More than a month after Mylan and Pfizer reported to Health Canada that there are new issues affecting some EpiPens, the companies and the FDA notified U.S. healthcare providers of the problem which can delay treatment when the pens are needed.
Mylan, Pfizer and the FDA Friday reported that some pens and their authorized generic versions may not easily slide out of their carrier tube and so could delay use of the pens. They said that in a very small number of cases, labels were not fully adhered to the surface of the auto-injector, causing the life-saving device to become stuck to the inside of the carrier tube. Health Canada made a similar announcement September 28.
The FDA said it has not learned of any adverse event reports associated with the labeling issue. Pfizer said the risk is low and is not recalling the pens. Instead it says that if consumers have any of the pens, they should make sure they can slide out of their carriers properly. Pfizer said the problem is only with the labels and that the pens are good to use.
The newest issue arises as Pfizer and Mylan have been working to ramp up supplies of the epinephrine dispensers which are often used to treat anaphylactic shock from allergic reactions. Spot shortages of the injectors began last year after an FDA inspection found serious problems at the Pfizer plant where they are made and which the FDA laid out in a warning letter.
The FDA in August took steps to mitigate the shortage of the ubiquitous EpiPens by allowing some expired devices to remain on the market by four months. The action came as parents were scrambling to find the devices as their children returned to school.
Pfizer acknowledged at the time that Meridian, the Pfizer subsidiary that manufactures the pens, continues to have “manufacturing constraints, but said it is working with Mylan to improve “consistent availability.”
The label sticking problem may affect EpiPen 0.3 mg (NDC 49502-500-02) and the Authorized Generic (NDC 49502-102-02) products expiring between June 2018 and February 2020 and EpiPen Jr 0.15 mg (NDC 49502-501-02) and the Authorized Generic (NDC 49502-101-02) products expiring between October 2018 and October 2019.
Tens of thousands of children and young people are being given the hormone melatonin to help them sleep, prompting concern that the medicine is being handed out too readily with little evidence of its long-term effectiveness or safety.
Melatonin, which is produced naturally by the body in dark environments to help sleep preparations, has been authorised for use by people aged over 55. It has been hailed as a less addictive alternative to insomnia drug treatments.
Despite the fact it is not licensed for use by any other age group, 117,085 people under 18 were given melatonin “off label” – the term used for when a drug is given for an unapproved indication or in an unapproved age group – to aid sleep in the 2017-18 financial year. In the first four months of the current financial year, 69,280 prescriptions were given to under-18s.
The number of children and young people given the hormone has risen year on year, increasing by 25% from 92,511 prescriptions in 2015-16 to the most recent full-year figure. The data was obtained from the NHS business services authority after a freedom of information request.
The rise has largely been driven by an increase in the number of children over the age of seven given the drug. Use of the modified release form of the medicine, which releases the hormone more slowly than the liquid and tablet forms, increased by 42% from 2015-16 to 2017-18, rising from 62,384 prescriptions to 88,944 in three years.
But experts have expressed concern that the hormone may be being overprescribed by paediatricians due to the fact that there are few alternatives to support children with insomnia and other problems.
“These figures show we need more services for children who have sleep problems,” said Mandy Gurney, a health visitor and founder of the Millpond Sleep Clinic. “You can get very good results just looking down the behavioural and sleep hygiene line … The question is: do they need melatonin? But that piece of research has not been done.”
Gurney said she had been asked to train nursery nurses and health visitors in Wales, due to the high melatonin prescription rate. “The feedback after training was that the melatonin prescribing rate had come down.”
Dr Neil Stanley, an independent sleep expert and former director of sleep research at the University of Surrey, said he was surprised by the high numbers as there was very limited evidence of effectiveness in children other than in severely autistic children and blind children. He also noted that there was no data on its long-term safety.
“It’s a prescription of desperation really; doctors don’t know what to do about sleep and feel they have no alternatives,” Stanley said. “That is terrible as it affects all body clocks and it will affect children’s developmental clocks and we have no idea what that does.”
When given as a medicine, melatonin is usually made synthetically in a laboratory. The short-term side effects are thought to be minimal, but it can cause headaches, nausea, dizziness and drowsiness. However, in the long term there are ongoing concerns based on studies in animals showing melatonin can affect puberty-related hormones.
Dr Michael Farquhar, a consultant in sleep medicine at the Evelina children’s hospital, part of Guy’s and St Thomas’ NHS foundation trust, was more cautious, describing the prescription of melatonin as “not a good or bad thing”.
He said: “It can be right for the right child in the right context … I would expect to see increase in use but whether it is a valid increase in prescription is hard to say. We would need to know the reason it is being prescribed and whether there was a benefit in its use … A much bigger piece of work is needed to find that out.”
Farquhar said he was concerned that some people saw melatonin as a quick fix. “Behaviour interventions are more likely to be effective in the long-term and a better paediatric principle,” he said.
The National Institute for Health and Clinical Excellence (Nice) says melatonin appears relatively safe in the short and medium term (up to 18 months). However beyond this the picture is unclear.
“It’s important to put numbers into context. So 117,000 patients: that is still 1% of the child population, roughly speaking. It’s not a small number but if you think it’s perfectly valid to give the hormone for sleep difficulties among children with autism, ADHD and learning difficulties as a minimum, you’re pushing 5% of the population,” said Dr Max Davie from the Royal College of Paediatrics and Child Health.
“What is important about the data is that it suggests a great need for sleep services within children’s health services. It is not enough to only have a bit of advice and if that doesn’t work then offer melatonin,” he said.
Davie said the evidence of melatonin being prescribed inappropriately was mainly anecdotal and was hard to police. “On the one hand I wish it wasn’t the only thing we had to offer, but on the other hand there isn’t anything else, so what have you got to do?”
The figures are published as experts warn that young people’s lack of sleep is a hidden health crisis. Last month, the Guardian revealed that thousands of children and teenagers faced a mounting sleeplessness crisis, after the number of admissions to hospital of young people with sleep disorders rose sharply in six years.
In October 1982, the U.S.Food and Drug Administration (FDA)approvedEli Lilly and Company’s Humulin, the first human insulin for diabetes treatment created using recombinant DNA technology. The story is not just a landmark event for technology, but instructive about problems with the FDA’s regulatory system.
Henry Miller, currently a Senior Fellow at the California Pacific Medical Center Research Institute, was the founding director of the FDA’s Office of Biotechnology. He was directly involved in the Humulin approval and writes about the subject for the Genetic Literacy Project.
Prior to the approval of Humulin, insulin was manufactured out of pig or cow pancreases. The non-human insulin has a slightly different chemical composition than human insulin. Miller points out that, “During the early 1970s, as the supply of animal pancreases declined and the prevalence of insulin-requiring diabetes grew, there were widespread fears of possible future shortages of insulin.”
It was around the same time, luckily, that recombinant DNA technology or genetic engineering, became available.
At that time Eli Lilly was one of the biggest companies handling insulin. They were quick to see the potential of recombinant DNA. They acquired recombinant E. coli that had the coding for synthesized human insulin from a small biotech startup called Genentech. Lilly then developed techniques for large-scale cultivation of the recombinant E. coli as well as for the purification and formulation of the insulin.
Lilly began clinical trials of the recombinant insulin in July 1980. As Miller says, “The product performed superbly. There were nonsystematic problems with treating ‘naïve’ patients (who had never before received injections of insulin) or those switched from animal to human insulin.”
In going back over the records, Miller finds several remarkable things—remarkable for the time, undoubtedly, but even more so now.
Lilly submitted the recombinant insulin to the FDA in May 1982. Miller was at that time a medical reviewer at the FDA and head of the evaluation team. “Over many years the FDA had had prodigious experience with insulins and also with drugs derived from various microorganisms, so it was decided that no fundamentally new regulatory paradigms were necessary to evaluate the recombinant human insulin.”
In other words, the agency decided that the recombinant DNA techniques were an extension and refinement of existing techniques.
Receiving the application in May 1982, the agency approved it in October 1982. It took only five months to approve.
At the time, the agency’s average approval time for new drugs was 30.5 months.
Even more remarkable is that Miller says he and his team were ready to approve after four months. “But when I took the packet to my supervisor, he said, ‘Four months? No way! If anything goes wrong with the product down the road, people will say we rushed it, and we’ll be toast.’”
A month later, the supervisor went on vacation and Miller submitted it to the division director, who signed off on it.
Miller feels this is representative of the bureaucratic mindset seen at the FDA (and probably everywhere), in which “self-interest” is an underlying theme. In other words, for the FDA, it’s in its self-interest to not approve too fast in case the drug or products experience unanticipated problems in the future.
At the time, Miller thought it was a sign of things to come that would lead to faster approvals and streamlined regulatory processes. He laments that, of course, that didn’t happen. He cites that, “Even with a toolbox of improved technologies available to both the FDA and industry, bringing a new drug to market on average now takes 10-12 years and costs, on average, over $2.5 billion.”
He also points out that other FDA-regulated sectors are an even bigger mess. Genetically engineered animals, for example, which the FDA regulates as “’new animal drugs,’ including a grotesquely prolonged, 20-plus year review of a faster-growing Atlantic salmon, and genetically engineered mosquitoes to control mosquitoes that carry viral diseases.” The FDA announced changes here just this week.
Miller concludes, “It’s too bad that government regulation hasn’t aged as gracefully as genetic engineering technology itself.”
Pacira Pharmaceuticals, Inc. (NSDQ: PCRX) today announced that the Centers for Medicare and Medicaid Services (CMS) has finalized a policy to provide separate Medicare reimbursement for EXPAREL® (bupivacaine liposome injectable suspension) when administered in ambulatory surgical centers (ASCs) through establishment of the product-specific billing code of C9290. This code, which will provide payment for EXPAREL at average sales price (ASP) + 6%, sets national Medicare reimbursement rates for EXPAREL administered in ASCs. In addition, the American Dental Association has established a separate D-code (D9613) to reimburse for EXPAREL infiltration in oral surgery procedures. Both codes become effective on January 1, 2019.
“We are pleased to receive separate reimbursement from Medicare in the ASC, and also to receive the unique D-code for EXPAREL from the ADA. We believe these developments will significantly simplify the reimbursement process for clinicians and facilities utilizing the product, thus improving patient access and accelerating the transition of certain procedures to the ambulatory surgical center setting,” said Dave Stack, Chairman and Chief Executive Officer of Pacira. “We expect the reinstatement of C9290—the original C-code for EXPAREL, which is still utilized by some commercial payers— to facilitate a more efficient rollout among commercial payers as they standardize around Medicare rates and practices. Further, we believe the D-code will meaningfully enhance the use of EXPAREL in oral surgery procedures, where young adult patients are often exposed to an opioid for the first time.”
Healthcare providers and suppliers use the Healthcare Common Procedure Coding System (HCPCS) code set to identify items and services on claims submitted to Medicare and other payors. HCPCS codes, such as the unique C code describing EXPAREL (C9290, injection, bupivacaine liposome) are used to report drugs, biologicals, and devices used in hospitals and ambulatory surgical settings.
EXPAREL is indicated for single-dose infiltration in adults to produce postsurgical local analgesia and as an interscalene brachial plexus nerve block to produce postsurgical regional analgesia. It has been used in over 4 million patients across the United States to date.
Coherus BioSciences, Inc. (NASDAQ: CHRS), today announced that the U.S. Food and Drug Administration(FDA) has approved UDENYCA™ (pegfilgrastim-cbqv), the first pegfilgrastim biosimilar approved by both the FDA and the European Commission (EC) for patients with cancer receiving myelosuppressive chemotherapy. UDENYCA™ is Coherus’ first drug to receive FDA or EC approval.
“We are excited to announce that Coherus has received FDA approval for UDENYCA. I want to thank the Coherus team, our strategic partners, and the U.S. Food and Drug Administration for this extraordinary achievement,” said Denny Lanfear, Chairman, CEO and President of Coherus BioSciences. “The list price of Neulasta has nearly tripled since approval in 2002 and now represents a $4 billion annual cost burden in the U.S.We believe that competition is essential in controlling burdensome price increases, and UDENYCA will play an important role in curbing that spend when launched. Our in-depth understanding of the market will allow us to deliver significant value to patients, payors, and providers in the U.S., including 340B hospitals, small clinics and small hospitals.”
“For a number of reasons we believe the oncology marketplace is ideal for biosimilars, and we are committed to a vigorous product launch,” said Chris Thompson, Senior Vice President of Sales. “Our oncology-focused, highly capable and fully-staffed commercial team is in place. We are confident that our U.S.-based manufacturing network has the finished goods in inventory to meet our highest expected demand for an extended period.”
The approval of UDENYCA™ was supported by a comprehensive analytical similarity package, as well as pharmacokinetic, pharmacodynamic and immunogenicity studies, including over 600 healthy subjects.
“UDENYCA’s robust clinical package includes a dedicated immunogenicity similarity study in over 300 healthy subjects,” said Barbara Finck, M.D., Chief Medical Officer of Coherus BioSciences. “In support of that study, and as part of our commitment to ensuring patient safety, we deployed a battery of sensitive immunogenicity assays. This effort not only supported the biosimilarity of UDENYCA, but also advanced the understanding of the immunogenic response of pegfilgrastim products.”
The European Commission approved UDENYCA™ on September 21, 2018.
The company will provide additional details with respect to pricing and launch timing on the November 8 earnings call.
Akcea Therapeutics – For Cambridge, Mass.-based Akcea Therapeutics, the past quarter has been one of triumph and defeat. In August, the company was stunned when the U.S.Food and Drug Administration (FDA)unexpectedlyrejected Waylivra (volanesorsen), a treatment for the rare lipid disorder familial chylomicronemia syndrome. The rebuff came only months after an advisory committee gave Waylivra the green light. The rejection sent share prices tumbling and led to a round of layoffs that saw about 10 percent of its staff cut. That stunning rejection though was salved in early October after the FDA approved Tegsedi, Akcea’s treatment for polyneuropathy of hereditary transthyretin-mediated amyloidosis in adults. Akcea is set to release its latest quarterly report on Nov. 5.
Mylan N.V. – Pennsylvania-based Mylan is set to release its quarterly report on Nov. 5. The generic drugmaker closed out the quarter with the European launch of Hulio, a biosimilar to AbbVie’s Humira. The company could be eying another biosimilar launch in Europe as well. On the same day, Hulio was cleared for market, Mylan reported that the European Medicines Agency‘s Committee for Medicinal Products for Human Use (CHMP) has issued a positive opinion recommending approval of Ogivri, a biosimilar to Roche‘s Herceptin (trastuzumab). The CHMP positive opinion will now be considered by the European Commission. The decision on approval is expected by the end of 2018. Not only is Mylan’s biosimilar line moving forward in Europe, but the company also saw some other positives during the most recent quarter. In September the company acquired Novartis’ cystic fibrosis products, including the TOBI Podhaler and TOBI solution, in a $463 million deal. Mylan also saw some legal victories in patent challenges against Acorda Therapeuticsovermultiple sclerosis drugAmpyra, as well as against Teva Pharmaceutical over patentsCopaxone, another MS drug.
Eli Lilly – Will pharma giant Eli Lilly follow up the positive financial news from its last quarterly report when it releases its latest financial numbers on Nov. 6? Over the past quarter, the Indianapolis-based company saw a number of significant positive events occur. Most recently, the company forged an agreement with Dicerna Pharmaceuticalfor its GalXC RNAi technology platform to develop therapies for cardio-metabolic, neurodegeneration and pain targets. The company also saw positive results from its late-stage clinical trial of tanezumab in patients with osteoarthritis. Phase III trial data showed that more than half of the patients who received tanezumab had a 50 percent or greater decrease in pain. Tanezumab, a humanized monoclonal antibody that targets nerve growth factor, is seen as a potential alternative to opioid treatment. If the drug is approved by regulators, it will be the first non-opioid treatment for osteoarthritis. The companies plan to seek FDA approval in 2019. Lilly also snagged FDA approval for its migraine medication, Emgality, a CGRP inhibitor. In addition to good news from its pipeline, Eli Lilly also made a strong HR move in the quarter. The company tapped Industry veteran Anne White to lead its oncology division. White replaced Sue Mahoney at the helm of Eli Lilly Oncology in September.
Regeneron – Tarrytown, N.Y.-based Regeneronwill announce its quarterly financial report on Nov. 6. The company started out the quarter with the news that fasinumab, the treatment for chronic pain from osteoarthritis (OA) of the knee or hip it co-developed with Teva, hits its mark in a Phase III trial. At 16 weeks patients experienced significantly less pain and also showed significantly improved functional ability from baseline. Regeneron also saw its blockbuster eye treatment Eylea snag FDA approval for another indication during the quarter. The regulatory agency approved a new dosing label for the drug in wet age-related macular degeneration (wet AMD). That approval came days after the FDA issued a Complete Response Letter for Regeneron’s attempt to secure a supplemental approval for Eylea. Regeneron and its longtime development partner Sanofi announced that its blockbuster drug Dupixent (dupilumab) hit the mark in two Phase III trials studying the drug as a treatment for adults with inadequately-controlled chronic rhinosinusitis with nasal polyps. In addition to its pipeline progress, Regeneron also snagged a different kind of approval during the quarter – one from its peers. The publication Science ranked Regeneron number one for innovation and work culture. This was the third year in a row that Regeneron received the honor and the sixth time since 2011.
The diagnosis was in, but Jessica Kulakowski still didn’t have the answers, so she started scouring the internet to find out why her son’s cold had left his right arm virtually lifeless.
Online she found case studies but nothing definitive about why her then-1-year-old boy, Chase, contracted the rare polio-like condition known as acute flaccid myelitis, or AFM. The condition, in the news as a spate of new cases have made headlines in Illinois and beyond, affects mostly children and causes muscles to atrophy, leaving some bedridden with paralysis and unable to breathe on their own. Medical experts have in some cases linked the syndrome to an enterovirus, which causes the common cold and other respiratory illnesses.
Two years after her son’s diagnosis, questions linger for the northwest Indiana mom, who worries anew each time the toddler complains of an ache or has the sniffles: Could this be another complication related to AFM?
“It’s like living in paranoia because there’s just no answer to anything,” Kulakowski said.
Nationwide, the rare condition has gotten more attention after federal health officials reported an increase in cases in recent weeks. They include at least 10 cases diagnosed in Illinois and at least seven in Minnesota, leaving parents like Kulakowski perplexed: How could such a complicated medical journey begin with their little one’s runny nose?
Now 3 years old, Chase races his toy dump trucks through the family’s Dyer, Ind., home, a stark difference from when the paralysis of his right arm caused him to lose his balance. His parents remember the agony of watching him fall as he tried to walk. But a nerve transfer — a procedure that restored movement to his shoulder and elbow — and continued physical therapy has enabled him to use his right arm again, though he continues to build up its strength. In therapy he’s using a bat and knocking things down to strengthen his arm.
“I’m not sure he’s ever going to fully recover from it,” Kulakowski said. “I don’t see it as a realistic outcome. I think he’s always going to know he’s different.”
Paralyzed after nap
Chase’s medical journey started with a runny nose in October 2016 that doctors initially thought was a respiratory infection. Then seemingly over a two-hour nap, Chase’s right arm became paralyzed. He had been under the watch of a baby sitter, but the caretaker only noticed that the boy was tired that day.
David Kulakowski, Chase’s father, knew something was seriously wrong that night while getting his son ready for a bath. He took off his son’s shirt and saw the small arm “just flop.” The father picked up the arm, let it go and watched the lifeless limb fall down. That prompted the couple to take the boy to a nearby urgent care center, where they were told it appeared the boy had AFM.
Skeptical of the quick diagnosis, the couple took the boy to two hospitals for second opinions. Chase spent three days at Lurie Children’s Hospital in Chicago where he underwent an MRI. He was diagnosed and discharged with a list of options for physical therapy.
Jessica Kulakowski found support in an online community of parents seeking answers about the condition. Chase had been around other children who probably got the same virus. Yet he was the only one who developed AFM.
“Why it continued to his spinal cord? They don’t know,” she said. “That’s the one thing they can’t answer, and here we are two years later and still nobody can answer it.”
Because one exact cause is not known, health officials have looked into possible clues in everything from viruses to environmental toxins to genetic disorders. Some AFM cases have been connected to a severe respiratory illness caused by enterovirus D68, but Chase tested negative for it, his mother said.
AFM happens when a virus travels to a person’s spinal cord, affecting the specific area that correlates with the person’s muscles. Chase didn’t show the most severe symptoms other children have shown, such as being unable to swallow or breathe. Some children start to show signs of weakness after a prolonged cold. Other warning signs include eyelid or facial dropping and difficulty moving the eyes.
Chase’s ‘batteries’
There is no cure for AFM, but doctors can provide supportive care to patients including physical and occupational therapy. Then the parents started to hear about nerve transfers to restore movement in the paralyzed limbs. A private Facebook group of parents dealing with AFM led the family last December to Shriners Hospitals for Children-Philadelphia for a nerve transfer.
Doctors moved nerves from Chase’s rib area — which were considered redundant because they perform the same function as other nerves — to his shoulder and elbow where the nerves weren’t working. The process is really reconnecting a person’s brain to the muscles, said Dr. Dan Zlotolow, an orthopedic hand surgeon who operated on Chase. The results are more promising the younger the patient is and the sooner it happens after the initial injury, Zlotolow said.
In Philadelphia, doctors have done nerve transfers in 16 children with AFM who had paralysis in their hand, arm or shoulder, Zlotolow said. Other doctors across the country have focused on doing the procedures on AFM patients with paralysis in the legs.
In the 16 cases, the children have regained movement, but building up the strength of the muscles will take time, Zlotolow said.
The nerve transfer was an hourslong procedure that was explained to Chase by telling him that doctors were going to try to make his arm work again, Jessica Kulakowski said.
“And he said, ‘Oh, he’s going to put batteries in there,’” she remembers her son saying. She commemorated the date of the surgery by getting a tattoo of batteries on her back.
Uptick in cases
The family made the drive back to Indiana from Philadelphia with Chase and a Spider-Man doll in identical bright-red casts. As his parents took care of Chase, the toddler took care of Spider-Man, making sure they took their medicine together. Three months after surgery, Chase was able to lift his arm and move his elbow with support from his father. Since then he’s continued therapy. He’s working on picking things up, and he tends to default to his left arm now to do things like toss a ball.
When Chase was first diagnosed, it was part of a wave of cases that were reported nationally from August to October 2016. The CDC is again seeing a rise in cases similar to increases in 2016 and 2014, but officials don’t know why more people are getting AFM every other year. The spikes tend to occur from August to October.
Dr. Nancy Messonnier, of the CDC, said in a recent conference call that there have been 62 confirmed cases — the majority involve minors — so far this year in 22 states. There are an additional 127 suspected cases of AFM that officials are further investigating. The CDC began tracking the cases in 2014 when it first started to see a bubble of cases.
Messonnier said the condition is rare, and doctors have been relying on an assessment of symptoms and MRI results to make an AFM diagnosis. The CDC investigates outbreaks of illnesses across the country by gathering information from state health officials, doing laboratory testing and by consulting medical experts, Messonnier said. Health officials still can’t pinpoint whether anyone in particular is more at risk or even why that person would be more likely to get it.
“There is a lot we don’t know about AFM, and I’m frustrated that despite all our efforts we haven’t been able to identify the cause of this mystery illness,” Messonnier said.
Though the condition has been compared with polio, the CDC reports that polio is not the cause of AFM, Messonnier said.
Jessica Kulakowski said she and other parents have been using the increase in cases to get the word out about the need for more research and resources. Her son was featured in a recently created Instagram account that features children with AFM. Among the hashtags used under a photo collage of Chase was #WENEEDRESEARCH.
The increase also means parents are now coming to her with questions. She still doesn’t have many answers.
“What are we supposed to do for our kids if nobody has any idea?” she said.
