• FDA Voice

The Case for Quality: Working with Stakeholders to Improve the Safety of Medical Devices for Patients

By: Howard Sklamberg, J.D., Jeffrey Shuren, M.D., J.D., and Melinda K. Plaisier, M.S.W.

Case for Quality (CfQ) : To identify and promote practices that will result in higher quality devices. 3 priorities:

Focus on Quality. Present in day-to-day device design and production, identify characteristics that are critical to the quality of a particular device. Shared understanding of product features and manufacturing processes most important to patient safety.

Stakeholder engagement. Collaborate and solicit feedback.

Data transparency.. Device data ( including recalls and adverse event reports) at open.fda.gov.

Expected Outcome : Allow stakeholders to focus resources on activities with the greatest impact on assuring that patients and users receive high-quality devices.



FDA approved

takedaNINLARO (ixazomib) capsules

Indication :  In combination with lenalidomide and dexamethasone for the treatment of patients with multiple myeloma who have received at least one prior therapy

Unmet Need:

  • 26,850 new cases and 11,240 related deaths in US
  • Blood cancer where cancerous cells multiply, produce an abnormal protein and push out other healthy blood cells from the bone marrow
    Disease may result in a weakened immune system and cause other bone or kidney problems.
  • Third treatment approved this year


Reg Pathway :  Priority review and orphan drug designations

Mechanism of Action: Reversible proteasome inhibitor  and induces apoptosis of multiple myeloma cell lines


  • Single randomized, double-blind, placebo-controlled, multicenter study  (n=722); Ninlaro plus combination vs Placebo plus combination
  • Primary Endpoint : Progression Free Survival (median) : 20.6 mo vs 14.7 mo, p=0.012
  • Time to response (median) : 1.1 mo. vs 1.9 mo.
  • Duration of response (median) : 20.5 mo. vs 15 mo.





Most common side effects : Diarrhea, constipation, low blood platelet count (thrombocytopenia), peripheral neuropathy (numbness and pain from nerve damage, usually in the hands and feet), nausea, peripheral edema (fluid under the skin causing swelling), vomiting and back pain



ADAPT  narcan NARCAN ((naloxone hydrochloride) nasal spray

Indication : Emergency treatment of known or suspected opioid overdose, for immediate administration as emergency therapy in settings where opioids may be present.

Unmet Need:

  • Opioid overdose leading cause of injury and death in US
  • Quick admn of naloxone counters effects, usually within 2 mins
  • Prior naloxone approval only for injectable form
  • This approval for nasal spray (no assembly reqd) for easier delivery

Reg Pathway : Fast Track, Priority Review.

  • The National Institute on Drug Abuse (NIDA) formed public-private partnership for design and clinical trial conduct of spray.  Worked with its private sector partners to obtain FDA approval

Mechanism of Action : Antagonizes opioid effects by competing for the same receptor sites.

Efficacy:  Similar relative bioavailability of nasal spray vs intramuscular injection


janssenDARZALEX (daratumumab) injection, human monoclonal antibody

 Indication:  Treatment of multiple myeloma who have received at least three prior lines of therapy including a proteasome inhibitor (PI) and an immunomodulatory agent or who are double-refractory to a PI and an immunomodulatory agent.

 Unmet Need:

  • 26,850 new cases and 11,240 related deaths in  US this year.
  • First monoclonal antibody provides another treatment option for patients who have become resistant to other therapies

Reg Pathway:  Breakthrough designation, Priority review, Orphan drug designation, Accelerated approval program

 Mechanism of Action: Binding to CD38 (transmembrane glycoprotein) and inhibition of growth of CD38 expressing tumor cells by inducing apoptosis and tumor cell lysis

 Efficacy: Approved under accelerated approval based on response rate; continued approval for this indication may be contingent upon successful confirmatory trials.

Study 1: Open-label trial (n=106);

  • Overall Response Rate : 29.2%, Time to response (median) : 1 mo.
  • Duration of response (median) : 7.4 mo.

Study 2 : Open-label dose escalation trial (n=42).

  • Overall response rate : 36%, Time to response (median) : 1 month
  • Duration of response (median) : not estimable


Most common side effects : Infusion-related reactions, fatigue, nausea, back pain, fever and cough, may result in low counts of infection-fighting white blood cells (lymphopenia, neutropenia, and leukopenia) or red blood cells (anemia) and low levels of blood platelets (thrombocytopenia).
Blood banks should be informed as drug may interfere with certain tests

AZ TAGRISSO (osimertinib) tablet

roche diagnostics Cobas     COBAS EGFR Mutation Test v2 (Companion diagnostic test ) to detect the type of EGFR resistance mutation that Tagrisso is known to target.

 Indication:  treatment of patients with metastatic epidermal growth factor receptor (EGFR) T790M mutation-positive non-small cell lung cancer (NSCLC), as detected by an FDA-approved test, who have progressed on or after EGFR tyrosine kinase inhibitor (TKI) therapy.

Unmet Need:

  • 221,200 new  diagnoses and 158,040 deaths in 2015 in US
  • Most common type, NSCLC – cancer cells form in lung  tissues
  • EGFR gene involved in the growth and spread of cancer cells.

Reg Pathway: Breakthrough therapy designation ,  Priority review designation,  Orphan drug designation, Accelerated approval program,

Mechanism of Action: Kinase inhibitor of the epidermal growth factor receptor (EGFR), which binds irreversibly to certain mutant forms of EGFR.  Anti-tumor activity against NSCLC lines harboring EGFR-mutations

 Efficacy: Approved under accelerated approval based on tumor response rate and duration of response; continued approval contingent upon successful confirmatory trials.

  • 2 multicenter, single-arm, open-label clinical trials


Safety: Most common side effects : Diarrhea, skin and nail conditions such as dry skin, rash and infection or redness around the fingernails.

genentechCOTELLIC   (cobimetinib) tablets

Indication : Treatment of patients with unresectable or metastatic melanoma with a 4 BRAF V600E or V600K mutation, in combination with vemurafenib (Zelbraf®).

Unmet Need:

  • For deadly and aggressive form of skin cancer
  • Targeted therapy for delaying disease progression and increase survival

Mechanism of Action : Reversible inhibitor of mitogen-activated protein kinase (MAPK)/extracellular signal 306 regulated kinase 1 (MEK1) and MEK2. Inhibits tumor cell growth.


  • Single multicenter, randomized (1:1), double-blinded trial (n= 495); Cotellic  + Zelbraf vs. placebo + Zelbraf
  • Progression Free Survival (median) : 12.3 mo vs 7.2 mo, p < 0.001
  • Overall Survival (interim analysis, # of deaths) : 79 vs 109
  • Objective response rate (tumor shrinkage)  : 70% vs 50 %  p<0.001


Safety :
– Risk of skin cancers, increased risk of bleeding, heart problems, rash, eye problems, abnormal liver test or liver injury, increased levels of an enzyme in the blood, and photosensitivity
– Most common side effects include diarrhea, sunburn or sun sensitivity, nausea, fever and vomiting. Cotellic can also cause changes in blood test results.

symbisSYMBIS stereotactic brain biopsy system, 510K Clearance. , Deerfield Imaging

  • Stereotactic brain biopsy
  • Minimally invasive neurosurgical procedures involving computer navigation and imaging to target and guide the removal of tissue for examination.
  • Allows biopsy while patient  inside MRI scanner
    Improved targeting, faster procedure times, improve tissue sampling, reduce repeat biopsies.


HIFUABLATHERM HIFU (high intensity focused ultrasound) device for prostate tissue ablation, 510K Clearance,  EDAP TMS

  • Patients with localized prostate cancer (stages T1-T2) who are not candidates for surgery or who prefer an alternative option, or for patients who failed radiotherapy treatment.
  • Probe that has both imaging and treatment transducers, allowing for planning and ablation in one quick procedure.
  • Following local or general anesthesia, the 7.5 MHz transducer on the probe creates a volumetric image of the prostate which the physician uses to create a treatment plan.
  • Once ready, the robotic probe becomes autonomous, moving around and ablating tissue targeted in the plan by raising its temperature to around 185° F (85° C).
  • It has built-in safety features, such as stopping in response any movements of the patient, detecting the rectal wall, and delivering rectal cooling.

FDA Voice

Why FDA Should Oversee Laboratory Developed Tests
By: Peter Lurie, M.D., M.P.H.

FDA Report:   http://www.fda.gov/downloads/AboutFDA/ReportsManualsForms/Reports/UCM472777.pdf

  •  Laboratory developed tests (LDTs) have become significantly more complex and higher risk, with several notable examples of inaccurate tests placing patients at otherwise avoidable risk.
  • Current Regulations : FD&C Act, Clinical Laboratory Improvement Amendments (CLIA).
  • FDA has generally exercised enforcement discretion
  • Examination of 20 LDTs : Harm to patients
    • False-positive results: Unnecessary distress and unneeded treatment
    • False-negative results : Undetected life-threatening diseases went undetected. As a result, patients failed to receive effective treatments.
  • Staggering cost of lack of oversight. CARE Clinical Autism Biomarkers Test alone – estimated public health cost of $66.1 million.
  • FDA will step up oversight of LDTs –  draft guidance




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