FDA Brief: Week of October 19, 2015 – Drug and Device Digest


CDRH prioritization of top 10 needs for regulatory decision making

• Leverage “Big Data”

• Leverage evidence form clinical program as well as other relevant domains

• Improve quality and effectiveness of reprocessing

• Develop computational modeling technologies

• Enhance performance of cybersecurity

• Incorporate human factors engineering principles

• Modernize biocompatibility / biological risk evaluation

• Advance methods to predict clinical performance

• Advance the use of patient reported outcome measures (PROMs)

• Collect and use patient experience/preference


FDA approvedalexionSTRENSIQ (asfotase alfa) administered via injection three or six times per week

Indication : Perinatal, infantile and juvenile-onset hypophosphatasia (HPP). – as the first approved treatment

Unmet Need:

  • Rare, genetic, progressive, metabolic disease leading to severe disability and life-threatening complications
  • Characterized by defective bone mineralization and skeletal abnormalities, muscle weakness, loss of mobility, seizures, pain, respiratory failure and premature death
  • Occurrence estimated one in 100,000 newborns; milder cases in childhood or adulthood more frequent

Reg Pathway : Breakthrough designation, Orphan Drug designation, Priority Review

Mechanism of Action: Replaces enzyme (tissue-nonspecific alkaline phosphatase) responsible for formation of an essential mineral in normal bone


  • 4 prospective, open-label studies (n=99), Alexion vs Natural History Study Group
  • Overall survival (1 yr) : 97% vs 42%
  • Ventilator-free survival (1 yr) : 85% vs 50%
  • Also improvements in growth and bone health, weight, stature, juvenile onset diabetes, healing of rickets


Safety : Injection site reactions, hypersensitivity reactions (difficulty breathing, nausea, dizziness and fever), lipodystrophy, ectopic calcifications of the eyes and kidney.


BELBUCA (buprenorphine) buccal film. Utilizes BioErodible MucoAdhesive (BEMA) drug delivery technology, Schedule III

Indication: Chronic pain severe enough to require daily, around-the-clock, long-term opioid treatment and for which alternative treatment options are inadequate

Unmet Need: Novel buccal film delivery system that adds convenience and flexibility.

Mechanism of Action: Mu-opioid receptor partial agonist and a potent analgesic with a long duration of action

Efficacy: 2 double-blind, randomized, placebo-controlled, enriched-enrollment Phase 3 studies in patients with moderate to severe chronic low back pain (n= 1,559). Improvement in pain scores assessed by Numeric Rating Scale (NRS)


  • Risks of addiction, abuse, and misuse which can lead to overdose and death
  • Serious, life-threatening, or fatal respiratory depression
  • Accidental exposure in children can be fatal
  •  Prolonged use in pregnancy can result in neonatal opioid withdrawal syndrome


YONDELIS (trabectedin) injection

Indication:  Treatment of patients with unresectable or metastatic liposarcoma or leiomyosarcoma who received a prior anthracycline-containing regimen

Unmet Need:

  • Liposarcoma and leiomyosarcoma are specific types of Soft Tissue Sarcoma (STS)
  •  STS can form almost anywhere in the body, but is most common in the head, neck, arms, legs, trunk and abdomen
  • In 2014, an estimated 12,000 cases of STS were diagnosed in US

Reg. Pathway: Standard

Mechanism of Action: Alkylating agent; binds guanine residues in DNA, forming adducts, that can affect activity of DNA binding proteins and DNA repair pathways, resulting in perturbation of the cell cycle and eventual cell death.


  • Randomized (2:1), open-label, active-controlled trial  (n= 528), Yondeis vs dacarbazine
  • Investigator-assessed Progression-Free Survival : 4.2 mo. vs 1.5 mo. (P<0.001), Fig 1.
  • Overall Survival: 13.7 mo. vs 13.1 mo. (P= NS)
  • Objective Response Rate : 23 pts vs 10 pts
  • Duration of Response : 6.9 mo. vs 4.2 mo.

Yondelis KM


  • Warning : Severe and fatal blood infections (neutropenic sepsis), muscle tissue breakdown (rhabdomyolysis), liver damage (hepatotoxicity), leakage around the vein or catheter (extravasation), tissue necrosis (breakdown) and heart failure (cardiomyopathy).
  • Other : Nausea, fatigue, vomiting, diarrhea, constipation, decreased appetite, shortness of breath, headache, peripheral edema, neutropenia, thrombocytopenia, anemia, elevated liver enzymes and decreases in albumin


ONIVYDE (irinotecan liposome injection)

Indication: In combination with fluorouracil and leucovorin, for the treatment of patients with metastatic adenocarcinoma of the pancreas after disease progression following gemcitabine-based therapy.

Unmet Need:

  • Pancreatic cancer can be difficult to diagnose early and treatment options are limited especially when the disease has spread to other parts of the body (metastatic disease) and surgery to remove the tumor is not possible
  • 48,960 new cases of pancreatic cancer diagnosed in the U.S. in 2015
  • 40,560 deaths caused by the disease

Reg. Pathway: Priority Review, Orphan Drug Designation

Mechanism of Action: Topoisomerase 1 inhibitor; bind reversibly to the topoisomerase 1-DNA complex and prevent re-ligation of the single-strand breaks, leading to double-strand DNA damage and cell death.


  • three-arm, randomized, open-label trial  (n=417),  Onivyde plus fluorouracil/leucovorin  vs. Onivyde alone vs.  fluorouracil/leucovorin. Onivyde plus fluorouracil/leucovorin performed better than  Onivyde, and vs  fluorouracil/leucovorin. Results of  Onivyde plus fluorouracil/leucovorin   vs  fluorouracil/leucovorin
  • Overall Survival: 6.1 mo vs 4.2 mo (p<0.014)
  • Progression Free Survival: 3.1 mo. vs 5.1 mo.



  • Boxed Warning: Risks of severe neutropenia and diarrhea
  • Other : diarrhea, fatigue, vomiting, nausea, decreased appetite, stomatitis) , pyrexia, lymphopenia, neutropenia), death   due to sepsis

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