegal remuneration (e.g. travel, advising, speaking) to get doctors to prescribe Seroquel for unapproved uses.

The allegations were said to have taken place between January 2001 through December 2006, in which the DOJ noted that AstraZeneca promoted Seroquel to psychiatrists and other physicians for certain uses that were not approved by the FDA as safe and effective (including aggression, Alzheimer’s disease, anger management, anxiety, attention deficit hyperactivity disorder, bipolar maintenance, dementia, depression, mood disorder, post-traumatic stress disorder, and sleeplessness).  These unapproved uses were not medically accepted indications for which the United States and the state Medicaid programs provided coverage for Seroquel.

According to the settlement agreement, AstraZeneca targeted its illegal marketing of the anti-psychotic Seroquel towards doctors who do not typically treat schizophrenia or bipolar disorder, such as physicians who treat the elderly, primary care physicians, pediatric and adolescent physicians, and in long-term care facilities and prisons. Reports have indicated that the drugs have caused rapid weight gain in children, and side effects including deaths.

As a result of the settlement, AstraZeneca has completed a deal to pay $520 million, of which, the federal government will receive $301,907,007 from the civil settlement, and the state Medicaid programs and the District of Columbia will share up to $218,092,993 of the civil settlement, depending on the number of states that participate in the settlement.

Various media sources have noted that AstraZeneca has now become the fourth pharmaceutical giant in the last three years to admit to federal charges of illegal marketing of antipsychotic drugs (Pfizer paid $2.3 billion last September for off-label marketing of the painkiller Bextra and other drugs; Eli Lilly paid $1.4 billion in January 2009 to settle investigations into illegal marketing of its antipsychotic drug Zyprexa; and Bristol-Myers Squibb and a subsidiary paid $515 million to settle federal and state investigations into marketing of its antipsychotic drug Abilify).

These settlements are significant considering antipsychotics have surpassed cholesterol-lowering drugs to become the nation’s top-selling category of medications, accounting for $14.6 billion of the nation’s $300 billion in drug spending last year, according to the research firm IMS Health. For Seroquel, the fifth-best-selling drug in the United States last year according to IMS, the impact of this agreement will be significant.

In addition to this settlement, AstraZeneca has already paid $656 million to defend itself in court against more than 25,000 civil lawsuits, and those cases are only recently beginning to reach trial. Throughout these legal matters, the company has argued that people who were found to have diabetes after taking Seroquel already had diabetes or had existing conditions that made them at high risk of the disease.

The company will also sign a Corporate Integrity Agreement (CIA) between AstraZeneca and the Office of Inspector General of the Department of Health and Human Services, although they will most likely not face criminal charges. The five-year CIA requires that:

· A board of directors committee annually review the company’s compliance program and certify its effectiveness;    

· Certain managers annually certify that their departments or functional areas are compliant;      

· AstraZeneca send doctors a letter notifying them about the settlement; and    

· The company post on its website information about payments to doctors, such as honoraria, travel or lodging. 

If the company violates the CIA, AstraZeneca is subject to exclusion from Federal health care programs, including Medicare and Medicaid, as well as monetary penalties for less significant breaches.

Accordingly, this recent settlement is part of the government’s emphasis on combating health care fraud and another step for the Health Care Fraud Enforcement Action Team (HEAT) initiative, which was announced by Attorney General Holder and Secretary Sebelius in May 2009.  Since January 2009, the partnership between the two departments has recovered almost $2.8 billion since January 2009 in cases involving fraud against federal health care programs, with an overall total of $3.75 billion.

CME

The CIA also has specific provisions dealing with continuing medical education (CME) regarding sponsorship and funding of medical education grants, which states that within 120 days after the Effective Date:

· Funding and/or sponsorship of, or participation in, any Third Party Educational Activity complies with all applicable Federal health care program and FDA requirements;

· Funding of, satisfies all applicable Federal health care program and FDA requirements;

· AstraZeneca and any AstraZeneca Affiliate disclose its financial support of the Third Party Educational Activity;

· AstraZeneca disclose any financial relationships with faculty, speakers, or organizers at a Third Party Educational Activity

· A third party must agree to disclose the company’s financial support of the Third Party Educational Activity and to require faculty, speakers, or organizers at such Activity to disclose any financial relationship with the applicable AstraZeneca entity;

· The Third Party Educational Activity have an educational focus;

· The content, organization, and operation of the Third Party Educational Activity be independent of the AstraZeneca entity’s control;

· AstraZeneca or the AstraZeneca Affiliate support only Third Party Educational Activity that is non-promotional in tone/nature; and

· AstraZeneca’s or any AstraZeneca Affiliate’s support of a Third Party Educational Activity must be contingent on the provider’s commitment to provide information at the Third Party Educational Activity that is fair, balanced, accurate and not misleading;

In addition to these requirements, the CIA maintains that at least one hour of General Training will be required for to each Covered Person, including Third Party Educational Providers. This training, at a minimum, will explain AstraZeneca’s CIA requirements; and AstraZeneca’s U.S. Compliance Program, including the Code of Conduct. The training will also include updates about AstraZeneca’s conformance with the requirements of its U.S. Compliance Program

Under the CIA, AstraZeneca must also create a Non-Promotional Monitoring Program to monitor medical education grants. The agreement notes that the company has already established a Medical Education Grants Office (MEGO) within its Medical Affairs Department as the exclusive mechanism through which requestors may seek or be awarded grants for independent medical education activities. There will also be a Grants Monitoring Program created by the CIA, which the company will use to:

· Conduct audits for each Reporting Period of at least 60 medical education grants;

· Select grants for review both on a risk-based targeting approach and on a sampling approach;       

· Allow U.S. compliance personnel conducting the Grants Monitoring Program to review proposal documents (including grant requests), approval documents, contracts, payments and materials relating to MEGO’s review of the requests, and documents and materials relating to the grants and any events or activities funded through the grants in order to assess whether the activities were conducted in a manner consistent with AstraZeneca’s Policies and Procedures.

AstraZeneca represents that its sales and marketing departments have no involvement in, or influence over, the review and approval of medical education grants. Grant requests are submitted through an on-line process and requests are processed in accordance with standardized criteria developed by MEGO.

From all these requirements, AstraZeneca will post on a bi-annual basis on its company website the following information with respect to both medical education grants and charitable contributions:

1)    The recipient organization’s name;    

2)    A brief description of the program for which the grant or charitable contribution was requested; and   

3)    The amount of the grant or charitable contribution.

Lastly, AstraZeneca must notify the OIG in writing at least 60 days prior to any change in the substance of its policies regarding the funding of medical education grants and charitable contributions or posting of the above-referenced information relating to such funding.

Clinical Trials

With regards to clinical trials, the CIA requires researchers to enter into written agreements with AstraZeneca:

· Describing the scope of the clinical research or other work to be performed;    

· The fees to be paid; and  

· Compliance obligations for the Researchers.

Accordingly, under the agreement, researchers will be paid according to a centrally managed, pre-set rate structure that is determined based on a fair-market value analysis conducted by AstraZeneca. The company will also have to create an annual Researcher budgeting plan to identify the budgeted amounts to be spent on Researcher-related activities during the year. This budget will be reviewed to ensure that Research arrangements and related events are used for legitimate purposes in accordance with AstraZeneca Policies and Procedures.

Finally, AstraZeneca will continue to post clinical study information as described above on the NIH website and the company’s website throughout the term of this CIA.

Comment

The Astra Zeneca settlement and corporate integrity agreement show an evolution in these types of settlements.

Documents

Settlement Agreement

Corporate Integrity Agreement

Press Release from U.S. Attorney’s Office

Press Release from HHS