AVANDIA CASE STUDYCASE STUDY FOR APPLICATION OF

STAMP

Case study outlineAVANDIA (rosiglitazone) was approved in the U.S. for the treatment of diabetes in 5/1999

Another drug from the same class, REZULIN (troglitazone), was already withdrawn from the market because of liver toxicity in 2000

In May 2007, concerns over AVANDIA cardiovascular safety caused public scandal- Dr Steve Nissen published meta-analysis of available studies in NEJM- The manuscript was leaked to the drug’s manufacturer, GlaxoSmithKline- Congressional hearing on FDA’s role in Avandia safety evaluation - U.S. Senate Finance Committee launched extensive investigation FDA demanded

inclusion of numerous warnings on the drug label later that yearIn 2/2010 U.S. Senate Finance Committee released report on GSK actions In 9/2010 the FDA severely restricted Avandia use, requested independent review of RECORD trial, and demanded GSK to amend REMS. EMA suspended Avandia saleIn 6/2011 French and German Agencies suspended the use of ACTOS (pioglitazone)In 11/2011 Avandia-Rosiglitazone Medicines Access Program implemented as part of REMSIn 7/2012 GSK agreed to pledge guilty and pay $3 billion to settle criminal and civil liabilityIn 2012 GSK agreed to pay $700 million to settle more than 15,000 patients’ claimsIn 2013 the FDA restrictions on Avandia were lifted

Case for regulatory reform in post-market surveillance

Interventional studies by phase and sponsor

ClinicalTrials.gov

Observational studies by phase and sponsor

ClinicalTrials.gov

All RSG studies by phase and sponsorClinicalTrials.gov

All RSG studies by location

ClinicalTrials.gov

GSK sponsored Phase III studies for T2DMClinicalTrials.gov

Phase III studies for T2DM

GSK registry

Phase III interventional studies for T2DM

Conducted by other industry sponsors

Number of subjects enrolled in clinical trials by condition

OVERVIEW OF ROSIGLITAZONE CLINICAL TRIALS

DIABETES MELLITUS IS A SERIOUS DISEASE• its complications affect about 20 million Americans• Prediabetes affects about 86 million Americans • Diabetes remains the 7th leading cause of death in the U.S.

COMPLICATIONS OF DIABETES• Hypoglycemia, Hypertension, Dyslipidemia, Cardiovascular conditions including heart

attack and stroke, kidney disease, and amputations• Advanced glycosylation end products play a role in damaging blood vessels, which can

lead to diabetes complications like neuropathy, nephropathy, and retinopathy• Glycosylated Hemoglobin is used as surrogate endpoint in diabetes medications studiesBiguanides and Thiazolidinediones improve insulin sensitivity as their primary effect• Troglitazone (Rezulin), was the first drug in this class to be marketed, but was removed

from the market in both the U.S. and U.K. because of hepatotoxicity• Two thiazolidinediones: rosiglitazone (Avandia, GSK) and pioglitazone (Actos, Takeda)

are currently available in the U.S. used as monotherapy or with sulfonylureas (SFU), metformin (MET), or insulin (INS)

MEDICAL NEED

• Pivotal studies (vs placebo / comparator) • Long term safety studies for registration• Local registration studies• Phase IIIA extension studies• Post marketing study commitments

• Studies intended to support publication, claims or to prepare launch, which start before approval but are not intended for Regulatory submissions

DEFINITIONS of PIVOTAL STUDIES

Phase IIIAA Pivotal study that is a trial designed & executed to get statistically significant evidence of efficacy and safety as required by HAs for NDA approval. - Studies aimed to include claims into the

label - Post-marketing commitments.

Phase IIIBA study started prior to approval and whose primary intention is support of publications rather than registration or label changes. The results are not intended to be included in the submission dossier.

PIVOTAL STUDIES NDA submission

ROSIGLITAZONEmonotherapy

ROSIGLITAZONE + METFORMIN MEDICAL REVIEW 011 CV SAFETY

Boxed Warning: Congestive heart failure, myocardial ischemiaIndications: RSG + insulin and nitrates not recommendedContraindications: NYHA III/IV heart failureWarnings: Cardiac Failure, Myocardial Ischemia, Fractures

Boxed Warning: myocardial infarction (instead of ischaemia)Indications: RSG + with insulin and nitrates not recommendedContraindications: NYHA III/IV heart failureWarnings: Cardiac Failure, Myocardial Ischemia, Fractures

1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014

Proposed: For the treatment of T2DM as monotherapy and in combination with metforminApproved: Monotherapy as an adjunct to diet and exercise in combination with metformin

+ combination with sulfonylurea

+ combination with insulin Warning: can cause fluid retention, which may exacerbate or lead to heart failure.

+ combination with metformin plus sulfonylurea

Patients who are already taking AVANDIA, or are unable to achieve adequate glycemic control on other diabetes medications, and have decided not to take pioglitazone for medical reasons. Patient counseling information and medication guide.

REMS Access program

Boxed Warning, AVANDIA-Rosiglitazone Medicines Access Program removal Indications: patient population restrictions removalWarnings: Cardiac Failure, MACE Rosiglitazone REMS Program removal

NDA 11/1998 Phase II/III• 4,598 patients• 3,673 patient years of exposure

AVANDIA LABELLING CHANGES 1999-2014

AVANDIA CURRENT U.S. LABELLING

“RISK” has different meaning for different people

CORPORATE PERSPECTIVEPUBLIC PERSPECTIVE

Definition and perception of risk depends on definition of vital interest

Intellectual property Limited access and cost

Criminal and civil liabilities

Public scandals

Regulatory limitations

Control over information flow

Adverse findings

Side effects and declared risks

Undetected hazards

Limitations on liability for injury

Delays in regulatory action

Healthcare system benefits

STAKEHOLDER VALUE ACCESS TO SAFE AND EFFECTIVE DRUGS

REGULATORS

Curbed fundingLimits on staffing Public scandals

Oversight failures Lost legal casesLoss of control

Corruption Loss of credibility

RISK EVALUATION & MITIGATION

Shareholders seek R.O.I

SB/GSK STRATEGY: • Initial indication covers new DM patients who require life-long treatment• Inclusion of combinations with SFU and INS• High-risk groups (CHF NYHA III/IV) excluded from CTs, not excluded on label • Warnings and Precautions included with long delay• Restrictions on target population only implemented in 11/2011 (REMS)• Eventual removal of the restrictions on patient access (2013)

MEANS & TOOLS: • Clinical trials delayed, underpowered, not designed to address concerns over

cardiovascular safety • Extensive and selective publication of the findings in medical journals • Intimidation of scientists who voiced concerns (U.S. Senate investigation)

CONSEQUENCES: • Disputed design of some of the studies (RECORD – led to EMA withdrawal)• ADOPT study requested by the FDA could not answer CV safety questions• Undisclosed CV risks which led to a series of restrictions and criminal charges• Concerns over CV safety led to thousands of lawsuits Outcome: Avandia remained on the market for almost the entire period covered by

patents without serious restrictions

GSK RISK MITIGATION STRATEGY

SmithKline Beecham (2000) GlaxoSmithKline

• At least 165 articles in scientific journals

• 23 studies – number of publications by the company not stated

• 9 studies not published at all• 3 studies published extensively

STUDY ID Publications49653/011 2049653/020 1449653/080 1249653/024 1149653/094 849653/015 749653/048 (ADOPT) 649653/127 6BRL-049653/231 (RECORD) 5AVD107642 (DREAM) 5

• Extensive selective publication of some studies models PERCEPTION within the scientific community

• Aggressive marketing in popular press drives demand

• Off-label marketing and direct to consumer advertising were important topics in the 6/2007 Congressional hearing as one of the key issues, addressed via False Claims Act

• Corporate free speech (U.S. v. Caronia, 2012) blurs the issue

• Dr Buse and Dr Nissen both intimidated by GSK for publishing their concerns, threatened by lawsuits

• Federal, state, and civil lawsuits against GSK regarding illegal marketing, failure to report certain safety information, and pricing issues

BLURRED LINE BETWEEN SCIENCE & MARKETING

POST-MARKET STUDIES & PUBLICATIONS

Source: ClinicalTrials.gov (11/11/2014)

RESPIRATORY (4 trials, phases 0, I, II, II/III) • Asthma (3), lung inflammation (1)

MUSCULOSKELETAL (4 trials, phase II) • Bone density (3), rheumatoid arthritis (1)

ONCOLOGY (11 trials, phases I, II, III) • Prostate AC, bladder cancer, RCC• Head and neck cancer, thyroid cancer• T-Cell lymphoma, mycosis fungoides• Solid tumors, sarcoma, breast cancer• Brain and CNS tumors

CNS (11 trials, phases I, II, III) • Alzheimer disease, cognitive impairment (15)• Schizophrenia (1), depression/bipolar (1)

Uro-genital (11 trials, phases I, II, II/III, III) • Glomerulosclerosis (2), nephropathy (4)• Kidney transplant (1)• Polycystic ovary syndrome (3) • Endometriosis (2)

GIT (7 trials, phases I/II, II, III, IV) • IBD, ulcerative colitis (3)• Fatty liver (4)

INFECTIONS (16 trials, phases I, I/II, II, IV) • HIV associated mtb syndrome (11)• Malaria (2)• Hepatitis C (3)

OTHER (5 trials, phases I, II, III) • Cushing’s disease (1)• Cystic fibrosis (1)• Erectile dysfunction (1)• Chemotherapy-induced nausea (1)• Multiple organ failure (1)

HEALTHY VOLUNTEERS (11 trials, phase I)

NEW INDICATIONS TESTED1999: Type 2 Diabetes Mellitus

Source: ClinicalTrials.gov (11/11/2014)

Refinement of target population for the treatment of T2DM & Metabolic Syndrome

Cardiovascular safety & efficacy studies

• Angina pectoris & Metabolic syndrome • Congestive heart failure• Coronary artery disease• Dilated cardiomyopathy• Inhibition of Platelet Aggregation • Atherosclerosis• Stroke• Hypercholesterolemia• Ischemia-Reperfusion Injury• Hypertension

• T2DM• Impaired Glucose Tolerance• Type 1 Diabetes in teenagers• Dyslipidemia• Diabetic nephropathy• Pre-diabetes• Metabolic Syndrome• Non-alcoholic Fatty Liver Disease• Obesity; Adipose Cell Turn Over• Insulin Resistance• Latent Autoimmune Diabetes in Adults

PHASE IV SAFETY & EFFICACY

DREAM

BARI 2D113332

ADOPT RECORD

TIDE

Requested as condition of approval

by the FDA8/2006

Requested by EMA to determine CV safety

12/2008

Progression to T2DMSponsor: Dr Herzel

9/2006

Risk of Fractures3/2010

Progression to T2DMSponsor: Dr Herzel

9/2006

CV outcome on TZD & vitamin D

halted 9/2010

IMPORTANT SAFETY STUDIES

Published in May 2007, triggered by publication of DREAM which showed increased CV events Examined data from GSK studies registry at study level, not patient levelIdentified increased potential risk of heart attack with Avandia CV Safety not a new concern:

– FDA required post-market study as condition of approval, worried about CHF and hepatotoxicity– Dr Buse (2000) worried about Avandia effects on cholesterol and lipid profile– WHO issued a warning on CV safety of TZDs in 2/2003– In 2005 GSK conducted internal review of CV safety, found increased risk of myocardial ischemia

CONSEQUENCES• The issue was widely publicized in both scientific and popular press, popular demand to withdraw the drug • Attacks against Dr Nissen and Dr Buse questioning their motivations and professional integrity• 6/2007 Congressional hearing, both Dr Buse and Dr Nissen testified, just like FDA officials• Both FDA and GSK both performed their own patient-level meta-analyses. Very similar findings, not

published, communicated to the HR Committee under Oath in 6/2007. • U.S. Senate Finance Committee investigation (report 2/2010)

DR NISSEN’S META-ANALYSIS

Committee on oversight and government reformHouse of Representatives 110th Congress First Session | June 6, 2007 | Serial No. 110-76

WITNESS STATEMENTS: Steven Nissen, Department of Cardiovascular Medicine, Cleveland Clinic John B Buse, University of North Carolina School of Medicine Bruce M Psaty, CV Health Research Unit, University of WA, Center for Health Studies, WAMoncef M Slaoui, chairman, research and development, GlaxoSmithKlineAndrew von Eschenbach, John K. Jenkins, Gerald Dal Pan, Food and Drug Administration

KEY POINTS: • DM is a serious disease, false alarm would cause harm to patients• Avandia lowers blood glucose, but there are concerns about CV safety (CHF, MI, lipids)• Large PM study a condition of FDA approval but did not insist on it (ADOPT, TIDE)• CV safety repeatedly questioned (Dr Buse, WHO, DREAM trial, Dr Nissen)• RECORD study required by EMA. Results inconclusive, completed 2009• AVANDIA: case study for reform of post-market surveillance. • FDA needs more resources, preferably from public funds rather than PDUFA• Post-market surveillance should be moved to a different group• How effective is FDA in collecting and analyzing data, how sensitive these tools are• Direct to consumer advertising a serious issue, not enough resources to address that

Intimidation of Dr Buse – “Avandia Renegade” by GSK in relation with Avandia CV safety was brought to the U.S. Senate Finance Committee in November 2007

FDA ROLE IN THE EVALUATION OF AVANDIA SAFETY

U.S. SENATE FINANCE COMMITTEE REPORT

• For the past 4 years, the staff of the Senate Committee on Finance (Committee) has been examining allegations that pharmaceutical companies attempt to manipulate science to improve the marketability of drugs, potentially at the expense of public safety.

• These allegations include intimidating scientists, ghostwriting studies for academic researchers, suppressing studies that may show that a drug could be dangerous, and selecting data to publish results that favor one product over another.

• Investigators reviewed 250,000 pages of documents provided by GSK, FDA and others• Investigation was triggered by Dr Nissen’s meta-analysis which linked Avandia to heart

attacks• GSK executives attempted to intimidate independent physicians, like Dr Nissen and Dr

Buse, and sought ways to downplay cardiovascular risks of Avandia.• GSK also sought to counter the study’s findings by quickly releasing preliminary results

from RECORD• Despite attempts to highlight the RECORD study, it appears that GSK knew for years that

the study was ‘‘underpowered,’’ i.e., the study did not provide sufficient data to test for cardiovascular safety. And executives appeared more concerned about designing a study to limit competition from ACTOS.

• Company was aware of the potential cardiovascular risks associated with Avandia sinc at least late 2004 or early 2005

Extensive investigation by special agents HHS-OIG, FDA, DOD, VA, DOL, TRICARE and FBI• GSK agreed to plead guilty and to pay $3 billion to resolve its criminal and civil liability

• unlawful promotion of Rx drugs Paxil, Wellbutrin, and Avdair• failure to report certain safety data on CV risks of Avandia• civil liability for alleged false price reporting practices

• Corporate integrity agreement with HHS-OIG to increase accountability and transparency

Criminal Plea Agreement• Between 2001 and 2007, GSK failed to report certain safety data about Avandia to

the FDA, including data regarding PM studies about CV safety of Avandia. • GSK pled guilty and paid $242,612,800 for its unlawful conduct concerning Avandia.

Civil Settlement Agreement• False and misleading statements concerning the safety of Avandia• Reporting false best prices under the Medicaid Drug Rebate Program• This settlement resolves 4 federal lawsuits under whistleblower provisions of the FCA

Health Care Fraud Prevention and Enforcement Action Team (HEAT) Initiative was announced in May 2009 by Attorney General Eric Holder and Kathleen Sebelius

DOJ release July 2, 2012

GSK PLED GUILTY, PAID $3 BILLION

Restrictions: 23 September 2010GSK will work with FDA to update rosiglitazone’s label and implement REMS for Avandia, Avandaryl and AvandametGSK will immediately cease promotion of rosiglitazone in all global marketsSafety review of Takeda’s pioglitazone (Actos®) for association with risk of bladder cancerSignificant restriction of the use of Avandia to patients with Type 2 diabetes who cannot control their diabetes on other medicationsClinical trial RECORD, which studied the cardiovascular safety of Avandia compared to standard diabetes drugs, to be reviewed by independent group of scientists because of questions about bias (DUKE)Clinical trial TIDE which compares Avandia to Actos and to standard diabetes drugs was halted

FDA RESTRICTIONS Restrictions: 25 November 2013

Recent data for rosiglitazone-containing drugs, such as Avandia, Avandamet, Avandaryl, and generics, do not show an increased risk of heart attack compared to the standard type 2 diabetes medicines metformin and sulfonylurea.

As a result, FDA is requiring removal of the prescribing and dispensing restrictions for rosiglitazone medicines that were put in place in 2010.

This decision is based on our review of data from a large, long-term clinical trial RECORD and is supported by a comprehensive, outside, expert re-evaluation of the data conducted by the Duke Clinical Research Institute (DCRI).

RISK EVALUTION AND MITIGATION STRATEGY

2008 2009 2010 2011 2012 2013 2014

12/2/2008AVANDARYL AVANDAMETMedication Guide and a timetable for submission of REMS assessments

5/18/2011AVANDIAAVANDARYL, AVANDAMETProposed modified REMS: Rev. Medication GuidesRisk of ischemic cardiovascular eventslisted in the labelingCommunication planETASUImplementation system Timetable for submission of REMS assessments

1/25/2013Conversion to a single shared REMS program that includes generics

11/13/2011AVANDIAAVANDARYL, AVANDAMETModified REMS: Communication plan REMS website - requirement for patients to be enrolled in the REMS Program

5/7/2014Most restrictions removed

9/16/2013Modified REMS: Package insert Medication Guide Description of tablets from “SB” to “GSK”

AVANDIA (rosiglitazone maleate)NDA 21-071

ETASU – Elements to assure safe use

5/30/2012 Modified REMS: Medication Guide ETASUImplementation system Timetable for REMS assessments

23/9/2010 Restrictions imposedInitial REMS with ETASU Approval: 05/18/2011 REMS launched: 11/04/2011Avandia-Rosiglitazone Medicines Access Program

• Healthcare providers must enroll in the if they wish to prescribe rosiglitazone medicines to outpatients or patients in long-term care facilities after November 18, 2011.

• After November 18, 2011, rosiglitazone medicine will only be available from specialized pharmacies.

• Enrollment in the Avandia-Rosiglitazone Medicines Access Program will be required for patients who wish to receive this medicine.

5/7/2014 Restrictions liftedThe FDA has determined that recent data for rosiglitazone-containing drugs, such as Avandia, Avandamet, Avandaryl, and generics, do not show an increased risk of heart attack compared to the standard type 2 diabetes medicines metformin and sulfonylurea. As a result, we are requiring removal of the prescribing and dispensing restrictions for rosiglitazone medicines that were put in place in 2010. This decision is based on our review of data from a large, long-term clinical trial and is supported by a comprehensive, outside, expert re-evaluation of the data conducted by the Duke Clinical Research Institute (DCRI).

RISK EVALUTION AND MITIGATION STRATEGY

NDA 21-071 AVANDIA (rosiglitazone maleate) NDA 21-410 AVANDAMET (rosiglitazone maleate and metformin hydrochloride) NDA 21-700 AVANDARYL (rosiglitazone maleate and glimepiride)

11/1998: NDA

FDA Approval

FDA Restrictions on Avandia prescription and dispensingregulatory decisions on RECORD and TIDE trials

PATENT EXPIRATION

Nissen’s Meta-analysis published in NEJM

Congressional hearing on FDA’s role in evaluation of safety of Avandia

U.S. Senate Finance Committee Investigation

FDA requires removal of the

2010 prescribing and dispensing

restrictions

1996: IND

REMS

LABELLING

4/20158/2008

TIMELINE

STUDIES

Dr Buse voiced concerns over Avandia’s CV safety

1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014

ADOPTDREAMBARI 2D

RECORD113332

TIDE

GSK pled guilty to criminal misconduct paid a $3 billion fine