The old adage of “if at first you don’t succeed, try, try again,” seems to be working for Pharmamar SA – at least when it comes to getting EU approval for its multiple myeloma drug, Aplidin (plitidepsin).

In a rare move Oct. 28, the EU General Court annulled the European Commission’s decision that refused marketing authorization for the drug and ordered the commission to pay all court costs.

Pharmamar, of Madrid, filed suit in the General Court Oct. 1, 2018, after the EMA’s Committee for Medicinal Products for Human Use, upon re-examination, decided once again that the drug’s risks didn’t outweigh its benefits.

The suit was based on the strict verification of conflicts of interest held by EMA-appointed experts and the correct analysis of the scientific evidence Pharmamar presented, the company said. In its suit, it also asked the court to clarify the procedural guarantees and examination criteria the EMA is to apply when considering a marketing authorization.

A few months before filing the suit, Pharmamar presented data at the American Society of Clinical Oncology from a re-evaluation of its phase III Admyre study that showed overall survival with plitidepsin plus dexamethasone was 11.6 months, a statistically significant improvement over the 6.4 months for the control arm of dexamethasone monotherapy.

An antitumor agent originally isolated from the Mediterranean tunicate Aplidium albicans developed in combination with dexamethasone in patients with relapsed/refractory multiple myeloma, Aplidin has a long history in the EU. The EMA granted it orphan drug status in 2003 for a leukemia indication. Over the years, it has been tested in other cancers and is currently being studied in patients hospitalized with COVID-19.

To date, Aplidin is only marketed in Australia, where it was approved in 2018 as a third- or fourth-line treatment for multiple myeloma.

Lawmakers spill Purdue documents on heels of settlement

Disappointed with the proposed $8 billion settlement between the U.S. Department of Justice (DoJ) and Purdue Pharma LP to resolve criminal and civil allegations stemming from the marketing of Oxycontin (oxycodone hydrochloride) and other opioid products, Rep. Carolyn Maloney (D-N.Y.), chair of the House Oversight Committee, released selected documents Oct. 27 that the committee obtained as part of its investigation into Purdue and members of the Sackler family, who have owned a controlling share of the company for more than half a century.

The documents “show that members of the Sackler family … recklessly pushed Purdue executives to flood the market with Oxycontin to maximize their personal wealth, even after the company reached a settlement with DoJ in 2007 for misleading marketing,” said Maloney and Rep. Mark DeSaulnier (D-Calif.).

“We are disappointed that DoJ forfeited yet another opportunity to hold members of the Sackler family fully accountable for their role in fueling the devastating opioid epidemic,” they added, referencing the proposed settlement announced last week.

The settlement, which has yet to be approved by the court handling Purdue’s bankruptcy proceedings, included an agreement by the Stamford, Conn.-based company to plead guilty to one count of conspiring to defraud the U.S. and to violate the Federal Food, Drug and Cosmetics Act and to two counts of conspiracy to violate the federal anti-kickback statute. The agreement didn’t include criminal charges against individual members of the Sackler family – something Maloney and DeSaulnier took issue with.

While family members agreed to pay $225 million to resolve False Claims Act allegations as part of a separate civil settlement, that amount represents only 2% of the family’s estimated $13 billion net worth, according to the lawmakers. They noted that the Sackler family has withdrawn more than $10 billion from Purdue since 2008.

However, in announcing the settlements with Purdue and the Sacklers, DoJ suggested criminal charges still may be pending, as it pointed out that the resolutions did not include the criminal release of individuals, including members of the Sackler family. The agreements also do not resolve civil claims that states may have against Purdue or the Sacklers, nor do they impede debtors’ ability to recover fraudulent transfers, DoJ said.

Maloney and DeSaulnier also questioned a provision in the settlement mandating the conversion of Purdue into a public benefit company managed by a trust. Earlier this month, 25 state attorneys general opposed that arrangement, “raising concerns that turning the Oxycontin business into a public trust would inappropriately entangle government officials in the sale of opioids, hamstring the government’s ability to appropriately regulate the industry and shield individual members of the Sackler family from individual, personal liability,” the lawmakers said.

The redacted Purdue documents were released in two parts, along with a separate table of contents. The first part includes 177 pages of presentations on Oxycontin growth opportunities and emails, many of which were to members of the Sackler family. The second part consists of 70 pages of email chains, most of which are from members of the family.

Western states join forces to review vaccines

An effort to independently review FDA-approved COVID-19 vaccines is taking hold in the U.S. as more states join California’s COVID-19 Scientific Safety Review Workgroup.

California Gov. Gavin Newsom appointed 11 “physician scientists” with expertise in immunization and public health to the workgroup last week, charging them with reviewing any COVID-19 vaccine that receives federal approval and verifying its safety before it can be distributed in the state.

“California leads in science and by bringing together our state’s brightest scientific minds, we can ensure that any vaccine distributed here meets safety requirements,” Newsom said at the time.

Now, Washington, Oregon and Nevada have signed on to the workgroup, and the governors of those states will be naming additional members to the panel, Newsom said Oct. 27.

The workgroup is a result of public distrust of the FDA approval process that has been whipped up by the political rhetoric that’s made COVID-19 a top campaign issue in the presidential election.

“When the time comes, Nevadans will be able to feel confident in the safety of the vaccine knowing that an independent review by experts across the West gave it their seal of approval,” Nevada Gov. Steve Sisolak said.

FDA finalizes nicotine drug guidance

The FDA finalized its 2018 draft guidance on nonclinical testing of orally inhaled drugs containing nicotine that are developed for smoking cessation and related chronic indications.

Since the products are expected to be used continuously or intermittently for six months or longer, the FDA said the nonclinical assessment for marketing approval should include general toxicity studies, developmental and reproductive toxicity studies, an assessment of carcinogenic potential, and supporting toxicokinetic and pharmacokinetic studies.

The final guidance released Oct. 28 differs from the draft in that it provides more information to guide the nonclinical development of an active ingredient in addition to nicotine and gives an example of how systemic toxicity could be addressed by a nonclinical toxicity study conducted with a noninhalation route of exposure. Other changes include clarification of how a sponsor can compare the exposure to nicotine in an approved drug by providing pharmacokinetic information from the proposed product.

CBER tackling guidance agenda

The FDA’s Center for Biologics Evaluation and Research (CBER) is making headway with its 2020 guidance agenda, but it still has more to do before year-end if it is to meet the goals it set at the beginning of the year.

In an update of where it stands with the agenda, CBER showed it has issued 20, or about 65%, of the 31 guidances it expected to release this year. Three of the 11 guidances yet to be issued are draft documents involving tissues and advanced therapies – guidance on gene therapies for neurodegenerative diseases, the development of human gene therapies incorporating genome editing and the development of CAR T-cell therapies.

CBER also planned to issue guidance on manufacturing considerations for licensed and investigational cellular and gene therapy products during the COVID-19 pandemic. Other guidances yet to come involve blood and blood components, as well as ones addressing interaction with the FDA on complex and innovative clinical trial designs and on chemistry, manufacturing and controls changes to an approved application for certain biological products.

Innovation Alliance voices support for PTAB changes

The Innovation Alliance published a letter from 324 innovators and patent holders to members of the U.S. House and Senate Judiciary Committees expressing support for changes made to operations at the Patent Trial and Appeal Board (PTAB) over the past several years.

The signers of the letter, a list that includes the Biotechnology Innovation Organization and the Medical Device Manufacturers Association, said the changes to the PTAB processes have restored “balance and confidence in the U.S. patent system,” particularly in reference to the operational effects of the America Invents Act of 2011.

Perhaps the most significant of the changes has been the use of the so-called Phillips standard for interpreting claims during patent litigation, the standard used in courts, rather than the broadest reasonable interpretation standard the PTAB had used.

The signers also lent their support for a rumored rulemaking that would allow the PTAB to deny institution of an inter partes review (IPR) when the same matter is pending in district court. The IPR process was intended as an alternative to district court litigation rather than as an addition, according to the letter.

Aside from the PTAB changes, the letter gave kudos to Andrei Iancu, director of the U.S. Patent and Trademark Office (PTO), saying that under his leadership, the PTO has “taken great strides toward restoring a predictable, reliable and consistent patent system that protects inventors and promotes U.S. leadership in global innovation.”