Issues to be aware of when applying alternative endpoints

On January 4th, the medical network published the "Technical Guide for the Conditional Approval of Drugs for Clinically Needed Drugs". The publication of the draft for comment is indeed a great encouragement to the new drug research and development industry. From this, we can feel that the Chinese pharmaceutical administration is deepening reform and bold. The power of innovation.

The Exposure Draft proposes that conditional approval for marketing may be granted in cases where the clinical outcome of a surrogate endpoint or intermediate clinical endpoint is predictive of a product that is likely to have efficacy and clinical benefit.

The two concepts of “alternative clinical endpoint” and “intermediate clinical endpoint” are mentioned here. In the course of clinical research, alternative endpoints should be used with caution, as surrogate endpoints and intermediate clinical endpoints sometimes do not necessarily reflect clinical outcomes. First, we refer to the ICH E9 point of view to introduce alternative clinical endpoints.

Alternative end point "Guide to use"

According to ICH E9, the Surrogate Variable is defined as “an indicator of indirect measurement of efficacy in cases where measurement of clinical efficacy is very difficult or unrealistic.” To date, some surrogate endpoints have been widely accepted in clinical studies and have been used in certain indications that are believed to reliably reflect the clinical efficacy of new drugs.

However, there are two main concerns when using surrogate endpoints for clinical evaluation.

First, surrogate endpoints may not really predict disease outcomes. For example, regardless of whether the outcome of the surrogate endpoint is negative or positive, the surrogate endpoint may only reflect the pharmaceutical mechanism of a particular aspect of the study drug, but not the entire pharmacological effect and the eventual outcome of the disease. For example, in many cases a treatment can make a surrogate endpoint showing very good positive results, but it is detrimental to the actual outcome of the disease. In contrast, some treatments can produce definite curative effects, but they are not reflected in the surrogate endpoints.

Second, in the treatment of a disease, under the premise of weighing the adverse events that occur during the treatment, the surrogate endpoints used do not quantitatively reflect the true benefit of a treatment. That is to say, after some treatment, although the surrogate endpoint has been improved, the physical condition has not been improved due to the adverse events experienced by the patient.

Although statistical criteria for surrogate endpoints have been proposed, experience with these statistical criteria is relatively limited.

In practice, the effectiveness of surrogate endpoints is determined by the following aspects: 1) biologically, biologically relevant; 2) epidemiological methods can be used to demonstrate alternative endpoints The value of the indicator indicates the outcome of the disease ; 3) evidence obtained through clinical studies indicates that the value of the surrogate endpoint is associated with the outcome of the disease.

It is worth noting that even for the same disease, a surrogate endpoint for a study drug use is associated with efficacy, and that does not mean that another study drug can achieve the same results when using the same surrogate endpoint. If another drug works differently.

There is a similar problem at the intermediate end point.

The intermediate clinical endpoint is itself a clinical endpoint for measuring a certain symptom or function, but is not directly related to the final outcome of the disease. Nonetheless, the improvement in the intermediate clinical endpoint remains clinically valuable, even if it does not ultimately reduce morbidity or mortality.

The intermediate clinical endpoint can be the clinical endpoint measured before the previously approved time point. The efficacy shown by the improvement of the intermediate clinical endpoint can predict a good outcome. At this time, the intermediate clinical endpoint serves as an alternative to the clinical endpoint. Of course, intermediate clinical endpoints also have the same problems as alternative clinical endpoints.

Therefore, the use of alternative clinical endpoints and intermediate clinical endpoints to evaluate new drugs is undoubtedly a major benefit for some clinically urgently needed drugs , but it also needs to be considered.

Rare disease drug import speed

This consultation draft has great encouragement for the development of rare diseases and brings good news to patients with rare diseases in China.

Due to the low incidence of rare diseases, clinical studies of rare diseases are unlikely to have statistically significant sample sizes as in routine clinical studies, and patient enrollment is often very difficult. Clinical research is time consuming and costly, and after the drug is marketed, the profit of the pharmaceutical company is limited due to the limited population used.

The United States enacted the orphan drug law in 1983, which has greatly promoted the treatment of rare diseases. In the United States, there were fewer than 10 rare disease drugs listed before the implementation of the Orphan Drug Act in 1983, and by December 2008, there were as many as 1,951 species. In 2015, the FDA approved a total of 45 new drugs, including 21 rare diseases, accounting for almost half of the new drugs approved this year (47%). The government's emphasis on the promotion of the industry can be seen.

US government initiatives to promote rare diseases include: 1) tax reduction; 2) enhanced patent protection and market possession; 3) government subsidies for clinical research on rare diseases; and 4) direct involvement of government agencies in research and development.

Although the Chinese pharmaceutical administration has not taken the same measures, the measures to speed up the import of rare diseases can also solve the problem of clinical supply shortage to a certain extent.