Upload
arete-zoe-llc
View
242
Download
4
Embed Size (px)
Citation preview
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Another drug from the same class, REZULIN (troglitazone), was already withdrawn from the market because of liver toxicity in 2000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