FDA Changes Opioid Label to Include Warnings

As part of implementing its Overdose Prevention Framework, the FDA updated its prescribing information for opioids to include not only warnings for patients about the risks for opioid misuse, overdose, addiction and death but also the risk for opioid-induced hyperalgesia (OIH), according to the agency.  The FDA noted that although the OIH can occur at any dosage, the increase in pain or increased sensitivity to pain associated with the condition occurs more frequently with higher opioid doses. The new guidelines require that the following information is included with safety labeling:

Overdose risk increases as dosage increases for all opioid pain medicines.

Immediate-release opioids should not be used for an extended period unless a patient’s pain remains severe and alternative treatment options continue to be inadequate.

Many acute pain conditions treated in an outpatient setting require no more than a few days of opioid pain medicine to be successful.

Extended-release/long-acting opioid pain medicines should be reserved for severe and persistent pain that requires daily opioid administration and for which alternative treatment options are inadequate.

Global pharmaceutical companies have long been under the spotlight for a variety of reasons, including cyclical and uneven availability; a lack of environmental, social and governance (ESG) transparency; and skyrocketing incidents of counterfeit medications.

This rising and widespread scrutiny means that Industry 3.0, which is the foundation of the manufacturing and distribution processes of the vast majority of today’s pharmaceutical companies, is no longer sufficient.  

A recent report in the International Journal of Pharmaceutics, titled "Industry 4.0 for pharmaceutical manufacturing: Preparing for the smart factories of the future," states that pharma companies will need to evolve to achieve an unprecedented level of data digitalization to include "supply chain-related information such as raw materials variability and global tracking of materials across facilities."

The reasons for more digitally mature pharmaceutical supply chains are multiple—and go beyond "simply" supply chain resilience and data-driven decision-making. End-to-end traceability also improves compliance with current and looming regulatory standards, helps to meet ESG targets and, inevitably, safeguards patients. 

Governments and regulatory agencies worldwide are imposing stricter regulations on the pharmaceutical industry to ensure drug safety and quality.

One example is the Drug Supply Chain Security Act (DSCSA) in the United States, which will require pharma businesses to implement a serialized, electronic and interoperable system to track and trace prescription drugs throughout a company’s supply chain and among all stakeholders. The deadline is coming up fast: November 27, 2023. 

Making ionocytes: A step toward cell or gene therapy for cystic fibrosis

Cystic fibrosis transmembrane conductance regulator (CFTR) modulators were a breakthrough for cystic fibrosis, improving the movement of chloride and water and moistening mucus secretions. But these drugs are expensive, don't work in all patients with cystic fibrosis, and have side effects and interactions with other drugs. People who do respond to CFTR modulators must take them for a lifetime.  Researcher Ruby Wang, MD, and Benjamin Raby, MD, MPH, chief of the Division of Pulmonary Medicine at Boston Children's Hospital, envision an alternative approach: cell therapy or gene therapy targeting a cell type that's only recently been discovered.  

In 2018, two studies published in Nature rocked the cystic fibrosis scientific community. They found that the CFTR gene mutation primarily affects ionocytes—previously unknown cells that make up just 1% of the airway's cells. Surprisingly, more than 90% of the CFTR protein was being made by these rare cells.

Now, in the American Journal of Respiratory and Critical Care Medicine, Wang and colleagues at Boston University report creating ionocytes from patients for the first time using stem cell technology. Collaborators at Boston Children's include Thorsten Schlaeger, Ph.D., and Yang Tang from the Stem Cell Research Program and Stuart Rollins, MD, and Chantelle Simone-Roach in Pulmonary Medicine.

The accomplishment means that ionocytes can now be studied in a dish to understand their biology—and their possible use as a treatment vehicle.

"Maybe we could correct patients' ionocytes and put them back in the lungs," Wang says. "This is why it's exciting."

For cell and gene therapies, all stages of the drug development life cycle are complex. The patient, product and supply chain require specialized sets of capabilities, as standards and protocols differ from more traditional therapy areas.

Specifically, cell and gene therapy development presents unique chemistry, manufacturing and controls (CMC) challenges because of inherent properties such as shorter shelf life, variability in starting and ancillary materials, manufacturing and logistical complexities and cost. 

Below is a case study in which strategic regulatory and CMC expertise from Cardinal Health Regulatory Sciences helped guide a biopharmaceutical company’s regulatory and development strategy for a cell and gene therapy product.

Avoiding a clinical hold

A biopharmaceutical company focused on developing novel autologous T cell therapies had promising findings targeting a rare-disease tumor type. The product had reached the stage in the development pipeline where the company was ready to assemble their Investigational New Drug application (IND). The company referenced a drug master file (DMF) filed by their contract manufacturer in order to provide required information for the IND, but upon submission, the FDA indicated that there was insufficient data within the master file. The company had only a matter of days to provide the required additional data to ensure that their IND review would continue and not lead to a clinical hold. Experts from Cardinal Health Regulatory Sciences were selected to quickly advise on next steps.

Additional submissions to advance IND review

The Cardinal Health Regulatory Sciences team began auditing the information that was originally submitted. They quickly recognized that insufficient process specific DMF information for this type of manufacturing process had been provided in the submission. Experience and fluency with these types of submissions allowed the team to quickly identify the issue. They realized that specific product quality information was needed on ancillary materials used in the manufacturing process as well as additional information about the manufacturing equipment to ensure that the product would not be contaminated during manufacturing. Within days, the team formulated a strategy and assembled all outstanding information required, ultimately receiving notification that the IND could proceed.

Recovering at-risk clinical batches

The biopharmaceutical company continued to partner with the Regulatory Sciences team to help address significant incidents or amendments that required a timely, strategic response. Some early clinical batches failed release specifications, so the team worked with the company to craft a package for review, to ensure that the batches could be used. The information packages included a summary of the investigation into the manufacturing process and analytical testing, the failed test result, justification and corrective actions as needed and a patient risk/benefit statement. As patients awaiting these therapies are often in dire need and the shelf life of autologous T cell therapies is extremely short, the submission was extremely time sensitive. The prompt and thorough submissions from the Regulatory Sciences team convinced the FDA to grant an exception for product release and ensured that the custom products were delivered.

Support during clinical development

CMC requirements are very complex for cell and gene therapies, with no room for error or contamination. The Cardinal Health Regulatory Sciences team continued to work with the company throughout the clinical trial and provided multiple follow-up IND amendments with improvements in analytical methods, including rapid microbiology methods and manufacturing processes. The Regulatory Sciences team advised on comparability protocols and data required to support changes in manufacturing sites, while still ensuring proper maintenance of product quality attributes. Their CMC expertise ensured that the company continuously provided improvements and amendments to their IND as advances were made throughout the development process. The orphan drug is currently in phase 1 clinical trials and multiple lots have been successfully administered.

At the beginning of the pandemic, some in-person inspections of drug manufacturing facilities were paused by the FDA – especially those conducted internationally. Over the past few months, these “Good Manufacturing Practices” (GMP) evaluations have resumed. In Digwal, India, the FDA conducted one of these physical surveys from March 27th to the 31st at a factory owned by Piramal Pharma LTD. The FDA found that the building’s operations were compliant as there were no “form-483 observations” – which represent failures to comply with industry standards.  

On the business side of things, this was welcomed news by the manufacturer. After the inspection results were made public, the corporation’s stock grew over 6% on April 3rd. Piramal Pharma has a 5-year loss of almost 75%* but the short-term boost and the positive report from the FDA could indicate things are looking up for the international company.

Also on Monday, April 3rd, a report from the FDA had the opposite impact for another company in the medicinal field, a Denmark company called Ascendis Pharma. The US federal agency reported that “deficiencies” were observed when studying the application of a possible treatment, developed by Ascendis, for a condition known as hypoparathyroidism. The pending drug under scrutiny is named TransCon PTH. Although the report did not go into detail regarding the deficiencies, the FDA did note that the findings were not reflective of a “final regulatory decision.” The company’s stock, which is traded on the NASDAQ, fell over 30% in a day* after the news became public on Friday March 31st. Over the past years, however, Ascendis has posted a gain of almost 25% over that last five years*.

 * as of 4:30 PM EST on 4/3/23 

While not surprising, the delay is a disappointment for BioMarin, which has already spent years trying to win U.S. approval of its gene therapy known as Roctavian.

The company appeared on track to bring a long-lasting therapy to patients who suffer from the genetic bleeding disease back in 2019, when it first sought approval for Roctavian. The next year, the FDA surprised the gene therapy world by rejecting it, saying the agency needed more evidence that the one-time treatment would provide lasting benefit.

BioMarin collected additional two-year follow-up data and resubmitted its application in 2022, later adding the information on patients tracked for three years. The company has also been working with the FDA on other fronts to get ready to sell Roctavian in the U.S. In December, the agency finished a pre-license inspection of its manufacturing facility.

The treatment is already approved in Europe, and BioMarin last month forecast $100 to $200 million in Roctavian sales this year, depending on U.S. approval and reimbursement in Germany.

Two antivirals added to list of drugs that cannot be exported or hoarded

Two antiviral drugs used to treat flu have been added to the list of medicines that cannot be exported or hoarded.

Oseltamivir (Tamiflu; Roche) and zanamivir (Relenza; GSK) were added to the list by the government on 20 December 2022, along with the antibiotic flucloxacillin.

On 14 December 2022, the antibiotics amoxicillin, cefalexin, phenoxymethylpenicillin (Penicillin V) and azithromycin oral suspension were added to the list, in response to rising demand as a result of an increase in Strep A infections.

Antibiotic shortages have been widely reported, but despite the addition of the antiviral flu drugs to the no-hoarding list, Leyla Hannbeck, chief executive officer of the Association of Independent Multiple Pharmacists, said her members had not reported shortages of flu drugs.

“These medicines [oseltamivir and zanamivir] are not very commonly used, so if there was an issue we wouldn’t notice immediately,” she said.

She said that the “precautionary measures” relating to flu drugs were “welcome” but added that there is still a need for “transparency across the supply chain”.

The Pharmaceutical Services Negotiating Committee said its dispensing and supply team had not received reports from contractors about shortages of oseltamivir or zanamivir.

Primary care surveillance reports  showed influenza-like illness rose in the week of 5 December 2022 to 11 December 2022 to 15.5 per 100,000 population, compared with 9.4 per 100,000 population the previous week. Laboratory data showed an increase in samples testing positive for influenza, from 16.2% in the week beginning 29 November2022 to 20.2% in the week beginning 5 December 2022. The highest positivity rate was among children aged 5 to 14 years.

Highly immune evasive omicron XBB.1.5 variant is quickly becoming dominant in U.S. as it doubles weekly

The Covid omicron XBB.1.5 variant is rapidly becoming dominant in the U.S. because it is highly immune evasive and appears more effective at binding to cells than related subvariants, scientists say.

XBB.1.5 now represents about 41% of new cases nationwide in the U.S., nearly doubling in prevalence over the past week, according to the data published Friday by the Centers for Disease Control and Prevention. The subvariant more than doubled as a share of cases every week through Dec. 24. In the past week, it nearly doubled from 21.7% prevalence.

Scientists and public health officials have been closely monitoring the XBB subvariant family for months because the strains have many mutations that could render the Covid-19 vaccines, including the omicron boosters, less effective and cause even more breakthrough infections.

Scientists at Columbia University, in a study published earlier this month in the journal Cell, warned that the rise of subvariants such as XBB could “further compromise the efficacy of current COVID-19 vaccines and result in a surge of breakthrough infections as well as re-infections.”

The XBB subvariants are also resistant to Evusheld, an antibody cocktail that many people with weak immune systems rely on for protection against Covid infection because they don’t mount a strong response to the vaccines.

The scientists described the resistance of the XBB subvariants to antibodies from vaccination and infection as “alarming.” The XBB subvariants were even more effective at dodging protection from the omicron boosters than the BQ subvariants, which are also highly immune evasive, the scientists found.

Health officials in the U.S. have repeatedly called on the elderly in particular to make sure they are up to date on their vaccines and get treated with the antiviral Paxlovid if they have a breakthrough infection.

 Omicron subvariants that more easily dodge immunity are causing more than 70% of U.S. infections

The most immune-evasive omicron subvariants yet are now causing more than 70% of new infections in the U.S., as millions of Americans prepare to travel and gather with family for the holidays.

The BQ.1 and BQ.1.1 subvariants taken together are now responsible for 68% of new cases, according to data published by the Centers for Disease Control and Prevention on Friday. The XBB subvariant is causing 4.7% of new Covid infections.

Scientists, in several independent studies, have described the BQ and XBB subvariants as more adept at evading immunity from vaccination and infection than prior versions of the virus.

They pose a significant threat to people with compromised immune systems because key antibody treatments are resistant to them. The Food and Drug Administration last week pulled bebtelovimab, a monoclonal antibody used to prevent people who catch Covid from developing severe illness.

Bebtelovimab was used by people who cannot take other FDA-authorized treatments, such as the antiviral Paxlovid. Many people with weak immune systems, such as organ transplant patients, cannot take Paxlovid with their other medications.

The BQ and XBB subvariants also are resistant to Evusheld, an antibody cocktail that many people with compromised immune systems rely on for protection because they do not mount an adequate response to the vaccines. The FDA still authorizes Evusheld for use.

CDC Director Dr. Rochelle Walensky encouraged the public to mask up this winter to help prevent the spread of respiratory illnesses, particularly people who are living in counties with high Covid levels.

The CDC is calling on everyone who is eligible to get their Covid booster and flu shot to help reduce the burden of disease this winter.

FDA Authorizes Bivalent COVID-19 Vaccine Booster for Children 6 Months to 4 Years of Age

The FDA has authorized expanded eligibility for the updated bivalent COVID-19 boosters for children between 6 months and 4 years of age, the agency announced today. Omicron variant-targeted booster shots made by Pfizer-BioNTech and Moderna were already available to individuals 5 years of age and older.

The FDA action authorizes children 6 months through 5 years of age who were administered the original monovalent Moderna COVID-19 vaccine to receive a single booster of the updated bivalent Moderna COVID-19 vaccine 2 months following completion of a primary series with the monovalent vaccine.

Both the Moderna and Pfizer-BioNTech bivalent COVID-19 vaccines include an mRNA component that corresponds to the original COVID-19 strain to induce a broadly protective immune response against COVID-19. The updated bivalent vaccines also contain an mRNA component that corresponds to the Omicron variant BA.4 and BA.5 lineages to confer superior protection against Omicron, according to the FDA.

In terms of adverse events (AEs), those administered the updated bivalent vaccines may experience similar AEs to individuals who were previously administered the original monovalent mRNA COVID-19 vaccines, according to the FDA.

“Vaccines remain the best defense against the most devastating consequences of disease caused by the currently circulating omicron variant, such as hospitalization and death. Based on available data, the updated, bivalent vaccines are expected to provide increased protection against COVID-19,” Peter Marks, MD, PhD, director of the FDA’s Center for Biologics Evaluation and Research, said in a press release. “Parents and caregivers can be assured that the FDA has taken a great deal of care in our review, and we encourage parents of children of any age who are eligible for primary vaccination or a bivalent COVID-19 vaccine booster dose to consider seeking vaccination now as it can potentially help protect them from COVID-19 during a time when cases are increasing.”

U.S. FDA advisers back Ardelyx's kidney disease drug

A panel of advisers to the U.S. health regulator on Wednesday recommended the approval of Ardelyx Inc's (ARDX.O) drug for chronic kidney disease patients on dialysis, more than a year after it was initially rejected.

The Food and Drug Administration's advisory panel voted 9-4 in favor of the drug, tenapanor, to be administered as a single therapy for treating high phosphate levels in the blood of patients on dialysis.

Tenapanor is an oral drug that reduces the level of phosphate in the body by targeting the pathway that absorbs it.

Currently, phosphate binders are the only approved therapy for hyperphosphatemia, a condition resulting in abnormally high levels of phosphorus in the blood, which is a sign of kidney damage. Around 37 million people, or one in seven people, in the United States have chronic kidney disease, as per a government report last year.

The advisers' vote followed the release of briefing documents on Monday, in which FDA's staff reviewers cited similar concerns about unclear benefits of the drug that the agency had mentioned in the complete response letter issued July last year.

The FDA had called the advisers' meeting due to Ardelyx's appeal against the drug's initial rejection.

Ardelyx Chief Executive Officer Mike Raab was optimistic about the FDA deciding on similar lines as the panel's vote.

FDA, which usually follows the recommendations of its expert panel, is expected to make its final decision on the drug within 30 days of the conclusion of the panel meeting.

Rivaroxaban plus aspirin improves outcomes in stable cardiovascular disease (COMPASS)

  Rivaroxaban plus aspirin improves survival and educes stroke and heart attack in patients with stable coronary or peripheral artery disease, according to late-breaking results from the COMPASS trial presented today in a Hot Line – LBCT Session at ESC Congress1 and published in the NEJM.

One-third of the 55 million deaths in the world each year are from cardiovascular causes. Patients with known coronary or peripheral artery disease are at risk of death, stroke and heart attack. Aspirin is the single most widely used treatment to prevent strokes and heart attacks but is only modestly effective.

The COMPASS trial2 tested two possible ways to improve on aspirin, by using the combination of rivaroxaban and aspirin, or by using rivaroxaban alone, to protect against heart attack and stroke in patients with stable coronary or peripheral artery disease. Data Safety Monitoring Board recommended that the rivaroxaban and aspirin arms be stopped because of a clear superiority of the combination of rivaroxaban and aspirin over aspirin alone.

The results indicate that the addition of rivaroxaban to aspirin, compared with aspirin alone, reduced cardiovascular death, stroke, or heart attack by 24%, and improved survival by 18%. Rivaroxaban 5mg twice daily was not superior to aspirin alone. The addition of rivaroxaban to aspirin increased bleeding, and the most common site of bleeding was in the stomach or lower bowel. There was no significant increase in fatal or brain bleeding. The substantial benefits seen with rivaroxaban and aspirin support the approach of using low doses of the two treatments in combination. Recent trials in other disease areas have demonstrated substantial benefits from using low doses of a combination of drugs and this concept is now further supported by the results of COMPASS.