Heated intraperitoneal chemotherapy (HIPEC) has several potential benefits. Higher doses of chemotherapy can be used with HIPEC because the plasma-peritoneal barrier results in little absorption into the blood stream. HIPEC offers higher peritoneal penetration in comparison to an intravenous (IV) regimen and does not have the traditional normothermic intraperitoneal (IP) regimen limitation of post-operative adhesions. Hyperthermia itself has cytotoxic effects and can potentiate antineoplastic effects of chemotherapy in part by increasing the depth of tumor penetration by up to 3 mm. For the treatment of ovarian cancer, HIPEC has been evaluated in the recurrent setting with secondary cytoreduction. Recent studies, including a prospective trial, have evaluated its role in primary management of ovarian cancer. This review summarizes previous and ongoing studies regarding the use of HIPEC in the management of ovarian cancer.
Risk-Based Predictive Stability (RBPS) tools, such as the Accelerated Stability Assessment Program (ASAP) and other models, are used routinely within pharmaceutical development to quickly assess stability characteristics, especially to understand mechanisms of degradation. These modeling tools provide stability insights within weeks that could take months or years to understand using long-term stability conditions only. Despite their usefulness, the knowledge gained through these tools are not as broadly used to support regulatory filing strategies. This paper aims to communicate how industry has used RBPS data to support regulatory submissions and discuss the regulatory feedback that was received.
In this paper, we remind readers of several ICH guideline documents such as ICH Q3A, Q3B, Q3C, Q3D, Q6A, Q6B, M7, and ICH S9 which are related to the drug substance and drug product impurity limit setting. In particular, ICH Q6A clearly states that "specifications should focus on those characteristics found to be useful in ensuring the safety and efficacy of the drug substance and drug product"; however, recent negotiations between health authority and applicants (company) related to proposed marketing applications show that on a global level, batch experience, even when limited, plays an overwhelming role in developing impurity acceptance criteria rather than clinical relevance. The drawback of such practice and the great need to establish patient centric specifications (PCS) are highlighted. Secondly, this paper proposes approaches on how to establish patient centric criteria for drug substance and drug product impurity limits based on the principles outlined in ICH guideline documents and scientific literature. Three case studies are presented to illustrate the challenges in establishing PCS and the divergence of regulatory acceptance to such specifications. We propose some approaches that can be considered for specification setting based on clinical relevance in the drug development, registration and post-approval phases of a product life-cycle. Lastly, we give thoughts on the future perspective of this movement and offer recommendations to foster discussions between regulatory agencies and pharmaceutical industry on getting medicinal products that are safe and effective to the patient sooner to meet unmet medical needs without supply interruption concerns.
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