Regulatory Alert

Beginning March 31st, the U.S. FDA Office of the Commissioner will reorganize and make several changes to various offices within FDA, including the Office of New Drugs (OND). With an eye toward efficiency and better connecting the Office of the Commissioner with center directors and other office leadership. A major change is the creation of the Office of Therapeutic Biologics and Biosimilars (OTBB) within OND. According to an email from Center for Drug Evaluation and Research (CDER) Director Janet Woodcock to staff, the OTBB will house policy and scientific review staff and realign staff from the OND Immediate Office to OTBB. Learn More

Novo Nordisk has submitted its oral semaglutide drug, a pill it hopes will transform the diabetes market, for approval in the United States. The world's biggest maker of diabetes drugs said this week that it had used a so-called priority review voucher to speed up the anticipated review time of the drug to six months. The tablet belongs to a blockbuster class of treatments known as GLP-1s that stimulate insulin production. So far, all have been via injection and a pill would make it quicker and easier for diabetics to take their medication. The semaglutide molecule is the backbone of Novo's future growth hopes amid intensifying pricing pressure in its traditional insulin business. Learn More

AbbVie has announced that the U.S. FDA has placed a partial clinical hold on all trials of its cancer drug Venclexta for multiple myeloma, after a review of data found a higher proportion of deaths in the Venclexta arm of the late-stage study compared to those given a placebo alongside other treatment. Patients who are currently enrolled in studies and receiving the therapy may continue with the treatment, but no new patients should be enrolled in trials testing Venclexta for multiple myeloma until further analysis of the data is completed, the drugmaker said. Venclexta is jointly sold by AbbVie and Roche AG in the United States, while AbbVie sells it in other markets. Learn More

Further modernizing generic drug and new drug reviews and development, improving medical device safety and additional efforts to support the opioid crisis will all see additional funding next year, according to the FY 2020 budget justification from the U.S FDA. The 384-page justification breaks down where all the newly requested funding is expected to go, with $27 million for generic drug reviews and includes a proposal to expand current efforts to streamline and automate the review of the drug quality section of abbreviated new drug applications to include other disciplines engaged in such application assessments. Learn More

Modernizing clinical trials is an agency-wide priority. As more diseases are being redefined based on genomic subtype, researchers have more novel targets and more opportunities to precisely modulate or even repair the basic biological drivers of illness. But these opportunities can be delayed or stymied by a clinical research enterprise that is often extraordinarily complex and expensive. Efforts to streamline medical product development based on advancing science can be frustrated by legacy business models that discourage collaboration and data sharing, and the adoption of disruptive technologies that make clinical research more effective. Learn More

The U.S. FDA, in a warning letter to Pfizer's subsidiary Hospira, says that products made at the company's facility in Tamil Nadu, India are adulterated as a result of data integrity breaches and laboratory testing shortcomings observed during a week-long inspection last spring. According to the FDA, Hospira's microbiology lab did not accurately report microbial growth test results. During the inspection, the FDA requested that Hospira retest multiple batches of its products that were all reported as passing by the company. Each batch was found to be out-of-specification during retesting. Learn More

The U.S. Department of Health and Human Services (HHS) announced this week that Dr. Ned Sharpless, current director of the National Cancer Institute (NCI) at the National Institutes of Health, will serve as acting commissioner of the U.S. FDA when Scott Gottlieb steps down next month. Sharpless, who has served as NCI director since October 2017, previously served as director of the University of North Carolina (UNC) Lineberger Comprehensive Cancer Center, a position he held since January 2014. No word yet on if he will be nominated by the White House to fill the position permanently and as such be subject to the confirmation process. Learn More

The U.S. FDA this week approved the 18th biosimilar, Pfizer's Trazimera, which is the fourth approved in the U.S. for Roche's Herceptin. Accoridng to published reports Pfizer is working to make Trazimera available to patients as soon as possible but has not provided a specific launch date. None of the other three approved Herceptin biosimilars have launched in the U.S. Competitors include Merck and Samsung Bioepis' Ontruzant, approved in January; Celltrion's Herzuma, approved in December 2018; and Mylan and Biocon's Ogivri, approved in December 2017. Learn More

In a rare move, the U.S. FDA this month has rescinded two companies' breakthrough therapy designations (BTDs) because of clinical trial data. For Tonix Pharmaceuticals, the FDA informed the company recently that the BTD granted in December 2016 for Tonmya has been rescinded because interim analysis data did not support the continuation of the BTD. Similarly, this week, based on the FDA's review of data from Trevena's Phase 3 studies of oliceridine, the FDA informed Trevena that under the conditions studied, "these data were not sufficient to support the continuation of FDA's previously granted Breakthrough Therapy designation." Learn More

The FDA says it no longer intends to retrospectively modify the names of biologics approved without an agency-designated suffix, according to updated draft guidance on the naming of biologics released this week. Under the naming convention, FDA adds a unique four-letter suffix that is devoid of meaning to non-proprietary names of all biologics, including originators and biosimilars. The draft guidance will revise 2017 final guidance on the topic, in which FDA said the suffix would apply to newly and previously approved biologics. In the draft guidance, the agency says it has decided to assign a unique suffix that distinguishes an interchangeable product from other biologics that share the same core name. Learn More

Teva subsidiary Actavis has received a warning letter from the U.S. FDA regarding quality unit concerns and inconsistencies with its manufacturing processes, among other violations at the company's Davie, Florida site. Of particular concern to FDA inspectors was the sites history of similar cGMP violations in three previous inspections in December 2013, January 2016 and November 2017. "These repeated failures demonstrate that executive management oversight and control over the manufacture of drugs is inadequate," the FDA said. Learn More

Scott Gottlieb, commissioner of the U.S. FDA has resigned, according to reports. Gottlieb will leave the regulatory agency in about a month. Gottlieb intends to spend more time with his family, according to published reports. At 46, he is the father of three children, nine-year-old twins and a five-year-old. He commutes weekly from Connecticut. Since taking over the role of commissioner in May 2017, Gottlieb has aggressively supported the approval of new branded drugs, as well as generics. Additionally, he has taken on multiple public health problems including the opioid epidemic sweeping the country and vaping. His decision to resign is said to have caught many by surprise, including the White House. Learn More

BioPharma companies and clinical trial sponsors have been directed to follow new guidelines for regulatory submissions that would have to be directly submitted to the UK's Medicines and Health products Agency (MHRA) if Britain leaves the EU without reaching an agreement by the end of this month. The guidance, posted this week, describes the steps applicants and sponsors need to follow for access to the new MHRA gateway for UK submissions from day one post-Brexit in a no-deal scenario. It also applies to all current Eudravigilance Gateway users seeking access to the MHRA submissions portal. Learn More

After 24 years in London, the European Medicines Agency (EMA) has officially departed and is on its way to Amsterdam following a Brexit relocation vote in November 2017. The EMA's permanent Amsterdam headquarters, a tailor-made building in the Zuidas business district, are planned for completion next November. On a temporary basis, the Dutch government has granted EMA the Spark building in the Sloterdijk area of Amsterdam until the permanent building is completed. The move to Amsterdam also comes with a time zone switch, which could have an impact on submissions and deadlines. Learn More

The U.S. FDA is backing early adopters of continuous manufacturing and other advanced manufacturing technologies through its Emerging Technology Team, and by requesting funding as part of the president's 2019 budget. The FDA has also issued draft guidance on the development and implementation of continuous manufacturing for brand, generic and over-the-counter drugs, which furthers a global effort among regulatory authorities to encourage adoption and implementation of the practice. Less than four years ago, only one drug made with continuous manufacturing had been approved. Now there are five products from four drugmakers, and more than 20 companies engaging with the FDA. Learn More

The Association for Accessible Medicines and its Biosimilars Council, as well as the Pharmaceutical Care Management Association, are backing a Pfizer petition that calls on the U.S. FDA to do more to counteract untruthful or misleading information on biosimilars. The AAM comment, related to Pfizer's petition, specifically targets the term "non-medical switching" and the concept of interchangeability as areas where originator biologic companies and others have been misleading. Learn More

The U.S. FDA this week issued a draft guidance laying out quality considerations for continuous manufacturing (CM) for new and generic drugs. The 27-page draft guidance is part of the FDA's effort to encourage the adoption of continuous manufacturing and covers quality considerations for solid oral small molecule drugs and builds on feedback from a public consultation launched in 2017. According to FDA Commissioner Scott Gottlieb and CDER Director Janet Woodcock, continuous manufacturing "transforms the traditional, step-wise manufacturing process into a single system that's based on modern process monitoring and controls. Learn More

As part of its push to increase generic competition, the U.S. FDA has published 74 product-specific guidances, including 22 new and 52 revised guidances. Four of the new draft guidances and 45 of the revised guidances are for complex drug products, including 16 products for which there are currently no approved abbreviated new drug applications (ANDAs). Among the new product-specific guidances is help for companies looking to develop generic versions of AstraZeneca's mantle cell lymphoma treatment Calquence, Vertex's cystic fibrosis treatment Symdeko and the antidepressant isocarboxazid, among others. Learn More

A great blog written by Aoife Brennan, CEO of Synlogic, has been posted on the Life Sci VC website this week. An excerpt from which reads "It was apparently random, although I secretly suspect it was karmic punishment for my lack of imagination in writing the 2019 quality goal. It has been 'Maintain the quality management system and documentation in inspection-ready form' for the past 3 years. While we take quality and regulation seriously, our assumption, like that of many early-phase companies, had been that an actual FDA inspection was several years off..." Be sure to read the rest of this posting, it is at once both informative and entertaining. Learn More

Canada's Competition Bureau this week discontinued its investigation into allegations that Johnson & Johnson subsidiary Janssen inhibited the entry of biosimilars that compete with its blockbuster Remicade (infliximab). The Bureau said that although it confirmed that Janssen has engaged in, and continues to engage in, conduct that could raise concerns, there was not adequate evidence "that this conduct was likely to substantially lessen or prevent competition." The Bureau said it will continue to monitor the biologic and biosimilar industries to identify other types of conduct by companies that sell reference biologics that could raise concerns. Learn More

Miniaturized stirred bioreactors (MSBRs) are gaining popularity as a cost-effective approach to scale-down experimentation. However, realizing conditions that reflect the large-scale process accurately can be challenging. This article highlights common challenges of using MSBRs for scale-down. The fundamental difference between oxygen mass transfer coefficient (kLa) and oxygen transfer rate scaling is addressed and the difficulty of achieving turbulent flow and industrially relevant tip speeds is described. By highlighting these challenges, the article aims to create more awareness of these difficulties and to contribute to improved design of scale-down experiments. Learn More

Roche may soon secure U.S. FDA approval for two of its experimental cancer medicines, announcing this week that the regulator had granted priority review to both entrectinib and polatuzumab vedotin. A decision on approval for entrectinib is set to occur by Aug. 18, 2019. If all goes well, entrectinib could be joined on market in the U.S. one day later by polatuzumab vedotin. The FDA has set a target action date of Aug. 19, 2019 for that drug. This comes amid the reality that Roche's three main cancer drugs; Herceptin, Rituxan and Avastin, are nearing the end of their patent protection. Learn More

Roche may soon secure U.S. FDA approval for two of its experimental cancer medicines, announcing this week that the regulator had granted priority review to both entrectinib and polatuzumab vedotin. A decision on approval for entrectinib is set to occur by Aug. 18, 2019. If all goes well, entrectinib could be joined on market in the U.S. one day later by polatuzumab vedotin. The FDA has set a target action date of Aug. 19, 2019 for that drug. This comes amid the reality that Roche's three main cancer drugs; Herceptin, Rituxan and Avastin, are nearing the end of their patent protection. Learn More

The U.S. FDA recently warned two drugmakers, Vasco Rx and Samson Pharmaceuticals, for GMP violations at their facilities. The FDA's warning letter to Vasco Rx comes after the agency inspected the company's manufacturing site in March and April 2018. At the end of the inspection in April, Vasco Rx stopped production and later voluntarily recalled all sterile drugs produced in its laminar airflow hood over sterility concerns. In December, the FDA sent a warning letter to Samson Pharmaceuticals over violations stemming from an inspection in January and February 2018 detailing issues with the company's aseptic processing and product testing practices. Learn More

The U.S. FDA has made public the Form 483 that was issued to Immunomedics documenting serious breaches of data integrity at the company's Morris Plains, New Jersey manufacturing facility. Among the 13 observations noted in the document are manipulation of bioburden samples, misrepresentation of a test procedure in the batch records and backdating of batch records, including the dates of analytical results. The FDA notes that it was unable to determine whether data integrity issues may have affected earlier batches because Immunomedics "questioned plant personnel under "attorney/client privilege and no additional documentation is available." Learn More

Biopharma community leaders, drug manufacturers and trade associations alike, have raised questions regarding two U.S. FDA guidance documents on biosimilars, including one explaining how the FDA plans to transfer drugs previously approved under new drug applications (NDAs) to be biologic license applications (BLAs). On this so-called "Deemed to be a License" guidance, which explains the NDA to BLA transition, all but one of the biopharma companies and industry groups took issue with the agency's approach to exclusivity. Learn More

In an email to staff this week, Janet Woodcock, director of the U.S. FDA's Center for Drug Evaluation and Research (CDER) announced that Sally Choe will take over for Kathleen Uhl as Director of the Office of Generic Drugs (OGD) upon Uhl's retirement at the end of the month after serving more than 20 years at the agency. Choe, who currently serves as the deputy director of the Office of Study Integrity and Surveillance (OSIS) within the Office of Translational Sciences (OTS), returned to the agency in 2017 after a six-year stint as a senior director at Parexel overseeing the firm's Asia-Pacific and Japan offices. Learn More

The U.S. FDA regulatory framework for the use of real-world evidence (RWE) drew positive reactions from biopharma companies in comments submitted to the docket, although certain recommendations and proposals were also made. The agency released the framework that describes its RWE program last December and has received 28 comments since then. The comment period remains open, but the submitted comments already offer a look into industry's take on the framework. Regeneron, Sanofi, Pfizer and Novartis are among those that have provided feedback alongside industry groups PhRMA and BIO. Learn More

Daiichi Sankyo has been granted a priority review from the U.S. FDA for its drug pexidartinib. The Japanese drugmaker filed for approval of pexidartinib based on a phase III study (ENLIVEN) in 120 people with TGCT, a non-malignant tumour of the joint or tendon sheath that can cause damage to the joints and surrounding tissues, and is now hoping for FDA approval by early August. The Japanese company acquired the drug when it bought Taiwanese biotech Plexxikon for a little under $1 billion back in 2011. Learn More

The U.S. FDA this week issued a call for nominations for nonvoting industry representatives to serve on 17 of the Center for Drug Evaluation and Research's (CDER) public advisory committees. The agency is also calling for industry groups to participate in the selection process. FDA advisory committees include four types of members, scientific and medical experts in the area of medicine or the scientific and technical field the committee covers, as well as a consumer, patient and industry representative. Industry representatives are charged with acting on the behalf of the regulated industry, but do not represent specific companies and do not vote on matters before the committees. Learn More

In a complaint filed against the U.S. FDA, Vanda Pharmaceuticals called on a federal district court to lift a partial clinical hold on its experimental drug tradipitant. The complaint, filed with the US District Court for the District of Columbia this week, alleged that the FDA acted in violation of the Administrative Procedure Act of 1946 (APA) in imposing the partial clinical hold last December. The hold was imposed on a protocol for a new clinical study and a proposed 52-week open-label extension study for patients who completed Phase II of the tradipitant clinical study originally initiated in 2016, according to court filings. Learn More

The Communist Party of China has expelled a former deputy director of the China Food and Drug Administration. Wu Zhen was ousted from the party following an anti-corruption investigation that began in the wake of the vaccine scandal that roiled China last year. According to the Chinese government, Wu took bribes, engaged in nepotism, accepted offers of trips and invitations to banquets and otherwise abused his position at the Chinese drug regulator. China's Central Commission for Discipline Inspection and the National Supervisory Commission made the allegations following an investigation that began in August. In addition to expelling Wu from the CPC, China has canceled his benefits and confiscated illicit gains. Learn More

The U.S. FDA has announced that Leah Christl, director of the Therapeutic Biologics and Biosimilars Staff (TBBS) in the Office of New Drugs (OND), has decided to leave the FDA and will depart February 22nd, 2019. Christl is moving to Amgen to become the executive director of global regulatory and R&D policy beginning March 11th, 2019. A frequent speaker at industry and other conferences, Christl "was instrumental in policy development and the interpretation and implementation of the Biologics Price Competition and Innovation (BPCI) Act for CDER and FDA, which has led to 17 FDA approved biosimilars to date," according to CDER Director Janet Woodcock and OND Director Peter Stein. Learn More

The U.S. FDA has announced that Leah Christl, director of the Therapeutic Biologics and Biosimilars Staff (TBBS) in the Office of New Drugs (OND), has decided to leave the FDA and will depart February 22nd, 2019. Christl is moving to Amgen to become the executive director of global regulatory and R&D policy beginning March 11th, 2019. A frequent speaker at industry and other conferences, Christl "was instrumental in policy development and the interpretation and implementation of the Biologics Price Competition and Innovation (BPCI) Act for CDER and FDA, which has led to 17 FDA approved biosimilars to date," according to CDER Director Janet Woodcock and OND Director Peter Stein. Learn More

The U.S. FDA has rejected a Sunovion Pharmaceuticals drug for Parkinson's disease, delaying the company in its bid to compete with Acorda Therapeutics, which has a similar product that was recently approved for the market. Sunovion said this week that the FDA asked for more information to support the application for its drug, APL-130277. But the Marlborough, MA-based company, a subsidiary of Japanese pharmaceutical firm Sumitomo Dainippon Pharma, said that the regulator did not ask for new clinical trials. Learn More

Roche Holding and partner AC Immune SA called a halt to two late-stage clinical trials of their crenezumab drug for early Alzheimer's, the latest in a string of failures to find a treatment for the progressive brain disease. The recent announcement comes after an interim analysis indicated it was unlikely to be effective. Shares of AC Immune fell 65% on the news. Drugmakers such as Eli Lilly, AstraZeneca Plc and Johnson and Johnson have all abandoned trials testing their associated experimental drugs. Learn More

The European Medicines Agency, one of the biggest EU regulators and one of the first casualties of Brexit, has closed its doors in the UK for the last time with the loss of 900 jobs. Staff lowered and folded up the 28 national flags that adorned the lobby in the company's Canary Wharf headquarters in London on Friday night, bidding it farewell before moving to their new offices in Amsterdam. Its departure from London was lamented widely as it marks not just the loss of highly skilled jobs but the UK's central place in pharmaceutical evaluation and monitoring. Learn More

Stressing the need for speed and efficiency, U.S. FDA Commissioner Scott Gottlieb this week offered a look at the FDA's plans around real-world data (RWD) and real-world evidence (RWE) in 2019. The speech at the Bipartisan Policy Center built off a framework, released in December, that sought to begin the conversation on how RWD and RWE can support changes to labeling, including adding or modifying an indication, changes in dose, dose regimen or route of administration; changing or adding new populations, or the addition of comparative effectiveness or safety information. Learn More

Advaxis this week announced receipt of notification from the U.S. FDA that the Company's ongoing Phase 3, randomized, double-blinded, placebo-controlled, pivotal study of axalimogene filolisbac (AXAL) in high-risk, locally advanced cervical cancer (AIM2CERV) has been placed on partial clinical hold. The FDA's recent communication, received late last week, states that the partial hold is related to their requests for additional information pertaining to certain AXAL chemistry, manufacturing and controls (CMC) matters. The Agency did not cite any safety issues related to the trial. However, no new patients can enroll in AIM2CERV until resolution of this partial hold. Learn More

Translate Bio this week announced that the Company has received verbal notification from the U.S. FDA that the Agency has completed its review of the Company's Investigational New Drug Application (IND) submission for MRT5201 and has additional clinical and nonclinical questions. The Company submitted the IND in December 2018 to support the initiation of a Phase 1/2 clinical trial in patients with OTC deficiency. The FDA is placing the IND on clinical hold until these questions are resolved. Learn More

Samsung Bioepis this week announced that the U.S. FDA has approved ONTRUZANT®, a biosimilar referencing HERCEPTIN® approved by the European Commission in November 2017, across all eligible indications, namely adjuvant treatment of HER2-overexpressing breast cancer, metastatic breast cancer and metastatic gastric cancer. ONTRUZANT® is Samsung Bioepis' first oncology biosimilar to receive FDA approval, and will be marketed and distributed in the U.S. by Merck, which is known as MSD outside of the U.S. and Canada. Learn More

As the government shutdown enters its second month, U.S. FDA Commissioner Scott Gottlieb and fellow leaders at the agency will be tasked with difficult decisions on who to furlough. The agency is expected to halt its review of prescription drug applications around the first week of February, and other medical products reviewed under user fee laws will follow suit in the coming months. According to new statistics, of the FDA's 17,397 staffers, 37% are exempt, 31% furloughed, 23% partially exempt/excepted/furloughed and 9% excepted. If the shutdown lasts until PDUFA funds run short, more employees in the exempt bucket will be shifted to the furloughed or excepted. Learn More

The U.S. FDA has approved Merck and Samsung Bioepis' Ontruzant, the third biosimilar approved in the US to Roche's Herceptin. In the US, where no Herceptin biosimilar has launched, there are two other competitors: Celltrion's Herzuma, approved in December 2018, and Mylan and Biocon's Ogivri, approved in December 2017. In Europe, Ontruzant launched in March. There are now four competitors for Herceptin in Europe: Celltrion's Herzuma, which launched in May 2018, Amgen's Kanjinti, which started showing up in June 2018 in Germany; and Pfizer's Trazimera, which was approved in July of 2018. Learn More

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 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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