Careful selection of reference preparation for bioequivalence test in Taiwan

Source: pharmaceutical economic news 2016-06-20 according to the previous cross strait medical and health cooperation agreement, mainland drug registration applicants can entrust 4 Taiwan hospitals to carry out drug clinical trials in accordance with the relevant regulatory requirements of the two sides, and the qualified clinical trial data can be used to apply for drug registration in the mainland Under the background of rapid promotion of generic drug conformity assessment, how to learn from the experience of drug review and registration in Taiwan, find another way to explore the possibility of carrying out conformity assessment has attracted the attention of many enterprises Taiwan be regulation generic drugs are known as "generic drugs" in Taiwan In November 1987, the release of "test standards for bioavailability (BA, bioavailability) and bioequivalence (be, bioequivalence)" opened the curtain of consistency evaluation of generic drugs in Taiwan According to the standard, for drugs listed in "monitoring new drug ingredients" in 1983, if their generic drugs are not administered intravascularly and can have systemic effects, the bioequivalence human test and Research Report must be tested and submitted before they are put on the market; for drugs with narrow therapeutic concentration or suspected bioavailability, the bioequivalence test is required to be added In fact, Taiwan's be regulations mainly refer to Europe and the United States, and make necessary adjustments in consideration of the actual situation of the industrial structure: the European Union requires that the number of subjects should be at least 12, and healthy subjects over 18 years old and with a BMI of 18.5-30 kg / m2 should be selected; The United States requires that the number of subjects should be no less than 24 (at least 12 subjects with acceptable pre-test be results), and healthy volunteers over 18 years old should be selected to be enrolled according to gender, age, race and other factors; In Taiwan, the number of subjects is required to be at least 12 The subjects choose healthy adult volunteers over 20 years old, taking into account gender, age, race and other factors Dr Bao Liheng, President of Taiwan Pharmaceutical Quality Association, a legal person of Taiwan Association of China, said that although the system requires at least 12 subjects, they are basically about 20, 18, 24 or 36 are relatively common, and the number of subjects must be determined by reference to the sample size "In terms of batch size, different batch sizes will lead to a huge difference in the variability of the preparation process In the past, Taiwan could use small batch for consistency evaluation, but now the regulations require that the batch of be must be 1 / 10 of the future production batch, or at least 100000 PCs, whichever is larger Some enterprises have been preparing for clinical consistency evaluation As a result, the batch of be is only 20000, and the actual production batch in the future is far more than 1 million No matter how well the clinical work is done, the batch is not in conformity " First of all, we need to pay special attention to the differences of supervision systems between the two sides of the Taiwan Strait when we look at the product classification selection to carry out consistency evaluation in Taiwan The registrants of pharmaceutical companies who have participated in the clinical research of drugs in Taiwan admitted to the reporter of pharmaceutical economic news that the consistency evaluation of mainland varieties in Taiwan depends on the classification of the ingredients and dosage forms of the products, the submitted materials and the reporting procedures "CFDA's new drug classification emphasizes" global new ", while Taiwan's is" Taiwan new ", which classifies innovative drugs according to whether they are listed in Taiwan or not," he said Therefore, to make be in Taiwan, if the enterprise's varieties are not generic drugs, in addition to the approval of the institutional ethics committee, it must be approved by the Taiwan FDA before implementation If the enterprise's varieties belong to generic drugs, it can be carried out only after finding a compliant clinical trial institution and qualified doctors, and with the consent of the institutional ethics committee " At present, the drug classification in Taiwan mainly follows the Taiwan pharmaceutical law, which is divided into new drugs and generic drugs Among them, the definition of new drugs in Article 7 is "drugs in Taiwan that are identified as new ingredients, new therapeutic compounds or new route preparations after examination by the competent health authorities." Article 4 of the criteria for examination of inspection registration in Taiwan clearly states that "generic drugs refer to preparations with the same composition, dosage form, dosage and efficacy as those approved in Taiwan." The hospitals in Taiwan were divided into four categories: Medical Center (Teaching), regional hospital (Teaching / non teaching), regional hospital (Teaching / non teaching) and clinic (non teaching), which were different from the first, second and third level hospitals in mainland China Article 78 of the Taiwan medical law requires that: in order to improve the medical technology level or disease prevention needs in Taiwan, teaching hospitals can carry out human body tests after drawing up plans and submitting them to the competent department for approval or entrusted by the competent department; Non teaching hospitals are not allowed to carry out human body tests If medical institutions have special expertise, human body tests can be carried out with the approval of the competent department It can be seen that in Taiwan, as long as the hospital with teaching function can carry out clinical trials in all phases, so the number of hospitals that can do consistency evaluation is more than 50 "Although the mainland only recognizes four institutions based on mutual recognition of data," said the registrant However, from the perspective of cost, be pre-test can be done in other hospitals, because it mainly involves the adjustment of product prescription process and the calculation of the number of main test cases The four hospitals can be selected for the main trial, because the ethical review cycle of large hospitals is relatively long, and the cost of clinical trials is also relatively expensive Take 12 pre trials as an example If other hospitals need to pay about 30000 yuan for a healthy volunteer, it may need about 50000 yuan in a large hospital " According to the reporter, among the four hospitals recognized by CFDA, Taida hospital and Changgeng hospital mainly focus on new drug registration and clinical research Rongmin general hospital and the Third Army General Hospital have rich experience in consistency evaluation In addition to the consistency evaluation of conventional drugs, tumor generic drugs, such as colorectal cancer, head and neck cancer, breast cancer, brain tumor, blood cancer and other drugs, involve recovery The experience of drug consistency evaluation in patients with miscellaneous tumors is also very rich The most perplexing problem in the consistency evaluation of carefully selected reference preparations is also an important reason for some Chinese pharmaceutical companies to consider using Taiwan for be Taking atorvastatin as an example, the FDA orange peel book requires the reference preparation to be the original product of Pfizer, which is not listed in the mainland, while in Taiwan, it is the original product of Pfizer There are many similar situations Jiang Tingyi, executive director of Tixiang Biotechnology Co., Ltd., said that Taiwan's regulations are very clear For drugs listed in "monitoring new drug ingredients", the reference drug should be the first product with data proving that it is the original research product or approved by the health authority for listing; For drugs not included in the "monitoring of new drug ingredients", the products of original research, or the products sold in Taiwan with known bioavailability, or the products that are bioequivalent with the products of original research or prove clinical effectiveness shall be selected "If there are local products of the same brand but different manufacturing plants for the reference preparation, relevant data should be provided to support the quality of the reference preparation," she said The approval cycle and procedures of imported drugs in Taiwan are faster As long as the approval letter of the human body test committee is obtained, and the clinical trial plan and the consent letter of the subject are attached, the import application to the Taiwan FDA can be completed within one month " It is worth noting that the data of clinical trials in Taiwan can be recognized by the United States and the European Union, so the clinical trials in Taiwan are also conducive to simultaneous declaration in Europe, the United States and China "It should be noted that the choice of the reference preparation The reference preparations in Europe and the United States are usually different For the products listed in Taiwan, the European products are the European manufacturers, and the American products are the American manufacturers However, if the European manufacturers are selected, the United States cannot declare them If the American manufacturers are selected, the European manufacturers cannot declare them It is hoped that the varieties of "double report" need to be planned in advance " Jiang pointed out