Avexis Inc.'s manipulation of raw data in a mouse potency assay used as a product release test during the early clinical development of gene therapy Zolgensma (onasemnogene abeparvovec) allegedly involved two senior executives who altered or instructed others to alter a small amount of the data, the Novartis AG subsidiary said in an Aug. 23 response to an FDA Form 483 inspection report. "Such conduct is unacceptable, and the two Avexis senior executives have been terminated," according to the company's response, which the FDA and Novartis posted Tuesday. As for the delay in disclosing the manipulation until nearly a month after the FDA had approved the $2.1 million spinal muscular atrophy therapy, Avexis said it conducted a complex, two-phase investigation into the allegations, which took significant resources and time. "We understand the FDA's concerns and appreciate that the circumstances presented by a new gene therapy is something that should be taken into account with regard to timing of FDA notifications of data integrity investigations," the Basel, Switzerland-based Novartis said in posting Avexis' response. "Although we are confident that the actions we are taking will prevent data integrity issues from occurring in the future, going forward we are making a voluntary commitment to notify the FDA within five business days of receipt by our quality organization of any credible allegation related to data integrity impacting any pending application in the Novartis Group. We will take a similar approach in other jurisdictions." Novartis acquired San Diego-based Avexis last year. (See BioWorld, Aug. 7, 2019.)

The FDA Tuesday released an updated preliminary list of approved new drug applications (NDAs) that will be deemed to be biologics license applications (BLAs) March 23. Current as of Aug. 31, the updated list consists of more than 90 simple proteins that were approved as NDAs, including nearly 30 insulin products. In the past, follow-ons of the NDAs were generally approved on the 505(b)(2) path, even though they were approved in other countries as biosimilars. Once they're deemed as BLAs, they will all be considered "new" biologics rather than biosimilars and can serve as reference products for biosimilars. The shift in regulatory paths was mandated by the 2010 Biologic Price Competition and Innovation Act, which gave the FDA 10 years to make the transition. The agency said it's working to ensure the shift is seamless so there are minimal impacts on manufacturers and patients.

The FDA this week finalized its guidance on developing drugs to treat amyotrophic lateral sclerosis (ALS) with the aim of fostering the availability of treatments for the complex neurological disease. "Despite years of research and the availability of some approved therapies, we know the lack of new treatments for ALS is deeply frustrating for patients and caregivers," the agency said. The guidance includes recommendations on clinical trial design and ways to measure effectiveness, answering some of the questions raised by stakeholders. While placebo controls may be the best way to determine the effectiveness of some products, the guidance emphasizes that no patients in ALS trials should be denied effective therapies so they can be randomized to a placebo-only arm. Instead, all patients in the trials should receive the best standard of care. The guidance explains various strategies – such as master protocols, adaptive designs and enrichment strategies – to minimize unnecessary exposure to placebo and expedite trials. Stressing its commitment to help patients with ALS access experimental treatment, the FDA asked companies developing ALS treatments to provide information about the status of their research and information on availability of their drug candidates through the agency's compassionate use or the Right to Try programs.

To minimize possible disruptions in the U.S. drug distribution supply chain, the FDA said this week it would delay, until Nov. 27, 2020, the requirement for wholesale distributors to verify a product identifier before further distributing returned drugs. The grace period is part of a final guidance the agency issued this week on its compliance policy for the wholesale distributor verification requirement for saleable returned drugs. The requirement is a provision of the Drug Supply Chain Security Act. Other requirements will still take effect Nov. 27, 2019, the agency said.

How much processing is involved will determine the regulatory route for fecal microbiota transplant (FMT) products in Australia, according to the Therapeutic Goods Administration (TGA). Under the TGA's new regulatory provisions, minimally manipulated FMTs will be regulated as either class I or 2 biologicals, based on where they are manufactured and used. Those used in the hospital where they were manufactured will be class 1 biologicals that will need to be included in the Australian Register of Therapeutic Goods (ARTG). However, the hospital will not need a good manufacturing practice (GMP) license or pre-market assessment. Minimally manipulated FMTs that are not manufactured in a hospital or are used in a hospital other than the one that manufactured them will be considered class 2. They must be included in the ARTG and GMP licensing of all manufacturing and testing facilities will be required. FMT products that have been processed in a way that alters biological characteristics or physiological functions will be regulated as class 3 or 4 biologicals or medicines, which are required to be included in the ARTG and have GMP licensing. The new provisions are expected to be implemented Jan. 1 with a 12-month transition period. Meanwhile, the TGA is developing more detailed guidance on the proposed regulation and it's working on an appropriate FMT standard to specify the minimal requirements for donor and product screening and provide specific guidance on manufacturing requirements.

Following agency reviews, Japan's Pharmaceuticals and Medical Devices Agency (PMDA) posted revisions Tuesday for the labeling precautions for arthritis drug Olumiant (baricitinib, Eli Lilly and Co.), cancer drug Tagrisso (osimertinib, Astrazeneca plc), and 13 oral and injectable fluoroquinolone and quinolone drugs. Since a causal relationship between Olumiant and a postmarket report of venous thromboembolism could not be ruled out, the PMDA said it was necessary to add venous thromboembolism to the clinically significant adverse reactions section of the drug's label. Noting that cases of toxic epidermal necrolysis, Stevens-Johnson syndrome and erythema multiforme have been reported worldwide in patients treated with Tagrisso, the PMDA is adding those conditions to the drug's clinically significant adverse reactions section. The PMDA revisions for the fluoroquinolone/quinolone label follow similar revisions in EMA and FDA labeling. They call for updates in the wording about tendon disorders and add peripheral neuropathy and psychiatric symptoms, along with descriptions, to the drugs' clinically significant adverse reactions section.

The World Health Organization launched its first strategic response plan (SRP) for a measles emergency Tuesday to ensure financial commitment to stop the spread of measles in Europe. More than 120,000 cases were reported in Europe between August 2018 and July 2019, and all but five of the 53 countries in the region have reported outbreaks. The SRP for the grade 2 emergency will extend through December 2020, providing a resource mobilization tool to accelerate tailored interventions in affected and at-risk countries. The plan calls for bringing the outbreaks under control, providing safe care to patients, increasing high-level commitment, strengthening vaccine acceptance and demand, increasing preparedness and risk mitigation, and reviewing outbreak response.

Ahead of what's expected to be a severe flu season, U.S. President Donald Trump signed an executive order last week to spur the development of new vaccine technologies, prioritize the production of flu vaccines and identify strategies to communicate the importance of vaccination. The administration is focused on reducing reliance on time-consuming, egg-based vaccine production. Improving the speed of production through new technologies will enable experts to better match vaccines to actively circulating viruses, according to the order. The administration also set up a task force to identify vaccine policy priorities and monitor progress.

In the first year of its global AMR Challenge, the U.S. Department of Health and Human Services (HHS) said it has received commitments from organizations representing more than 10,000 health care facilities around the world, with nearly half of the commitments focused on improving antibiotic use to slow the development of antimicrobial resistance (AMR). In addition, more than 55 pharmaceutical and biotech groups have committed to develop or provide access to products that will prevent and treat resistant infections, according to HHS.

Paul Elmer, former president and owner of Pharmakon Pharmaceuticals Inc., was sentenced last week to 33 months in prison and fined $25,000 after being convicted by a jury of one count of conspiring to defraud the FDA and obstructing inspections and of multiple counts of distributing adulterated drugs. A Noblesville, Ind.-based compounder, Pharmakon made and distributed compounded, sterile, intravenous drugs to military and civilian hospitals throughout the U.S. From 2013 to 2016, at Elmer's direction, Pharmakon shipped compounded drugs to hospitals before receiving lab results verifying the drugs' strength, according to the U.S. Department of Justice. Then, after receiving test results showing potency failures, Elmer didn't recall the drugs, notify the FDA of the potency failures or investigate the cause of the problem. At least 70 lots of over- or under-potent drugs were shipped to customers. In one instance, Pharmakon distributed 2,460% super-potent morphine sulfate to hospitals where it was unknowingly administered to infants. In another instance, the company distributed 200% potent midazolam, a sedative used to treat premature infants. Adverse events prompted three FDA inspections, in which Elmer and Caprice Bearden, Pharmakon's former compliance director, interfered and misled agency investigators, according to former employees who testified at the eight-day trial. Bearden pleaded guilty to conspiracy and adulteration charges earlier this year and was sentenced in April to five months in prison.

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