1“Integrated risk assessment” is the concept of cardiovascular safety evaluation

Dr. Miyazaki, thank you for the opportunity today! Let me begin by asking about the very basics. In what context has the evaluation of the cardiovascular system been considered important in drug development?

In the 1990s, a lethal arrhythmia, “Torsade de Pointes,” caused by the antihistamine Terfenadine, was reported in the West. It turned out that several other non-antiarrhythmic drugs were also found to have QT-prolonging effects, which were considered to be the cause of lethal arrhythmias. These drugs were withdrawn from the market one-by-one. From then on, the accurate assessment of the presence or absence of proarrhythmic effect has been an important issue in drug development. In response to this necessity, study methods have become more sophisticated, and in 1997, CPMP* released “Points to Consider” regarding the evaluation of potential QT prolongation associated with non-antiarrhythmic drugs. Test systems to evaluate QT prolongation have proactively been discussed. In Japan, “QT PRODACT,” a joint research project, was launched by the Japan Pharmaceutical Manufacturers Association (JPMA) and the Japan Association of Contract Laboratories for Safety Evaluation (JACL). Fundamental data were collected for guidelines. In 2005, the non-clinical guideline, ICH**-S7B***, and the clinical guideline, ICH-E14****, were established jointly by the regulatory authorities of Japan, the US and Europe. S7B complements the safety pharmacological study guideline S7A agreed upon in 2000.

* CPMP: Committee of European Agency for Proprietary Medicinal Products, ** ICH: International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use, *** S7B: The Non-clinical Evaluation of the Potential for Delayed Ventricular Repolarization (QT Interval Prolongation) by Human Pharmaceuticals, **** E14: Clinical Evaluation of QT/QTc Interval Prolongation and Proarrhythmic Potential for Non-antiarrhythmic Drugs

How do you actually perform these tests?

Generally, blood pressure, heart rate and electrocardiogram, which are evaluation items designated by the S7A guideline, and risk of QT prolongation designated by S7B, are concurrently assessed in the same study using a telemetry system*. In vitro studies are independently performed. However, the results of the in vitro study are indispensable in in vivo study design and the evaluation of the results.

* Telemetry system: a computerized system that analyzes vital signs such as electrocardiogram, blood pressure, heart rate, respiratory rate and body temperature, which are obtained over a long period via a sensor implanted into the body of an unrestrained animal

I see. The result of in vitro studies is also taken into account in the evaluation.

That’s right. As described in the S7B guideline, the risk of QT prolongation should be assessed not only in a single study. It is important to evaluate the risks comprehensively based on in vitro, in vivo, and clinical data, which is called “integrated risk assessment.” We comprehensively perform assessment based on not only safety pharmacology studies, but also the findings obtained from structures of compounds and the results of toxicity studies.
* Citation from ICH S7B guideline

Were any changes made to this guideline recently?

Yes. E14 stipulates that non-clinical data may decrease the necessity of clinical QT studies, but no consensus was reached on how to use non-clinical data for clinical QT study design and interpretation of data. S7B also recommends a follow-up study in cases where the test article inhibits hERG, or prolongs QT, but did not specify practical measures. In such circumstances, the FDA proposed an approach using the new technologies at CiPA Initiative*. The contents are discussed as S7B/E14 Q&A by the ICH Assembly.
* CiPA Initiative: Comprehensive In Vitro Proarrhythmia Assay (CiPA) Initiative

2Proposal of an optimal strategy based on the latest trends

While various new approaches are being proposed, it seems to be getting even more difficult to select an optimal test system and formulate a protocol.

Exactly. The emergence of new technology or approaches naturally requires a change to screening strategies and protocol regarding when to perform which test in which order. We should sufficiently understand the characteristics of individual approaches, new and old ones alike. It is reassuring that we, Axcelead DDP, have reassuring specialists. As for FDA’s CiPA Initiative that I mentioned earlier, the same consortium has been established in Japan as well. Dr. Takasuna*, who appeared in the previous interview, was the leader in the consortium! The strength of Axcelead DDP is proposing optimal screening strategies for our customers, and comprehensive risk assessment of the cardiovascular system covering both in vitro and in vivo, that have been prepared through discussions with Dr. Takasuna.
* Interview vol.1 “Let’s explore the appeal of Axcelead Drug Discovery Partners’ hERG current assay!“, (Dr. Takasuna, a senior investigator)

In the previous interview, Dr. Takasuna also said, “We are aiming to make Axcelead DDP strong in integrated assessment of the cardiac toxicity, covering both in vitro and in vivo”! More specifically, what kind of collaboration do you have in mind?

Takasuna Group practically covers almost all of the test systems necessary for the early stages of drug discovery, mainly in vitro. Our group deals with the studies required for IND application, including preparatory studies, and can propose and implement integrated screening strategies suitable for diverse profiles of individual test articles. For unexpected adverse effects, we will share information with Takasuna Group to propose an optimal solution.

Will a strategy that integrates both in vitro and in vivo studies shorten the speed of research and reduce the cost?

Well, the selection, order and timing of the test system will significantly change the speed and cost of development. It is also important to detect lethal adverse effects as early as possible because the probability of successful drug development is quite low. Axcelead DDP has many researchers who were once engaged in drug research and development at pharmaceutical companies and understand that the importance better than anyone. We will fully utilize the knowhow obtained through their experience which will contribute to cost reduction and the acceleration of development for our customers.