By Phil Crooker, VP – Technical, Regulatory & Access, Parexel
In what seems like a lifetime ago - back in December 2019 - the U.S. Food and Drug Administration (FDA) published a proposed final rule on the importation of prescription drugs in the Federal Register. You can find a link to the proposed final rule and all the other documents – including public comments – here https://beta.regulations.gov/docket/FDA-2019-N-5711/document.
Despite the incredible resource drain on FDA from COVID-19, the agency has managed to review the extensive public comments (more than 1,000 submissions to the docket) on the proposed final rule and make revisions. On September 24, the FDA published a final rule and a companion guidance document to fulfill a plan for safe importation of certain prescription drugs originally intended for foreign markets. You can find the final rule, guidance document and other background information on the FDA website here - https://www.fda.gov/news-events/press-announcements/fda-takes-actions-help-lower-us-prescription-drug-prices.
Since the final rule is lengthy and the companion guidance document provides the FDA’s interpretation of how to implement the final rule, this blog will focus on unpacking the important points made in the companion Guidance for Industry – Importation of Certain FDA-Approved Human Prescription Drugs, Including Biological Products, and Combination Products under Section 801(d)(1)(B) of the Federal Food, Druga and Cosmetic Act. Interestingly, the guidance is classified as “Pharmaceutical Quality/CMC” but as we’ll see later in the article the FDA recommends that the information to be reviewed by FDA is normally submitted in a labeling supplement.
The guidance outlines a pathway by which manufacturers could obtain a New Drug Code (NDC) for an FDA-approved drug that was originally intended to be marketed in a foreign country and is also authorized for sale in that country. These drugs are called “multi-market approved products” or “MMA products” by the FDA. It also describes the recommended procedures for submitting information to demonstrate that the drug being offered for import, although originally intended for marketing in a foreign country, is in fact an FDA-approved drug and meets the required specifications in the approved New Drug Application (NDA) or Biologics License Application (BLA).
There is a trilogy of sections that contain the most critical information in the guidance document – (1) Quality attributes and labeling that a product would need to meet to be considered an MMA product; (2) the submission of a supplement for an MMA product; and (3) the manufacturer’s authorization. The FDA didn’t use its “bulleted” approach in writing this guidance, so I’ll unpack the elements of each of these sections so they can be readily digested.
Description and Labeling of An MMA Product
These are the criteria that FDA will use to determine if a drug or biologic is considered to be an MMA product:
- Originally manufactured outside the U.S. and is authorized for marketing by another country’s regulatory authority.
- A supplemental application has been submitted to an approved NDA or BLA with all the information recommended in the guidance.
- Is imported into the U.S. and authorized by the manufacturer to be sold in the U.S.
- Meets the quality standards in the approved application for sale in the U.S. (note - the guidance does not define the scope of quality standards but it appears to be very broad including all information contained in an executed master batch record in addition to specifications for input materials, intermediates, components and finished drug substance and drug product).
- Continues to meet the quality standards for marketing in the originally intended market(s).
- The only difference from the FDA-approved drug or FDA-licensed biological product are the labeling appearance and statements recommended in the guidance.
The FDA laid out several very specific criteria that it will use to determine that the MMA is a drug product approved by the FDA. An MMA drug product should:
- Use the same formulation, manufacturing process and specifications for active ingredients and drug product as the Chemistry, Manufacturing and Controls (CMC) section of the approved NDA.
- Conforms to the specifications in the approved NDA, including quality of active ingredients, drug products, intermediates, raw materials, reagents, components, in-process materials, container-closure system and other materials used in the production of the drug.
- Continue to have the same appearance as the FDA-approved drug product.
- Be manufactured, packaged, labeled and tested at the facility(ies) approved in the NDA, including specific production lines and quality systems.
The FDA included very similar criteria for a biological or combination MAA product.
Any MMA product must have the FDA-approved labeling. The FDA made specific recommendations that the container label and carton or package labeling of an MMA product bear features that allow the MMA product to be easily distinguishable from non-MMA products. These include:
- Narrow, transparent colored stripe (yellow is recommended) horizontally printed on the top half of the container label and carton or package label.
- Container label and carton or package labeling should prominently display with the stripe the statement – “Imported following the procedures recommended in FDA Guidance; see [current link to this guidance on FDA.gov].”
Submission of a Supplement for an MMA Product
The FDA recommends that an applicant seeking to market an MMA product submit a supplement, generally a labeling supplement, to an approved NDA or BLA under 21 C.F.R. § 314.70 or 601.12(f). The agency states that the information outlined in the guidance is not appropriate to be submitted in an Annual Report. The guidance does not otherwise specify the classification of the supplement – whether a Prior Approval Supplement or Changes Being Effected Supplement.
Before outlining the information that is expected to be included in the supplement, the FDA recommends that certain information is provided by attestation and that the information in the supplement should be known to the applicant (emphasis added). This raises two questions: (1) what is an attestation; and (2) what is required for information to be known by the applicant?
- In its simplest form, an attestation is affirming that the information is true or genuine. The guidance did not indicate that it needs to be accompanied by signature of a witness for authentication.
- By making a specific point that the information should be known to the applicant, it appears that the FDA is distinguishing actual knowledge from either constructive or implied knowledge. In a recent case that involved retirement plans (albeit a different context than food and drug law), the Supreme Court defined actual knowledge. In its decision, the court the Court cited regular and legal dictionary definitions indicating that “actual knowledge” means something that an individual is actually aware of and is distinct from imputed or presumed knowledge. To have “actual knowledge” of a piece of information, a party must in fact be aware of it. The Court distinguished between “actual knowledge” versus hypothetical knowledge a reasonably diligent party would know from reviewing information from suppliers of services. The Court held that “actual knowledge” requires more than disclosing all relevant information; the party to whom the information is disclosed must in fact have become aware of that information. Intel Corp. Inv. Policy Comm. v. Sulyma, 2020 WL 908881 (U.S. 2020). This section has implications for how information is exchanged between the applicant holders and all its suppliers involved in the supply chain for the MMA product.
In the NDA supplement seeking to change the FDA-approved labeling for an MMA product, FDA recommends that the following information is submitted.
- Demonstration that the product originally intended for sale in another country is the FDA-approved product and is manufactured in accordance with the FDA-approved NDA, with the exception of the limited labeling differences discussed in the guidance.
- Establish that the composition of the drug product, as well as the entirety of the manufacturing process, from active pharmaceutical ingredient through finished product, meets all of the specifications in the CMC section in the NDA for the FDA-approved drug product and any applicable Drug Master File (DMF).
- An executed batch record, including a Certificate of Analysis (COA), for at least one commercial scale batch of the MMA product produced using each of the intended manufacturing line(s).
- For comparative purposes, an executed batch record, including a Certificate of Analysis (COA), for at least one recently manufactured commercial scale batch produced and released for distribution to the U.S. market.
- Evaluate and address the potential impact of shipping conditions, including holding and warehousing, necessary to import the MMA product, on the safety, efficacy, and quality of the MMA product – with a particular emphasis on product stability. Supporting data can be referenced in the approved application or provided in the supplement.
- An attestation in the cover letter stating the following information:
- The drug product has not left the control of the applicant prior to or during the manufacturing, labeling, packaging and testing operations.
- The MMA product has the active ingredient(s), active ingredient source (including manufacturing facility(ies), inactive ingredients, dosage form, strength(s), route(s) of administration, and device constituent part(s) as applicable described in the NDA.
- Information specifying the non-U.S. regulatory authority that has authorized the drug product for marketing in a non-U.S. jurisdiction.
- Commitment that the MMA product will continue to meet the quality standards for marketing in its originally intended market.
- The MMA product conforms to the information described in the approved application regarding the quality of active ingredients, drug products, intermediates, raw materials, reagents, components, in-process materials, container-closure systems and other materials used in the production of the drug.
- The MMA product, including the device constituent part(s) (as applicable) is manufactured, packaged, labeled and tested at the facility(ies) approved in the NDA – including specific site(s), production lines and quality system(s).
Very similar information was also included for BLA supplements. When discussing the executed batch records for biological products though, the guidance specifically mentions that the batch record should contain all relevant information regarding the manufacturing process and controls to support the demonstration that the batches of MMA product intended for importation are the FDA-licensed biological product (emphasis added).
Manufacturer Authorization for MMA Products
Any shipment of a purported MMA product that is offered for importation would be subject to refusal (“import alert”) unless the manufacturer has authorized the MMA product to be marketed in the U.S. The guidance notes that it is essential that FDA is provided the information needed to confirm that each shipment offered for importation has been authorized for marketing in the U.S. and is not counterfeit (emphasis added).
The FDA strongly encourages applicants to submit a report using the Electronic Submissions Gateway (ESG) to notify the agency of the importation of an MMA product 10 days in advance of the first import entry of the product. The report should be referenced and placed in Module 1 of the Electronic Common Technical Document (eCTD) of the approved application and include the following information:
- The MMA product name.
- The dosage form.
- The quantity of MMA product (note: the guidance does not specify to use the number of lots or total number of dosage units).
- The name, address, and telephone number of the authorized importer.
- Any temporal or other limitations the manufacturer has placed on the authorized importer, such as multiple shipments for a specified period of time.
In addition to these specific recommendations, the guidance wouldn’t be complete without reminding industry that any MMA product cannot be lawfully imported if it is in violation of the Food, Drug and Cosmetic Act (FDCA) for adulteration and misbranding. Since any MMA product cannot receive marketing approval without submission and approval of a supplemental application, the FDA can use its discretion to schedule CGMP inspections at any of the facilities identified in the approved marketing application as part of the review and approval process.
The guidance document does an admirable job in navigating regulated industry through a pathway to market an MMA product based on a long and complex final rule. This may be a mechanism that helps lower the cost of prescription drugs in the U.S. in the long run. Industry should recognize that the regulatory process is not trivial and has several components that need to work in alignment, increases the scope of FDA review and situations which could result in a product failing to meet the MMA criteria (such as the regulatory status of the product in its original foreign market(s)), it will rely in large measure on actual knowledge of the applicant with its heightened level of due diligence, and sets up a very narrow window for marketing an MMA product. The execution and results of the program will be interesting to follow in the coming years.
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