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| Conformance evaluation: why is "consistent with the same effect"? |
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| Author：中國銘鉉 企劃部 Release Time：2017-8-17 14:47:35 Number Browse：681 |
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The evaluation of the quality and efficacy of generic drugs in China was re-opened in March 2016. As the work progressed, the importance of the preparation that had been neglected for years was widely recognized. Because the work is only aimed at oral solid preparation, the neglected in vitro dissolution study has become the focus of the industry.
This reminds me of the drug quality reevaluation project (hereinafter referred to as "project") carried out by Japan's pharmaceutical administration in 1997. Due to the history of the pharmaceutical industry in both countries are very similar, the problems the same (oral solid preparation already on the market of security is invalid), so the practice and experience is worthy of reference for our country to follow and the country.
Therefore, in this paper, the engineering chief designer Mr Green willows god male (then Japanese state drug inspection department is a department of drug) in August 2002 published "the Japanese version of the Orange Book" for translation and interpretation. Through the introduction of the background of "the Japanese version of the Orange Book" and the development course of dissolution in vitro and in vivo was described and the relationships between the clinical efficacy of three, generic drugs and oral solid preparation quality evaluation are discussed, for the colleague reference.
Notable is, "the Japanese version of Orange Book" includes confirmed by the "drug quality evaluation project again" with the original drugs with the same generic drug dissolution behavior, also documented dissolution test method, quality standards and to evaluate the progress of information; Especially presents the reference preparation in various physiological pH value more than the dissolution curve, is quality supervision and forecast for the future have many aspects, such as drug in the body to absorb provides strong technical support.
The author in August 2003 - February 2004 in Japan's national drug inspection medicine department of education, from the green willow teacher, systematically studied the project implementation details, and deeply felt Japan official's philosophy with work is not the pursuit of perfect and comprehensive, but according to its present situation and the domestic enterprise actual situation, to formulate the policy requirements of adjust measures to local conditions, active learning, so as to realize the regulatory framework to help and promote enterprise development, and the use of the professional very emphasis on practicability and maneuverability.
The PK of Japanese orange peel book
The Japanese version attaches importance to the test of extracorporeal dissolution, and the American version attaches great importance to being tested in vivo
"The American version of orange peel" includes generic drugs with the same bioavailability as the original drug. The "Japanese version of Orange Book" contains generic drugs that are consistent with the original solution.
In terms of the quality evaluation of the oral solid preparation of generic drugs, the Japanese government mainly has the following three viewpoints: as long as the dissolution behavior in vitro is consistent with the original medicine, the clinical efficacy of the two is nearly identical. There are few failures in the bioequivalence (BE) experiment, so the BE experiment can BE ignored to some extent. The evaluation system of generic drugs "dissolution + BE test = the same effect" can BE changed into "consistent results".
In contrast, the FDA is more focused on being tested in vivo and less attached to it (but perhaps conceding a low profile).
The Orange Book was first released by the us FDA. Because the cover is orange, people used to call it "Orange Book", which is known as "officially approved, clinical efficacy of the same medicine". Since there are a large number of generic drugs, they can only BE distinguished by different names of goods, but these generics have been tested with the original drug. The aim of the book is to publish generic drugs that have the same clinical effect as the original drug, thereby promoting the use of generic drugs and ultimately contributing to lower patient health care costs and national health care expenditures.
Japanese edition also used the orange, but the name to the drugs quality information set for medical use (third) and Japanese pharmacopoeia ", by the health and drug administration review management course (equivalent to the registration division), issued by the pharmaceutical affairs daily. The Japanese drug administration has made the "Orange Book" as the third part of the Japanese pharmacopoeia, which shows its importance to the test of dissolution. And because the book is a part of the pharmacopoeia, it lays the legal basis for the future market supervision to check the number of dissolution curves.
In 1997, in Japan began to drug quality evaluation of the project is through dissolution behavior consistency evaluation means to verify that the generic drugs already on the market (including the body BE test verified) has been adopted a quality equal to the original medicine. The test covers the digestive tract in the human body pH range (1.2 ~ 6.8), all of this book contains the officially recognized the reference preparation each type of multiple characteristics dissolution curve, and the scientific accurately established these curves, the five steps of the process.
Due to the Japanese version is stripping consistency as evaluation index, although with the United States to BE test for different evaluation indexes, but the goal is consistent, which prompted the clinical curative effect of generic drugs is equivalent to the original drugs, only by means of different of them.
Why is the solubility test favoured?
Japan attaches great importance to the three reasons for the test of dissolution in vitro
So is there a consistent clinical efficacy that is consistent with dissolution? The author's answer is: although can not assure completely, but can significantly prevent clinical efficacy inconsistencies! At the same time, the solubility test has many advantages, such as the efficiency and efficiency of the experiment.
It is well known that the reason for the "Japanese Orange Book" is that the government encourages the use of generic drugs to reduce the cost of medical expenses; Secondly, it is derived from the development of bioequivalence test of generic drugs.
The governments of both countries are keenly aware that only a large number of cheap generic drugs can control the rising cost of health care. The premise of achieving this goal is that the generic drug quality should be equal to the original medicine; Assuming inferior to the original medicine, cannot and should not use this generic medicine.
Reason 1 differentiates between generic and original drug quality
The difference in efficacy of generic drugs and original drugs was reported in the United States and Europe as early as 1960. The reason is that the difference between the prescription and the process leads to the dissolution and absorption of the main components in the body, which eventually makes the blood drug concentration different.
Thus, in order to ensure the clinical curative effect of generic drugs is equivalent to the original drug, both in vivo bioavailability shall, first of all, the same, which is usually need to BE test, national food and drug administration are introduced a generic drug research and development for this declaration must carry out the test regulation, namely the AUC, Cmax, Tmax parameters to evaluate the degree of absorption rate and are consistent in the body.
At the same time, with the development of in vitro dissolution test technology and progress, people gradually aware: the experiment can be used to infer the release of drug in the body characteristics, and gradually evolved into the experiment is adopted to improve the drug quality control.
Japan Orange Book wrote, although there is no generic drugs and the original drug treatment effects appear obvious difference, but the dissolution behavior and bioavailability differences research report are not uncommon, even after taking pills did not collapse, the prototype is being drained out of the report. Therefore, there is reason to suspect that the clinical efficacy of generic drugs in the above situations will be problematic and it is the responsibility to immediately stop the supply of these safe and ineffective drugs.
Reasons 2 make up for the limitations of BE test
According to the Japanese Orange Book, the bioavailability of generic drugs differs from that of the original drug, mainly because of the problem of the evaluation method adopted by the government. Before 1980, the Japanese national bureau only asked for animal experiments to verify the consistency of blood drug concentration, but this could not be consistent with the bioavailability of the guarantor. 1980 years later, although the requirements change the animal to human body, but does not require companies to generic preparations in vitro dissolution behavior comprehensive comparative study with the original development agent, therefore quality supervision is still inadequate, mainly because the BE caused by the deficiency existing in test itself.
The American Hatch Waxman act has one core premise when it comes to BE: assuming that the bioequivalence of research data obtained in healthy people is equivalent to the patient. Japanese scholar studies found that in many cases this assumption is not set up, for young people in the environment and the elderly is far, but suffer from ethical requirement cannot BE used in the form of all ages and gender parity BE test; And the trial cost is high, the enterprise cannot bear. Therefore, Japan pioneered the use of extracorporeal dissolution evaluation to compensate for the limitations of the BE test.
In addition, with the progress of aging society in Japan, there is a growing shortage of stomach acid. Studies have shown that pH changes will significantly affect the bioavailability of drugs. This reveals that the enterprise should be required to carry out the comparative study of multi-medium dissolution behavior in the development of generic drugs, and should be consistent.
In 1997, according to the above research conclusion, heath revised the generics bioequivalence test guiding principles and requirements of generic drugs research and development must be carried out when the pH range of 1.0 ~ 7.0 the dissolution behavior of comparison research, and should be consistent. If there is an inconsistency, subsequent bioequivalence tests must BE conducted with a stomach acid deficiency or the drug indication population as a test subject. Through this revision, the Japanese authorities were confident that the quality of their approved generic drugs would be almost non-existent in the clinical efficacy of the original drug.
Another case, such as generic "finasteride preparation" and "tan solo symplectic hydrochloride sustained-release preparations", if there is inconsistent with the in vitro dissolution behavior for a dissolution curve, Japanese food and drug administration will require generics companies must use the 18 ~ 24 elderly men as BE test subjects, because the indications for the drug only for such a crowd. Thus, Japanese generics companies have been extremely pragmatic in applying the dissolving curves to the same degree, which greatly promoted the improvement of the level of preparations in the country.
Reason 3 to replace the "BE test" of listed generic drug reevaluation work.
"Generics bioequivalence test guidelines" revised, derived "has been approved, the evaluation method of generic drugs according to the new event in vitro dissolution behavior do not agree with the original drug phenomenon, how to deal with" the new topic. To this end, the ministry of health of the ministry of health has set up a research project and national project to "re-evaluate the quality of listed drugs".
Studies, Japan found that a lot of in vitro dissolution behavior of drugs already on the market do not agree with the original drug, worried that these drugs in vivo bioavailability in certain patients will also do not agree with the original drug, which affects the clinical curative effect. To this, Japanese experts agree that if the body BE test to review a lot of drugs already on the market, both in many aspects, such as time, cost and resources are facing huge challenges, the thought of using simple dissolution test alternative to BE test. Compared with the latter, the former can be keenly reveals the dissolution behavior are consistent between different source preparation, and once appear, there is likely to be in certain patients with in vivo bioavailability is inconsistent.
In the end, the expert group agreed that, for generic drugs, the probability of biological nonequivalence would be extremely low by comparing the pH 1.0 to 7.0 with the original drug. At the same time, it also confirmed the objective fact that "in vitro dissolution and inconsistency of bioavailability in vivo are rare". To do this, the expert group for the concept of the major foothold began to implement quality evaluation project again, and will confirm the consistency of the dissolution behavior of generic drugs directory contains published in "Orange Book" in Japan.
From the context of the "Japanese version of Orange Book", the Japanese scholars are not only the American leaders, but the path-breaking method of using multiple solutions curve, which is worth pondering.
The dissolution test is of high value
It can play an important role in the development, production, quality control, supervision and clinical use of generic drugs
Due to the "Orange Book" Japan recorded the detailed reference preparation dissolution test of each type method, multiple characteristics dissolution curve, dissolution quality standards, quality evaluation progress steps again, such as large amounts of information, so it has very high use value. It is the first in the world to "reveal and open a number of characteristic dissolution curves" in the range of pH 1.2 ~ 6.8.
First of all, we can from these curves to predict the shape of drug release behavior of the digestive tract in the body, such as the pH value are consistent with the drug dissolution curve, we can believe that in the body to absorb, namely the effective blood drug concentration will not be affected by the environment of the human body, which in any population in vivo bioavailability are good; Conversely, the release of slow drugs in 6.8 media can be inferred that there may be problems with the release of the drug in patients with gastric acid deficiency, leading to the problem of effectiveness.
Secondly, the solubility of the shape of the curve and the solution of the API in various pH mediums are also available. In addition to the slow controlled release preparation and enteric preparation, the dissolution behavior in the pH media should be positively correlated with the solubility. If this is not the case, we suspect the quality of the preparation is questionable.
Thirdly, we can monitor whether the products of generics companies are consistent with the open reference. This practice rules in the dissolution of the lower limit, is much more strict quality standards to lead us to the agency to implement the long-term and effective supervision on the quality of generic drugs, and ultimately to shoulder "for the general public to provide good quality, quality uniform atomization generics" lofty mission.
These characteristics of dissolution test is incomparable BE experiment, and BE test only once, the future can't reproduce, this evaluation method, we have necessary to the past? |
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