As Jan. 1, 2021, draws closer, the U.K.’s Medicines and Healthcare Products Regulatory Agency (MHRA) is trying to help drug and device companies prepare for the end of the Brexit transition period as the U.K. separates itself from the EU.

The move will enable the U.K. to “offer fully independent regulatory decisions for both devices and pharmaceuticals, both nationally and in joint work with other international regulators,” according to the MHRA. But it will mean a lot of changes. Thus, the agency has been churning out numerous guidances on how it will proceed come Jan. 1. The latest batch, issued Oct. 27, consists of the following guidances:

  • a note on new assessment routes, including the prioritization of new medicines, an accelerated assessment procedure, and a rolling review for novel drugs and biologics, as well as biosimilars;
  • variations to marketing authorizations (MAs);
  • procedures for U.K. pediatric investigation plans (PIPs), the process for applying for a waiver and details for applicants that had an EU-PIP in place before 2021;
  • pharmacovigilance procedures.

Some of the guidances are intended to simplify processes. For instance, the MHRA said it would offer an expedited PIP assessment where possible and mirror the submission format and terminology of the EU-PIP system. That will keep the scientific content and assessment in line with EMA guidance.

However, geographic differences in the U.K. could add some complexity to new drug and device regulations. While the MHRA will retain responsibility for pharmacovigilance across the U.K., some requirements will differ in Northern Ireland, which, in general, will align with EU pharmacovigilance, pediatric and other EMA requirements. Meanwhile, Great Britain – including England, Scotland and Wales – will follow the new MHRA requirements.

Beginning Jan. 1, holders of marketing authorizations for drugs in Great Britain will be required to submit pharmacovigilance data to the MHRA, including U.K. and non-U.K. individual case safety reports, periodic safety update reports, risk management plans, and post-authorization safety study protocols and final study reports. Subsequent pharmacovigilance decisions will be made reflecting U.K. clinical practice, the MHRA said.

The agency noted that the EMA’s Good Vigilance Practices modules will remain in force in the U.K., but the MHRA plans to publish a note on the exceptions and modifications it is making to that guidance.

FDA clarifies terms for generics

As part of its Drug Competition Action Plan, the FDA finalized its 2017 draft guidance “Referencing approved drug products in abbreviated new drug application (ANDA) submissions.”

Intended to clear up past confusion over the meaning of “reference listed drug” (RLD), “reference standard” and “basis of submission,” the guidance explains the terms and clarifies the differences among them. In addition, the guidance advises on accurately using the terms in an ANDA, requesting FDA designation of an RLD and requesting the FDA to select a reference standard.

The agency’s Center for Drug Evaluation and Research acknowledged that because of the past confusion regarding use of the terms, previously issued guidance may not use the terms as they are defined in the Oct. 27 guidance.

The final guidance also clarifies references to approved drugs that appear on the “Discontinued Drug Product List” and the FDA’s identification of certain reference standards as RLDs in its Orange Book.

FDA to hold public meeting on DSCSA

The FDA’s Drug Supply Chain Security Act (DSCSA) Pilot Project Program will be the topic of conversation at a virtual public meeting to be held Dec. 8 and 9.

Part of the Drug Quality and Security Act signed into law in November 2013, the DSCSA outlined critical steps for building an electronic, interoperable track-and-trace system by 2023 to enhance the FDA’s ability to detect and remove potentially dangerous drugs – including those that are counterfeit, diverted, stolen or intentionally adulterated – from the U.S. supply chain.

The meeting also will give members of the biopharma distribution supply chain and other stakeholders an opportunity to provide input on strategies and issues related to the enhanced drug distribution security provisions of the law, according to a notice set for publication in the Oct. 28 Federal Register.

Other items to be discussed are the system attributes necessary for enabling secure tracing of drugs at the package level. Such attributes would include interoperability among trading partners, the FDA and other federal or state officials; enhanced product tracing activities involving the secure exchange of data; the use of aggregation and inference for product tracing or verification; and enhanced verification activities.

Written comments on the pilot project and enhanced drug distribution security should be submitted to Docket No. FDA-2020-N-1862 by Dec. 27.

Russia updates COVID-19 guidelines

The Russian Ministry of Health this week updated its guidelines for COVID-19 prevention, diagnosis and treatment.

The ninth version of the guidelines contains what the ministry called important changes related to diagnostics and the treatment of patients on an outpatient basis. For instance, it includes new treatment regimens making it possible to not only treat individuals with a mild infection on an outpatient basis, but also to treat adults with moderate disease severity without risk factors as outpatients.

First Circuit: Prescriber’s perk indeed a kickback

In a decision replete with sarcasm and wordplay, the U.S. Court of Appeals for the First Circuit last week upheld a New Hampshire jury verdict against Christopher Clough, a physician assistant at a pain management clinic, who was convicted of taking kickbacks through a speaker’s program for prescribing Insys Therapeutics Inc.’s Subsys, an expensive potent fentanyl-based spray.

In appealing the verdict, which resulted in a four-year prison sentence and an order to pay $700,000 in restitution, Clough claimed the government introduced insufficient evidence to support his conviction and that the district court failed to instruct the jury about the Anti-Kickback Statute's personal services safe harbor provision.

“Clough concedes that the Insys speaker program was an illegal scheme designed to incentivize physicians and providers to prescribe Subsys. He just contends he kept free from the taint,” Judge Ojetta Rogeriee Thompson wrote in the unanimous decision for the appeals court.

However, according to the court, Insys paid Clough nearly $50,000 for participating in an average of one speaker program per week from September 2013 to October 2014, even though no other providers showed up for most of those dinners. To make it look like the payments were within the personal services safe harbor, Clough gave an Insys sales rep the names of providers, mostly his colleagues, and then forged their signatures on a sign-in sheet for the dinners.

The appeals court described Clough as “one of the country's top-five prescribers of Subsys,” who meted “out Subsys to an increasing number of patients in increasing dosages, sometimes without ever informing his patients of the prescription or the substantial risks associated with the drug, let alone telling them about his financial interest in the success of Subsys.” As a result, Medicare paid about $2.1 million for a portion of the Subsys prescriptions Clough wrote.

Companies warned for documentation, FAR violations

The FDA posted warning letters Oct. 27 for a KVK-Tech Inc. facility in Newtown, Pa., and Shilpa Medicare Ltd.’s manufacturing plant in Polepally, India.

The letter to KVK-Tech noted that the company was suspending manufacturing at the facility and pointed out that similar violations had been cited at KVK-Tech’s other facilities. “These repeated failures at multiple sites demonstrate that management oversight and control over the manufacture of drugs is inadequate,” the FDA said.

Problems cited in the letter included failure to validate the processes used to clean nondedicated packaging equipment and documentation issues. For example, employees failed to record the actual readings for the air pressure for several pieces of packaging equipment.

In another instance, the cleaning validation sample for oxybutynin chloride tablets was documented as being received about five hours after the chromatographic analysis for the sample was documented as being completed.

The letter to Shilpa cited the company’s failure to conduct adequate out-of-specification and complaint investigations in several instances for sterile injectables and solid dosage drugs.

The FDA also took the company to task for its handling of oral and written complaints about its drugs and its failure to comply with field alert reporting (FAR) requirements. Under FAR, drug companies are required to notify the FDA within three working days of receiving a complaint concerning bacteriological contamination, or any significant chemical, physical or other change or deterioration in a distributed drug.

The letter referenced eight customer complaints, between December 2017 and December 2018, that were related to particles found in vials from different batches. In each instance, Shilpa determined an initial FAR was not required.