Posts Tagged ‘FDA Warning Letter’

Curation of Recently Halted Oncology Trials Due to Serious Adverse Events – 2015

Curator: Stephen J. Williams, Ph.D.

The following is reports of oncology clinical trials in 2015 which have been halted for Serious Adverse Events (SAE), in most instances of an idiopathic nature. For comparison I have listed (as of this writing) the oncology drug approvals (8) for 2015. (from CenterWatch.com)

Oncology Drugs Approved in 2015

Farydak (panobinostat); Novartis; For the treatment of multiple myeloma, Approved February 2015

Ibrance (palbociclib); Pfizer; For the treatment of ER-positive, HER2-negative breast cancer, Approved February 2015

Lenvima (lenvatinib); Eisai; For the treatment of thyroid cancer, Approved February 2015

Lonsurf (trifluridine and tipiracil); Taiho Oncology; For the treatment of metastatic colorectal cancer , Approved September 2015

Odomzo (sonidegib); Novartis; For the treatment of locally advanced basal cell carcinoma, July 2015

Opdivo (nivolumab); Bristol-Myers Squibb; For the treatment of metastatic squamous non-small cell lung cancer, Approved March 2015

Unituxin (dinutuximab); United Therapeutics; For the treatment of pediatrics with high-risk neuroblastoma, Approved March 2015

Varubi (rolapitant); Tesaro; For the prevention of delayed nausea and vomiting associated with chemotherapy, Approved September 2015

Death Forces FDA to Place Clinical Hold on Advaxis (ADXS) Cancer Drug

from Biospace News

October 7, 2015
By Alex Keown, BioSpace.com Breaking News Staff

PRINCETON, N.J. – Following the death of a patient, the U.S. Food and Drug Administration (FDA) placed a hold on Advaxis (ADXS)’s experimental cancer treatment axalimogene filolisbac, which is currently in mid-stage trials.

In a statement issued this morning, Advaxis maintains the patient’s death was a result of the severity of her cancer and not due to the company’s experimental cancer treatment. It is seeking proof from the FDA that the drug was not a factor in the death. Still, the hold on the experimental cancer drug will cause the company to halt four clinical trials, Advaxis said. Other clinical trials, including those with the experimental ADXS-PSA and ADXS-HER2, are not affected by this hold. The company said it will continue to actively enroll and dose patients.

The FDA placed a hold on the drug on Oct. 2 after the company submitted a safety report to the regulatory agency that week. The drug is being developed to treat patients with persistent or recurrent metastatic (squamous or non-squamous cell) carcinoma of the cervix (PRmCC) who have progressed on at least one prior line of systemic therapy. Phase I trials released at the end of September showed treatment with axalimogene filolisbac resulted in a 38.5 percent 12-month overall survival rate in 26 patients. Patients typically fighting PRmCC who have failed at least one line of therapy have a typical survival rate of four to seven months.

Read full story here

FDA Halts Trial of Halozyme’s PEGPH20 for Pancreatic Cancer

Apr 9, 2014 Alex Philippidis

Halozyme Therapeutics acknowledged today that the FDA placed a formal clinical hold on its troubled Study 202 assessing its experimental drug PEGPH20 in patients with pancreatic cancer—less than a week after the company temporarily halted enrolling and dosing patients in the ongoing Phase II trial.

The agency told Halozyme it placed the clinical hold following the company’s pause in study activity. The trial’s independent data monitoring committee is evaluating data from the trial to learn why patients treated with PEGPH20 as well as nab-paclitaxel and gemcitabine saw a higher rate of blood clots and other thromboembolic events compared with patients treated with nab-paclitaxel and gemcitabine alone.

“We will be providing this information to the data monitoring committee and the FDA in parallel so they can complete their respective assessments,” Helen Torley, M.B. Ch.B., M.R.C.P., Halozyme’s president and CEO, said in a statement.

“Pancreatic cancer has one of the lowest survival rates of any cancer. We remain committed to evaluating PEGPH20 as a possible therapy to address this devastating disease,” Dr. Torley added.

As with Halozyme’s statement last week, the company’s latest remarks did not indicate when Halozyme expects to resume enrolling and dosing patients in Study 202, or how many patients had been enrolled and dosed when the temporary halt occurred.

The trial was envisioned as having 124 subjects, divided evenly between a treatment arm of PEGPH20 and nab-paclitaxel, and a gemcitabine arm, preceded by eight subject “run-in” phase assessing safety and tolerability, according to Study 202’s page on ClinicalTrials.gov (NCT01839487), last updated on January 27.

The study is one of two Phase II trials for PEGPH20; the other, SWOG, also aims to assess the drug for pancreatic cancer.

PEGPH20 is an investigational PEGylated form of Halozyme’s FDA-approved recombinant human hyaluronidase rHuPH20 (marketed as Hylenex®), designed to dramatically increases the half-life of the compound in the blood and allow for intravenous administration.

The temporary halt for Study 202 came two months after Halozyme publicly cited “potential acceleration of the PEGPH20 program” among several R&D programs for which it raised funds through a public offering of common stock that closed in February and generated approximately $107.8 million in net proceeds.

Read more at GenNEWS

FDA orders CytRx to halt patient enrollment after death of a cancer patient

CytRx ($CYTR) has run into an unexpected roadblock with its cancer drug conjugate aldoxorubicin, slamming the brakes on new patient recruitment in all their clinical trials after the FDA dropped a partial clinical hold on the program. According to the biotech the hold was forced by the death of a patient who was given the drug through a compassionate use program.

LA-based CytRx execs say that patients already enrolled in the studies will continue to receive the therapy as investigators added new safety measures, retooling trial protocols to include an “appropriate inclusion/exclusion criteria, an additional patient screening assessment and an evaluation of serum electrolytes prior to aldoxorubicin administration.” The patient who died, they added, had not qualified for any of its studies.

As it stands now, the biotech doesn’t know exactly how long the partial hold will last, but their announcement sought to calm jumpy investors, saying they expected to resolve the FDA’s demands “expeditiously” and can stick to their current timelines. CytRx says it expects to report preliminary results from their mid-stage study of Kaposi’s sarcoma in the second quarter of 2015 and preliminary results from the ongoing Phase II clinical trial of aldoxorubicin in glioblastoma multiforme in the first half of 2015. The company added that it is committed to completing enrollment in their Phase III trial by the end of next year.

hat reassurance appears to have helped with investors, who seemed to count this as more of a temporary setback than a catastrophe. Shares for CytRx were down about 9% in mid-morning trading.

Aldoxorubicin uses a linker molecule to attach to albumin in the blood and concentrate in tumors, where the acidic environment releases the chemotherapy doxorubicin in doses up to four times higher than what’s used now. Late last year their stock soared after their drug scored promising results for progression-free survival in a Phase IIb trial.

This case illustrates one reason why biotechs often quietly squirm under the pressure of compassionate use programs. They can be expensive to operate, time-consuming and raise fresh concerns when a patient dies or experiences a setback. On the other hand, if regulators take action like this following the death of an advanced stage cancer patient, there may have been something about the case that triggered broader concerns for the entire patient population

Clot risk in Lilly lung-cancer drug raises FDA concerns

July 7, 2015

Eli Lilly and Co.’s experimental lung cancer drug has raised concerns with U.S. regulators that it may increase patients’ risk of suffering potentially deadly blood clots.

The drug, known as necitumumab, improved patients’ overall chances of survival, yet people taking the medicine also experienced more risk, Food and Drug Administration staff said in a report Tuesday. Indianapolis-based Lilly is seeking to sell the medicine to treat a subset of the most common type of lung cancer.

FDA advisers will meet Thursday to discuss the risks and benefits of necitumumab for patients with advanced squamous non-small cell lung cancer, in combination with chemotherapy. The FDA is expected to decide if Lilly can sell the drug by the end of the year.

While the safety of necitumumab reflects that of similar drugs, the increased danger of clotting “in this already high risk population is of concern,” FDA staff wrote.

One study showed that out of 538 patients taking necitumumab and chemotherapy, 9 percent experienced a serious clot, compared with 5 percent of 541 patients given only chemotherapy, according to the staff report.

Squamous lung cancer accounts for 25 percent to 30 percent of all lung cancer, according to the American Cancer Society.

Patients in a clinical trial who took necitumumab lived a median of 11.5 months, 1.6 months longer than those who got only chemotherapy, the FDA staff report said.

Opdivo Side Effects Center (as seen on Rxlist.com) (NOTE:TRIAL NOT HALTED)

Last reviewed on RxList 10/05/2015

Opdivo (nivolumab) is a human monoclonal antibody used to treat patients with unresectable or metastatic melanoma and disease progression following ipilimumab and, if BRAF V600 mutation positive, a BRAF inhibitor; and to treat metastatic squamous non-small cell lung cancer with progression on or after platinum-based chemotherapy. Common side effects of Opdivo include fatigue, rash, itching, cough, upper respiratory tract infection, swelling of the extremities, shortness of breath, muscle pain, decreased appetite, nausea, vomiting, constipation, diarrhea, weakness, swelling, fever, abdominal pain, chest pain, joint pain, and weight loss.

Opdivo FDA Prescribing Information: Side Effects
(Adverse Reactions)

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.

The data described in the WARNINGS AND PRECAUTIONS section and below reflect exposure to OPDIVO in Trial 1, a randomized trial in patients with unresectable or metastatic melanoma and in Trial 3, a single-arm trial in patients with metastatic squamous non-small cell lung cancer (NSCLC).

Clinically significant adverse reactions were evaluated in a total of 691 patients enrolled in Trials 1, 3, or an additional dose finding study (n=306) administering OPDIVO at doses of 0.1 to 10 mg/kg every 2 weeks [see WARNINGS AND PRECAUTIONS].

Unresectable or Metastatic Melanoma

The safety of OPDIVO was evaluated in Trial 1, a randomized, open-label trial in which 370 patients with unresectable or metastatic melanoma received OPDIVO 3 mg/kg every 2 weeks (n=268) or investigator’s choice of chemotherapy (n=102), either dacarbazine 1000 mg/m² every 3 weeks or the combination of carboplatin AUC 6 every 3 weeks plus paclitaxel 175 mg/m² every 3 weeks [see Clinical Studies]. The median duration of exposure was 5.3 months (range: 1 day to 13.8+ months) with a median of eight doses (range: 1 to 31) in OPDIVO-treated patients and was 2 months (range: 1 day to 9.6+ months) in chemotherapy treated patients. In this ongoing trial, 24% of patients received OPDIVO for greater than 6 months and 3% of patients received OPDIVO for greater than 1 year.

In Trial 1, patients had documented disease progression following treatment with ipilimumab and, if BRAF V600 mutation positive, a BRAF inhibitor. The trial excluded patients with autoimmune disease, prior ipilimumab-related Grade 4 adverse reactions (except for endocrinopathies) or Grade 3 ipilimumab-related adverse reactions that had not resolved or were inadequately controlled within 12 weeks of the initiating event, patients with a condition requiring chronic systemic treatment with corticosteroids ( > 10 mg daily prednisone equivalent) or other immunosuppressive medications, a positive test for hepatitis B or C, and a history of HIV.

The study population characteristics in the OPDIVO group and the chemotherapy group were similar: 66% male, median age 59.5 years, 98% white, baseline ECOG performance status 0 (59%) or 1 (41%), 74% with M1c stage disease, 73% with cutaneous melanoma, 11% with mucosal melanoma, 73% received two or more prior therapies for advanced or metastatic disease, and 18% had brain metastasis. There were more patients in the OPDIVO group with elevated LDH at baseline (51% vs. 38%).

OPDIVO was discontinued for adverse reactions in 9% of patients. Twenty-six percent of patients receiving OPDIVO had a drug delay for an adverse reaction. Serious adverse reactions occurred in 41% of patients receiving OPDIVO. Grade 3 and 4 adverse reactions occurred in 42% of patients receiving OPDIVO. The most frequent Grade 3 and 4 adverse reactions reported in 2% to less than 5% of patients receiving OPDIVO were abdominal pain, hyponatremia, increased aspartate aminotransferase, and increased lipase.

FDA Approves Eisai’s LENVIMA™ (lenvatinib) for the Treatment of Patients with Locally Recurrent or Metastatic, Progressive, Radioactive Iodine-Refractory Differentiated Thyroid Cancer

– Press release from Eisai (NOTE: TRIAL NOT HALTED)

Feb 13, 2015

WOODCLIFF LAKE, N.J., Feb. 13, 2015 /PRNewswire/ — Eisai Inc. announced today that the U.S. Food and Drug Administration (FDA) approved the company’s receptor tyrosine kinase inhibitor LENVIMA™ (lenvatinib) for the treatment of locally recurrent or metastatic, progressive, radioactive iodine-refractory differentiated thyroid cancer (RAI-R DTC). LENVIMA was approved following a priority review by the FDA, which is designated for drugs the FDA believes have the potential to provide a significant improvement in the treatment of a serious condition. LENVIMA demonstrated a statistically significant progression-free survival (PFS) prolongation and response rate in patients with progressive, differentiated thyroid cancer who had become refractory to radioactive iodine (RAI) therapy.

In the clinical trial, adverse events led to dose reductions in 68% of patients who received LENVIMA and 5% of patients who received placebo. Some patients will need to discontinue treatment for serious adverse reactions. In the trial, 18% of patients treated with LENVIMA and 5% who received placebo discontinued treatment. The most common adverse reactions (at least 10%) that resulted in dose reductions of LENVIMA were hypertension (13%), proteinuria (11%), decreased appetite (10%), and diarrhea (10%).

AstraZeneca halts a pair of lung cancer trials over a safety scare

From October 9, 2015 | By of FierceBiotech

“AstraZeneca ($AZN) is pressing pause on trials combining two of its most important pipeline cancer treatments after tracking reports of lung disease, halting enrollment as it gathers more information.

The company is testing a combination of AZD9291 and durvalumab, formerly MEDI4736, in two studies involving patients with non-small cell lung cancer. Late last month, AstraZeneca hit the brakes on enrollment in both trials due to an increase in reports of interstitial lung disease, which can lead to dangerous scarring and impaired pulmonary function. The pauses are temporary, the company stressed in an emailed statement, and patients already enrolled in the study will be given new consent forms to ensure they understand the risks before choosing whether keep getting treatment.”

Other posts on this site on Cytotoxicity and Cancer include

Novel Approaches to Cancer Therapy [11.1]

Misfolded Proteins – from Little Villains to Little Helpers… Against Cancer

Multiple Lung Cancer Genomic Projects Suggest New Targets, Research Directions for Non-Small Cell Lung Cancer

A Synthesis of the Beauty and Complexity of How We View Cancer

Good and Bad News Reported for Ovarian Cancer Therapy

Read Full Post »

Reporter: Aviva Lev-Ari, PhD, RN


The technology functionality of da Vinci Surgical Robot of Intuitive Surgical is described in

3D Cardiovascular Theater – Hybrid Cath Lab/OR Suite, HybridSurgery, Complications Post PCI and Repeat Sternotomy


FDA Letter for Inspection dates 04/01/2013 – 05/30/2013

Observation 1:

A correction or removal, conducted to reduce a risk to health posed by a device, was not reported in writing to FDA.

Observation 2:

Illnesses or injuries that have occurred with use of devices subject to corrections or removals have not been reported

Observation 3:

Procedures for design change have not been adequately established.

Observation 4:

Design input requirements were not adequately documented.


Intuitive Surgical Declines on Warning Letter From FDA

By Robert Langreth – Jul 19, 2013 4:07 PM ET
BSIP/UIG via Getty Images
At the Lyon Hospital in France, they use a surgical robotic system called Da Vinci Surgical System, made by Intuitive Surgical, designed to facilitate complex surgery using a minimally invasive approach.

Intuitive Surgical Inc. (ISRG), the robot surgery company, has lost about $7 billion in value over five months after disclosures about adverse events with its products, a recent recall and, now, a regulatory warning it hasn’t adequately reported on issues concerning the devices.

In February, Bloomberg News reported that the FDA was surveying surgeons on the robots following a rise in reports that included as many as 70 deaths since 2009. A review of Food and Drug Administration records now shows the reports of injuries involving robot procedures have doubled in the first six months of 2013, compared with a year earlier.

On July 8, the Sunnyvale, California-based company reported that sales slowed for its robots in the second quarter, and four days later Intuitive said that 30 of its devices were recalled because they may not have been properly tested. Yesterday’s announcement, coming after the close of trading, prompted JMP Securities LLC to cut its rating on Intuitive to market underperform with a target of $275, a drop from yesterday’s closing price of $421.27.

“We see little reason to own shares at the current levels,” J.T. Haresco, a San Francisco-based analyst at JMP Securities, said today in a note to investors.

Intuitive’s shares fell 6.8 percent to $392.67 at the close in New York after Chief Executive Officer Gary Guthart yesterday advised investors about the July 17 warning in a conference call. The company has lost 32 percent of its market value, or about $7 billion, since Feb. 27, the day before Bloomberg News reported that the FDA was surveying surgeons about the safety of its robot products.

FDA Inspections

FDA inspections in April and May found the most recent deficiencies, according to a report dated May 30. Guthart said the agency is asking for additional steps to resolve two of the observations in the inspection report.

“We believe these issues are addressable and will continue to work with the FDA to ensure this is resolved to their satisfaction,” Angela Wonson, a company spokeswoman, said in an e-mail after the call.

Safety and cost effectiveness of the company’s da Vinci robot devices have been under scrutiny since the disclosure that the FDA was studying how the robot surgeons were being used.

“Rates of adverse events have remained low and in line with historical trends,” Wonson said today in an e-mail.

Robot Use

The robots, in more than 1,300 U.S. hospitals, cost $1.5 million each and were used in 367,000 U.S. procedures in 2012. They are the company’s primary product and have been the subject of negligence lawsuits alleging that patients were injured during surgeries. Cancer surgery, hysterectomies and gall bladder removals are among the procedures conducted with the robot.

Yesterday, Calvin Darling, the company’s senior director of finance, said 2013 revenue is expected to range from unchanged to an increase of 7 percent from 2012. Intuitive in Januaryforecast annual sales growth of 16 percent to 19 percent and in April said it expected the higher end of the range.

“The company will survive but maybe not as-is,” said Erik Gordon, a business professor at the University of Michigan in Ann Arbor. “The pounding down of the share price is fresh bait for activist investors like Carl Icahn and for strategic acquirers. The warning letter puts a dent in the reputation of a company that had once been viewed as a shiny new Porsche.

‘‘They enjoyed some easier, boom years when doctors and patients were awed by the thought of surgical robotics turning surgeons into super-surgeons,’’ Gordon said in an e-mail today. ‘‘Now, the people who pay for the surgery are stepping in and questioning whether the robots are worth the extra cost.’’


With more changes approaching from the Affordable Care Act, community hospitals are likely to reconsider whether it makes sense to do ‘‘money-losing procedures’’ on the pricey robot, Suraj Kalia, an analyst for Northland Securities, wrote today in a report to clients. In particular, using the robot for simple gall bladder surgeries is ‘‘prohibitively expensive,’’ he wrote.

Intuitive’s forecasts suggests new installations of the expensive robot in the U.S. are ‘‘hitting a brick wall,’’ Kalia wrote.

JMP’s Haresco also questioned the company’s future, saying that more use of personalized medicine will make it easier for physicians to tailor medical therapy and treat patients conservatively, that insurers will continue to drive procedures to outpatient settings, limiting the need for robotics, and that recent declines in benign hysterectomy appear to be the start of a long-term decline.

‘Outright Invalid’

‘‘While we still believe that robotic surgery will play a central role in the delivery of medicine, we also believe that some of the underlying assumptions that define the market potential are questionable, if not outright invalid,” Haresco said today in his note.

One of the two issues Intuitive has been asked to respond to by the agency in its warning letter is the observation that some device corrections hadn’t been adequately reported, Wonson said. She couldn’t provide a copy of the agency’s letter.

In the inspection report, FDA officials also said the company didn’t document the need for surgeons to sometimes clean robotic instruments during procedures. Intuitive has received complaints about arcing of energized surgical instruments after some surgeons cleaned off instruments by scraping them against each other during surgery, the agency said.

The scraping “led to tears or holes in protective tip covers that led to arcing that in turn led to injuries to patients,” the agency said in the report.

Intuitive Surgical also yesterday reported second-quarter net income rose 2.7 percent to $159.1 million, or $3.90 a share, from $154.9 million, or $3.75 a share. Revenue gained 7.8 percent to $578.5 million, missing the average of $596 million of 17 analysts’ estimates compiled by Bloomberg.

While sales of instruments and accessories increased 18 percent during the quarter, revenue from systems declined 6 percent, the company said.

To contact the reporter on this story: Robert Langreth in New York at rlangreth@bloomberg.net

To contact the editor responsible for this story: Reg Gale at rgale5@bloomberg.net




Intuitive Surgical’s ($ISRG) share price plunged more than 13% in extended trading after the company disclosed July 18 it had received an FDA warning letter, adding to the cracks beginning to form in its da Vinci surgical robot track record.


The stock price listed at $363.91 in pre-market trading on July 19, down a whopping 13.6% from its $421.47 closing price at the end of trading on July 18. It had gained a healthy amount at the end of trading, in the wake of Intuitive’s generally positive 2013 second quarter earnings release.


But as Bloomberg reports, the company’s stock price went into a spiral after CEO Gary Guthard disclosed Intuitive’s July 17 warning letter during an analyst conference call held late afternoon to discuss second-quarter earnings. Regulators inspected the company in April and May, after which they cited Intuitive for not adequately reporting device corrections to regulators or patient “adverse events.” (Regulators detailed their initial concerns in a Form 483 issued earlier this year, which generally precedes a formal warning letter.) Additionally, the FDA faulted Intuitive for not documenting the need for surgeons using the da Vinci system to sometimes have to scrape instruments against each other during a procedure in order to clean them. This causes arcing and injured some patients, according to FDA concerns detailed in the story.


An Intuitive spokeswoman told Bloomberg that the issues cited with the FDA are “addressable” and that the company will continue working with regulators to solve the problem.


But investors are watching closely to see if company obstacles become more widespread. As The Wall Street Journal reported before Intuitive’s earning release, some hospitals and surgeons have said they are more heavily scrutinizing their use of da Vinci products in the wake of controversies over their safety and price tag (an average $1.55 million apiece).  Experts are questioning da Vinci’s benefits compared to standard hysterectomy procedures, for example, versus the extra cost of the machine and procedure.


Observers predicted that Intuitive’s stock would take major hits if its growth momentum slowed any more, the article noted. The new warning letter against the company pointed to a “growth momentum” risk, and investors reacted accordingly.


While 2013 second quarter results are generally good, there are signs of trouble. Sure, second-quarter revenue hit the $579 million mark, up 8% from the $537 million figure generated by the company over the 2012 second quarter. But analysts had expected much higher than this, The Wall Street Journal notes. And net income reached $159 million ($3.90 per diluted share), a moderate rise from $155 million in net revenue a year ago ($3.75 per diluted share).


Broken down, it’s more of a mixed bag.


Second-quarter systems revenue for 2013 dipped 6% to $216 million, versus $229 million over the same period last year, as the California company sold fewer da Vinci Surgical Systems, a trend it blamed in part on hospitals cutting back their spending. But more da Vinci surgical procedures and greater demand for new products bumped instruments and accessories to $265 million, an 18% jump over $224 million in revenue generated during the 2012 second quarter. Service revenue also enjoyed a double-digit jump, thanks to a greater installed base of the company’s surgical robots.


Spencer Nam, an equity analyst at Janney Montgomery Scott, noted to The Wall Street Journal that this was the first time since mid-2009 that Intuitive sold fewer da Vinci systems than it did in the previous year.


When Intuitive released its preliminary second-quarter results a week ago, Guthart said in a statement that the company was “disappointed” in its performance during the quarter but remained confident in the value Intuitive’s products offered. Meanwhile, the company’s stock closed July 18 at $421.57, up nearly 1.5%, after some wild fluctuation during the day.



Read Full Post »