[Talking about Medicine Garden] Dry goods! In-depth analysis of 500 reference preparations that failed to pass the review.
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In order to promote the consistency evaluation, the General Administration announced the catalogue of generic reference preparations in batches from March 17, 2017, and began to publicize the draft of the catalogue of generic reference preparations on March 28, 2019.
In the Catalogue of Reference Preparations for Chemical Generic Drugs (25th Batch) (Draft for Comment), the list of varieties that failed to pass the review began to be updated. By the end of the Catalogue of Reference Preparations for Chemical Generic Drugs (59th Batch) (Draft for Comment), 620 failed product specifications had been updated, and 93 were reviewed by the consistency evaluation expert committee again after receiving the objection application from the enterprise. The experts maintained their original conclusions and failed the second review.
The following figure shows that the historical batches of the exposure draft have not passed the review and reference publication:
The main reasons for not passing the review are as follows:
A has no reference preparation status.
According to the Procedure for Selection and Determination of Reference Preparations for Chemical Generic Drugs, the order of selecting reference preparations is: original research imported, original research not imported, original research localized and internationally recognized drugs of the same kind.
Of the 527 failed quality regulations, 280 were rejected because they did not have the status of reference preparations. Analysis of the reasons for not having the status of reference preparation can also be divided into the following situations:
1. Clearly do not recommend reference preparations.
The reference preparation is not recommended for the trial varieties that can BE exempted or simplified in human bioequivalence (BE) issued by the National Bureau. For example, Compound Polyethylene Glycol Electrolyte Powder (V), similar varieties have been clearly not recommended in the notice (No.136, 2018) issued by the National Bureau on the exemption or simplification of human bioequivalence (BE) test varieties. It has not passed the review.
2. There is no such dosage form in the original research.
Because the reference preparations to be declared are varieties with modified specifications, the original research did not have this specification and failed to pass the review, such as acarbose chewable tablets, pantoprazole sodium enteric-coated capsules, acetaminophen dry suspension, betamethasone sodium phosphate injection, etc.
3. Compared with the published reference preparation, it has no obvious advantage.
3.1 The concentration of the reference preparation to be applied for is the same as that of the published reference preparation, but the loading quantity is different.
We can find that the specification of 4.5354g/7.5ml of Bayer Healthcare Pharmaceuticals was published in the 27th batch, and the specification of 9.0708g/15ml was published in the 28th batch.
In the Catalogue of Reference Preparations for Chemical Generic Drugs (Fifty-ninth Batch) (Draft for Comment), 1.20944g/2ml, 6.0472g/10ml, 18.1416g/30ml and 39.3068g/65ml of gadolinium butoxide injection of Bayer Healthcare Pharmaceuticals Inc were rejected because they were different from the published reference.
3.2 The published reference preparations are prescription drugs listed in the United States, and it is not recommended to add OTC drugs as reference preparations.
Omeprazole sodium bicarbonate capsules are managed separately according to prescription drugs and OTC in the United States. The published reference preparations are prescription drugs listed in the United States, and it is not recommended to add OTC drugs as reference preparations.
3.3 Compared with published reference preparations, there is no clinical advantage.
Piperacillin sodium tazobactam sodium for injection by Dapeng Chemical Industry Co., Ltd. was rejected because the powder-liquid double-chamber bag was not widely used and the cost was high. The orally disintegrating tablet of montelukast sodium from MSD Co., Ltd. was not approved because the dosage form to be applied for was orally disintegrating tablet, which only provided a choice of dosage form for clinic, and had no clinical application advantage compared with other oral preparations on the market. Cefalexin fine granules of Gonghe Chemical Industry Co., Ltd. were not approved because the published reference preparation of Cefalexin dry suspension could basically cover the usage and dosage required by children patients.
3.4 Non-original research and no reference preparation status
The metronidazole vaginal gel of Oceanside Pharmaceuticals is a generic drug authorized by the original research, but it is a generic drug listed in the United States and does not have the status of reference preparation; Pravastatin sodium tablets (4 specifications) of Teva Pharmaceuticals Usa Inc are internationally recognized as the same drug, but the reference preparation to be applied for is a generic drug listed in the United States, which does not have the status of reference preparation and is not approved.
B lack of complete and sufficient safety and effectiveness data.
A total of 104 quality regulations failed due to the lack of complete and sufficient safety and effectiveness data, of which 22 were reviewed by the consistency evaluation expert Committee again after receiving the objection application from the enterprise, and the experts maintained the original conclusion and failed the second review.
Most of the reasons why this kind of drug failed to pass the review were that the data of safety and effectiveness provided by the applicant were not sufficient, and it was impossible to determine that it was a drug with safety, effectiveness and quality controllability. In addition, Alfasigma Romania S.R.L’ s creatine phosphate sodium for injection is the original research drug listed in China, but this product has been included in the first batch of national key monitoring drugs list, and the relevant safety and effectiveness data are limited, so the review failed; Pidotimod oral solution of Polichem S.R.L was not approved due to insufficient evidence of clinical effectiveness according to the Notice of the General Administration on Starting Clinical Efficacy Test of Pidotimod Oral Liquid (No.31 [2018] of Food and Drug Administration); Alfasigma S.p.A’ s Levocarnitine Hydrochloride Enteric-coated Tablets was declared for import in the original research, and the application materials were not enough to support the effectiveness of this product for the applied indications. The conclusion was that it was not approved and the review was not passed.
C does not meet the domestic indications, usage and dosage
There are 64 product specifications involved because they do not meet the domestic indications and usage and dosage. Subdivided into the following three reasons:
The specification of oxytocin injection of Takeda Chemical Industry Co., Ltd./ぁすかかかか Co., Ltd. is 1 unit /ml, and the specification of 1 unit /ml of this product is unreasonable, which is less than the minimum dose recommended by the instructions for single use (2.5 units/ml); The specification of Pioglitazone Hydrochloride Tablets of TAKEDA PHARMACEUTICALS USA INC is 45mg. In the past, an expert consultation meeting was held for hypoglycemic drugs. Clinical experts reported that the maximum dosage of this product used in China is usually 30mg, and the specification of the reference preparation to be applied is greater than the maximum dosage, which was not approved. Naproxen is a non-mainstream non-steroidal anti-inflammatory drug in China. Naproxen, esmomeprazole and magnesium enteric-coated tablets of Horizon Medicines LLC, the compound does not meet the requirements of domestic clinical practice and compound preparation for the time being, and the review was not passed.
D. The listed areas are not in the European Union, the United States and Japan (with relatively perfect regulatory system).
There are 46 quality regulations that have been rejected because the listed areas are not in the European Union, the United States and Japan. In order to ensure the quality of reference preparations, it is suggested that the reference preparations should be the original drugs approved for listing by institutions with relatively perfect regulatory systems such as the European Union, the United States and Japan, and the review failed.
There are mainly the following 12 listed regions that failed to pass the review:
E has certain security risks.
There are 21 quality regulations that failed due to certain safety risks, and 8 of them were reviewed by the consistency evaluation expert Committee again after receiving the objection application from the enterprise. The experts maintained the original conclusion and failed the second review.
It is worth noting that injections and eye drops without preservatives and antioxidants have more advantages as reference preparations.
F process quality does not meet the requirements.
There are 12 product specifications that failed because the process quality did not meet the requirements, and four of them were reviewed by the consistency evaluation expert Committee again after receiving the objection application from the enterprise. The experts maintained the original conclusion and failed the second review.
Oxaliplatin for injection of Sanofi-Aventis France is the reference preparation published in the 27th batch. After deliberation by the expert committee for consistency evaluation, the oxaliplatin injection prepared by terminal sterilization process can meet the requirements of product impurity control and stability, and oxaliplatin injection with terminal sterilization should be the first choice, and oxaliplatin for injection is an unreasonable dosage form, so it should be transferred. If the reference is rejected, the declared product has no possibility of approval.
tag
The selection of reference preparation is the key in the process of generic drug research and development. If the selection is wrong, the project progress will be delayed, and the blood will be lost. By studying the reasons why the reference preparation failed the audit, we can learn a lot of experience in project risk assessment and product research, and clearly judge the value orientation of the country to generic drugs. When researching products, we should not only pay attention to foreign data, but also pay attention to the performance of drugs in China. Try to avoid the embarrassment that the application for reference preparation was rejected, and pay more attention to avoid the tragedy that the selected reference preparation was transferred out of the catalogue.