What It Means to Be “Breakthrough”: The Story Behind The FDA Designation

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December 15, 2020

What It Means to Be “Breakthrough”: The Story Behind The FDA Designation

FDA’s Breakthrough Therapy Program

CMC Considerations when a Drug Development Project is Assigned Breakthrough Therapy Status

The FDA’s Breakthrough Therapy Program was created by the Food and Drug Administration Safety and Innovation Act (“FDASIA”) that was signed into law, on July 9, 2012. This bill expanded many of the existing governing powers of the FDA but also added one intriguing new provision: the breakthrough therapy (BT) designation, intended to expedite the development and review of drugs for serious or life-threatening conditions. 

The criteria for breakthrough therapy designation requires preliminary clinical evidence that demonstrates the drug may have substantial improvement on at least one clinically significant endpoint over available therapy. FDA’s guidance was highly anticipated, and offers the agency’s interpretation of the breakthrough therapy designation program.

To determine whether the improvement over available therapy is “substantial,” FDA weights the magnitude of the treatment eect and the importance of the observed clinical outcome. Preliminary clinical evidence should show a clear advantage over available therapy.

Potential accelerated clinical development timelines could lead to insufficient time to complete all “traditional” CMC studies for approval and delivery to the patient within the boundaries of completing the clinical development program, for example:

  • May have reduced real time stability for commercial material and need to leverage stability information from development studies
  • Likely to have limited manufacturing experience at commercial scale, which presents the opportunity to leverage life cycle validation principles
  • May need to consider launch with initial commercial supplies from a clinical manufacturing facility with clinical fit-for-purpose formulations and then convert over to a commercial formulation and plant immediately postapproval.
  • The formulation and process could be ready for transfer, but the commercial facility is unavailable or not ready.
  • Limited data sets from which to derive specification acceptance criteria

Some Topics for Discussion with the FDA Relating to Breakthrough Designation

Formulation Development and Bioequivalence – A robust formulation is required to supply patients bioequivalent to the formulation used in the pivotal Phase 2/3 clinical studies.

Present your approach to formulation development. There is good assurance that the commercial scale drug product of this BCS Class 1 drug will be bioequivalent to the formulation used in Phase 2/3 studies. Bioequivalence data are provided in the NDA comparing pilot scale commercial formulation and Phase 2/3 formulation, and additional data are provided during review showing in vitro equivalence of commercial scale and pilot scale batches of commercial formulation.

Shelf Life, Drug Product – A shelf life of at least 18 months of shelf life is needed to maintain small molecule drug product in the supply chain for patient availability given the long lead-time for production and potentially low demand, at least initially.

Initiate the CMC section submission with 12 months data from three laboratory scale batches and six months data from three pilot scale batches of the commercial product packaged in the commercial pack assuming with a commitment to provide additional data during review and normal post approval commitments.

Stress and accelerated studies during development demonstrate that the product is not prone to significant degradation or changes, confirmed by 12 months laboratory scale date. There are also data from stress and accelerated studies showing that there is no impact of scale on drug product chemical, physical and subjective stability. Assuming a rolling submission as proposed, further data could be provided during review.

Storage Period, Drug Substance – A storage period of at least 12 months is required especially for the large molecule drug substance to provide sufficient time to allow compounding into multiple batches of drug product without waste

Non-Standard Stability Package for Phase 2 Formulation Marketing Application – A shelf life of at least 18 months is needed to maintain product in the supply chain for patient availability given the long lead-time for production and potentially low demand, at least initially. A retest date of at least 12 months is required to support smooth progression of drug substance into drug product. At the time of marketing application for the Phase 2 formulation manufactured at the clinical manufacturing site the stability package does not comply with ICH Q1A(R2).

Stability data at time of filing of Phase 2 formulation marketing application:

  • 3 month of 3 batches of drug substance manufactured at pilot scale using commercial synthetic route supported by 12 months from >1 batch manufactured by an earlier synthetic route
  • >12 month from 1 batch of drug product packaged in the clinical pack
  • 6 months from 3 batches of drug product manufactured from an earlier synthetic route packaged in commercial pack
  • 3 months from 3 batches of drug product manufactured using final route synthesis drug substance and packaged in commercial packs available during review

Process Performance and Qualification – Clinical approval overlaps with the execution of the process qualification studies for drug substance and drug product, which for a marketing application results are required in a new drug submission. The product has a long lead-time in production. The production timing is such that to have material available for launch supplies as soon as possible following clinical approval, it will be necessary to utilize the Qualification batches for commercial supply.

  • Submit the available scale-up, comparability and characterization data along with the process protocol with a commitment to provide the data as it becomes available during review and, depending on timing, concurrent with product release. This assumes data meet all requirements under the protocol.
  • Submit drug substance comparability protocol and data, and Qualification protocols for drug substance and drug product in the NDA/BLA. Provide all data for drug substance, which should be completed, during review. For drug product, provide all available data during review.
  • Drug product is proposed for supply to patients using material from Qualification batches complying with protocol criteria

Formulation and Site of Manufacture Change –  The clinical formulation and site of manufacture are not suitable for long term supply to patients.The clinical formulation is fit-for-purpose for Phase 2 clinical studies, which are blinded. It is not viable for long term commercial supply to patients. In order to meet patient needs at the time of proposed clinical approval it is proposed to supply Phase 2 clinical formulation sourced from the clinical manufacturing site. Change to an “improved” formulation to meet patient needs better and to source from a commercial manufacturing site is proposed with the marketing application submitted before approval of the Phase 2 formulation.

File Marketing Application for New Formulation Before Phase 2 Formulation Approved –  It is proposed to file the new formulation and site based on the information given above during review of Phase 2 formulation (for example about one month before expected approval) with the proposal that review of this application is also subject to BT timelines. The benefit would be a more reliable supply of quality product to patients.

This non-standard regulatory process would require much discussion and prior agreement from the agency. There are many points of discussion, however, to take stability and bioavailability of drug product as an example, the following data should be

Site of Manufacture Change, and Commercial Scale-Up and Validation Studies

This CMC scenario is considerably different from a “traditional” submission and would require substantial discussion with the Agency, an example of major differences from the ‘traditional’ approach being: Filing with limited qualification data from pilot scale.

Protocol and study design for Qualification/Validation studies to support a application for pilot scale manufacture requires discussion and agreement with the Agency, potentially on more than one occasion. During these discussions, it would be appropriate to agree studies to support commercial scale manufacture and the timing of the proposed marketing application for commercial scale manufacture.

FDA is stressing that the ability to meet the expedited review goals of the BT pathway will hinge on the sponsor intensifying its upfront chemistry, manufacturing, and control (CMC) coordination and communication internally; with outside contractors involved with drug substance and product manufacturing, testing, and packaging; and with the agency. The Guidance Page explains how the BT pathway fits in with and combines elements of three other programs—fast track, accelerated approval, and priority review—that FDA already had in place to facilitate and expedite the development and review of new drugs and biologics that target unmet medical needs.

The February issue of the AAPS News magazine reviewed some challenges and opportunities for commercial manufacturing readiness in BT programs and the impact of accelerated development for these kinds of products on CMC and good manufacturing practices issues that need to be considered in developing both large-and small-molecule drugs.

Read What It Means to Be “Breakthrough”: Expediting Drug Development—The New FDA Breakthrough Therapy Designation, from the Regulatory Sciences section of AAPS. Then participate in the discussion question below.

Accelerated clinical and safety programs under the BT designation could lead to marketing applications up to two years or more earlier than a more conventional clinical development program. Review of potential CMC development programs required developing a formulation and manufacturing process capable of providing a sufficient reliable supply of product to patients at the time of approval on an indication designated as BT is likely to occur before all “traditional” CMC studies and data sets can be completed. This will require risk-based prioritization of time, resources and materials to accelerate certain activities and provide sufficient data and information to ensure an adequate supply of quality product for patients at the time of approval.

If a drug is designated a breakthrough therapy, will the timeline for bringing a revolutionary drug to market be reduced ?

If a development project generates outstanding clinical data for a serious disease or condition, it is likely that a company or the FDA will request that formal application is made for BT designation. If the development project team considers this a good possibility, the implications on CMC development are significant. For example:

  • BT nomination could give insufficient time to complete all ‘traditional’ CMC studies.
  • BT CMC work for filing should use a risk-based approach to prioritize time, resources and materials to provide data and information to support a BT NDA filing, and to ensure supply of quality product to patients.
  • Given the assumption that CMC is not complete, there is likely to be more post approval activity, for example:
    • More stability data
    • Additional confirmatory validation (process robustness) studies
    • hanges of site, scale of manufacture, raw material supplier – Changes of drug substance synthetic route
    • Change of formulation with supporting bioavailability studies

In conclusion, there is sufficient justification in all the above cases studies to discuss with the Agency filing using more flexible regulatory approaches to provide patients with an exciting new drug based on providing assurance of quality.

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