The ability to facilitate the regeneration of parts of the human body is “no longer the stuff of science fiction” according to FDA Commissioner Scott Gottlieb.[i] According to Commissioner Gottlieb, the cell based therapies and their use in regenerative medicine is one of the most promising fields of science already producing “improbable advances.” At the current early stages of development, deceptive claims from unscrupulous actors risks “jeopardizing the legitimacy and advancement of the entire field.” In order to curb such deception while simultaneously providing a clear and efficient path for product developers, the FDA has recently published a suite of four new guidance documents related to their regenerative medicine policy framework.

These four guidance documents represent a broad policy framework by the FDA building upon the framework put into effect in 2005. In its never ending battle to ensure the safety and efficacy of medical products while simultaneously supporting innovation, the FDA’s new approach will undoubtedly entail additional requirements on those innovators in the regenerative medicine field. It is important to review the guidance documents to ensure compliance with the FDA, but also to take advantage of the various opportunities for approval for those medicines and products that meet certain criteria. For this purpose, below is a brief summary of what the guidance documents include.

As guidance documents, the information provided does not create legally enforceable responsibilities, but rather they provide a glimpse into how the FDA is currently thinking and how the FDA will likely apply the existing laws and regulations that govern regenerative medicine products. Two of the documents are final guidance documents now in effect with the remaining two documents in draft form allowing the public to provide their comments.

Final guidance documents

The first guidance document titled “Same Surgical Procedure Exception under 21 CFR 1271.15(b): Questions and Answers Regarding the Scope of the Exception”[ii] provides clarity on when cell and tissue-based products would be excepted from the current regulations if they are removed from and implanted into the same individual during the same surgical procedure and remain in their original form.

The second guidance document titled “Regulatory Considerations for Human, Cell, Tissues, and Cellular and Tissue-Based Products: Minimal Manipulation and Homologous Use”[iii] clarifies how the FDA interprets the regulatory definitions for “minimal manipulation” and “homologous use.” This guidance is particularly helpful in that these concepts establish the legal threshold for when a particular product is subject to the FDA’s premarket approval requirements. In light of the how this new interpretation will effect manufacturers, healthcare providers, the FDA plans to exercise ‘enforcement discretion’ to those products that do not pose a potential significant safety concern for 36 months.

Draft guidance documents

The first draft guidance document titled “Evaluation of Devices Used with Regenerative Medicine Advanced Therapies”[iv] attempts to clarify how the FDA will evaluate devices referred to as “regenerative medicine advanced therapies” or “RMATs” in accordance with the regenerative medicine provisions in the 21st Century Cures Act. These devices include medical devices used in the recovery, isolation, or delivery of RMATs. It is the goal of the FDA to simplify and streamline the application of the regulatory requirements of RMATs.

The second draft guidance document titled “Expedited Programs for Regenerative Medicine Therapies for Serious Conditions”[v] describes, unsurprisingly, various expedited programs to sponsors of RMATs. In addition, the guidance also describes the new RMAT designation process to be used.

The two draft guidance documents were posted to the Federal Register on November 17, 2017, with a comment period ending February 15, 2018. There is ample time for interested parties to assist the FDA in finalizing the draft guidance documents by submitting a comment by the February 15, 2018, deadline.

These guidance documents may provide new opportunities or new requirements for those operating in the field of regenerative medicines. They should be reviewed to ensure compliance with existing laws and regulations while also looking to take advantage of the programs to accelerate FDA approval.


[i] “Statement from FDA Commissioner Scott Gottlieb, M.D. on FDA’s comprehensive new policy approach to facilitating the development of innovative regenerative medicine products to improve human health” posted November 16, 2017, available at https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm585342.htm; see also, “FDA announces comprehensive regenerative medicine policy framework” posted November 16, 2017, available at https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm585345.htm.

[ii]  Available at https://www.fda.gov/downloads/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/Guidances/Tissue/UCM419926.pdf.

[iii] Available at https://www.fda.gov/downloads/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/Guidances/CellularandGeneTherapy/UCM585403.pdf.

[iv] Available at https://www.fda.gov/downloads/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/Guidances/CellularandGeneTherapy/UCM585417.pdf.

[v] Available at https://www.fda.gov/downloads/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/Guidances/CellularandGeneTherapy/UCM585414.pdf.

This article provides a summary of the draft guidance[1] released by the FDA to assist applicants in determining which one of the abbreviated approval pathways under the Federal Food, Drug and Cosmetic Act (FD&C Act) is appropriate for the submission of a marketing application to the FDA. The draft guidance was released on October 13, 2017, for which comments are due by December 12, 2017.

The guidance expanded on the different pathways for obtaining approval of new drug applications (NDAs) and abbreviated new drug applications (ANDAs), which became available with the passage of the Hatch-Waxman Amendments. In addition, the guidance discussed the regulatory and scientific considerations for determining whether to file an ANDA or a 505(b)(2) Application.

Abbreviated Approval Pathways:

1. Stand-Alone NDA Application:

  • Submitted under section 505(b)(1) and approved under section 505(c) of the FD&C Act and contains “full reports of investigations of safety and effectiveness that were conducted by or for the applicant or for which the applicant has a right of reference or use.”

The guidance did not discuss stand-alone NDAs. It focused on those applications that can be submitted as ANDAs under section 505(j) of the FD&C Act, petitioned ANDAs under 505(j)(2)(c) of the FD&C Act, or NDAs pursuant to section 505(b)(2) of the FD&C Act.

2. 505(b)(2) Application:

  • Submitted under § 505(b)(1) and approved under § 505(c) of the FD&C Act, and contains “full reports of investigations of safety and effectiveness, where at least some of the information required for approval comes from studies not conducted by or for the applicant and for which the applicant has not obtained a right of reference or use.”
  • May rely on the FDA’s safety and/or efficacy findings for a listed drug only to the extent that the proposed product of the 505(b)(2) application shares characteristics in common with the listed drug.
    • NOTE: A drug product in a 505(b)(2) application will not necessarily be treated as bioequivalent or therapeutically equivalent to the listed drug(s) relied upon. The applicant is expected to establish a bridge (e.g., by using comparative bioavailability data) between the proposed drug product and each listed drug that the applicant seeks to rely upon to demonstrate that reliance on the listed drug is scientifically justified.
  • Must include sufficient data to support the differences, to the extent that the listed drug and the proposed § 505(b)(2) drug differ.

3. ANDAs

  • Submitted and approved under section 505(j) of the FD&C Act.
  • Must establish that the proposed generic product (1) is the same as the reference listed drug (RLD) with respect to the active ingredient(s), dosage form, route of administration, strength, previously approved conditions of use, and labeling (with permissible differences), and (2) is bioequivalent to the RLD.
  • May not be submitted if studies are necessary to establish the safety and effectiveness of the proposed product because it relies on FDA’s finding of safety and effectiveness for an RLD.

4. Petitioned ANDAs:

  • Submitted and approved under § 505(j) of the FD&C Act.
  • A type of ANDA for a drug product that differs from the RLD in its dosage form, route of administration, strength, or active ingredient (in a product with more than one active ingredient), and for which, in response to a petition under § 505(j)(2)(c) of the FD&C Act, the FDA has determined that safety and efficacy studies are not necessary for the proposed drug product.

Regulatory Considerations for ANDAs and 505(b)(2) Applications:

1. Duplicates:

  • The FDA generally will refuse a 505(b)(2) application for a drug that is a duplicate of a listed drug and eligible for approval under § 505(j) of the FD&C Act.
    • However, if FDA approves a duplicate product after a § 505(b)(2) application is submitted, but before the § 505(b)(2) application is approved, the 505(b)(2) application would remain eligible for approval.

2. Petitioned ANDAs:

  • An applicant may submit a petition under § 505(j)(2)(c) of the FD&C Act (a suitability petition) to FDA requesting permission to submit an ANDA for a generic drug product that differs from an RLD in its route of administration, dosage form, or strength or that has one different active ingredient in a fixed-combination drug product.
  • A suitability petition will generally be approved unless (1) the FDA determines that the safety and effectiveness of the proposed change from the RLD cannot be adequately evaluated without data from investigations that exceed what may be required for an ANDA, or (2) the petition is for a drug product for which a pharmaceutical equivalent has been approved in an NDA.

3. Bundling:

  • An applicant may seek approval for multiple drug products containing thesame active ingredient(s) when some of these products would qualify for approval under the section 505(j) pathway and some would qualify for approval under the 505(b)(2) pathway.
  • FDA has permitted an applicant to submit a single “bundled” 505(b)(2) application forall such multiple drug products.

Scientific Considerations for ANDAs and § 505(b)(2) Applications:

1. Limited Confirmatory Studies:

  • If the safety or effectiveness of a proposed drug product must be established by investigations, then an ANDA application is not appropriate.
  • However, data from limited confirmatory testing to show that the characteristics that make the proposed drug product different from the listed drug do not alter its safety and effectiveness may be submitted in an ANDA.

2. Active Ingredient Sameness Evaluation:

  • “If the active ingredient in an applicant’s proposed drug product cannot be demonstrated to be the same as the active ingredient in the RLD by using the information and data that may be submitted in connection with an ANDA, the drug product should not be submitted for approval in an ANDA.”
  • In situations where current limitations of scientific understanding and technology may preclude approval of an ANDA with the data permitted for submission in an ANDA, FDA may be able to receive, review and approve ANDAs as the scientific understanding and technology evolve.

3. Intentional Differences Between the Proposed Drug Product and an RLD:

Differences in Formulation:

  • An ANDA must include information regarding the identity and quantity of all active and inactive ingredients of the proposed drug product and a characterization of any permitted differences between the formulations of the proposed drug product and the RLD, along with a justification demonstrating that the safety and effectiveness of the proposed drug product is not adversely affected by these differences. If the proposed drug product contains changes to its formulation that are not permissible in an ANDA, the applicant should consider submitting a 505(b)(2) application.

Differences in Bioequivalence and/or Bioavailability Differences:

  • An ANDA must contain information to show that the proposed drug product is bioequivalent to the RLD, such as (i) the rate and extent of absorption of the proposed drug do not show a significant difference from that of the RLD when administered at the same molar dose of the therapeutic ingredient under similar experimental conditions in either a single dose or multiple doses.
    • NOTE: “[(w]here there is an intentional difference in rate (e.g., in certain extended-release dosage forms), certain pharmaceutical equivalents or alternatives may be considered bioequivalent if there is no significant difference in the extent to which the active ingredient or moiety from each product becomes available at the site of drug action.”
  • An application for a proposed drug product where the rate and/or extent of absorption exceed, or are otherwise different from, the 505(j) standards for bioequivalence may be submitted under the 505(b)(2) pathway and may require studies to show the safety and efficacy of the proposed product at the different rate and/or extent of delivery.  However, the FDA generally will not accept a 505(b)(2) application for a drug product where the only difference from a listed drug is that (1) the extent to, or (2) the rate at, which its active ingredient is absorbed or otherwise made available at the site of action isless than that of the RLD.

Differences in Conditions of Use:

  • A § 505(j) application must include a statement that the conditions of use prescribed, recommended, or suggested in the labeling for the proposed drug product have been previously approved for the RLD. The application cannot be approved as an ANDA if the proposed drug product has added a new indication. However, the FDA will not refuse to approve an ANDA whose proposed labeling excludes conditions of use approved for the RLD because of patents or exclusivity.

4. Other Differences:

  • Drug products that differ considerably from the RLD are generally not candidates for the § 505(j) pathway. In assessing whether differences between a proposed generic drug product and the RLD would necessitate additional data or information to establish the safety or efficacy of the proposed drug product, FDA will examine the individual differences between the products and the combined effects of those differences.

 


[1] https://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM579751.pdf