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Establishing predictive analytical workflows for complex biopharmaceutical molecules.

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Technology Forum: The Next Steps for Pharma Manufacturing Efficiency and Effectiveness

UK Approves Moderna for Adolescents; Updates on Solidarity Plus Trial

Pfizer Vaccine Approval Key to Boosting Vaccination Rates

Pfizer and BioNTech announced on Sept. 20, 2021 that topline data from their Phase II/III COVID-19 vaccine in children aged 5 to 11 demonstrated positive results. According to a Pfizer press release, the results demonstrated that the vaccine was safe, well-tolerated, and showed robust neutralizing antibody responses.

In the trial, participants were given a two-dose regimen of 10 µg administered 21 days apart. This is a smaller dose than the 30 µg dose used for people 12 and older, but was selected for this demographic because of concerns surrounding safety, tolerability, and immunogenicity.

The antibody responses were comparable to those in a previous study in people aged 16-25 who were immunized with 30 µg doses. The SARS-CoV-2–neutralizing antibody geometric mean titer (GMT) in this trial was 1197.6 one month after the second dose. This was non-inferior to the GMT of 1146.5 from participants ages 16 to 25 years old, used as the control group for this analysis. Additionally, the COVID-19 vaccine was well tolerated, with side effects generally comparable to those observed in participants 16 to 25 years of age.

“Since July, pediatric cases of COVID-19 have risen by about 240 percent in the US–underscoring the public health need for vaccination,” said Albert Bourla, chairman and CEO, Pfizer, in the press release. “These trial results provide a strong foundation for seeking authorization of our vaccine for children 5 to 11 years old, and we plan to submit them to the FDA and other regulators with urgency.”

Articles

The topline data from Pfizer and BioNTech’s trial suggests that a 10 µg vaccine is safe and effective among the 5 to 11 age group.

 Pfizer and BioNTech Announce Positive Results In COVID-19 Vaccine Trial for Children Ages 5 to 11

FDA announced on Sept. 17, 2021, that it has approved the first biosimilar to Lucentis (ranibizumab injection). Byooviz (ranibizumab-nuna), a monthly intravitreal injection, has been approved to treat eye diseases such as neovascular age-related macular degeneration (nAMD), macular edema following retinal vein occlusion, and myopic choroidal neovascularization. The agency based the approval on evidence that included structural and functional characterization, comparative clinical efficacy, and safety evaluations.

“Today’s approval provides another treatment option for millions of people whose vision is impaired and is another step forward in our commitment to provide access to safe, effective and high-quality biological products,” said Sarah Yim, M.D., director of FDA’s Office of Therapeutic Biologics and Biosimilars, in a 

. “Continuing to grow the number of biosimilar approvals is a key part of our efforts to provide greater access to treatment options for patients, increase competition and potentially lower costs.”

The agency approved Byooviz (ranibizumab-nuna), a biosimilar to Lucentis (ranibizumab injection), for the treatment of several eye diseases.

FDA Approves Biosimilar for Treatment of Eye Disease

 Washington Editor, jillwechsler7@gmail.com.

If the debate has been heated over vaccines for adults and on the need for extra booster shots, FDA and its expert advisors will face even more scrutiny over the safety and value of vaccinating children under age 12. This population generally has had much lower COVID-19 infection rates than adults, but hospitalizations now have increased dramatically with the spread of the Delta variant, plus the return to school and other activities. The rise in pediatric COVID cases has alarmed the medical community, yet widespread vaccine hesitancy among many parents will make it critical to present strong safety results to gain broad protection for children.

The issue has moved to center stage as Pfizer-BioNTech announced plans to seek FDA approval this month of a smaller dose of its Comirnaty vaccine for children ages 5–11, as well as similar approval from the European Medicines Agency and other regulatory authorities. As Pfizer did in expanding use of its vaccine to younger adolescents, the 

company will file an Emergency Use Authorization

 (EUA) application with FDA, based on results from a Phase II/III study of a two-dose regimen on more than 4000 participants aged 6 months to 11 years [see ]. The study shows, according to Pfizer, that a lower 10-microgram shot for the 5–11 age group, one-third the dose for adults and adolescents, provides a sufficiently robust neutralizing antibody response, while also supporting safety and tolerability in these young subjects.

The clinical trial also enrolled similar numbers of younger children ages 6 months to 5 years and hopes to provide topline readouts for this group by year-end. Children under age 5 received a lower 3 microgram dose for each of two injections, and results will be evaluated for two age cohorts, children 2–5 years of age and those 6 months to 2 years old.

This initial Pfizer-BioNTech statement did not present specific study data, but the sponsor said it will submit its research results for publication in a scientific peer-reviewed journal, while also preparing its filing for FDA. The announcement specified that clinical trials in multiple regions enrolled 2268 children ages 5–11, with one-third receiving placebo. However, due to the generally lower infection rate among youngsters, there were too few numbers of ill participants to determine higher protection from the vaccine vs. placebo; that conclusion is based on a comparison of higher immune response levels in vaccinated vs. unvaccinated study participants.

The sponsor also notes that the lower dose for children can be linked to fewer side effects. In an early study that administered higher doses to young participants, adverse events were higher, although still comparable to older patients. But those children who received the lower dose experienced fewer incidences of fever, headache, and fatigue, while also showing a strong antibody response. Even after increasing the size of the pediatric trial at FDA’s request, Pfizer found no cases of heart inflammation or other serious side effects that have occurred after vaccination with some older individuals, although the sponsors continue to monitor study participants for ongoing effects.

FDA staff will review the Pfizer data closely following its submission and is expected to ask its Vaccine and Related Biological Products Advisory Committee to weigh the results and make recommendations. If approved, the Advisory Committee on Immunization Policy at the Centers for Disease Control and Prevention then will propose a specific vaccination schedule.

In response to earlier pressure from some quarters for FDA to quickly authorize preventives for younger children, agency leaders explained the need for very careful scientific evaluation to ensure that any vaccines for children are safe, as well as effective. FDA Acting Commissioner Janet Woodcock and Peter Marks, director of the Center for Biologics Evaluation and Research, penned a statement in early September emphasizing that FDA “will follow the science” to fully assess the safety of current vaccines. Woodcock and Marks also 

warned parents not to pressure pediatricians 

to provide their children with a vaccine approved for adults and adolescents:as far as vaccines go, children are not just young adults.

Pfizer-BioNTech announced plans to seek FDA approval this month of a smaller dose of its Comirnaty vaccine for children ages 5–11.

Next Big COVID Challenge: Vaccines for Little Kids

Amidst political pressures and dissension on multiple fronts, FDA and its panel of vaccine experts weighed the evidence and worked to ensure a science-based decision on whether to authorize additional shots of Pfizer’s COVID-19 vaccine to further protect those that already received the recommended doses. The 

of FDA’s Vaccines and Related Biological Products Advisory Committee (VRBPAC) concluded with the panel recommending that a third dose of the Pfizer/BioNTech Comirnaty vaccine be authorized only for people over age 65, plus those at high risk of infection related to occupation, such as health care workers and teachers.

A formal recommendation from FDA on the Pfizer booster, likely to be issued today, will be considered this week by the Advisory Committee on Immunization Policy (ACIP) at the Centers for Disease Control & Prevention (CDC). That panel will advise practitioners and health agencies on when and where to administer any additional shots in ongoing efforts to curb the COVID-19 pandemic.

The FDA advisors agreed unanimously on the more limited booster plan after soundly rejecting Pfizer’s original request to authorize its third shot for everyone over age 16, as covered by the biologics license application (BLA) for the vaccine approved by FDA’s Center for Biologics Evaluation and Research (CBER). The panel felt there was insufficient data to support more widespread administration and that boosters could pose added risks for men under age 40, who have experienced rare cases of myocarditis following vaccination. A main point of discussion was whether waning immunity from the initial two-dose vaccine regimen was due to effects of the Delta variant or to limitations of the Pfizer vaccine itself. Pfizer researchers published 

 summarizing its research to support a booster dose, but that failed to convince the advisory panel of the need for widespread third shots.

The debate over the issue was intensified by the recent announcement of pending departures of leading FDA officials who had expressed dismay over earlier statements by President Biden backing booster shots in the United States while FDA was examining the issue. Marion Gruber, long-time Director of CBER’s Office of Vaccine Research & Review (OVRR), and OVRR Deputy Director Phillip Krause announced last month that they would both retire from FDA after many years of service, most recently shepherding through speedy emergency approvals for effective COVID-19 vaccines.

In addition, Gruber and Krause were prominent co-authors of a 

 questioning booster shots while much of the world still awaited initial COVID-19 vaccines. The article by a group of vaccine scientists formed by the World Health Organization (WHO) argues that much uncertainty remains about the timing and value of extra shots, and that boosters for healthy adults should be delayed until at least 40% of the global population is vaccinated.

The debate within the Biden administration and FDA opened the door to widespread criticism and questioning of the booster shot policy. Leading House Republicans charged FDA officials with caving to White House pressure to speed access to booster shots and demanded that FDA Acting Commissioner Janet Woodcock provide them with all documents related to the study and implementation of a booster shot option 

plus communications between the agency and the White House 

While the politicians look to make points over the policy debate, the VRBPAC panel weighed the scientific evidence presented at the September 17 session. That included current data on COVID-19 prevalence, infection and hospitalization rates from the CDC and from the United Kingdom. Of particular interest was a report on how a recent Pfizer vaccine booster program in Israel reduced infection rates and hospitalizations. Pfizer presented its own analysis on how protection by Comirnaty waned over six months after initial doses and how boosters could provide important added protection. But the advisors found the Israeli and Pfizer data too limited and unconvincing to approve boosters for the entire US population. The narrower recommendation to add shots for the elderly and immune-compromised is seen as a compromise to provide protection where most needed while sponsors gain added information.

A main issue for the international health research community is whether limited supplies of effective preventives should be provided to those already protected by authorized shots, while vaccines remain severely limited in many regions of the world. The advisory panel did not address that question directly, and ample vaccine supplies in the US appeared to offset the issue.

Members of the advisory panel and experts from CDC and FDA did agree that more widespread vaccination of the American public would do more to prevent high COVID-19 infection rates than booster shots for those already benefitting from protection. However, that possibility was further countered by the ranting of vaccine opponents about the safety and value of any COVID-19 preventive, as heard in multiple presentations during the usual one-hour public comment period at the VRBPAC meeting.

The debate will continue, as Moderna has announced it also will seek FDA approval of a third shot to its two-dose vaccine regimen, citing similar waning of antibodies six months after the second shot and no added safety concerns. Perhaps Moderna will consider closely the recent debate and target its booster plan to the higher-risk population, as recommended by the advisory panel for the Pfizer preventive.

FDA advisors agreed unanimously on a more limited booster plan after rejecting Pfizer’s original request to authorize its third shot for everyone over age 16.

Vaccine Booster Battle Reveals Rifts Among Regulators and Sponsors

The University of California Riverside (UCR) announced in a Sept. 16, 2021, press release that their scientists are researching whether a plant-based messenger RNA (mRNA) vaccine can be created. This vaccine would not have restrictions that require refrigeration during transport and storage, such as those used for the COVID-19 vaccines. 

The goal for this project is to show that DNA containing the mRNA vaccines can be successfully delivered into the part of plant cells where it can replicate. This would demonstrate the plants can produce enough mRNA to rival a traditional vaccine or injection. They also hope to determine the proper dosage.

The key to making this work are chloroplasts, which are small organs in plant cells that convert sunlight into energy the plant can use. These chloroplasts produce sugar and other molecules that allow the plant to grow. In the past, Juan Pablo Giraldo, an associate professor in UCR’s Department of Botany and Plant Sciences and research lead, found it is possible for chloroplasts to express genes that aren’t naturally part of the plant after conducting prior research where he sent foreign genetic material into plant cells inside a protective casing.

“Ideally, a single plant would produce enough mRNA to vaccinate a single person,” said Giraldo in UCR’s press release. “We are testing this approach with spinach and lettuce and have long-term goals of people growing it in their own gardens. Farmers could also eventually grow entire fields of it.”

The National Science Foundation contributed a $500,000 grant toward their research, which is being performed in collaboration with scientists from UC San Diego and Carnegie Mellon University.

UCR scientists are researching whether a plant-based messenger RNA vaccine can be created and aim to eliminate the need for the refrigeration of mRNA vaccines during transport and storage.

Researchers from the University of California Riverside Investigate Plant-Based mRNA Vaccines

Health Canada approved the new drug submission (NDS-CV) for Spikevax (elasomeran mRNA vaccine)—more commonly known as the Moderna COVID-19 vaccine—for active immunization to prevent COVID-19 in individuals 12 years of age and older, according to Moderna’s Sept. 16, 2021, press release.

The NDS-CV for Spikevax was approved based on clinical data from the Phase III COVE study of the Moderna COVID-19 vaccine, which enrolled more than 30,000 participants in the United States. The final analysis of Spikevax showed 93% efficacy , with the efficacy remaining durable through six months after administration of the second dose. In addition, the safety profile was consistent with the Phase III COVE study primary results.

Spikevax was originally authorized in Canada under an interim order for individuals 18 years of age and older, which was granted by Health Canada on Dec. 23, 2020. On Aug. 27, 2021, the interim order authorization for the Moderna COVID-19 vaccine was expanded to include adolescents 12 years of age and older.

“Health Canada’s approval of our COVID-19 vaccine is an important milestone as it is our first full approval for Spikevax,” said Stéphane Bancel, CEO of Moderna, in the company press release. “I would like to thank Health Canada for their hard work throughout the process. I would also like to thank the Government of Canada for the partnership they have built with us and for their confidence in our mRNA platform in addressing the COVID-19 pandemic.”

Health Canada approved the new drug submission for Spikevax—more commonly known as the Moderna COVID-19 vaccine—for active immunization to prevent COVID-19 in individuals 12 years of age and older.

Health Canada Approves Moderna’s COVID-19 Vaccine, Spikevax, for 12 Years & Up

On Sept. 16, 2021, FDA revised the emergency use authorization (EUA) for bamlanivimab and etesevimab (administered together) to 

include emergency use as post-exposure prophylaxis (prevention) for COVID-19

 in patients 12 years of age and older who weigh at least 40 kg and are at high risk for progression to severe COVID-19, including hospitalization or death. Bamlanivimab and etesevimab are monoclonal antibodies (mAbs).

Bamlanivimab and etesevimab (administered together) are now authorized for use after exposure to the SARS-CoV-2 virus in this revision of the EUA. The mAbs are not authorized for pre-exposure prophylaxis to prevent COVID-19 before being exposed to the virus.

These mAbs may only be used when administered together as post-exposure prophylaxis for patients 12 years of age and older weighing at least 40 kg who:

Are at high risk for progression to severe COVID-19, including hospitalization or death

Are not fully vaccinated or who are not expected to have an adequate immune response to complete COVID-19 vaccination

Have been exposed to an individual infected with SARS-CoV-2 consistent with close contact criteria, per the CDC

Are at high risk of exposure to an individual infected with SARS-CoV-2 in the same institutional setting (such as nursing homes)

In addition, bamlanivimab and etesevimab (administered together) remain authorized for the treatment of mild to moderate COVID-19 in patients 12 years of age and older weighing at least 40 kg with positive results of direct SARS-CoV-2 viral testing, and who are at high risk for progression to severe COVID-19, including hospitalization or death.

FDA revised the emergency use authorization for bamlanivimab and etesevimab (administered together) to include emergency use as post-exposure prophylaxis (prevention) for COVID-19.

FDA Revises EUA for Use of Bamlanivimab and Etesevimab for Post-Exposure Prophylaxis Prevention for COVID-19

Moderna released an analysis surrounding several studies on their COVID-19 vaccine on Sept. 15, 2021. In it, the company shared data surrounding the efficacy of the vaccine amidst the Delta variant surge, the risk of breakthrough infections, and the need for booster shots.

According to Moderna, a prospective cohort study of 352,878 recipients found that there was a vaccine effectiveness of 87% against COVID-19 diagnosis and 96% against COVID-19 hospitalization. The study was conducted during the emergence of the Delta variant, which was identified in 47% of cases in fully vaccinated individuals.

Moderna also did an analysis of data provided by CDC on breakthrough infections among individuals who received the vaccine. They found that their COVID-19 vaccine provided 92% efficacy against COVID-19 urgent care or emergency visit at a median of 96 days post-vaccination, and 95% efficacy against hospitalization at a median of 106 days after hospitalization.

In the Coronavirus Efficacy and Safety Study (COVE) study, an analysis comparing individuals vaccinated between July and October of 2020 and December 2020 and March of 2021, 88 breakthrough cases of COVID-19 occurred in the more recently vaccinated group (49.0 cases per 1000 people) compared to 162 cases in the group vaccinated last year (77.1 cases per 1000 people). Moderna believes that the impact of waning immunity provides evidence of the potential benefit of a booster dose of mRNA-1273.

“It is promising to see clinical and real-world evidence adding to the growing body of data on the effectiveness of the Moderna COVID-19 vaccine,” said Stéphane Bancel, CEO of Moderna, in a company press release. “The increased risk of breakthrough infections in COVE study participants who were vaccinated last year compared to more recently illustrates the impact of waning immunity and supports the need for a booster to maintain high levels of protection. We hope these findings are helpful as health authorities and regulators continue to assess strategies for ending this pandemic.”

Moderna’s newest insights include an overall efficacy review, a study on breakthrough infections, and a study on long-term immunity.

Moderna Releases New Clinical Data on COVID-19 Vaccine

In a move that revealed just how difficult it is to craft policies designed to curb industry pricing practices, Democrats failed to gain sufficient support this week to advance long-debated legislation to permit Medicare drug price negotiations. Three centrist Democrats opposed the measure in debate on Sept. 15, 2021, sufficient to block the bill from moving out of the key House Energy and Commerce Committee.

The vote put a temporary halt on efforts to approve the Democrats’ lead proposal to permit government negotiations of reimbursement for certain medicines covered by Medicare, a key provision to help pay for the $3.5 trillion budget package on a tight schedule for moving through Congress. Opposition from Reps. Kurt Schrader (D-Or), Scott Peters (D-Ca), and Kathleen Rice (D-NY) has sent party leaders back to the drawing boards in search of drug pricing reform provisions more acceptable to moderates in both the House and Senate. The spending bill may move forward without this provision from the House Ways & Means Committee, which continues to debate related health care spending provisions.

The three centrists offered a more modest drug pricing measure, which they claim would lower consumer out-of-pocket costs, while also maintaining incentives for private investment and innovation. A major change here would limit price negotiations to fewer medicines covered by Medicare Part B—only those drugs that lack competition or patent exclusivity. Such a revision would raise much less revenue and is adamantly opposed by progressive Democrats. They see it as caving in to Big Pharma and severely limiting savings for patients.

These developments on drug pricing legislation reflects the success of industry in raising fears that such measures will block patient access to needed medicines and dry up investment in important R&D on new therapies. Pharmaceutical Research and Manufacturers of America (PhRMA) is spending more than $1 million on TV ads as part of a massive lobbying and communications campaign emphasizing the potential harm to patients seeking cures for deadly diseases. A 

 ran on Sept. 15, 2021 to highlight how Medicare price negotiations threatens “patient’s ability to get the medicines they need” and that one legislative proposal “would cut $1.5 trillion from innovative research companies” over 10 years. In countries with such price controls, claims the letter signed by all of PhRMA’s members, new cancer therapies and breakthroughs are “either delayed or not available at all.”

Smaller biotech firms and financial investors similarly emphasize that drug price negotiations won’t just harm Big Pharma but will dry up investment in vital R&D operations. A 

letter to the White House and to House and Senate leaders on September 8

, which was signed by 400 small biotech company heads and leading investment companies in the field, emphasized that “draconian” price negotiation legislation “would immediately halt private funding of drug discovery and development."

Meanwhile, legislators backing the Medicare price negotiation plan counter-charge that industry is exploiting consumer fears and using its vast resources to block any fair and reasonable cost-cutting efforts. But opposition to the Democrats’ main price cutting proposal already is stronger in the Senate, where many key members have voiced concerns about government interference in private sector investment. The situation sets the stage for intense negotiations and Congressional infighting in the coming weeks.

Democrats failed to gain sufficient support to advance long-debated legislation to permit Medicare drug price negotiations.

Pharma Blocks Democrats’ Drug Pricing Plan

FDA announced the reorganization of the agency’s information technology (IT), data management, and cybersecurity function into the new Office of Digital Transformation (ODT) on Sept. 15, 2021. Vid Desai has been appointed as the ODT’s chief information officer.

ODT will function on an agency level and report directly to the FDA commissioner. The goal behind this reorganization, according to the press release, is to transform the way the agency handles IT via improved data and IT competencies. It will streamline various FDA operations by reducing duplicate processes, implementing technological efficiencies through projects that deliver maximum customer benefits, and promoting shared services within agency offices.

The ODT is the latest step in FDA’s Technology Modernization Action Plan from 2019, which laid the groundwork to innovate the agency’s approach to data management and review process. It was followed by the Data Modernization Action Plan in 2021, which further iterated on various streamlining and processing improvements that began in 2019 by identifying high value driver projects for individual centers and the agency.

“Good data management, built into all of our work, ultimately helps us meet and advance the FDA’s mission to ensure safe and effective products for American families,” said Janet Woodcock, acting FDA commissioner, in the press release. “By prioritizing data and information stewardship throughout all of our operations, the American public is better assured of the safety of the nation’s food, drugs, medical devices, and other products that [FDA] regulates in this complex world.”

The new FDA office will reorganize IT, data, and cybersecurity functions to an agency level.

FDA Introduces Office of Digital Transformation

Takeda Pharmaceutical Company announced FDA approval of Exkivity (mobocertinib) for treatment of patients with a specific form of lung cancer on Sept. 15, 2021. Mobocertinib is intended for patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) exon 20 insertion mutations whose disease has progressed on or after platinum-based chemotherapy.

Mobocertinib is an oral tyrosine kinase inhibitor specifically designed to selectively target EGFR exon 20 insertion mutations. FDA previously granted it orphan drug designation, breakthrough therapy designation, and fast track designation.

Per the terms of the approval, Exon 20 insertion mutations must be detected by an FDA-approved test. At the same time as mobocertinib was approved, Thermo Fisher Scientific’s Oncomine Dx Target Test was approved. This will serve as a companion diagnostic designed to identify NSCLC patients with EGFR exon 20 insertions.

“The approval of EXKIVITY introduces a new and effective treatment option for patients with EGFR [exon 20] insertion+ NSCLC, fulfilling an urgent need for this difficult-to-treat cancer,” said Teresa Bitetti, president of the Global Oncology Business Unit at Takeda, in a company press release. “EXKIVITY is the first and only oral therapy specifically designed to target EGFR [exon 20] insertions, and we are particularly encouraged by the duration of the responses observed with a median of approximately 1.5 years. This approval milestone reinforces our commitment to meeting the needs of underserved patient populations within the oncology community.”

Takeda’s Exkivity (mobocertinib) was approved by FDA for the treatment of patients with lung cancer.

Takeda’s Exkivity Approved by FDA

CPC (Colder Products Company), an operating company within Dover, announced a new series of ultra-compact sterile connectors, the MicroCNX Series Connectors, on Sept. 2, 2021. According to a company press release, this product is the first alternative to tube welding for small-volume, closed aseptic processes.

MicroCNX connectors are specifically designed for small-volume processes involving 1/16 in. (1.6 mm), 3/32 in. (2.4mm), and 1/8 in. (3.2mm) small-bore tubing. Some of the more common uses for these tubings are sampling, seed train expansion, and early cell-culture processes that involve shaker flasks and rocker tables. The connectors can be incorporated into pre-made tubing assemblies. 

To use the aseptic connector, users must pinch to remove the protective cover, click together the connector halves, and pull out the protective membranes to allow flow to begin. This process is intended to be a simpler solution to traditional tube welding, which requires maneuvering the tube welder into position, equipment maintenance, and precise technique.

“MicroCNX connectors are a critically important option for a range of bioprocessing, cell therapy and gene therapy workflows,” said Troy Ostreng, senior product manager for CPC’s biopharmaceutical business, in the press release. “Until now, cumbersome tube welding has been the only way to make sterile closed connections of very small-bore tubing. The MicroCNX connector represents a huge innovation for the industry.”

CPC’s MicroCNX Series Connectors provide an alternative to tube welding at small tubing sizes.