January 2020 Regulatory Updates

Join us at weekly Journal Club meetings and connect with students, faculty and staff of Regulatory Science Program. Read the latest Regulatory Updates January 2020. For general information on Education Initiatives, click hereHighlight posted on February 1st, 2020


Lokelma Approved in China for Adult Patients with Hyperkalaemia

The China National Medical Products Administration (NMPA) approved AstraZeneca’s Lokelma (sodium zirconium cyclosilicate) for treatment of adult patients with elevated levels of potassium in their blood. The approval was based on results of four studies in which patients receiving Lokelma experienced a significant reduction of their blood potassium level. The drug is approved in the U.S., Canada and the E.U. for treatment of hyperkalaemia. It is undergoing regulatory review in Japan, with a decision expected in the first half of 2020.

Ibrance Given National Institute for Health and Care Excellence (NICE) Green Light for Breast Cancer

Pfizer has announced approval of Ibrance (palbociclib) by the United Kingdom National Institute for Health and Care Excellence (NICE). The potentially life-extending drug will now be available for patients with hormone receptor-positive, human epidermal growth factor receptor 2 (HER2)-negative, advanced breast cancer, who have already undergone endocrine therapy. Ibrance, which will be available on the Cancer Drugs Fund in combination with fulvestrant, joins two other NICE-approved drugs – Kisqali (ribociclib) and Verzenios (abemaciclib) – as an option at this stage of the treatment pathway. Pfizer says that because of the approval, the treatment could be an option for up to 3,300 women who have already had endocrine treatment and where exemestane plus everolimus would be the most appropriate alternative to a CDK 4/6 inhibitor.

U.S. FDA Approves Blueprint’s Therapy for Rare Type of Stomach Cancer

The oral drug, Ayvakit, by Blueprint, is the first treatment approved by the U.S. Food and Drug Administration (FDA) for a small subset of patients with a mutation of gastrointestinal stromal tumor (GIST) cancer. Blueprint is also pursuing FDA approval for use of Ayvakit in patients in advanced stages of GIST who have exhausted all other options of care – a much larger population of patients. According to the company, Ayvakit is having significant impact on shrinking patient tumors and keeping them disease progression free for very long periods of time. GIST patients who have undergone surgery are typically given Novartis AG’s Gleevec for twelve months in an effort to delay the spread or recurrence of cancer. However, the drug has not been effective in treating patients with the mutation targeted by Ayvakit.

FDA Warns of Potential Cancer Risk with Weight Loss Drug

The U.S. Food and Drug Administration (FDA) on Tuesday alerted the public to results from a clinical trial that showed a possible increased risk of cancer with Eisai’s weight management drug Belviq (lorcaserin), including the extended release version. The cause of the cancer is unclear, and the FDA cannot conclude if lorcaserin contributes to the cancer risk. The FDA wanted to make the public aware of the concern and will continue to evaluate the clinical trial results.

Celgene Backs Out of $55 Million Revlimid Settlement

Celgene has backed out of a class-action lawsuit in the U.S. District Court for New Jersey that alleges that it illegally blocked generic versions of Revlimidcancer treatments by refusing to sell samples to generic manufacturers and fraudulently obtaining patents to obstruct generic competition and filing litigation against generic drugmakers to stop their proposed generics from reaching market. The decision leaves Celgene to deal with more than 9,000 plaintiffs.

FDA Offers Q&As on Submission of Initial Pediatric Study Plans (iPSPs) for Cancer Drugs

The U.S. Food and Drug Administration (FDA) released a  draft document, the form of questions and answers (Q&As), discussing everything from when an Initial Pediatric Study Plans (iPSPs) for cancer drugs are required, to when an iPSP can be abbreviated for sponsors seeking a waiver, to whether sponsors of combination drugs need to submit separate iPSPs for each of the drugs in the combination.

On or after 18 August 2020, the Q&A says sponsors of original or supplemental applications seeking a full waiver of pediatric studies for cancer drugs containing a new active ingredient, including for products directed at a molecular target included on FDA’s list of ”Non-Relevant Molecular Targets which Warrant Waiver”, should also submit an abbreviated iPSP as described in the 2016 draft guidance. Even for products whose marketing applications are likely to be submitted before August 18, 2020, FDA recommends submission of an iPSP and early discussion with the agency prior to application submission which may facilitate the development of studies to ensure that all relevant Pediatric Research Equity Act requirements are met.

FDA to Allow Online Submissions of Orphan Designation Requests

The U.S. Food and Drug Administration (FDA) announced that later this year it will move from a paper-based process to a new cloud-based online submission portal for orphan drug designation requests. The Orphan Drug Technology Modernization effort will allow for a more connected information technology system, advanced analytics, and improvements in facilitating knowledge management. In addition, it will provide external sponsors with more efficient submission of documents and enhanced direct communication with the FDA.

EU-China Working Group to Address API Manufacturing Concerns

The China National Medical Products Administration (NMPA) has agreed to work with the European Commission Directorate-General for Health and Food Safety, European Medicines Agency (EMA) and others to identify common ground between China and E.U. regulatory systems for active pharmaceutical ingredient (APIs). The European Commission says it has conducted a gap analysis, which would be used to identify Chinese training needs in the API space. E.U. experts will also conduct a fact-finding visit to China to assess the regulatory, control and enforcement system governing implementation of Good Manufacturing Practice standards. The commission also says it has contacted the U.S. Food and Drug Administration (FDA) for a project on a joint training plan for inspectors from India and China of API manufacturing sites. Information on recent inspection trainings in China and India were requested by EMA, FDA, Japanese Ministry of Health & Welfare and the World Health Organization.

Quality Systems
FDA Recognizes New Version of ISO 14971

The newly revised International Organization for Standardization (ISO) risk management standard for medical devices, ISO 14971:2019, are wide ranging, covering topics such as anesthesiology, biocompatibility, materials, physical medicine, radiology, software and sterility. As for the transition to ISO 14971:2019, the U.S. Food and Drug Administration (FDA) announced it will still accept declarations of conformity to the previous version, ISO 14971:2007, in support of premarket submissions until 25 December 2022.

MAPP Further Explains FDA Process for Reviewing REMS Assessment Reports

The U.S. Food and Drug Administration (FDA) last month offered a new Manual of Policies and Procedures (MAPP), effective 18 December 2019, to explain how the Center for Drug Evaluation and Research (CDER) reviews risk evaluation and mitigation strategy (REMS) assessment reports submitted to the agency.

Clinical Decision Support (CDS) Software: Stakeholders Seek More Clarity from FDA Draft Guidance

The U.S. Food and Drug Administration (FDA) released clarification on the categories of CDS software subject to agency oversight, as well as low-risk categories of CDS software for which FDA does not intend to enforce regulatory requirements and CDS categories that do not meet the definition of a device. It remains unclear what regulatory recommendations should be considered when using CDS that is not 510K cleared in a clinical trial and when the use is for a critical or serious condition


Gilead Claims Truvada Patents in HHS Complaint are Invalid

The U.S. Department of Health and Human Services (HHS) took the rare step of filing a complaint against Gilead for infringing on government-owned patents related to the HIV drug Truvada for pre-exposure prophylaxis (PrEP). The HHS complaint explained how Gilead had failed to address  that the Centers for Disease Control and Prevention (CDC) “is widely acknowledged as being the first to demonstrate that FTC/tenofovir prodrug regimens are highly effective in preventing HIV infections and resulted in immediate changes to large human trials related to Truvada for PrEP. These trials directly led to FDA approval of that regimen.” Gilead filed its retort, indicating that it does not believe it has infringed on the CDC Truvada patents because they are invalid.

FDA Approves First Treatment Option Specifically for Patients with Epithelioid Sarcoma, a Rare Soft Tissue Cancer

The U.S. Food and Drug Administration (FDA) granted accelerated approval to Tazverik (tazemetostat) for the treatment of adult and pediatric (aged 16 years and older) patients with metastatic or locally advanced epithelioid sarcoma not eligible for complete resection. Tazverik also received an orphan drug designation. In the clinical trial, the overall response rate was 15%, with 1.6% of patients having complete response and 13% having a partial response. Of nine patients that had a response, six patients had a response lasting six months or longer.

Drug-Drug Interactions: FDA Issues Guidance on Clinical, In Vitro Studies

The U.S. Food and Drug Administration (FDA) finalized two guidance recommendations to drugmakers on evaluating potential drug-drug interactions (DDIs) for new drugs through clinical and in vitro testing. The FDA In Vitro Drug Interaction Studies guidance discusses approaches to evaluate the DDI potential of investigational drugs and how those studies can inform clinical DDI studies. In Clinical Drug Interaction Studies, the FDA explains when DDI studies should be conducted and provides recommendations for the design, conduct and interpretation of those studies.

FDA Finalizes 2018 Guidance on Use of Minimal Residual Disease

The U.S. Food and Drug Administration (FDA) finalized guidance to help sponsors planning to use minimal residual disease (MRD) as a biomarker in clinical trials for treating specific hematologic malignancies. The guidance discusses technology that can detect the persistence of malignancy. These technologies measure cell characteristics such as genetic mutations, cell surface markers, or specific DNA gene rearrangements. Depending on the clinical setting, MRD may be used to reflect a patient’s response to treatment or as a prognostic tool to assess a patient’s risk of future relapse.

FDA Issues Guidance on Clinical, In Vitro Studies

The U.S. Food and Drug Administration (FDA) finalized two guidance documents providing recommendations to drug makers on evaluating potential drug-drug interactions (DDIs) for new drugs through clinical and in vitro testing. The two final guidance describe a systematic risk-based approach to evaluation and communication of DDIs. Additionally, the guidance discusses different DDI study designs and considerations for prospective DDI studies.

CMA Pins Down Tiofarma for Illegal Market Sharing

The U.K. Competition and Markets Authority (CMA) provisionally found that three drug firms – Aspen, Amilco and Tiofarma – signed an illegal agreement that resulted in significant price hikes for an essential medicine. The drug in question – fludrocortisone – is a life-saving medicine that thousands of patients rely on to treat adrenal insufficiency, commonly known as Addison’s Disease. The CMA announced that it alleges, and provisionally found, that the agreement between Aspen, Tiofarma and Amilco contributed to the price of fludrocortisone acetate tablets supplied to the National Health Service increasing by up to 1800%. Tiofarma has agreed to pay a maximum fine of £186,000 if there is a formal final decision that the law has been broken. However, Amilco has made no admission of liability and so the CMA probe is ongoing.

Sarepta Got a Scathing Rejection from the FDA

The U.S. Food and Drug Administration (FDA) rejected Sarepta’s application for golodirsen. The rejection was scathing, focusing on a number of reported infections related to administration of eteplirsen, another Sarepta drug for Duchenne muscular dystrophy. The FDA called into question the benefit of golodirsen and criticized Sarepta for not running a confirmatory trial required under the terms of approval of eteplirsen. The newly revealed details of the regulatory exchange appear to be raising concerns about the fate of casimersen, a third drug for Duchenne muscular dystrophy, which the company said on January 13, 2020 it had begun to submit for FDA approval on a rolling basis.

Brexit Withdrawal Signed Ahead of UK’s 31 January Departure

Presidents of the European Commission and European Council and U.K. Prime Minister Boris Johnson on 24 January 2020, signed a withdrawal agreement that will see the U.K. continue to follow E.U. rules through the end of the year while seeking a deal for future ties with the E.U. The European Medicines Agency and the European Commission have provided a collection of guidance documents for drugmakers to follow to ensure their products are in compliance, post-Brexit. For the U.K., the Medicines and Healthcare products Regulatory Agency (MHRA) has compiled a set of guidance documents and publications covering drug and medical device regulation in the U.K. in the event that a Brexit deal is not reached. For medical devices and in vitro diagnostics, the current EU directives will still apply to the U.K. via the Medical Devices Regulations 2002 as amended by The Medical Devices (Amendments etc.) (EU Exit) Regulations 2019, which transpose the upcoming E.U. Medical Devices Regulation (MDR) and In Vitro Diagnostic Regulation (IVDR) into U.K. law.

EMA to Use ISO International Format for Reporting Individual Side Effects

The European Medicines Agency announced that starting in June 2022, side effects will need to be submitted to the EudraVigilance safety monitoring system using the individual case safety report (ICSR) format, which provides a common set of data points for adverse drug reactions, adverse events, infections and incidents that can occur from drug administration. The new format will generate higher quality, easier-to-analyze data that “will better support regulatory authorities and companies to detect and address safety issues with medicines and therefore protect patients,” the agency said.

Medical Devices
FDA Warns of Cyber Risks with Certain GE Devices  

The U.S. Food and Drug Administration (FDA) issued a cyber risk warning concerning GE’s Clinical Information Central Stations and Telemetry Servers, which the FDA says are mostly used for displaying information such as a patient’s temperature, heartbeat and blood pressure, as well as monitoring a patient’s status from a central location in a facility, such as a nurse’s workstation. GE said there have been no reported cyberattacks or any reported injuries associated with any of these vulnerabilities. The company also said the devices can continue to be used and hospitals should properly configure the devices’ Mission Critical (MC) and/or Information Exchange (IX) networks to ensure their isolation and prevent hacking.

Quality Systems
FDA Warns N.J. Drugmaker for Subpar Quality Unit

The New Jersey drugmaker Health Pharma USA drew a warning letter from the U.S. Food and Drug Administration (FDA) because an agency inspection of the facility revealed that the quality unit wasn’t making sure that its products met identity, strength, quality and purity requirements. Specifically, the agency called out the drugmaker for shipping products before the quality unit reviewed them, noting one lot of aspirin 81 mg that was shipped before final quality review, and lots of aspirin 81 mg and acetaminophen 325mg were delivered despite incomplete quality testing. The agency also flagged inadequate process validations for aspirin and acetaminophen products, and not routinely performing identity testing for incoming product components.