SQA Regulatory Surveillance Summary | June 2020
By Laurel Hacche and Debra Cortner, SQA Associates
United States Food and Drug Administration (US FDA) Guidances
US FDA is publishing a series of guidances (a total of four) intended to facilitate the advancement and use of systematic approaches to collect and use robust and meaningful patient and caregiver input that can better inform medical product development and regulatory decision-making. The topics and questions that each guidance document will address are described below.
- Guidance 1 discusses sampling methods that could be used when planning a study to collect patient input. It also provides a general overview of the relationship between potential research question(s) and method(s) when deciding from whom to get input (including defining the target population and development of the sampling strategy).
- Guidance 2 will discuss methods for eliciting information from individuals identified in Guidance 1, gathering information about what aspects of symptoms, impacts of their disease, and other issues are important to patients. It will discuss best practices in conducting qualitative research and reference-related resources.
- Guidance 3 will address refining the list of concepts of interest important to patients for measurement. Given that not everything identified as important by patients, caregivers, and clinicians can be addressed by an investigational treatment or be measured, this guidance will address issues related to selecting what to measure in a medical product development program and identification or development of fit-for-purpose Clinical Outcome Assessments (COAs) to assess outcomes of importance to patients.
- Guidance 4 will address topics related to incorporating COAs into endpoints for regulatory decision-making including COA-related endpoint development, defining meaningful within-patient score changes, and collection, analysis, interpretation, and submission of data.
The US FDA has issued a guidance for GMP Considerations for Responding to COVID-19 infections in employees in drug and biological products manufacturing. The guidance provides recommendations to drug and biological product manufacturers, regarding:
- Manufacturing controls to prevent contamination of drugs
- Risk assessment of SARS-CoV-2 as it relates to drug safety or quality
- Continuity of manufacturing operations
This guidance is intended to remain in effect only for the duration of the public health emergency related to COVID-19 declared by the Secretary of Health and Human Services (HHS), effective on 27 January 2020, including any renewals made by the HHS Secretary in accordance with section 319(a)(2) of the Public Health Service Act (PHS Act) (42 U.S.C. 247d(a)(2)). However, the recommendations described in this guidance are expected to assist the US FDA more broadly in its continued efforts to assure the safety and quality of drugs and maintain the drug supply beyond the termination of the COVID-19 public health emergency and reflects the US FDA’s current thinking on this issue. Therefore, within 60 days following the termination of the public health emergency, US FDA intends to revise and replace this guidance with any appropriate changes based on comments received on this guidance and the US FDA’s experience with implementation.
United States Food and Drug Administration (US FDA) Notifications to Consumers and Healthcare Providers
In response to public health and safety concerns about the appropriateness of decontaminating certain respirators, the agency is reissuing certain emergency use authorizations (EUAs) to specify which respirators are appropriate for decontamination. Based on the US FDA’s increased understanding of the performance and design of these respirators, the agency has decided that certain respirators should not be decontaminated for reuse by health care personnel. For example, the FDA has learned from the Centers for Disease Control and Prevention’s (CDC) National Institute for Occupational Safety and Health (NIOSH) testing that authorized respirators manufactured in China may vary in their design and performance. As such, the FDA has determined that the available information does not support the decontamination of these respirators and has accordingly revised the relevant EUAs. In addition, the FDA is also revising relevant EUAs to no longer authorize decontamination or reuse of respirators that have exhalation valves.
The US FDA has advised consumers not to use any hand sanitizer manufactured by Eskbiochem SA de CV in Mexico, due to the potential presence of methanol (wood alcohol), a substance that can be toxic when absorbed through the skin or ingested. FDA has identified the following products manufactured by Eskbiochem:
- All-Clean Hand Sanitizer (NDC: 74589-002-01)
- Esk Biochem Hand Sanitizer (NDC: 74589-007-01)
- CleanCare NoGerm Advanced Hand Sanitizer 75% Alcohol (NDC: 74589-008-04)
- Lavar 70 Gel Hand Sanitizer (NDC: 74589-006-01)
- The Good Gel Antibacterial Gel Hand Sanitizer (NDC: 74589-010-10)
- CleanCare NoGerm Advanced Hand Sanitizer 80% Alcohol (NDC: 74589-005-03)
- CleanCare NoGerm Advanced Hand Sanitizer 75% Alcohol (NDC: 74589-009-01)
- CleanCare NoGerm Advanced Hand Sanitizer 80% Alcohol (NDC: 74589-003-01)
- Saniderm Advanced Hand Sanitizer (NDC: 74589-001-01)
The US FDA tested samples of Lavar Gel and CleanCare NoGerm. Lavar Gel contained 81 percent (v/v) methanol and no ethyl alcohol, and CleanCare No Germ contained 28 percent (v/v) methanol. Methanol is not an acceptable ingredient for hand sanitizers and should not be used due to its toxic effects.
United States Food and Drug Administration (US FDA) Recalls
Endologix, Inc. is recalling the Ovation iX due to risks of liquid polymer leaks during implantation. Previously on 05 August 2018, Endologix, Inc. issued an Important Safety Update to their customers reporting the polymer leaks were due to incorrect use of the device. By issuing the recall on 06 May 2020, Endologix is clarifying that the root cause for most polymer leaks is a material weakness caused during the manufacturing process. The weakened area may gap or open during use, which can cause liquid polymer to leak outside of the device as it is filled. If there is not enough liquid polymer in the device to seal the aneurysm, blood may continue to flow into the aneurysm, requiring additional procedures to properly seal off the aneurysm. Liquid polymer may leak into the patient’s body. This may cause serious health consequences, including severe allergic type reactions, unstable blood pressure, tissue damage (necrosis), organ failure, cardiac arrest, central nervous system problems, and death.
GSK Consumer Healthcare Issues Voluntary Nationwide Recall of Children’s Robitussin® Honey Cough and Chest Congestion DM and Dimetapp® Cold and Cough Due to Dosing Cups Missing Some Graduation Markings, 18 June 2020
GSK Consumer Healthcare is voluntarily recalling to the retail level two lots of Children’s Robitussin® Honey Cough and Chest Congestion DM and one lot of Children’s Dimetapp® Cold and Cough, due to the inclusion of incorrect dosing cups. During the review of the packaging documents for these products, GSK discovered that the dosing cups for the Children’s Robitussin® Honey product are missing the 5 mL and 10 mL graduations, while the dosing cups for the Children’s Dimetapp® product are missing the 10 mL graduation. The dosing cups packaged with both products only have the 20 mL graduation. There is a potential risk of accidental overdose if caregivers dispensing the syrup do not notice the discrepancies between the graduations printed on the dosing cups and the indicated amounts to be administered (as directed in the instructions for use). Children’s Robitussin Honey Cough & Chest Congestion DM contains 10 mg dextromethorphan HBr USP and guaifenesin USP 100 mg per 10 mL, and is labeled for children age four and older, as well as adults. Children’s Dimetapp Cold & Cough contains 2 mg brompheniramine maleate USP, 10 mg dextromethorphan HBr USP, and 5 mg phenylephrine HCl USP per 10 mL, and is labeled for children age six and older, as well as adults. Symptoms of overdose of either product may include any of the following: impaired coordination; brain stimulation causing increase in energy, elevation in blood pressure, heart rate, and respiration; a lack of energy and enthusiasm; severe dizziness or drowsiness; slow heart rate; fainting; psychotic behavior; restlessness; seizure; decreased respiration; nausea; vomiting; constipation; diarrhea; abdominal pain; visual and hearing hallucinations; urinary retention. As of the date of the recall announcement, GSK Consumer Healthcare has not received any adverse events related to these products or consumer complaints regarding the incorrect dosing cups supplied with the product.
United States Food and Drug Administration (US FDA) Warning Letters
The US FDA issued a warning letter to Rapid Equine Solutions, LLC relating to the animal drugs compounded from bulk drug substances. From 22 July 2019 to 09 August 2019, the US FDA conducted an inspection of the company’s compounding pharmacy located at 31a Mount Pleasant Road in Aston, Pennsylvania. The inspection was initiated following the death of three horses that were given an animal drug compounded at this pharmacy. The animal drug was an oral paste containing toltrazuril and pyrimethamine. The US FDA’s inspection revealed that animal drug products compounded by the firm were adulterated and misbranded under the Federal Food, Drug, and Cosmetic Act (FD&C Act). Areas of concern highlighted in the warning letter with respect to adulteration were insanitary conditions and potency issues. With respect to misbranding the warning letter stated that the toltrazuril/pyrimethamine paste drug product, Lot # 20190509-11, with a beyond use date of 05 November 2019, compounded by the firm on 09 May 2019, was misbranded, as the product labeling was false and misleading. Product sample test results indicated that the toltrazuril/pyrimethamine paste drug product was subpotent with respect to toltrazuril and super-potent with respect to pyrimethamine compared to the amounts declared on the label, which makes the labeling false.
The US FDA has issued warning letters to four companies for selling unapproved injectable drug products labeled as homeopathic that can pose serious risks to patient health and violate federal law, as part of the US FDA’s efforts to protect Americans from potentially harmful products that are labeled as homeopathic. The US FDA is particularly concerned about unapproved injectable drug products labeled as homeopathic because they are injected directly into the body, often directly into the bloodstream and bypass some of the body’s key natural defenses against toxins, toxic ingredients and dangerous organisms that can cause serious and life-threatening harm. Additionally, unapproved drugs that claim to cure, treat or prevent serious conditions may cause consumers to delay or stop medical treatments that have been found safe and effective through the FDA review process.
No currently marketed drug products labeled as homeopathic have been approved by the US FDA for any use and the agency cannot assure these drugs meet modern standards for safety, effectiveness and quality. Products labeled as homeopathic can be made from a wide range of substances, including ingredients derived from plants, healthy or diseased animal or human sources, minerals and chemicals, and they can include known poisons or toxins. These drugs are often marketed as natural, safe and effective alternatives to approved prescription and nonprescription products and are widely available in the marketplace. Additionally, the lack of premarket quality review is particularly concerning for injectable drugs, which generally pose a greater risk of harm to users because the route of administration for these products bypasses some of the body’s natural defenses.
The US FDA issued the warning letters to Hevert Pharmaceuticals, LLC; MediNatura, Inc.; 8046255 Canada, Inc., doing business as Viatrexx; and World Health Advanced Technologies, Ltd. The products included in the warning letters are new drugs because they are not generally recognized as safe and effective for their labeled uses, and US FDA has not approved these products.
ANVISA, Brazil Regulations
ANVISA has enacted Resolution RDC 378/2020, authorizing the import, sale and donation of used equipment that are essential in Intensive Care Units (ICU). The measure is already in effect and was adopted taking into account the COVID-19 pandemic. The authorization includes ventilators, vital signs monitors, infusion pumps, oximetry equipment (which measure the level of oxygen in the blood), and capnography equipment (which record the partial pressure of CO2 – carbon dioxide – during the respiratory cycle). The norm is applicable to currently registered products or to products that have had a registration by ANVISA. However, medical equipment whose registration has been canceled due to safety or efficacy problems are not included in the authorization. The regulation is atypical, and temporary, and will be in force until the end of the current national public health emergency situation, as defined by the Ministry of Health.
China Medical Device Regulations
CMDE Announcement Number 16 of 2020 establishes procedures and requirements that provide further standardization of the administrative filing review for registration applications, including the acceptance of corrections. This complements the initial batch of filing review requirements laid out in Announcement Number 42 of 2019, which began trial implementation on 01 September 2019.
CMDE Announcement Number 17 of 2020 stipulates registration withdrawal and re-application procedures for imported medical devices that were submitted for registration as Class II devices, but upon technical review were found to fall into Class III. In such cases, the CMDE will issue a medical device/IVD reagent non-approval document stating the reasons for the non-registration. A copy of this document is required to be included in the documents submitted during the re-application process, along with an explanation of the circumstances leading to the re-application. The application fee already paid for Class II registration will be applied toward re-registration, and the applicant will be required to pay the remainder of the Class III fee.
Therapeutic Goods Administration (TGA), Australia, Medical Device Regulations
Reflecting the challenges identified by the medical devices industry and healthcare professionals as they have focused on the COVID-19 crisis, the Australian Government intends asking the Governor-General in Council to agree to the proposed delay of the commencement of a number of medical device reforms. The delay would also support additional time for the TGA to consult with the medical device industry and health care professionals on guidance material relating to the reforms. The Australian Medical Device Regulations would be amended to delay implementation of the reforms from 25 August 2020 to:
- 25 November 2021 for reclassification of certain devices, including:
- spinal implantable medical devices
- active implantable medical devices
- medical devices that administer medicines or biologicals by inhalation
- medical devices that are substances (or combinations of substances) for introduction into the body
- active medical devices for therapy that include a diagnostic function to significantly determine patient management, and
- medical devices that are intended to be used in direct contact with the heart, the central circulatory system or the central nervous system
- 25 February 2021 for medical device software
- 25 February 2021 for personalized medical devices (including 3D printed devices) and
- 25 November 2021 for systems or procedure packs
Further information about the reforms will continue to be published, with the TGA working closely with stakeholders to identify opportunities for continued consultation on guidance material over the coming months.