RE:RE:Keytruda+Chemo neoadjuvant in early ER+/HER2- breast cancerSpecific terms and phrases are defined as follows:
• The phrase early-stage breast cancer refers to invasive breast cancer without distant metastases
• The phrase high-risk refers to patients with early-stage breast cancer who continue to have a high risk of distant disease recurrence and death despite use of optimal modern local and systemic adjuvant therapy
• The terms neoadjuvant and preoperative are used interchangeably to refer to systemic therapy that is given before lumpectomy or mastectomy to reduce the risk of breast cancer recurrence
• The term clinical benefit in an early-stage breast cancer population refers to a clinically meaningful and statistically significant improvement in event-free survival (EFS), disease-free survival (DFS), or overall survival (OS)
The Accelerated Approval Program
The FDA’s accelerated approval program is intended to facilitate development of drugs for treatment of a serious or life-threatening disease that provide meaningful therapeutic benefit over available therapy. We recognize that, despite advances in adjuvant systemic therapy of breast cancer over the past few decades, there remains a significant unmet medical need for certain high-risk or poor prognosis subsets of early-stage breast cancer patients. Consideration of pCR as an acceptable study endpoint for accelerated approval in the neoadjuvant setting may encourage industry innovation and expedite the development of novel therapies to treat high-risk early-stage breast cancer.
Section 506(c) of the Federal Food, Drug, and Cosmetic Act (FD&C Act), 21 U.S.C. 356(b), as amended by the Food and Drug Administration Safety and Innovation Act of 2012, provides that:
The FDA may grant accelerated approval “. . . upon a determination that the product has an effect on a surrogate endpoint that is reasonably likely to predict clinical benefit, or on a clinical endpoint that can be measured earlier than an effect on irreversible morbidity or mortality, that is reasonably likely to predict an effect on irreversible morbidity or mortality or other clinical benefit, taking into account the severity, rarity, or prevalence of the condition and the availability or lack of alternative treatments.”
The FDA acknowledges that important regulatory questions persist regarding use of pCR to support accelerated approval in high-risk early-stage breast cancer. A trial-level relationship between improvement in pCR and improvement in long-term outcome has not been established. If such a relationship exists, it is unknown whether the necessary magnitude of improvement in pCR will differ according to breast cancer subtype or drug class. Hence, we recommend that sponsors pursuing a neoadjuvant indication meet early with the FDA to discuss their plans for designing a neoadjuvant trial in the context of a robust breast cancer drug development program. These discussions should include a justification for the proposed magnitude of improvement in pCR rate and long-term outcome, additional trials that would provide supporting evidence of clinical benefit in breast cancer, and the anticipated safety database to support the drug’s use in a curative intent setting.
https://www.fda.gov/media/83507/download#:~:text=Pathological%20complete%20response%20(pCR)%20is,completion%20of%20neoadjuvant%20systemic%20therapy