FDA Regulatory and Compliance Monthly Recap – March 2020

• FDA to accelerate access to potential COVID-19 treatments, issues guidance documents on clinical trials, adverse event reporting pandemic 
• OPDP issues first warning letter of 2020 to Outlook Pharmaceuticals for misleading sponsored ad on Google, failure to present established name
• FDA issues final guidance on BPCIA transition, final rule defining biological product
• FDA finalizes guidance on criteria, device eligibility for 510(k) Third Party Review Program

FDA to accelerate access to potential COVID-19 treatments, issues guidance documents on clinical trials, adverse event reporting pandemic 

The FDA has taken several steps to respond to the COVID-19 pandemic, including efforts to accelerate access to potential treatments and limit import requirements for certain medical devices. The agency has also published guidance to help sponsors navigate the impacts of the pandemic on clinical trials and to update postmarket adverse event reporting during the pandemic.

As the COVID-19 pandemic forces lockdowns and a litany of government responses across the U.S., President Donald Trump said the FDA will look to expedite access to potential treatments. Speaking alongside FDA Commissioner Stephen Hahn, Trump cited the FDA’s Right-to-Try law and discussed potential treatments such as chloroquine, which is approved for the treatment of malaria, and Gilead’s experimental antiviral remdesivir, which has been used on a compassionate use basis in the U.S. Hahn noted that unlike trials using Right-to-Try, compassionate use permits the agency to immediately collect information on experimental treatments to make decisions about safety and effectiveness. Hahn added that large clinical trials may be needed to ascertain whether the use of chloroquine can be expanded to COVID-19. He also said the agency has provided assistance on a treatment called convalescent plasma, which is derived from people who have recovered from the virus. 

Separately, the FDA eased import requirements for certain medical devices and increased the availability of personal protective equipment. The agency has also lessened laboratory testing and imaging requirements for certain drugs with risk evaluation and mitigation strategies that include elements to ensure safe use that mandate such measures. The FDA said it will not take enforcement action against sponsors that don’t adhere to testing or imaging requirements that may be challenging to conduct during the pandemic. 

To help industry navigate the impacts of COVID-19, the FDA also published guidance to address how sponsors can assure the safety of trial participants, maintain compliance with good clinical practice and reduce the risks to trial integrity during the pandemic. The agency acknowledges that protocol adjustments may be required and there may be unavoidable protocol deviations as a result of the pandemic. The guidance directs sponsors and clinical investigators to engage institutional review boards (IRBs) or independent ethics committees as early as possible when urgent or emergent adjustments to the protocol or informed consent are anticipated. The guidance also indicates, however, that changes to the protocol or investigational plan to reduce or eliminate immediate risks or to protect the life and well-being of participants may be implemented without IRB approval or before filing any amendments to the Investigational New Drug (IND) application or Investigational Device Exemption  (IDE). The guidance also directs sponsors and clinical investigators to document how COVID 19-related limitations led to modifications in study conduct, along with the duration of those changes. The FDA is also encouraging sponsors to consider alternative methods for safety assessments in the face of challenges in getting prospective patients to trial sites, including phone contact or virtual visits. 

The FDA also published final guidance outlining its approach to enforcing adverse event (AE) reporting requirements for drugs, biologics, medical devices, combination products and dietary supplements during pandemics. The guidance acknowledges that widespread illness will impact the industry’s typical functions and directs manufacturers to develop continuity of operations plans. As FDA and industry workforces are impacted by the pandemic and AE reporting increases because of the widespread use of medical products indicated to treat COVID-19, the guidance indicates that the FDA does not intend to object if firms do not submit certain required AE reports within the time frames mandated by statute and regulation. However, firms must submit any delayed reports within six months of restoring the AE reporting processes to pre-pandemic states.

The FDA is implementing guidance documents related to the pandemic without prior public participation. However, it will continue to solicit and review comments and will revise the guidance documents as appropriate. Updates on the FDA’s ongoing response to COVID-19 can be found here. 

OPDP issues first warning letter of 2020 to Outlook Pharmaceuticals for misleading sponsored ad on Google, failure to present established name

The letter raises concerns about a link sponsored by Outlook Pharmaceuticals on Google for its attention deficit disorder treatment ProCentra. The sponsored link contains claims that may appeal to parents as desirable for a pediatric drug, without disclosing risk information. It also criticizes the ad for not presenting the established name alongside the proprietary name. 

In its first warning letter of 2020, the FDA’s Office of Prescription Drug Promotion (OPDP) reprimanded Outlook Pharmaceuticals over a false or misleading sponsored link on Google for its attention deficit disorder treatment, ProCentra. The FDA’s review of the sponsored link, triggered by several complaints filed under the Bad Ad Program, found it presented information about the benefits of the treatment without disclosing any risk information, though the drug is a Schedule II controlled substance, it is associated with a number of serious risks, and it is subject to a boxed warning regarding abuse potential. 

The FDA explains that determining whether an ad is misleading involves not only examining the representations or suggestions made but also the failure to disclose material facts in light of those representations or with respect to consequences that may result from the use of a drug as recommended or suggested. The warning letter cites claims on the sponsored link directing viewers to “Explore your ADHD medication options for your child,” but it fails to disclose any information about the potential adverse events from using the treatment. The failure to disclose risk information creates a misleading impression of the drug’s safety, which the FDA notes is particularly concerning given that the ad uses claims that may appeal to parents as desirable properties for a pediatric drug, such as “liquid treatment option” and “bubblegum flavor.” The FDA also deemed ProCentra to be misbranded, as the sponsored link fails to present the established name of the drug prominently and in direct conjunction with the proprietary name. 

The warning letter directs Outlook to immediately stop distributing the violative material and/or stop introducing the misbranded product to the market. The FDA requests that Outlook provide a list of all promotional material for the drug that may contain similar statements, along with a plan for discontinuing use of the violative material and a plan to disseminate truthful, nonmisleading and complete corrective messages. The OPDP recommends the corrective messaging include a description of the violative material and any information to correct each violative message, without promotional claims or representations. 

FDA issues final guidance on BPCIA transition, final rule defining biological product

The FDA published a final rule updating its definition of “biological product” ahead of the transition under the BPCIA of certain biological products from NDAs to BLAs. Separately, the agency published final guidance on its implementation of the transition, outlining its compliance policy for the labeling of biologicals that are the subject of deemed BLAs. 

Ahead of the transition of applications for certain biological products to be deemed to be licensed as biologics under the Biologics Price Competition and Innovation Act of 2009 (BPCIA), the FDA issued a final rule updating its definition of “biological product.” Under the so-called transition provision of the BPCIA, effective March 23, an approved marketing application for a biological product under section 505 of the Federal Food, Drug, and Cosmetic Act (FDCA) must be considered a license for the biological product (i.e., an approved biologics license application [BLA]) under section 351 of the Public Health Services Act (PHSA). As of March 23, approximately 100 products approved under new drug applications (NDAs) have transitioned to BLAs, opening them up to biosimilar competition.

The final rule brings the agency’s definition of “biological product” in line with the statutory definition established by the BPCIA, as amended by the Further Consolidated Appropriations Act, 2020 (FCA). Under BPCIA, the definition of “biological product” was amended to include a “protein (except any chemically synthesized polypeptide).” The FCA further updated the definition by removing the exception for chemically synthesized polypeptide. As such, the final rule amends the FDA’s regulations to codify the agency’s interpretation of the statutory term “protein” to reduce regulatory uncertainty about whether products are regulated as drugs or biologicals. The FDA says it is applying scientific expertise to interpret the term in a manner that creates a “scientifically reasonable bright-line rule” that offers clarity and facilitates BPCIA implementation. The agency maintains that such a bright-line approach will allow the FDA and industry to avoid spending time and resources on case-by-case determinations for each product. Per the rule, the term protein means “any alpha amino acid polymer with a specific defined sequence that is greater than 40 amino acids in size.” 

The FDA also published a final Q&A guidance to address common concerns about the transition and outline its compliance policy for the labeling of biologicals that are the subject of deemed BLAs. Per the guidance, the prescription or OTC status of a biological with an approved application under section 505 of the FDCA will not change when the application is deemed to be a license for the biological product under section 351 of the PHSA. The guidance makes clear that the holder of an approved application does not need to take any affirmative steps for the NDA to be deemed a BLA. It also indicates that the FDA plans to assign the same application number used for the approved NDA to the deemed BLA, which will be considered 351(a) BLAs and not 351(k) BLAs. Every establishment listed in an approved NDA as involved in the manufacture of a biological product as of the transition date will be considered a licensed establishment. The agency does not plan to carry out pre-license inspections of manufacturers of the transitioning products, as they would have been inspected in connection with the previously approved NDAs. 

The guidance outlines how the FDA will use its enforcement discretion to reduce the burden of labeling changes on application holders and mitigate potential disruptions. The FDA does not intend to object to the labeling of a deemed BLA product that does not conform to certain labeling requirements until March 23, 2025, so long as it complies with other applicable labeling requirements. This will provide the application holders with time to revise the product labeling to conform to requirements under section 351 of the PHSA. Per the guidance, the FDA recommends that deemed BLA holders submit a prior approval supplement with proposed revised product labeling between March 23, 2020, and March 23, 2022. Under the PHSA, each “package” of a biological product must be plainly marked with the proper name of the biological and information on the manufacturer. Per the guidance, “package” means the “immediate carton, receptacle, or wrapper, including all labeling matter therein and thereon, and the contents of the one or more enclosed containers. If no package, as defined in the preceding sentence, is used, the container shall be deemed to be the package.” 

According to the FDA, the transition will allow for the submission and approval of marketing applications for new biosimilar or interchangeable products. Commissioner Stephen Hahn said the transition opens “new pathways for manufacturers to bring biosimilar and interchangeable versions of insulin and other transitioning products to market, facilitating greater competition in the marketplace.” The finalized Q&A guidance notes that a biological approved in an NDA that is deemed licensed under 351(a) of the PHSA may be a reference for a 351(k) BLA. Any person, including the holder of a deemed BLA, may seek a determination of biosimilarity or interchangeability under section 351(k). The FDA said it plans to work with applicants to address scientific or regulatory issues emerging in the context of such development programs.

FDA finalizes guidance on criteria, device eligibility for 510(k) Third Party Review Program

The guidance describes the FDA’s process and criteria for determining whether different types of devices are eligible for its 510(k) Third Party Review Program and outlines how third-party review organizations are recognized. The guidance reflects the FDA’s mandate under Medical Device User Fee Amendments of 2017 (MDUFA IV) to eliminate the need for routine, substantive re-review by the agency by ensuring the quality of work done by third-party organizations. 

The FDA published final guidance outlining how third-party review organizations are recognized under its 510(k) Third Party Review Program (3P510k) (formally known as the Accredited Persons Program) and describing the factors it will consider in determining whether different types of devices are eligible for third-party review. The guidance is meant to ensure the quality of work done by 3P510k review organizations as part of the agency’s mandate under MDUFA IV “to eliminate the need for routine, substantive re-review by FDA.” The program was implemented in an effort to enable the FDA to center its internal scientific review resources on high-risk and complex devices while providing a voluntary alternative review process that may provide quicker decisions on 510(k)s for manufacturers. 

The guidance outlines six criteria that will be considered when determining the types of Class I and II devices eligible for third-party review:

1. The risk of the device type, which is based on the risks associated with the device and whether general controls are adequate to provide a reasonable assurance of the safety and effectiveness of the devices or whether there is enough information to establish controls to mitigate such risks. Class III devices are ineligible for the program. 
2. Whether the device type is intended to be permanently implanted or is meant to sustain or support human life. 
3. The degree to which the device type is well understood. 
4. The degree to which the information needed to make a well-informed recommendation is available to third-party review organizations. In instances where information pertinent to assessing the device is proprietary and cannot be shared outside the FDA, the device may be ineligible for the program. 
5. The extent to which the review of the device type would necessitate “multifaceted, interdisciplinary expertise.” For instance, cases in which consultation across different FDA organizational components is required may be ineligible for the program. Similarly, if a device type raises novel cross-labeling considerations, such as the potential for off-label use of drugs (e.g., syringes), the device may be ineligible for third-party review. 
6. The availability of postmarket data indicating that the device type is the subject of safety signals, such as safety communications or high-risk recalls. 

The guidance notes that if a device type is considered eligible for the program but a modification to the device type for a specific submission raises different concerns, the submission may be deemed ineligible. 

Per the FDA, a third-party review organization must be an independent organization that is not controlled or owned by a manufacturer, supplier or vendor of devices. Similarly, it may not engage in the design, manufacture, promotion or sale of devices. The FDA also expects that third-party review organizations will be impartial and “free from any commercial, financial, and other pressures that might present a conflict of interest or an appearance of a conflict of interest.” The agency also recommends that third-party review organizations not participate in the preparation of 510(k)s if involved in 510(k) reviews and not use individuals who were employed by the 510(k) submitters in the past 12 months to review a submission. The guidance cautions against third-party review organizations promising or advertising guarantees for FDA clearance. 

The guidance stressed the importance of using guidance from the International Medical Device Regulators Forum, particularly criteria from the Medical Device Single Audit Program (MDSAP) and Good Regulatory Review Practices (GRRP) on reviewer competence, training and conduct. The FDA notes that there are many shared elements between its statutory and regulatory criteria for 3P510k review organizations and MDSAP guidance and GRRP guidance. As such, the FDA believes that potential third-party review organizations in compliance with those guidance documents are likely to be in compliance with most FDA requirements. Such organizations can use existing documents in their applications to the FDA and for ongoing record-keeping rather than having to generate new documentation for the FDA.