In our previous post, we outlined the dangers of Cytokine Release Syndrome (CRS) and the importance of preclinical Cytokine Release Assays (CRAs) when developing monoclonal antibodies (mAbs) that interact with the patient’s immune system. In this second post, we describe the different kinds of assays in use and how these may fit into your drug development program. An alternative type of CRA, peripheral blood mononuclear cell (PBMC) blood outgrowth endothelial cell (BOEC) co-culture, will be discussed in more detail in our next blog post.Continue reading
What is a cytokine storm?
Cytokine Release Syndrome (CRS), otherwise known as cytokine storm, is a systemic inflammatory response caused by complications due to disease, infection or an adverse effect of biologic therapy. The clinical symptoms of a cytokine storm are massive release of a potent cocktail of pro-inflammatory cytokines into the general circulatory system, leading to severe multi-organ damage, failure or potentially death. This is an extremely unwanted immunotoxicological side effect in drug development.Continue reading
The SEND [Standard for Exchange of Nonclinical Data] Implementation Guide v3.1, “SEND 3.1,” changes the model for the reporting of cardiovascular and respiratory endpoints.
SEND 3.1 became effective 15 March 2019 for NDA/BLA submissions; and it will become effective 15 March 2020 for IND submissions, overlapping with the effective period of the previous version, SEND 3.0. (See chart below.)
Chart 1. SEND 3.0 and 3.1 roll-outs.
Some additional regulatory considerations during this transition period include:
- The SEND version required for your submission is determined by the study start date (aka protocol finalization date).
- If you are including non-GLP studies in a regulatory submission, a SEND dataset is also required.
- If you have legacy studies in your submission, an abbreviated TS file (Trial Summary file) is required for each one.
Drug abuse and potential drug abuse are critical issues for today’s pharmaceutical industry and the health of patients. Understanding the latest FDA regulatory requirements, different study types, relevant timelines and logistics can be challenging. Conducted at a critical stage of drug development, the assessment for drug abuse potential is complex and must be acceptable to regulators.
If a drug or its major metabolite penetrates the brain, then an abuse potential assessment is required, regardless of the therapeutic indication.
Developing a strategy around relevant timelines
The doses for drug abuse testing are selected based on the exposure/plasma levels produced in humans by the highest therapeutic dose. Therefore, drug abuse studies are not recommended until the human therapeutic dose range has been determined; however, your testing strategy should begin much earlier. Continue reading
The immune system is the body’s main defense against foreign materials and biologic agents such as bacteria, viruses, chemicals, and foreign cells and tissues. The immune response includes specific action of lymphocytes (one type of white blood cell) and is facilitated by other white blood cells, including neutrophils, monocytes, macrophages, eosinophils and basophils. The immune system can be viewed as a system controlled by negative feedback, meaning that normally it must reduce the effects of disturbance or invaders through self-regulation. Continue reading
Each assessment for abuse liability is as unique as the molecule in question, reiterating the importance of early awareness, understanding the current regulatory landscape, and being able to plan your development and post-marketing accordingly.
In our previous blog post, we focused on the value of early drug abuse potential testing. In this blog, we’ll delve into important regulatory and market access considerations for abuse liability testing that can help drug developers maximize the potential of their molecule.
Assessment of abuse potential of compounds in development is one of the most complex regulatory requirements and constitutes a critical exercise for sponsors and regulators. The strategy for the assessment of abuse potential cannot be customized and requires individual evaluation of the compound, its target indication and the entirety of the nonclinical and clinical safety database. In July 2016, the United States Congress passed the Comprehensive Addiction and Recovery Act (CARA) bill to address prescription opioid abuse and overdoses that have killed more than 165,000 people between 1999 and 20141.
Given this increased spotlight and focus on preventing opioid abuse and deaths in the US and abroad, it has become more critical than ever to better understand the abuse liability potential of a drug as early as possible in the development process. As part of the overall assessment of drug safety for a New Drug Application (NDA) in the United States or a Market Authorization Application (MAA) outside the United States, drug abuse potential testing is required – regardless of indication – on any drug that is active in the brain. This encompasses all properties of the drug (e.g., chemical, pharmacological, pharmacokinetic, clinical safety, etc.).
In the first of a two-part blog, we share important early considerations for abuse liability testing to help drug developers test the abuse potential of their molecule and better understand their path to viability in this changing landscape.
There’s no denying that studies are only as strong as their resulting data—and nonclinical studies produce a lot of data. A two-week study can easily generate more than 2 million results, while a two-year study can contain upward of 500 million data points. In an effort to process and easily interpret these massive data files, the FDA has developed SEND (Standard for Exchange of Nonclinical Data).
While it’s easy to think of SEND as another obstacle, it’s actually an opportunity to reveal new insights and gain efficiencies in data management. Exchanging information in a standard format can ease knowledge transfer between internal and external databases, as well as provide a common framework to support a more robust submission process. Coupled with the emergence of new tools for visualization and statistical analyses, SEND has the power to revolutionize the way data drive drug development decision making. Continue reading