Pharma/Biotech – USA, Europe Regulatory News, March 2023 Vol. 1

US

FDA Offers Advice on Macular Degeneration Drug Trials

The FDA outlined drug trial options for developers of neovascular age-related macular degeneration drugs in a newly published draft guidance. The 8-page draft  which includes recommendations on trial eligibility criteria, efficacy endpoints and trial design considerations  recommends that sponsors consider parallel-group, double-masked trials randomized by patient that aim to show the investigational drug group’s superiority over the control group. Sponsors can also consider an alternative trial approach that uses the same design but shows the investigational drug’s noninferiority to either ranibizumab injection given intravitreally every four weeks, or to aflibercept given intravitreally either every four weeks or eight weeks (after three monthly injections), the agency says.

FDA issues guidance on drug development for neovascular age-related AMD

The US Food and Drug Administration (FDA) has issued draft guidance for industry on the development of drugs to treat neovascular or “wet” age-related macular degeneration, an eye disorder that can lead to blindness. The draft guidance, issued on 24 February 2023, offers the agency’s recommendations for clinical trials of drugs and biologics, including eligibility criteria, trial design and efficacy endpoints. The document was developed jointly by the FDA’s Center for Drug Evaluation and Research (CDER) and the Center for Biologics Evaluation and Research (CBER).

ICH to adopt final guideline on drug interaction studies early next year

The pharmaceutical industry would like to get more clarity on the timing of drug-drug interaction (DDI) studies and the scope of these DDI studies in their comments to regulators on the proposed International Council for Harmonization’s (ICH) M12 guideline, said a regulator at an ICH regional meeting sponsored by the US Food and Drug Administration (FDA) and Health Canada on 24 February. Rajanikanth Madabushi, associate director for guidance and scientific policy at FDA’s Office of Pharmacology, and a member of the M12 working group, provided an update on the status of the revision at the meeting. The objective of the guideline, which was released last year for public comment, is to promote a consistent approach in designing and conducting DDI studies during the development of a new therapeutic product, said Madabushi.

FDA plans to launch communications pilot for promising rare disease gene therapies

The head of the US Food and Drug Administration’s (FDA) biologics center said the agency will soon launch a pilot to apply the lessons it learned from the COVID-19 pandemic to accelerate development of certain gene therapies for rare diseases. Peter Marks, director of the Center for Biologics Evaluation and Research (CBER), said his office is trying to find ways to accommodate companies who are developing treatments for rare diseases. One of the ways they are trying to help companies is by giving promising rare disease gene therapy developers a chance to increase interactions with the FDA during the development phase.

FDA inspections will start looking at DSCSA compliance

Pharmaceutical manufacturers and their trading partners should ensure their distribution systems fully adhere to the Drug Supply Chain Security Act (DSCSA), as once the law takes full effect this November, the US Food and Drug Administration (FDA) will begin inspecting firms to verify their compliance, asserted Howard Sklamberg, a partner at Arnold & Porter. He outlined what FDA will be looking for in inspections at a 22 February webinar sponsored by the Food and Drug Law Institute (FDLI). Sklamberg was the director of FDA’s Office of Compliance in 2013, when DSCSA was enacted.

Industry groups call for changes in ICH M11 guideline on harmonized protocols

In comments to the US Food and Drug Administration (FDA), pharmaceutical industry groups called for revisions to the International Council for Harmonisation’s (ICH) M11 guidance establishing a harmonized template for clinical trial protocols. The groups said the document should be revised to broaden the definition of a protocol, recommended that the use of estimands be justified in the protocol and include more examples of real-world data (RWD). The guidance also includes a template for the format called the “Clinical Electronic Structured Harmonized Protocol (CeSHarP), as well as a set of specifications.

Researchers Urge FDA to Quickly Withdraw Accelerated Approvals After Negative Trial Data

The FDA should move more quickly to withdraw its approval of drugs granted Accelerated Approval (AA) when negative confirmatory trial data emerge, said members of a research team that studied cancer patients treated with AA drugs.

HHS prioritizing FDA labeling, DTC advertising, and compounded drug rules

The US Department of Health and Human Services (HHS) on Tuesday published a list of regulations its agencies will prioritize over the coming year. It includes several rules that the Food and Drug Administration (FDA) will work on to address issues such as patient labeling, conduct of clinical trials and drug compounding. On 22 February, HHS published its semiannual regulatory agenda, which included a number of rules either under development or set to be finalized by FDA, as well as a timetable for expected completion. Notably, several of the rules, including a rule on medication guides, have been listed in the regulatory agenda for multiple years.

FDA details ANDA PSG meetings under GDUFA III

The US Food and Drug Administration (FDA) last week issued draft guidance that details its thinking on conducting product-specific guidance (PSG) meetings with generic drugmakers. The document is meant to reflect the agency’s commitment to increased communication under the latest generic drug user fee deal. Almost five months after the Generic Drug User Fee Amendments (GDUFA III) were signed into law, FDA has published another guidance that addresses performance goals negotiated with industry. The draft guidance details the agency’s performance goals and how it plans to engage sponsors. The guidance also sheds light on how regulators will determine the right types of meeting depending on the stage of the sponsors application and how it will address issues such as rescheduling meetings.

Stakeholders want clarity from FDA on circumstances for delaying or limiting inspections

The Advanced Medical Technology Association (AdvaMed) and ophthalmology product maker Alcon urged the US Food and Drug Administration (FDA) to allow manufacturers more latitude in being able to delay or limit inspections before deeming products adulterated. They also urged FDA to clarify what constitutes a reasonable explanation for delaying, denying or refusing an inspection. These comments were in response to FDA’s revised draft guidance issued in December 2022 on circumstances for delaying, denying or limiting an inspection. Under current FDA guidance, only drugs can be adulterated if FDA inspectors are barred the door. The draft guidance aligns with an update in the law under the FDA Reauthorization Act (FDARA), which requires devices to be deemed adulterated and refused entry for firms that block FDA inspections. FDA Offers Advice on Neovascular Age-Related Macular Degeneration Drug Trials.

OPQ touts progress on quality management maturity, KASA in annual report

The US Food and Drug Administration’s (FDA) Office of Pharmaceutical Quality (OPQ) reported that progress has been made over the past year in advancing its quality management maturity initiative and in its quality assessment review process in its 2022 annual report. The report also describes progress made in other areas under OPQ’s remit. The office’s previous two reports focused largely on its COVID-19 response. The agency addressed some of the progress that has been made in its quality management maturity (QMM) initiative, which aims to measure the strength of facilities’ quality practices. FDA said it concluded two QMM pilots in February 2022 to develop such benchmarks for domestic finished dosage form manufacturers and international active pharmaceutical ingredient manufacturers.

FDA Spells Out Its Commitments on Product-Specific Guidance Meetings

The FDA has released new details for companies preparing to submit an abbreviated new drug application (ANDA) on how to request meetings relating to a new or revised product-specific guidance (PSG) that may impact their application. PSGs describe the FDA’s current thinking on the evidence needed to demonstrate that an ANDA is therapeutically equivalent to a specific reference product. In a 23-page draft guidance, the agency offered updated timeframes and procedures for requesting PSG teleconferences as well as presubmission and postsubmission meetings.

FDA May Ask Congress for Expanded Authority Over Opioids

The FDA is considering asking Congress for enhanced authority over opioid approvals and marketing to ensure that new products offer “material safety advantages” over existing approved opioid analgesics.

HHS Pilots Will Explore Ways to Lower Drug Prices

HHS has proposed three pilot programs designed to make therapeutics more affordable for Medicare and Medicaid beneficiaries. The three model programs address prescription drugs, cellular and gene therapies, and drugs developed through the Accelerated Approval pathway. The Medicare High-Value Drug List Model would create a standardized list similar to those offered by many large retail pharmacy chains but be tailored for Part D beneficiaries and plans. The Cell and Gene Therapy Access Model would establish a partnership between the Centers for Medicare and Medicaid Services (CMS), manufacturers, and state Medicaid agencies and would tie payment to clinical outcomes.

OPQ Conducts More Remote Preapproval Inspections in 2022

Despite continuing pandemic conditions, the FDA’s Office of Pharmaceutical Quality (OPQ) was able to conduct 65 on-site pre-license inspections in 18 countries in 2022 up from 47 in 2021 and used remote regulatory assessments to gather information needed to move forward on 85 more submissions, according to OPQ’s just-released annual report.

One-Fifth of Drugs Approved in U.S. Were Rejected Elsewhere, Study Shows

More than one-fifth of the new drugs approved by the FDA from 2017 through 2020 were either refused marketing authorization or not recommended for reimbursement in Australia, Canada, or the UK due to unfavorable benefit-to-risk profiles, uncertain clinical benefit or unacceptably high price.

FDA Adds New Product-Specific Guidances, Reopens Comment Period

The FDA has reopened the comment period for 29 new product-specific draft guidances and 22 revised draft guidances for complex and non-complex generic drug products, with a new deadline for comments of April 18. The agency has also issued 15 new draft product-specific guidances, which include sirolimus and sotorasib, and six revised draft product-specific guidances for drug products such as hydroxyurea and mirabegron. The deadline for comments of these new and revised draft product-specific guidances is also April 18.

CMS Will Require Drug makers to Pay if Price Hikes Exceed Inflation

Newly released federal guidance details how the government will punish drug companies who hike prices faster than the rate of inflation for some prescription Medicare medicines. Administered by the Centers for Medicare and Medicaid Services (CMS), the Medicare Prescription Drug Inflation Rebate Program requires drug companies to pay Medicare a rebate if they raise their prices for certain Part B and Part D drugs faster than the rate of inflation. CMS will calculate the rebate and the money will be deposited in a supplementary medical insurance trust fund. For Part D drugs, rebates would be retroactive to Oct. 1, 2022. For Part B drugs, the price tracking began on Jan. 1.

FDA On Track With PDUFA VII Goals Centered on DHT-Related Submissions

By the end of March, the Center for Drug Evaluation and Research (CDER)’s Office of Strategic Programs (OSP) will have met its first Prescription Drug User Fee Act (PDUFA) VII goal: enhancing internal systems review of digital health technology (DHT)-related submissions enabling the agency to better receive and digest submissions that contain reams of data from, for example, wearable devices.

FDA Calls for Long-Term Safety Studies in Neonatal Product Development

The FDA highlighted the need for long-term neurodevelopmental studies by sponsors of neonatal medical products — whether a drug, biologic product or device in a new draft guidance released Friday.

Drug makers Seek Clarification of Draft Guidance on Bioequivalence

Drug makers have asked for several clarifications in the draft guidance the agency released in December on the use of statistical approaches in bioequivalence (BE) studies.

FDA Issues Draft Guidance on Externally Controlled Trials

The FDA says trial sponsors and investigators may use patient-level data from other trials and/or real-world data (RWD) sources as an external control arm in a new draft guidance.

FDA Updates Policy Manual on Voluntary Withdrawal of Approved ANDAs

The FDA has updated its Manual of Policies and Procedures (MAPP) concerning receiving and processing a request for voluntary withdrawal of an approved abbreviated new drug application (ANDA) to reflect the current procedures in the Office of Generic Drugs (OGD).The revision of the original Oct. 4, 2017 document was done to include minor clarifications and explain the current process regarding the information that is sent in an ANDA withdrawal request acknowledgment letter. Until a withdrawal of approval of an ANDA is effective, the ANDA holder must comply with post-approval reporting requirements and payment of any required fees, the agency said.

FDA Seeks Comments on ICH Draft Guideline on Bioequivalence Testing for Solid Oral Drugs

The FDA has asked for feedback on an International Council for Harmonization (ICH) draft guideline on bioequivalence (BE) studies for immediate-release solid oral drugs.

Extrapolation used in more than half of pediatric drug labeling changes

Some form of data extrapolation – either full or partial – was used in making more than 63% of pediatric labeling changes in the United States between 2015 and 2021, according to a new analysis. The findings, which were published in the Journal of Biopharmaceutical Statistics, revealed that the use of extrapolation increased the rates of new and expanded pediatric indications during the study period. “Extrapolation is a key tool in pediatric drug development to systematically identify the knowledge gap between the reference population and target population, therefore, to limit the number of pediatric studies and the number of children recruited to each to fill the knowledge gap, along with an ethical argument of not randomizing children to placebo unnecessarily,” wrote Jingjing Ye of BeiGene and colleagues at Servier Pharmaceuticals, UCB Pharma, Flatiron Health, St. Jude Children’s Research Hospital, GlaxoSmithKline, and Pfizer.

EU

EMA Clarifies Its Policy on Biosimilar Interchangeability

The European Medicines Agency’s (EMA) policy on the interchangeability of biosimilars relates only to the active substance and formulated product, the agency said in a clarifying statement. Referring to an EMA policy statement issued last fall about biosimilar interchangeability, the agency noted that the statement “does not include potential issues related to the handling of different administration devices,” such as the need for patient training when using a new device, or “physician or patient perception of biosimilars.” “As for any biological medicinal product, traceability should also be ensured for biosimilars to allow for proper root cause analyses in case adverse drug reactions occur,” the clarifying statement said.

UK government orders review of commercial clinical trials landscape

Against a backdrop of falling investment in commercial clinical trials, the UK government will undertake an independent review under Lord James O’Shaughnessy to find and clear potential barriers. Data collated by pharma trade group ABPI show the number of industry clinical trials initiated in the UK has fallen each year since 2017, the year after the vote to leave the European Union. The steepest fall in activity happened during the pandemic years. By 2021, the number of clinical trials initiated by the drug industry had fallen to 394, down from 667 in 2017. Declines affected all therapeutic areas, with oncology study starts dropping most dramatically, from 234 in 2017 to 139 in 2021. Research on cardiometabolic and immune diseases is down too.

Transparency, transition period addressed in new EMA Q&A guidance on CTR implementation

The European Medicines Agency (EMA) has issued a guidance in a question-and-answer format to assist sponsors in navigating the Clinical Trials Regulation (CTR) and the new clinical trials information system (CTIS) portal. Use of the CTIS became mandatory on 31 January. The Q&A was developed by EMA’s Query Management Working Group (QMWG) to clarify some areas of ambiguity raised by stakeholders, which included the Association of Clinical Research Organizations (ACRO), the European Federation of Pharmaceutical Industries and Associations (EFPIA), the European Confederation of Pharmaceutical Entrepreneurs (EUCOPE) and the European Clinical Research Organization Federation (EUCROF).

European Parliament votes to extend MDR transition period

The European Parliament on Thursday voted overwhelmingly to extend the Medical Devices Regulation (MDR) transition periods to avoid a shortage of life-saving products in the economic region. The vote also supported nixing the sell-off date provision for existing products specified in the MDR and In Vitro Diagnostic Medical Devices Regulation (IVDR). In a 537-3 vote, with 24 abstentions, the European Parliament adopted a proposal by the European Commission to delay the transition period due to concerns about device supply, notified body capacity and manufacturer preparedness. The vote was taken by Katarina Barley, vice president of the European Parliament, and the parliamentarians decided to move forward with the vote without a discussion due to the urgent nature of the legislation.