FDA Needs to Step Up As Use of Third-Party Manufacturers Leads to Rejections

It was a tough week for biopharma companies that rely on contract manufacturing, which is pretty much all the major industry players these days. The FDA on Tuesday again issued a Complete Response Letter (CRL) to AbbVie rejecting ABBV-951, a proposed treatment for motor fluctuations in adults with advanced Parkinson’s disease. Then on Thursday, the agency declined to approve Merck and Daiichi Sankyo’s HER3-targeted antibody-drug conjugate patritumab deruxtecan for lung cancer. In both cases, the FDA cited issues with third-party manufacturers.

While some might argue that the rise in outsourcing of manufacturing is helping biopharma companies to focus on their core capabilities, it’s also an Achilles’ heel. Out of a total of 238 CRLs issued between 2017 and 2023, 30% involved quality/manufacturing issues—particularly problems with manufacturing processes, facility inspections, or chemical, manufacturing and controls (CMC).  

AbbVie and Merck/Daiichi did not provide details about the problems identified by the regulator in their respective CRLs. In its letter, AbbVie said the FDA cited “observations” that were identified during inspection of a third-party manufacturer, but hastened to add that it did not involve ABBV-951. Merck and Daiichi only reported that their CRL “results from findings pertaining to an inspection of a third-party manufacturing facility.”

I’m one of those industry observers who believes it is time for the FDA to publicly release CRLs, or at least some kind of summary. It’s critical because biopharma companies are not being transparent. One study concluded: “Press releases are incomplete substitutes for the detailed information contained in Complete Response Letters.”

The details of the manufacturing issues aside, just the fact that these CRLs focused on them over any clinical issues is cause for concern. At the same time, the FDA itself has been struggling for years with its inspection program.

A December 2023 study in Health Affairs revealed that FDA inspections of drug manufacturing facilities in the U.S. and especially abroad dropped well below pre-pandemic levels between 2020 and 2022 and have not yet bounced back. As the agency begins to pick up the pace of foreign inspections, the import of several drugs from these facilities has been halted, leading to a spike in drug shortages. India-based Intas Pharmaceuticals, for example, has received warning letters from the FDA and is on the agency’s import alert list due to failures to comply with Current Good Manufacturing Practice (CGMP) regulations and poor data integrity.

India’s own regulator has also been cracking down on manufacturing problems in the country. Reuters on Thursday reported that more than 36% of the 400 drug manufacturing units inspected since last year in India were ordered to be shut by the country’s drug regulator, after deaths linked to substandard cough syrups prompted an increase in scrutiny.

While India is responding on some level, a ProPublica investigation last year of FDA oversight following deaths from bacteria-tainted eyedrops made in an Indian plant showed “the agency’s inspections of overseas drug manufacturers, located mostly in India and China, has dropped precipitously even as the number of manufacturers has remained relatively steady.”

Neither AbbVie or Merck/Daiichi gave any indication of whether their CRLs involved foreign third-party manufacturers, but it wouldn’t be a surprise. More than 50% of manufacturers supplying the U.S. market are located overseas—mainly in India and China. With biopharma companies relying on the outsourcing of manufacturing, especially overseas, the FDA must do more to ensure quality controls are being implemented by third-party manufacturers.

I’m not alone in this belief. A letter last week to FDA Commissioner Robert Califf from the chairs of the House Energy and Commerce Committee and two subcommittees pressed the agency for more information regarding “large variations” in its foreign drug inspection program. And in February, Mary Denigan-Macauley, the director of healthcare at the Government Accountability Office, testified before a congressional subcommittee that the FDA continues to face “persistent challenges” overseeing foreign drug manufacturing.

That same month, the FDA said it planned to increase inspections of Indian manufacturing facilities this year. Whether that is happening remains to be seen.

https://www.biospace.com/article/fda-needs-to-step-up-as-third-party-manufacturers-lead-to-rejections/

ICER Doubles Down on Critique of Lykos’ MDMA Therapy, Cites Data Concerns

 An independent drug pricing watchdog on Thursday concluded that there is not enough evidence to support Lykos Therapeutics’ MDMA-based treatment for post-traumatic stress disorder—and that the proposed regimen cannot be compared with other psychotherapies.

The Institute for Clinical and Economic Review (ICER) in a final report flagged “substantial concerns” with the “validity” of the data that Lykos used to support its drug application for an investigational MDMA-assisted psychotherapy (MDMA-AP) for patients with post-traumatic stress disorder (PTSD).

ICER pointed out that Lykos’ trials were “essentially, unblinded, with nearly all patients who received MDMA correctly identifying that they were in the MDMA arm of the trials.” The watchdog also cited multiple experts who said that those who were involved in the trials—participants, therapists and investigators—harbored “very strong beliefs” about the benefits of MDMA-AP, which further exacerbated the concerns of bias.

There were also instances of patients having been “encouraged” by study therapists to provide favorable reports of MDMA-AP while some therapists also “discouraged negative reports,” according to ICER.

The watchdog also found that there were not enough publicly available data to comprehensively assess the frequency of misreporting, participant beliefs and bias. This led the ICER to conclude that there is currently “insufficient” evidence backing MDMA-AP, and that the available data are also not enough to compare Lykos’ proposed regimen with other psychotherapies.

ICER’s final report on Thursday comes after Lykos suffered an overwhelming defeat in front of the FDA’s Psychopharmacologic Drugs Advisory Committee earlier this month. Voting 10-1, the panel of external experts agreed that even with a strict risk evaluation and mitigation strategy, MDMA-AP’s benefits do not outweigh its risks.

The advisory committee voted 9-2 that Lykos did not provide enough data to support the efficacy of its proposed regimen in PTSD. A consumer representative, who sat on the panel and voted against Lykos, also raised concerns about “selection bias, the functional unblinding” and the “potential for some misconduct and manipulating the trial results.”

ICER also held its own virtual public meeting to assess Lykos’ MDMA-AP. The majority of its panelists agreed that the biotech’s evidence was “not adequate” to illustrate a “net health benefit” for the proposed treatment regimen.

Centered on a popular psychedelic called 3,4-methylenedioxymethamphetamine, commonly known as ecstasy, Lykos’ MDMA-AP combines the psychoactive drug with psychotherapy and supportive mental health services for the treatment of PTSD.

The company’s drug application, which the FDA accepted in February 2024, is backed by data from several studies including the Phase III MAPP1 and MAPP2 trials. Late-stage evidence showed that MDMA-AP could significantly ease PTSD symptom burden in patients, while also providing significant functional improvements.

The FDA’s target decision date is set for Aug. 11, 2024.

https://www.biospace.com/article/icer-doubles-down-on-critique-of-lykos-mdma-therapy-cites-data-concerns/

Mayorkas must hand over docs on illegal migrants accused of disabled teen’s rape, NYPD mob attack

 Homeland Security Secretary Alejandro Mayorkas was hit with a House Judiciary Committee subpoena Friday demanding he produce long-awaited records on nine migrants suspected of sickening crimes, including the rape of a disabled teen girl and a mob assault on two NYPD cops.

DHS must hand over documents on the accused criminals by 9 a.m. on July 17, according to documents exclusively obtained by The Post.

The committee is seeking records on Cory Alvarez, who was arrested for allegedly raping a disabled girl in March.Boston Globe via Getty Images

“Your response, to date, without compulsory process has been inadequate,” Committee Chairman Rep. Him Jordan (R-Ohio) wrote in the filing’s scathing cover letter.

Jordan accused Mayorkas of deliberately dragging his feet “for months on end” as the committee made repeated requests for information starting in October 2023.

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“Accordingly, nine A-files prioritized by the Committee — in addition to three A-Files the Department is compelled to produce pursuant to the Committee’s December 8, 2023, subpoena — remain outstanding,” Jordan wrote, referring to a list of 20 priority cases given to Mayorkas’ agency on April 11.

The A-files have information about interactions between illegal immigrants and US Customs and Border Patrol.

One of the remaining requests involves Cory Alvarez, a 26-year-old Haitian migrant who was arrested in March for allegedly raping a disabled teenage girl at a migrant shelter outside Boston.

Alvarez — released on a paltry $500 bail this week — entered the US in June 2023 through President Biden’s controversial parole program for Cubans, Haitians, Nicaraguans and Venezuelans (CHNV).

Jordan’s committee is now seeking his “A-file” as well as any other material related to his immigration case.

Alvarez was bailed earlier this week.Plymouth County DA's Office

“DHS’s failure to produce these materials hinders the Committee’s ability to fulfill its constitutional oversight obligations,” Jordan insisted.

A lack of serious oversight, Jordan warned, allowed for “vulnerabilities” that “violent criminal aliens” could exploit in order to enter the US.

In addition to Alvarez, the committee is seeking documentation on six men who were linked to the assault of two NYPD officers in Times Square on Jan. 27.

One of the six, Jhoan Boada, 22, was already “exonerated” in that case after an investigation revealed he had been misidentified.

The committee is also demanding information on Renzo Mendoza Montes, who was arrested in February for allegedly raping a teen girl in Virginia, and Carlos Obed Yepez-Bedoya, who was on the terror watchlist when he was nabbed at Eagle Pass, Texas, in March.

The DHS did not immediately respond to The Post’s request for a comment on the subpoena.

In February, the House voted 214-213 to pass two articles of impeachment against Mayorkas on charges of “willful and systemic refusal to comply” with federal immigration law and lying to Congress about the border being “secure.”

https://nypost.com/2024/06/28/us-news/mayorkas-must-give-docs-on-illegal-migrants-accused-of-heinous-crimes-house-subpoena/