Regulatory Alert

An experimental Amgen osteoporosis drug that had sparked concern about cardiovascular side effects has won the backing of an FDA advisory panel. A total of 15 panelists this week voted that the benefits of the drug, romosozumab (Evenity), outweigh its risks, and are enough to support its approval. But many of those panelists also said the drug should carry a warning on its label, and that the FDA should require Amgen to conduct more studies to better understand the heart risks. Learn More

Unimed Pharma, a Slovakia-based pharmaceutical manufacturer, drew a statement of noncompliance after an inspection revealed two critical and 21 major good manufacturing practices (GMP) deficiencies. The statement of noncompliance took issue with the firm's manufacturing operations for sterile products, including aseptically prepared small volume liquids and batch certification. The statement was issued by the Slovakian State Institute for Drug Control (SIDC), following an inspection conducted last December. Learn More

The past year proved to be a big one for the U.S. FDA and the approval of novel drugs. Over the course of 2018, the FDA approved 59 different novel drugs that range for the treatment of various cancers, chronic obstructive pulmonary disease (COPD), traveler's diarrhea, migraine headaches and more. Over the past 190 years, the FDA has averaged an approval of 33 novel drugs each year, with 2018 having the highest number. In 2017, the FDA approved 46 novel drugs, but only 22 in 2016. Learn More

As UK Prime Minister Theresa May's Brexit deal is expected to be rejected today in a House of Commons vote, the EMA has said that after closely monitoring staffers' intentions to relocate to Amsterdam, it currently expects a staff loss of about 25%. The 25% figure might seem like a lot of staffers to lose, but that figure is on the low end of predictions from a survey in September 2017 that found EMA expected to lose at least 19% of its staffers no matter which city was selected. In addition to the staffing losses, the EMA says it will further temporarily reduce or suspend activities in the first half of 2019 as it moves into the final phase of its physical relocation. Learn More

Akorn has announced the receipt of a warning letter from the U.S. FDA following an inspection of the company's Decatur, Illinois manufacturing plant. The warning letter lists violations related to the agency's current good manufacturing practice regulations, which include poor aseptic behavior, as well as those related to environmental and personnel monitoring. The Lake Forest, Illinois-based company also failed to follow "appropriate written procedures" to prevent microbiological contamination of the drugs being produced at the plant, the letter said. The regulator also noted that foreign fibers and other contaminants were found on gloves that were supposed to be sterile. Learn More

Nearly every person who's run the U.S. FDA in recent history agrees the agency should break free from its political supervisors - a rare consensus from commissioners who served under Republican and Democratic administrations alike. In two papers published this week, all seven of the FDA's most recent commissioners wrote that the current setup - in which the agency is a mere subdivision of the Department of Health and Human Services - interferes with the ability of its scientists to protect the health of the public. They described a situation in which a tangled web of responsibilities, along with political overseers who aren't necessarily motivated by science, all make it harder for the FDA to keep people safe. Learn More

The U.S. FDA plans to create a new office to improve the review of new medicines - one that will develop a standardized approach to using personalized medicine, digital data, and patients' own reports, according to Commissioner Scott Gottlieb. Gottlieb will outline the plan for the new 52-person group, called the Office of Drug Evaluation Science (ODES), as part of a talk at the annual J.P. Morgan Healthcare Conference this week. Learn More

Novartis, Regeneron, Pfizer and industry group BIO called on the US Food and Drug Administration (FDA) to expand a recently released draft guidance on master protocols to make it applicable beyond oncology. The 21-page draft guidance on master protocols, also known as "umbrella," "basket" or "platform" trial designs, is meant to help sponsors of cancer drugs or biologics regarding the design and conduct of clinical trials intended to simultaneously evaluate more than one investigational drug and/or more than one cancer type within the same overall trial structure in adult and pediatric cancers. Learn More

The U.S. FDA and other parts of the federal government may be headed for a shutdown after President Donald Trump said he would not sign a Senate-passed continuing resolution (CR) to keep the government open. If a shutdown takes place, the FDA would, in addition to keeping essential public health-related employees working, continue specific activities within its user fee programs, including work on prescription drugs, generic drugs, biosimilars, medical devices, animal drugs and tobacco products, according to the Department of Health and Human Services' contingency plans. About 7,000 FDA staff, or 41%, would be furloughed if the shutdown occurs, while the remaining 10,344 would be retained, according to the plans. Learn More

The U.S. FDA has approved a BLA for Herceptin biosimilar Herzuma from Celltrion. In April, Celltrion received complete response letters from the FDA for Herzuma and Truxima rituximab-abbs, its Rituxan biosimilar. Celltrion said at the time the letters were directly related to the FDA's January warning letter describing GMP violations observed during a visit to Celltrion's manufacturing facility. Celltrion resubmitted the BLA for Herzuma in June, and in November the FDA approved a resubmitted BLA for Truxima to treat non-Hodgkin lymphoma. Teva has exclusive rights to commercialize both biosimilars in the U.S. and Canada. Learn More

The U.S. FDA is backing off a 2013 proposal that could have opened generic drugmakers to potential lawsuits over the side effects of medications. This decision comes in the form of a statement from FDA Commissioner Scott Gottlieb and CDER Director Janet Woodcock noting that the regulatory agency has withdrawn its proposal for that rule, keeping the drug manufacturers safe from those kinds of lawsuits. Alert readers will recall that back in 2013 the FDA proposed the rule called Supplemental Applications Proposing Labeling Changes for Approved Drugs and Biological Products. Learn More

A political stalemate in Washington is raising the possibility of a partial government shutdown beginning December 21st, 2018 when a stopgap federal funding bill expires. Such a shutdown could limit the FDA's ability to review NDAs. While the agency would be able to continue ongoing drug reviews during a shutdown, it could be barred from accepting new applications. A FY19 bill funding NIH and CMS has been enacted, so these agencies would not be affected by a shutdown. The FDA's response to a partial government shutdown in January 2018, in which it made public plans to furlough 42% of its staff, provides a road map to the agency's likely response to a future shutdown. Learn More

The U.S. FDA this week finalized its questions and answers guidance on complying with data integrity requirements under current good manufacturing practice (CGMP) for drugs and biologics. The guidance updates a draft version released in 2016 and has been revised to include additional information on the agency's current thinking on data integrity to help drugmakers identify lapses and implement best practices to shore up any gaps in their data integrity processes. The FDA says the guidance was developed in response to an increase in data integrity violations observed during inspections that have resulted in warning letters, import alerts and consent decrees in recent years. Learn More

The U.S. FDA this week released two new draft Q&A guidance documents on biosimilar development and the deemed to be a license provision of the Biologics Price Competition and Innovation Act of 2009 (BPCIA), as well as two final guidance documents on the same topics and one proposed rule amending the definition of a biological product. The efforts are part of the FDA's decade-long work to begin, starting in March 2020, transitioning the approved marketing applications for a subset of biological products, such as insulin and human growth hormone - which were previously approved as drugs under section 505 of the FD&C Act - to be deemed to be biologics licenses. Learn More

As data integrity violations continue to be found in Form 483s and warning letters, the Pharmaceutical Inspection Convention/Pharmaceutical Inspection Cooperation Scheme (PIC/S) released a 52-page draft guidance outlining how an inspector should inspect facilities that must adhere to Good Manufacturing Practice (GMP) and Good Distribution Practice (GDP) standards. The guidance, which will be open for consultation until February 28th2019, was directed by the Australian and British-led PIC/S Working Group on Data Integrity. It is meant to facilitate a harmonized approach to inspections. Learn More

An inspection by the U.S. FDA at the McPherson, KS plant of Pfizer's Hospira business revealed eight repeat FDA Form 483 citations dating back to 2012. FDA investigators conducted an inspection of the human sterile drug manufacturing site from late July to early August 2018, with the agency posting the Form 483 to its website late last week. The latest 483 comes after Hospira's Kansas plant drew an FDA warning letter last year, with significant violations of good manufacturing practices, such as an inadequate investigation into the detected presence of cardboard in vial samples. Learn More

The U.S. FDA this week unveiled a new framework discussing how the agency will use real world evidence (RWE) and real-world data (RWD) to help companies win new indications for approved drugs and biologics, expand labels or satisfy post-approval study requirements. As far as what the framework will guide the FDA on specifically, the agency said its RWE program will evaluate the potential use of RWE to support changes to labeling about drug product effectiveness, including adding or modifying an indication. Learn More

The U.S. FDA this week made public a warning letter sent November 28th, 2018 to Korea-based Barox for significant violations of current good manufacturing practice (CGMP) regulations. The FDA said the firm relabels over-the-counter drug products manufactured by a contract manufacturer and then distributes the drugs to the U.S. The warning letter also calls the company out for not having procedures for its relabeling operations, including the issuance and reconciliation of labels. The firm, which appears to distribute pain relief creams among other products, was also found to have no procedures for how it stores and warehouses drugs. Learn More

Leaders from all three countries signed the United States-Mexico-Canada Agreement (USMCA) at the recent G20 meeting in Argentina. The agreement includes a commitment to extend biologics market protection to 10 years. The agreement still needs to be ratified by Congress and the legislatures of Mexico and Canada. Stephen Ubl, president and CEO of PhRMA, commended the deal and said, "The IP standards in the USMCA far exceed those in any other international trade agreement." Learn More

The U.S. FDA this week approved Celltrion and Teva's Truxima as the first biosimilar to Rituxan. This is the FDA's 15th biosimilar approval overall, the third in the last month and the first for rituximab in the US. Only six biosimilars are currently on the U.S. market. In the EU, two rituximab biosimilars are currently marketed - Celltrion's Truxima and Sandoz's Rixathon. The two biosimilars have captured 46% of the rituximab market in the EU, according to Bernstein analyst Ronny Gal. It remains unknown when this biosimilar will launch in the U.S. Alert readers will recall that Celltrion previously received a complete response letter for its application due to manufacturing issues. Learn More

The U.S. FDA earlier this month confirmed the capabilities of Belgium, Denmark, Finland and Latvia so that the FDA can now rely on the inspections in each of those countries, reducing the need for duplicative work. A total of 19-member states in the EU are now qualified by the FDA as having the capability, capacity and procedures in place to carry out GMP inspections at a level equivalent to the U.S. However, the EMA notes that imported products still need to be batch tested until the FDA recognizes all member states' authorities for human pharmaceuticals, which is expected to be completed no later than July of 2019. Learn More

The U.S. FDA has expanded the approved use of Adcetris injection in combination with chemotherapy for certain types of peripheral T-cell lymphoma (PTCL). This is the first FDA approval for treatment of newly diagnosed PTCL, and the agency used a new review program to complete the approval more quickly. "The Real-Time Oncology Review (RTOR) program allows the FDA to access key data prior to the official submission of the application allowing the review team to begin their review earlier and communicate with the sponsor prior to the application's actual submission," said Richard Pazdur, MD, director of the FDA's Oncology Center of Excellence. Learn More

Building off a Pfizer citizen petition on biosimilar misinformation, Novartis is calling on the FDA to set the record straight on what information can be disseminated. The misinformation campaigns, as explained in Pfizer's petition from August, "further demonstrate efforts to foster fear and highlight hypothetical yet unproven risks associated with the use of FDA-approved biosimilars," Novartis said. Amgen, Genentech and others are called out for these campaigns that not only question the legal framework enacted by Congress but also question the safety of switching to a biosimilar, "thereby questioning the validity of an FDA decision that a biosimilar is safe and effective for use," Novartis said. Learn More

Three of the U.S. Food and Drug Administration's (FDA) directors - Richard Pazdur, Peter Marks and Janet Woodcock - took the stage this week at Prevision Policy's Biopharma Congress to discuss all things FDA - from why the agency is viewed more positively now than in the past to what needs to happen in each of their centers. The views they shared on everything from real-time review to manufacturing practices and more can be found at RAPS. Learn More

While AmerisourceBergen has made strides to correct violations in its compounding business, the drug distributor doesn't know when regulators will allow commercial operations there to resume, according to a document recently filed with the Securities and Exchange Commission. PharMEDium, a drug compounder and subsidiary of AmerisourceBergen, received a series of Form 483s over the last year as regulators observed issues at several of its manufacturing plants. Some of the more common issues included failing to have procedures that adequately protect against contamination or ensure quality control. Learn More

As six companies have now settled with AbbVie over when they can launch their Humira biosimilars in 2023, Boehringer Ingelheim continues to wrangle in court with AbbVie. According to documents released this week from the suit between Boehringer and AbbVie, Boehringer said AbbVie's generalizations "are unproductive and inaccurate." AbbVie, meanwhile, claims that Boehringer "refuses to produce fulsome corporate testimony in response to nearly every topic" related to eight patents in the suit, "unnecessarily enlarging the scope of the parties' dispute." The comments from both sides offer a window into a dispute that's continued now for more than a year. Learn More

Teva has "earned nothing, let alone entitlement to 180-day exclusivity," the U.S. FDA said in a court filing this week after Teva filed suit last month over its first filer status regarding generic versions of Restasis. Calling Teva's demands "baseless and premature," the agency noted that although Teva submitted its abbreviated new drug application (ANDA) for a cyclosporine generic in January 2012, Teva has yet to win FDA approval or even a tentative approval, which FDA makes clear "is a necessary predicate for Teva's proposed product to meet the statutory criteria to be eligible for a 180-day exclusivity period. The response from the FDA follows Teva's seeking declaratory and injunctive relief. Learn More

In a recently released inspection report the U.S. FDA details 11 observations from an inspection of Akorn's Somerset, New Jersey facility in July and August of this year. This is the second Form 483 Akorn has received in 2018. In May the company was handed a Form 483 listing a total of 13 observations from an inspection of the company's Decatur, IL facility, the third inspection report issued for that facility in three years. In the 22-page inspection report, the FDA lists 11 observations related to Akorn's quality system, laboratory controls and production processes. According to the FDA, Akorn failed to adequately investigate out-of-specification test results for batches of some of its drugs. Learn More

An advisory panel to the U.S. FDA has voted against approving Alkermes' treatment for depression in patients with an inadequate response to standard antidepressant therapies. The decision comes just days after FDA staff reviewers flagged abuse potential for the opioid-based depression treatment and raised questions on its efficacy. The panel voted 21-2 against the drug, ALKS 5461, a once-daily pill combining samidorphan and buprenorphine developed as an add-on treatment for major depressive disorder (MDD), saying the data did not support a favorable benefit-risk profile. Learn More

In its latest update on the investigation into impurities detected in a growing body of sartan products, the U.S. FDA has issued alerts to recalls initiated by two firms over the presence of the second probable human carcinogen to have been tied to the scandal. ScieGen is recalling certain lots of its irbesartan because after finding that they contain NDEA, which is a known animal and suspected human carcinogen, according to the FDA. The manufacturer of the API ScieGen used for its irbesartan products-Aurobindo-is also recalling all unexpired lots of its irbesartan API supplied to the U.S. market with NDEA. This recall was initiated after laboratory testing confirmed the presence of NDEA is certain lots of Aurbindo's Irbesartan. Learn More

The U.S. FDA's Oncologic Drugs Advisory Committee (ODAC) voted 16-0 that Celltrion's and Teva's CT-P10, a biosimilar to Roche's Rituxan (rituximab), should be approved for three indications of the reference product. The vote followed a presentation in which FDA and Celltrion showed that CT-P10 was highly similar and as safe as Rituxan. The companies said they sought approval for the three proposed non-Hodgkin's lymphoma indications because of the current patent and exclusivity landscape, a Teva representative said. Learn More

The U.S. FDA recently posted a Form 483 sent in July to the nation's largest drug distributor, McKesson, and questioned the firm on how it detects illegitimate products. The release of the Form 483 follows an investigation last year from the Washington Post and 60 Minutes highlighting McKesson's failure to report suspicious orders involving millions of painkillers and opioids sent between facilities, some of which were reported to be fraudulent pharmacies. The findings from that Washington Post/60 Minutes report mirrors this latest Form 483 from the FDA, which includes three observations following inspections conducted in June and July at the wholesale distributor's San Francisco site. Learn More

The U.S. FDA has issued a revised draft guidance designed to allow for it to reject 505(q) petitions if the agency determines the primary purpose of the petition is to delay the approval of an abbreviated new drug application (ANDA). The new approach to reviewing petitions would also help the FDA focus its resources on addressing petitions that are most likely to present an obstacle to the availability of generic drugs. To further dissuade companies from improperly using these petitions, the FDA says it intends to refer these matters to the U.S. Federal Trade Commission.
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The U.S. FDA's Purple Book for biosimilars needs some modifications and new information to be more useful, biopharma companies told the FDA in recent comments. According to the FDA, the Purple Book includes the date a biosimilar or biologic was licensed and whether FDA evaluated the biological product for reference product exclusivity. It also includes whether a biological product has been determined by FDA to be biosimilar to or interchangeable with a reference product. But drugmakers are pushing back on this limited scope. Learn More

Mylan and Novartis are taking issue with the fact that the U.S. FDA has yet to begin issuing random suffixes for biologics' names and so far has only used these suffixes for biosimilars and a few recently approved biologics, according to recent comments. "The agency has not yet retroactively issued suffixes to any reference product for which there is a corresponding biosimilar. Given the agency's silence about this practice, there are senior scientists and prominent physicians in the U.S. that believe that this disparity is intentional," Novartis said in its comment on the recent biosimilar meeting at the FDA. Learn More

The U.S. FDA this week released a warning letter sent to India-based Wilson Medicine for significant violations of current good manufacturing practice (CGMP) regulations for finished pharmaceuticals. Following an inspection from February 26thto March 1st, FDA investigators found the company not only did not demonstrate that its manufacturing processes are reproducible and controlled to consistently yield drugs of uniform character and quality, but also did not conduct equipment qualification. The company was also found to not have validated or verified test methods used to determine the acceptability of drug products prior to release.
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The U.S. FDA has once again warned a biopharma lab just outside Chicago to cease operation of a microbrewery within its lab. A recent inspection of Pharmaceutical Laboratories and Consultants in Addison, Illinois found brewery supplies casually mixed in with equipment used to evaluate over-the-counter drug products. In one instance, the facility had stored a beer fermenter and created a workspace for a brewery employee preparing kegs, all within 10 feet of an area where microbiological material is kept. The dual-use facility poses "unacceptable risks," the agency said, including the contamination of materials used to test over-the-counter drug products. Learn More

The U.S. FDA has unveiled a Form 483 from April for ADMA Biologics, a company that previously received a complete response letter related to manufacturing deficiencies. Earlier this month and prior to the 483's release, however, ADMA said FDA's inspection database classification website has been updated and "confirms ADMA's compliance status has improved to Voluntary Action Indicated (VAI)." FDA explains the VAI designation as: "Objectionable conditions were found but the problems do not justify further regulatory action. Any corrective action is left to the investigator to take voluntarily."
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Just days after the U.S. FDA joined the EMA and Health Canada in announcing a second impurity, called NDEA, has been found in valsartan manufactured by Zhejiang Huahai Pharmaceuticals the FDA has released a third Form 483 to the company. Following inspections in July and August, the FDA issued the 483 with 11 observations, with perhaps not surprisingly specific issues raised about the firm's quality unit. The FDA also found the firm's change control system, designed to evaluate all changes that may affect production to be inadequate. Learn More

When a pharmaceutical or active pharmaceutical ingredient manufacturer has data integrity issues, that's likely the tip of the iceberg, Sarah Barkow, of FDA's Office of Manufacturing Quality, told attendees at an annual conference in Rockville, MD. "You need to worry about from all levels of the supply chain," she said. "Once there are data integrity lapses, you know there are other things you don't know." In terms of remediation, she said companies need to follow three steps: conduct a comprehensive investigation, perform risk assessments and form a remediation and management strategy that includes a corrective action plan. Learn More

As part of the U.S. FDA's action plan on biosimilars, Commissioner Scott Gottlieb said in July the agency is "actively exploring" whether "in some circumstances" FDA can "facilitate the increased use of non-U.S.-licensed comparator products in certain studies to support" biosimilar applications. The change would allow biosimilar developers to purchase reference product to demonstrate biosimilarity from Europe or other region without further demonstrating that the EU-licensed and US-licensed reference products are similar. Gottlieb explained in his action plan speech, echoing earlier comments, that biosimilar developers could cut costs by using biologic reference products sourced outside the US. Learn More

Inspectors from the U.S. FDA spotted new issues at Sun Pharma's manufacturing plant in Halol, Gujarat, India during an August inspection, putting the key facility back under scrutiny after it had received a green light from U.S. regulators in June. Following a pre-approval inspection, the FDA issued a Form 483 to Sun with six observations, including issues with the plant's test procedures for drug products. This inspection report comes just a few months after the FDA finally resolved a long-running regulatory challenge for Sun and its Halol plant. In 2015, the FDA issued a warning letter to the facility, holding up new U.S. approvals for drugs produced at the site. Learn More

Members of the biopharmaceutical industry and pharmacists are calling for changes to the U.S. FDA's recently released draft guidance on the Indications and Usage section of drug and biologics labeling. Notably, the draft guidance sets out FDA's expectations for the content and format of the Indications and Usage section of labeling, explains the circumstances in which an indication can be broader or narrower than what was studied in the clinical trials that supported the product's approval and provides recommendations for including and placing limitations of use in the labeling. Learn More

The U.S. FDA this week released an internal Manual of Policies and Procedures (MAPP) on how biopharma manufacturing sites are prioritized and selected for surveillance inspections. The release of the 7-page MAPP comes as FDA's inspections program in Fiscal Year 2017 had to decide what sites to inspect from about 5,063 human pharmaceutical sites worldwide, 3,025 of which are outside the US. In 2017, FDA conducted 1,453 inspections, including 762 on foreign soil, to ensure manufacturers were following Current Good Manufacturing Practice (CGMP) requirements.
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Vertex and partner CRISPR Therapeutics have begun enrolling patients in the first U.S. company-sponsored trial using CRISPR/Cas9 editing. The European Phase I/II trial is evaluating CTX001, which comprises autologous CRISPR-modified human hematopoietic stem and progenitor cells, in transfusion-dependent β thalassemia patients. Vertex spokesperson Heather Nichols said, "It's the first clinical trial of a CRISPR therapy in the Western world." Last November, Sangamo Therapeutics became the first company to treat a patient with an in vivo gene editing therapeutic. Learn More

U.S. FDA Commissioner Scott Gottlieb this week announced that the agency intends to withdraw its 2014 draft guidance on developing drugs and biologics to treat pain and replace it with at least four new guidance documents over the coming year. The move is part of the agency's efforts to respond to the ongoing opioid epidemic which has so far included expanding risk evaluation and mitigation strategy. According to Gottlieb, the 2014 draft guidance Analgesic Indications: Developing Drugs and Biological Products is overly broad and requires too many studies to obtain a general chronic pain indication. Learn More

The U.S. FDA has announced a new pilot program aimed at encouraging the use of complex innovative trial designs in the development of drugs and biologics. Sponsors selected by the FDA based on the criteria for participation in the "Complex Innovative Designs Pilot Meeting Program" will be able to engage staff in early discussions on approaches to complex designs. The pilot will remain operational through September 30th, 2022, but sponsors have until June 30th, 2022 to submit meeting requests. Meetings under the pilot will be conducted by FDA's Center for Drug Evaluation and Research or its Center for Biologics Evaluation and Research. Learn More

Zimmer Biomet announced in an SEC filing that it has received a warning letter related to observed non-conformities with CGMP requirements of the quality system regulation at its manufacturing facility in Warsaw, Indiana. The warning letter follows a lengthy Form 483 for the facility in May and another 483 dating back to 2016, though the company said it believes that FDA's concerns "can be resolved without a material impact to our financial results." The facility has had a history of inspectional issues, though Zimmer said it has provided written responses "detailing corrective actions underway to address the FDA's observations..." Learn More

The U.S. FDA has called on biopharma companies to submit site visit proposals for 2019 as part of a voluntary learning program for agency staff. The Staff Experiential Learning Site Visit (ELSV) Program, first announced in 2016, aims to provide staff at the Office of Pharmaceutical Quality within FDA's Center for Drug Evaluation and Research (CDER) new learning opportunities with in-person visits to drug manufacturing sites. The current four main areas of interest to FDA staff include drug products; API's manufactured by chemical synthesis, fermentation or biotechnology; design, development, manufacturing and controls; and emerging technologies. Learn More

The U.S. FDA this week warned two drug manufacturing facilities in Japan and China over failures to ensure data integrity and validate processes, among other violations. The warning letters, issued to Kyowa Hakko Bio and Hangzhou Karic, were made public following FDA site inspections that revealed significant violations of good manufacturing practices (GMP) for finished pharmaceuticals and for active pharmaceutical ingredients (APIs). The firms' drug products are considered adulterated as a result of the cited GMP violations. Learn More

The Chinese government this week removed from office local leaders representing the city and region home to the headquarters of Changchun Changsheng Life Sciences. The biopharma at the center of the vaccine scandal effecting 900,000+ children in China and counting. A deputy director of China's drug regulator was also dismissed, while another has been announced as the subject of an investigation. This comes after the company's CEO and 14 other officials were reported to have been detained. Alert readers will recall that back in 2007 China executed the man then in charge of its drug regulator following 10 deaths attributed to an antibiotic whose approval had been bought with bribes. Learn More

Leaders of CDER at the U.S. FDA, including Director Janet Woodcock, have shared their view on the role of real world evidence in JAMA this week. This is in response to a requirement of the 21st Century Cures Act that the FDA have a framework to evaluate the use of RWE by the end of this year. The idea is to leverage real-world evidence to support the approval of new indications for approved drugs or to satisfy post-approval study requirements. According to the FDA, RWE is defined as "the clinical evidence regarding the usage and potential benefits or risks of a medical product derived from analysis of RWD ." Learn More

In a sign that quality defects were known well before the recent valsartan recalls, the U.S. FDA late last week released two Form 483s sent to China-based Zhejiang Huahai Pharmaceuticals in November 2016 and May 2017. Zhejiang Huahai is the manufacturer at the center of the EU and U.S. recalls of valsartan due to the presence of an N-nitrosodimethylamine (NDMA) impurity-classified as a probable human carcinogen-in the company's high blood pressure and heart drugs. According to the Form 483 from 2016, Zhejiang Huahai was cited for four observations. The integrity of the company's analytical testing was questioned in the other Form 483 from 2017. Learn More

The EMA has overhauled a regulatory question and answer document about preventing cross-contamination at multi-product manufacturing facilities after a draft version was strongly criticized by leading drugmakers and trade groups. The EMA created the Q&A after receiving feedback about its 2015 cross-contamination guideline from regulators and industry. The feedback questioned the need to apply the guideline to all products, leading EMA to discuss different approaches to highly hazardous substances and lower-risk materials in its Q&A. This proved to be a contentious decision among manufacturers, including Gilead Sciences and the trade groups that represent them. Learn More

The U.S. FDA this week made public a Form 483 with no fewer than eight observations for Celltrion's South Korean site. The observations deal with a lack of written procedures for production and process controls, a lack of employee training and routine checking of automatic equipment not being performed according to the procedures written by Celltrion. Other violations found in the most recent Form 483, following an inspection in July, include deficient procedures describing the calibration of instruments and others with sections that are heavily redacted. This latest Form 483 follows two CRLs in April and a prior Form 483 roughly this time last year. Learn More

The U.S. FDA issued its final guidance this week which explains when to conduct risk assessments for elemental impurities in drug products. The recommendations outlined throughout the guidance provide a risk-based approach to the control of elemental impurities. The approach is intended to ease the regulatory burden in conducting this type of risk assessment as it was developed via the International Council for Harmonization (ICH). Europe and Canada are among the other ICH member countries that have already adopted the guideline. Learn More

The U.S. FDA issued its final guidance this week which explains when to conduct risk assessments for elemental impurities in drug products. The recommendations outlined throughout the guidance provide a risk-based approach to the control of elemental impurities. The approach is intended to ease the regulatory burden in conducting this type of risk assessment as it was developed via the International Council for Harmonization (ICH). Europe and Canada are among the other ICH member countries that have already adopted the guideline. Learn More

The folks over at Regulatory Focus have published a lightly edited transcript of the questions and answers from their recent interview with Janet Woodcock, Director of the FDA's CDER that provides some additional insight into the direction of the FDA generally and CDER specifically.
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The U.S. Senate this week passed 92-6 a minibus that includes more than $5.4 billion for the FDA. H.R. 6147 is the seventh fiscal 2019 appropriations bill the Senate has passed this year, marking the first time in years that it's passed the majority of its spending bills by August. Nearly a third of the FDA funding, about $1.721 billion, will go to the Center for Drug Evaluation and Research while the Center for Biologics Evaluation and Research will receive about $369.9 million. Under the bill, the agency is authorized to spend nearly $960.6 million in prescription drug fees, about $501.4 million in generic drug fees, more than $40.9 million in biosimilar fees and nearly $196.7 million in medical device fees. Learn More

A Tokyo-based manufacturer of APIs failed to report all laboratory testing data on released lots, according to a warning letter from the U.S. FDA's Center for Drug Evaluation and Research. An agency investigator conducted a site inspection last November and found analyses with out-of-specification results went unreported, despite the data being obtained on the same date that the company, Yuki Gosei Kogyo, reported passing results in 2015 for the same lot released in the U.S. As a result of the incomplete batch record, the firm's quality unit failed to conduct a review of all data from testing the API lot prior to release. Learn More

As part of plans to clarify earlier biosimilar guidance, the WHO has drafted a new document outlining answers to questions regulators posed over the past eight years. The more than 30 pages of questions and answers, most of which fall into the quality and clinical evaluation sections, range from the most basic, "What is a similar biotherapeutic product (SBP)?" to more complex questions, like: "Would it be beneficial to review/discuss post-marketing commitments from each NRA after extrapolation of indications?" The creation of this latest Q&A follows the 2009 "Guidelines on Evaluation of SBPs" and in 2016 another guideline on mAb biosimilars. Learn More

China's cabinet investigation group has found that vaccine maker Changsheng Bio-technology broke the law in manufacturing rabies vaccines, according to reporting by the state news agency Xinhua. The investigation group said the company had systematically falsified production and testing records to avoid regulatory scrutiny. China has launched sweeping spot checks on vaccine makers around the country after Changsheng was found to have falsified data and sold ineffective vaccines for children. President Xi Jinping has ordered all relevant departments to investigate the scandal, which has triggered public outrage in what is the latest case of tainted medical products. Learn More

The U.S. FDA this week released a draft guidance to help sponsors understand the evidence necessary to demonstrate the effectiveness of new drugs, including biologics, or new drug uses intended for slowly progressive, low-prevalence rare diseases that are associated with substrate deposition and are caused by single enzyme defects. In addition to the recommendation that sponsors perform genetic testing for the defect(s) of interest in all clinical trial subjects, the FDA explains how in the absence of a way to "directly characterize the clinical response to the drug of interest, the nonclinical and, in particular, the clinical pharmacology components of the drug." Learn More

One week after releasing its 11-part biosimilar action plan, the U.S. FDA announced it will hold a public hearing to gather input on how it can facilitate the development of biosimilars and ensure they enter the market in a timely fashion. At the hearing, set to take place on September 4th, 2018 at FDA's White Oak headquarters. The FDA will solicit input from stakeholders on nine questions on the scientific and legal challenges to bringing biosimilars to market and how to reduce barriers to competition once they are on the market. Learn More

The U.S. FDA has placed a partial hold on the early stage clinical trial of Mersana Therapeutics' lead cancer drug. This follows the death of a patient in the study whose physician noted the cause as "possibly drug related". The news sent the companies share price plunging roughly 40%. Alert readers will recall that Mersana has a partnership deal with Takeda worth more than $1 Billion if milestones are met.
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Earlier this year Fresenius and Akorn traded accusations as to whether Akorn breached FDA data integrity requirements that threatened the German drugmaker's $4.3 billion offer to purchase the generics maker. Then in March details on why Fresenius sought to terminate its acquisition of Akorn became public, with Fresenius alleging a top executive at Akorn had knowingly submitted fabricated data to the FDA, leading to Fresenius pulling out of the deal in the Spring of this year. Now a Form 483 for Akorn's manufacturing site in Decatur, IL., the second 483 for the site in less than three years, offers a look inside what the FDA found during an inspection in April and May. Learn More

The U.S. FDA this week published a warning letter sent July 5th, 2018 to a Baxter-owned manufacturing site following a nine-day inspection last July and August. In two instances, the Claris Injectables Ahmedabad, India based site, was found to have invalidated out-of-specification (OOS) results without adequate investigation and scientific justification. Alert readers will recall that Baxter the site as part of a more than $600 million acquisition that closed in July 2017. In a statement, Baxter notes that its ownership of the site had occurred just hours after the FDA's inspection had already begun but said it was committed to fully implementing the requisite corrective and preventive actions. Learn More

Earlier this month, the European Medicines Agency (EMA) initiated recalls of certain valsartan-containing medicines with active substance supplied by China-based Zhejiang Huahai Pharmaceuticals, pending a review of an impurity. Now the U.S. FDA is announcing a similar voluntary recall. Both recalls are due to an impurity, N-nitrosodimethylamine (NDMA), which was found in the recalled products. However, the FDA says, not all products containing valsartan are being recalled. Learn More

FDA Commissioner Scott Gottlieb, writing in the FDA Voice, notes that the FDA is focused on facilitating the adoption of advanced manufacturing practices by biopharma. As for what makes up advanced manufacturing in the eyes of the agency, it includes the principles and practices of continuous manufacturing and the application of 3D printing. However, Commissioner Gottlieb acknowledges that guidance must proceed adoption. With that in mind, he notes that the agency's 2019 budget includes $58 million to accelerate the development of the regulatory and scientific architecture, leading to the requisite guidance needed to progress the adoption of advanced manufacturing. Learn More

As first announced in January, the U.S. FDA's Center for Biologics Evaluation and Research (CBER) this week offered a swath of new draft guidance documents on human gene therapies, offering a look at what it expects from an industry that's beginning to take off. The six guidance documents focus on developing hemophilia, rare disease and retinal disorder gene therapies, and include one on chemistry, manufacturing and control (CMC) information, one on long term follow-up observational studies collecting data on adverse events and one on the testing of retroviral vector-based therapies. Learn More

The U.S. FDA this week published a warning letter sent to China based Zhuhai United Laboratories for significant deviations from CGMP for API. The FDA inspectors found the manufacturer lacked adequate procedures for investigating, and scientific justification to invalidate, out-of-specification (OOS) results.The warning letter also cites the API manufacturer for failing to adequately investigate findings from a February 2015 retrospective review of analytical chromatography data irregularities. FDA inspectors also found additional examples of incomplete data relating to Zhuhai's sterile manufacturing operations evaluated as part of FDA's pre-approval inspection. Learn More

A team of EMA officials have expressed caution about the utility of data from real world evidence in regulatory decision-making. In a newly published analysis in BMJ Open, five officials from EMA's Pharmacovigilance and Epidemiology Department find that "the immediate utilization of their outputs to support regulatory decision-making is limited, often due to insufficient available information and to discrepancies between outputs and objectives." Despite these issues, the authors emphasize that real world evidence is needed to supplement data from randomized clinical trials (RCTs). Learn More

The U.S. FDA this week finalized its guidance to help sponsors understand how the review goals established as part of the Generic Drug User Fee Amendments Reauthorization of 2017 (GDUFA II) apply to amendments to either abbreviated new drug applications (ANDAs) or prior approval supplements (PASs). The 32-page final guidance contains clarifications to the draft guidance of the same title that published in October 2017, the agency says. The GDUFA II Commitment Letter includes changes in the classification of and review goals for amendments to ANDAs and PASs under GDUFA I, when amendments got classified into a Tier-based system. Learn More

Mylan's manufacturing facility in Morgantown, WV, has received an FDA Form 483 listing inspectional observations, some of which were due to failures of its quality control unit.
Agency investigators who visited the firm during a 12-day site inspection earlier this year, noted 13 situations of noncompliance to good manufacturing practices in the 32-page Form 483. From a lack of appropriate oversight and documentation on written procedures changes to an inadequately validated cleaning process and established time limits on drug products, seven observations described the firm's quality control unit. Learn More

In a hard hitting article published in ProPublica this week, the author argues that with biopharma underwriting roughly 75% of the FDA's budget for scientific reviews, it is perhaps not a coincidence that the agency is increasingly fast-tracking expensive drugs with significant side effects and unproven health benefits. She notes that once widely assailed for moving slowly, today the FDA reviews and approves drugs faster than any other regulatory agency in the world. Between 2011 and 2015, the FDA reviewed NDA's more than 60 days faster on average than did its couterparets at the EMA. Learn More

The U.S. FDA has warned Chinese API manufacturer Henan Lihua Pharmaceutical Co. Ltd. for good manufacturing practice (GMP) violations stemming from an inspection last December. During the inspection, the FDA says its on-site investigators observed lapses in oversight by the company's quality unit and deviations related to record keeping at the Henan province-based facility. These issues resulted in the agency placing the company on import alert in March. The FDA also says the company rubber stamped manufacturing records and did not control access to those forms or the stamps. Learn More

The U.S. FDA this week approved the country's first drug derived from marijuana, a medication that treats two rare and devastating forms of epilepsy. The drug, GW Pharmaceuticals' Epidiolex, is made of cannabidiol, or CBD, a component of marijuana that does not give users a high. It is given as an oil, and in clinical trials, it was shown to reduce the number of seizures by about 40 percent in patients with Dravet or Lennox-Gastaut syndromes. The FDA's decision was expected after an advisory panel had unanimously recommended it. Learn More

The Trump administration has proposed a fundamental change to the mission of the U.S. Food and Drug Administration, one that would transfer most of the responsibility for regulating food safety to the Department of Agriculture and rename the FDA the "Federal Drug Administration." The idea of changing a key mission of the FDA comes amid a turf war between the FDA and the USDA. The two agencies have recently battled over who gets to regulate lab-grown meat, Politico reported last week. And in May, FDA Commissioner Scott Gottlieb spoke about the importance of his agency regulating genetically engineered animals. Learn More

In response to industry concerns, the U.S. FDA this week announced it has withdrawn its draft guidance on evaluating studies used to demonstrate analytical similarity between a biosimilar and reference biologic.The FDA says it plans to reissue the draft guidance after considering changes to the document that will "promote a more efficient pathway for the development of biosimilar products."To date, the FDA has approved 11 biosimilars to eight reference biologics since approving its first biosimilar in 2015. However, only a fraction of those biosimilars are available on the market, with legal challenges often adding years between approval and commercial launch. Learn More

Ziopharm Oncology has announced that the U.S. FDA has placed a clinical hold on a Phase 1 trial to evaluate CD19-specific CAR-T therapies manufactured under point-of-care and requested additional information in support of the investigational new drug (IND) application for the trial. The FDA has requested additional information relative to Chemistry, Manufacturing and Controls. Ziopharm and its partners will address the FDA's requests, and the initiation of this trial may be delayed. Learn More

With the publication of a final guidance, the U.S. FDA has adopted the International Council for Harmonization's (ICH) questions and answers guideline on the nonclinical evaluation of drugs intended to treat cancer.The final guidance comes less than two months after ICH advanced the document for international implementation in late April. The guideline, which contains 41 questions and answers aimed at providing additional clarity about oncology drug development, is meant to be read alongside ICH's 2009 guideline S9 Nonclinical Evaluation for Anticancer Pharmaceuticals. Learn More

Mylan has announced that the U.S. FDA will issue a Complete Response Letter for the drugmaker's generic version of GlaxoSmithKline's Advair Diskus on June 27th, 2018. The generic drugmaker said the agency "identified minor deficiencies" that will be communicated in the CRL. Once the official rejection is received, Mylan will determine what impact it will have on its financial outlook for the year. Mylan was quick to point out the abbreviated New Drug Application for the generic asthma drug had a priority review and could be approved ahead of the 90-day period typical after a response to a CRL, suggesting the generic could still be approved this year. Learn More

As part of an effort spur the development of new antimicrobial drugs intended for limited patient populations, the U.S. FDA this week issued a draft guidance with recommendations for demonstrating the safety and effectiveness of such drugs. In recent years, the U.S. Congress has attempted to address shortfalls in the development of new antimicrobial drugs as resistance to existing drugs mounts and questions about the economic viability of new antimicrobial drugs loom."...there has unfortunately been an overall decline in antibiotic drug research driven largely by the significant obstacles to developing innovations in this category," FDA Commissioner Scott Gottlieb said. Learn More

The Scottish government has dismissed the possibility of using compulsory licensing to get a copy of Roche's breast cancer drug Perjeta to patients. A politician floated the idea of enacting a Crown use licence to bypass the pricing impasse that is stopping HER2-positive secondary breast cancer patients from accessing the biologic but has struggled to garner support at the top. Roche tried to secure reimbursement for the drug last year but the Scottish Medicines Consortium (SMC) ruled it was "very expensive" and a poor use of limited healthcare resources. Since then, Roche has met with Scottish officials with a view to coming to an agreement but is yet to file a new submission. Learn More

Roche has been given fast-track review by the U.S. FDA this week for its Hemlibra treatment for people with a form of haemophilia. The Basel company said the FDA has granted priority review for the drug for children and adults with hemophilia A without factor VIII inhibitors, with a decision on approval expected on October 4, 2018. Hemlibra had already received breakthrough therapy designation for the medicine to be used in people who have not yet developed resistance to conventional treatments, called inhibitors, Roche said in April. Learn More

Janet Woodcock, Director of the U.S. FDA's CDER, has made public her recently proposed changes to CDER's new drug regulatory program. In which she notes that these changes are intended to free up resources so that her scientists and physicians have more time to focus on drug development, particularly for unmet medical needs, and on the multiple collaborations needed to make sure candidate drugs are developed and assessed properly, with appropriate input from external scientists, expert physicians and patient communities. The proposals include regulatory and review process changes, organizational restructuring and improved support structures. Learn More

The U.S. FDA has announced the capability of two additional EU member states, Lithuania and Ireland, to carry out good manufacturing practice (GMP) inspections at a level equivalent to the US, the European Medicines Agency (EMA). Fourteen EU member states are now included in an agreement that allows the FDA to rely on their inspection results to replace their own inspections. Last June, the European Commission confirmed that FDA has the capability, capacity, and procedures to carry out GMP inspections at a level equivalent to the EU. Learn More

The U.S. FDA has placed a clinical hold on CRISPR Therapeutics' lead candidate, spurring a double-digit drop in the company's stock value this week. The hold targets the Investigational New Drug application for CTX001, an ex vivo gene-editing therapy that CRISPR and partner Vertex are testing as a treatment for sickle cell disease in the U.S. and beta-thalassemia in Europe. CRISPR and Vertex said they are awaiting more information from the FDA about the rationale behind its hold. The drugmakers received a thumbs up from European regulators earlier this year to start a trial of CTX001, and plans for that Phase 1/2 study remain "unchanged". Learn More

The U.S. FDA has published an International Council for Harmonisation (ICH) draft guidance on technical and regulatory considerations for biopharma lifecycle management. The 34-page draft aims to help facilitate the successful management of post-approval chemistry, manufacturing and controls (CMC) changes for new and marketed biopharma drug substances and drug products.
The draft features a decision tree on established conditions for manufacturing and control, noting when notification or prior approval is necessary based on the level of potential risk of a proposed change. Learn More

The U.S. FDA issued a Warning Letter citing GMP violations, flagged during a four-day FDA site inspection last November, to Jilin Shulan Synthetic Pharmaceutical. Among the issues cited is a lack of documentation for deviations in the firm's laboratory testing results, insufficient data-protection controls on its chromatography computer systems as well as record-keeping delays when performing manufacturing operations.
Inadequate handling of data generated on the firm's computerized systems, such as the use of a portable drive that was not password-protected, was cited as well. Learn More

The U.S. FDA has approved BioMarin's drug Palynziq. This comes more than two years after turning in disappointing results from a phase 3 trial of Palynziq to treat the rare inherited blood disorder phenylketonuria (PKU). However, the approval comes with a black box warning on the label, and an estimated average cost of $192,000, a 28% premium to BioMarin's older drug to treat the same condition, Kuvan. Amid this news analysts are already wondering whether the product will be the blockbuster they've long been predicting.
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Novartis has announced that its Sandoz division received approval from the European Commission for its biosimilar Zessly (infliximab). Zessly is approved for use in all indications of the reference medicine including rheumatoid arthritis, adult and pediatric Crohn's disease, adult and pediatric ulcerative colitis, ankylosing spondylitis, psoriatic arthritis and plaque psoriasis according to Novartis. Zessly is the sixth approved biosimilar medicine for Sandoz, with several more major oncology and immunology launches expected globally by 2020. Learn More

The U.S. House of Representatives this week passed a Senate-passed version of a bill, known as "Right-to-Try," and President Donald Trump has indicated he will sign it. The House's passage of the Senate bill from last August, after a previous House bill passed but was not taken up by the Senate, and after a previous House version failed to pass, also follows the Right-to-Try movement's spread across state legislatures. President Donald Trump has said he would sign the bill and Vice President Mike Pence said it was a priority for him. Learn More

The U.S. FDA this week finalized a guidance revised in 2013 to help companies validate bioanalytical methods used in human clinical pharmacology, bioavailability (BA) and bioequivalence (BE) studies that require pharmacokinetic, toxicokinetic or biomarker concentration evaluation. The differences between the draft and final guidance, which is 10 pages longer, include a re-working of the text, a new title for Section III, which was previously named "Chromatographic methods" but is now "Bioanalytical method development and validation," and new sections on parameters of chromatographic assays (CCs) and ligand binding assays (LBAs). Learn More

The FDA has announced the approval of Amgen's migraine drug Aimovig. This drug, the first FDA approved migraine prevention drug for use in adult populations, falls under a "new class of drugs that work by blocking the activity of calcitonin gene-related peptide, a molecule that is involved in migraine attacks," according to an FDA announcement. During the process of reviewing the drug the FDA evaluated results from three clinical trials involving more than 3,000 patients suffering from chronic or episodic migraines. The most commonly reported adverse reactions being injection site reactions and constipation says Amgen. Learn More

The U.S. FDA is reversing a decision to award a no-bid $4.2 million grant to a policy center at Duke University headed by former FDA commissioner and current paid board member for Johnson & Johnson Mark McClellan. The funding opportunity was posted in late April as a five-year grant for which only a single institution, the Duke-Robert J. Margolis Center for Health Policy, was eligible to apply. The grant's purpose was to "to help advance regulatory science to promote the increased availability of safe and effective drugs to the public," according to the request for application. The FDA now says that it is in the process of opening the grant application to other institutions. Learn More

A report from the Centre for Innovation in Regulatory Science (CIRS) released this month finds that the U.S. FDA has reclaimed its position as the fastest major regulator for approving new drugs and biologics. According to the report, the FDA spent a median 243 days to approve products with a new active substance (NAS) in 2017, 90 days faster than its closest peer, Japan's Pharmaceuticals and Medical Devices Agency (PMDA), which took a median 333 days. While the FDA has typically taken less time to approve NASs than other prominent regulators over the last decade, efforts by Japan to speed drug evaluations led PMDA to edge FDA out for quickest reviews from 2014-2016. Learn More

The U.S. FDA has issued a warning letter to CMO Ei LLC after an inspection of the company's Kannapolis, North Carolina site found that the company manufactured topical drugs and pesticides using the same equipment in the same building. "It is unacceptable as a matter of cGMP to continue manufacturing drugs using the same equipment that you use to manufacture pesticides or other non-pharmaceutical products due to the risk of cross-contamination," the FDA wrote. The FDA also noted that the company did not adequately validate its cleaning procedures to ensure against cross-contamination between different drugs manufactured using the same equipment. Learn More

The Pharmaceutical Inspection Co-operation Scheme (PIC/S) has announced that it has adopted new guidance on good manufacturing practice (GMP) inspections, outlining a process for "desk-top assessment" of overseas facilities to identify instances when an acceptable level of GMP compliance can be confirmed and assured without on-site inspections. Based on a draft from the International Coalition of Medicines Regulatory Authorities (ICMRA), PIC/S said the guidance provides a tool and framework aiming to help competent authorities (CAs) prioritize resources for GMP inspections for human and veterinary medicines. Learn More

The U.S. FDA has denied Mylan's petition that sought to block certain generic applications for Advair. After receiving a CRL for its generic Advair in March 2017, Mylan had argued in a December 2017 petition that the FDA refrain from approving generic versions of Advair, which are inhalers for asthma and COPD made by GSK, if they rely on multiple-batch pharmacokinetic bioequivalence study designs unless the FDA concludes that such study designs are valid. Some have suggested the petition targeted Sandoz's Advair generic. In its response rejecting the petition, the FDA says it has not made any final determinations on approving generic versions of the inhaler. The FDA also rejected previous citizen petitions from GSK and Sandoz. Learn More