How ARIA Analyses Have Been Used by FDA

This page summarizes how select analyses conducted in Sentinel's Active Risk Identification and Analysis (ARIA) system have been used by FDA since Sentinel's official launch in February 2016. ARIA can contribute to FDA’s regulatory process in a variety of ways, such as contributing evidence to support a label change, respond to a Citizens Petition, or become part of an Advisory Committee deliberation. Information from ARIA can also provide evidence that alleviates concerns about a particular safety issue and might lead FDA to determine that no regulatory action is necessary based on the available information.

Each ARIA analysis listed below contributed in some material way to inform an important regulatory discussion or action. FDA makes decisions about drug safety issues based upon the totality of evidence. The listing of an ARIA analysis in the table means that Sentinel’s ARIA system was one important source of evidence considered.

 

Drug Name

Outcome Assessed

ARIA Analysis

Regulatory Determination / Use

Date Posted
Non-insulin antidiabetics
  • Duration of follow-up
  • Duration of use
Level 1

Feasibility assessment that supported an ARIA sufficiency determination to replace a sponsor postmarketing requirement (PMR) safety study for canagliflozin and renal cell carcinoma.

04/02/2019

Sodium-glucose cotransporter-2 (SGLT-2) inhibitors

  • Use in type 1 diabetes mellitus (T1DM)
  • Diabetic ketoacidosis (DKA)
Level 1

In response to clinical trials showing an increased risk of DKA with sotagliflozin in T1DM, FDA assessed off-label use of SGLT2 inhibitors (approved for use in T2DM) and real-world rates of DKA when used in patients with T1DM. Elevated rates of DKA with off label SGLT2 inhibitor use among patients with T1DM were seen compared to clinical trials. These findings were presented at the Advisory Committee meeting for sotagliflozin, and this helped inform the committee member discussion on the benefit-risk assessment.

04/01/2019

Dolutegravir (Tivicay and combination products Juluca, Triumeq)

  • Exposure in pregnancy
Level 1

FDA assessed the feasibility of conducting a postmarket study in Sentinel to further investigate preliminary results from an observational study suggesting a higher risk of neural tube defects among offspring of pregnant women using dolutegravir (see the related FDA Drug Safety Communication here). The Sentinel query identified insufficient product exposure in pregnant women to support a robust safety assessment.

03/28/2019

Phosphodiesterase type 5 (PDE5) inhibitors

  • Exposure in pregnancy
Level 1

Use of PDE5 inhibitors was assessed among reproductive age women, including among pregnant women, to investigate a concern arising from an international clinical trial.  FDA decided that no action is necessary at this time, based on available information.

03/18/2019
Uloric (febuxostat)
  • User characteristics
  • Duration of use
  • Switching between urate lowering therapies
Level 1

FDA conducted a study to further investigate a post-market clinical trial that identified an elevated risk of cardiovascular events. Sentinel was used to describe the real-world utilization of urate lowering therapies to help inform the committee’s determination that a population exists for whom the benefit-risk is favorable.

03/07/2019
Ranexa (ranolazine)
  • Seizures
Level 1, Level 2

Combined with evidence from the Centers for Medicare & Medicaid Services, risk of seizure was determined to be driven primarily by underlying comorbidities. FDA decided that no action is necessary at this time, based on available information.

01/03/2019
Multiple sclerosis (MS) drugs
  • Exposure before, during, and after pregnancy
Level 1

Contextualized enrollment and recruitment in MS pregnancy registries. Described patterns of drug use before, during, and after pregnancy.

12/6/2018
Interleukin-1/-6 inhibitors
  • Pulmonary arterial hypertension
  • Interstitial lung disease
Level 1

Feasibility assessment of ARIA to conduct a postmarket safety study. FDA decided that no action is necessary at this time, based on available information.

12/3/2018
Forteo (teriparatide)
  • Duration of use
Level 1

Contributed to the decision regarding continuation of sponsor Postmarket Requirement for teriparatide

11/30/2018
Medications for attention deficit hyperactivity disorder
  • Heart failure
  • Cardiomyopathy
Level 1

Follow up investigation of case reports of cardiac events after long term stimulant use. FDA decided that no action is necessary at this time, based on available information.

8/30/2018
Actemra (tocilizumab)
  • Exposure in pregnancy
Level 1

Provided information to evaluate reported difficulties in enrollment in ongoing pregnancy registry

8/7/2018
Multiple
  • Drug utilization in pregnancy to evaluate enrollment in pregnancy registries compared with spontaneous reports 
Prototype L1**

FDA is using these findings, in addition to input received from the 2014 FDA Public Meeting, to evaluate safety data collection in pregnant women

7/26/2018

Continuous or extended cycle oral contraceptives
  • Venous thromboembolism
Level 1, Level 2

FDA decided that no action is necessary at this time, based on available information.

3/5/2018
Sinuva (mometasone furoate)
  • Cataracts
  • Glaucoma
Level 1

Feasibility assessment of ARIA sufficiency to replace a sponsor postmarketing requirement (PMR) safety study

2/5/2018
None
  • Respiratory syncytial virus associated illness (RSV-AI)
Level 1

Epidemiological assessment of RSV-AI and patterns of health care utilization to help inform development of novel RSV therapeutics 

1/25/2018
TNF-alpha inhibitors
  • Exposure in pregnancy
Level 1

Drug Safety Label Change, Pregnancy and Lactation 

12/21/2017
Gadolinium-based contrast agents
  • Exposure in pregnancy
Level 1

Advisory Committee Presentation & FDA Drug Safety Communication

12/19/2017
Antipsychotic agents (including haloperidol injection)
  • Ischemic stroke
  • Hemorrhagic stroke
Level 1, Level 2

Sentinel data was used to support decisions around potential labeling changes for antipsychotics and stroke risk. FDA decided that no action is necessary at this time, based on available information.

12/8/2017
Ketoconazole oral tablets
  • Drug use trends after safety label change
  • Use in labeled indications
Level 1

Citizen Petition Response

12/4/2017
Keppra (levetiracetam)
  • Anaphylaxis
  • Angioedema
Level 1

Drug Safety Label Change, Warnings and Precautions

11/30/2017

How Mini-Sentinel Analyses Have Been Used By FDA

Drug Name

Outcome Assessed

Analysis

Regulatory Determination / Use

Date Posted

Intravenous iron products

  • Anaphylaxis
Protocol-based assessment

FDA decided that no action is necessary at this time, based on available information.

2/12/2018
Onglyza (saxagliptin) and Januvia (sitagliptin)
  • Hospitalized heart failure
Protocol-based assessment**

Advisory Committee Presentation 

2/2/2018
Onglyza (saxagliptin) and Januvia (sitagliptin)
  • Acute myocardial infarction
Protocol-based assessment**

Advisory Committee Presentation 

2/2/2018
Second generation antipsychotic agents
  • Metabolic effects in children (Type 2 diabetes, metabolic syndrome, weight gain)
Protocol-based assessment**

FDA decided that no new action on behalf of pediatrics is necessary at this time, based on available information.

2/2/2018
Xarelto (rivaroxaban)
  • Intracranial hemorrhage
  • Gastrointestinal bleed
  • Ischemic stroke
Level 3

FDA decided that no action is necessary at this time, based on available information.

1/24/2018
Olmesartan medoximil
  • Intestinal sprue
Level 1*

Safety Labeling Change, Warnings and Precautions; Drug Safety Communication

1/24/2018
Pradaxa (dabigatran etexilate)
  • Intracranial hemorrhage
  • Gastrointestinal bleed
Level 1*

FDA decided that no action is necessary at this time, based on available information.

1/24/2018

*This query was performed using Mini-Sentinel’s Modular Program 3, the precursor to an ARIA L1 analysis.

**Complete results are contained in the associated publications and/or final written reports.