Cheng Yuan,Tian Lijuan

(School of Business Administration Shenyang Pharmaceutical University,Shenyang 110016,China)

Abstract Objective To study whether the reference preparations of 289 list are determined and to analyze why some reference preparations are not put on file,and suggestions are raised for follow-up work.Methods Selection principles,situations of filing and releasing of reference preparations were clarified,289 listed items were classified and each reference preparation was discussed respectively.Results and Conclusion Reference preparations of 289 list were determined basically.Up to February 2018,42 drugs had not been put on file,18 of which had no other dosage form of same generic names filing at the same time.Besides,4 of these 18 varieties had been removed from the National Essential Medicine List.The clinical alternatives of the remaining 14 varieties should be further evaluated so as to avoid the cases that the low-cost drugs will be removed from the National Essential Medicine List due to failure of consistency evaluation.Meanwhile,those irrational dosage forms that cannot pass the consistency evaluation should be removed from the National Essential Medicine List gradually.

Keywords:consistency evaluation;289 list;reference preparation

In March 2016,Opinions of General Office of the State Council on the Consistency Evaluation of Quality and Efficacy of Generic Drugs (No.8)[1]was officially issued,which clarified the name and time limit of the generic drugs for consistency evaluation in batches.Since then,this work was carried out comprehensively.In May 2016,a List of 289 Varieties was issued by the former China Food and Drug Administration (hereinafter referred to as“CFDA”)[2].It determined the first batch of varieties that had to pass the consistency evaluation before the end of 2018,with a total of 17 740 approval numbers.The 289 list of chemical oral solid preparations were in the National Essential Drug List (Edition of 2012)approved before October 1,2007.These varieties were widely used which could meet the basic needs of the public[3].However,the evaluation progress was slow for only 38 varieties in the list had passed the consistency evaluation by the end of 2018 according to the statistics.Although the evaluation time limit has been canceled,the National Essential Drug List(Edition of 2018)and the consistency evaluation are dynamically linked[4].As the starting point and decisive factor of the consistency evaluation,it is worth studying the reference preparations.

1 Selecting reference preparations

1.1 Principles of selecting reference preparations

Reference preparation refers to the control drug used for the evaluation of the quality and efficacy of a generic drug,which is usually the object to be imitated,such as an original drug or an internationally recognized drug of the same variety.A reference preparation should be a drug with stable quality and good curative effect.In March 2016,CFDA determined“Guidelines for Selection and Determination of Reference Preparation for Oral Solid Drugs”[5],requiring pharmaceutical manufacturers,industry associations,manufacturers of original drugs,and manufacturers producing internationally recognized drug of the same variety to select reference preparations by filing,recommending and applying.The order of selection is:imported original drugs that have been listed domestically ＞ the drugs from original research companies manufactured and listed in China ＞ internationally recognized drugs of the same variety that have been listed domestically ＞drugs approved and listed in EU,US or Japan as reference preparations.

On August 25,2017,CFDA issued a document[6]to adjust the selection order.The order of selection was:imported original drugs ＞ the drugs from original research companies manufactured and listed in China＞ domestic original drugs ＞ drugs approved and listed in US,Japan or EU as reference preparations.

According to statistics,about 210 varieties in the list don't have imported or locally produced reference preparations.Therefore,most of them have to choose original drug or drugs approved and listed in US,Japan or EU as reference preparations.This means that companies will spend a certain amount of time selecting and importing reference preparations.Although 213 varieties can be identified as original drugs,only 117 domestic drugs have the same dosage forms as the imported ones.Besides,35 varieties have the same specifications as original drugs[7].Therefore,a large number of varieties have modified specifications,dosage forms or base forms.

1.2 Filing and releasing the list of reference preparations

Initially,National Institutes for Food and Drug Control was responsible for the management of the platform for selecting reference preparations.After January 3,2018,Center for Drug Evaluation(hereinafter referred to as“CDE”)took it over.In September 2016,National Institutes for Food and Drug Control published information of reference preparations filing from May 20,2016 to November 20,2017,involving more than 900 varieties.After experts' reviewing,information,CFDA published the List of Reference Preparations.Since the release of the first batch of reference preparations in March 2017,20 batches were published,involving more than 600 varieties with a total of 1 166 specifications.

On December 9th,2017,CDE released the Basic Information Table of Reference Preparations of 289 List,disclosing the varieties in details.On February 14,2018,according to the newly released List of Generic Drug Reference Preparations (11th to 13th batch),Notice on Further Improving the Consistency Evaluation of Domestic Varieties in the 289 List and the latest enterprises' filings,CDE updated the basic information table[8].The list of 14 to 20 batches was studied and the in-depth analysis and classification on the 289 list was conducted.

2 Classification of 289 list

2.1 Relevant documents of reference preparations

For different types of varieties in the list,the selection of reference preparations was based on the following documents and principles.See Table 1 below.It can be seen that with the deepening of the consistency evaluation,the requirements for some varieties are also changing.

2.2 Publishing 193 varieties in the list

In 289 list,reference preparations of 193 varieties were published,of which 3 varieties were more complicated.Vitamin B6 Tablets was a modified specification variety,although the preparation of its original specification was published,according to the Exemption or Simplification of Human Bioequivalence (BE)Test[9],it didn't need anypreparation.The 5 mg specification of Folic Acid Tablets published its preparation,while the 0.4 mg specification didn't need any preparation.The 200 mg specification of Mifepristone Tablets also published its preparation,while its 10 mg and 25 mg specifications belonged to specific domestic drugs.According to“Special Recommendations for Domestic Varieties in the List”[10],they didn't need any preparations or they could be taken as passing the consistency evaluation after meeting the corresponding requirements.Now,in the list of the 20th batch,the Mifepristone Tablets of 10 mg and 25 mg manufactured by Huarun Zizhu Pharmaceutical Co.,Ltd.become specific domestic reference preparations.

Table1 Relevant documents for the selection of reference preparations

Some of the 193 varieties published reference preparations with all specifications,and others published reference preparations with certain specifications (Unpublished specifications were modified specifications).Even some specifications were all modified but their original specifications had been published.The preparation list of 1-8 batches was published from March 17 to July 21,2017 which covered 183 varieties.Among them,15 reference preparations published in the eighth batch were modified specification varieties with original specifications.After this,most of the reference preparations published was the original drugs manufactured and marketed in China or supplementary reference preparations.

The sources of reference preparations for these 193 varieties included original imported drugs,US Orange Book,US approving and marketing,EU approving and marketing,Japanese Orange Book,internationally recognized imported drugs from Australia,Canada,Switzerland and Turkey,original drugs manufactured and marketed in China,FDA authorized generics,and domestic endemic specifications.Some of the varieties (specifications)had multiple reference preparations.As the publishing 1-20 batches of reference preparations,a certain variety (specification)can be supplemented with reference preparations from other sources.For example,the third batch of preparation list determined that the preparation of Azithromycin Tablet with the specification of 0.25 g was“Azitromycin 250 TEVA”from TevaPharma BV marketed in the EU(manufacturing area:Croatia).And the seventh batch added Zithromax in the US Orange Book from PFIZER INC as a supplementary reference preparation.

2.3 Seven varieties need no reference preparations

According to the Exemption or Simplification of Human Bioequivalence (BE)Test,7 varieties don't need any reference preparations including Oral Rehydration Salt Powder (I),Oral Rehydration Salt Powder (II),Vitamin B6 Tablets,Vitamin B2 Tablets,Calcium Gluconate Tablets,Sodium Bicarbonate Tablets and Folic Acid Tablets (0.4 mg)as they can meet the requirements of pharmaceutical research and evaluation.

2.4 Fifty four varieties with modified dosage (salt base)forms

Although 54 varieties with modified dosage(base)forms didn't publish their reference preparations,their original dosage forms released reference preparations.That means they have reference preparations.However,due to the release of the reference preparations of the original dosage forms,manufacturers often choose the original dosage forms for consistency evaluation in priority.Therefore,the progress of changing such modified dosage (base)forms is slow.As to some varieties with unreasonable dosage forms,they may face elimination in the future.

2.5 Twenty four domestic endemic varieties

Two of the 24 domestic endemic varieties were not filed,namely Berberine Tannas Tablets and Compound Megestrol Acetate Tablets.Therefore,reference preparations were not recommended to them for the time being.The remaining 22 varieties were evaluated according to Special Recommendations for Domestic Endemic Varieties in the List.Clinical trials were not required for 14 varieties,in which the Compound Naphthoquine Phosphate Tablets was an exclusive approval.And after improving the pharmaceutical quality,can it be recommended as a reference preparation.Besides,the Mifepristone Tablets (10 mg,25 mg)approved by the standardized clinical trials meeting pharmaceutical research and evaluation requirements can be recommended as a preparation or passing the consistency evaluation,but their generic drugs must be tested for bioequivalence.The remaining 12 varieties didn't need any reference preparations,but specific varieties had to supplement with different research materials,to meet the requirements for pharmaceutical research and evaluation,revised specifications and pharmacokinetic studiesin vivo.In addition,6 varieties should have clinical trials and 2 varieties should be given up,namely Bifendate Tablets and Bifendate Pills.Otherwise,adequate evidence of clinical effectiveness should be given.

2.6 Ten varieties were not recommended to have reference preparations because of no filings

10 varieties were not recommended to have reference preparations because there were no preparation filings from enterprises.They were Berberine Tannas Tablets,Compound Megestrol Acetate Tablets,Menadiol Diacetate Tablets,Penfluridol Tablets,Ferrous Sulfate Substained Release Tablets,Oxacillin Sodium Capsules,Cefradine Tablets,Oxacillin Sodium Tablets,Hydrocortisone Acetate Tablets and Ethinylestradiol Tablet.Two of these varieties,namely Berberine Tannas Tablets and Compound Megestrol Acetate Tablets also belonged to the above-mentioned domestic endemic varieties.

2.7 Seven other varieties

At present,5 varieties are narcotic drugs requiring special control,one of which belongs to the domestic endemic varieties,namely Bucinnazine Hydrochloride Tablets.Its reference preparation is not recommended.The other 4 varieties are Morphine Hydrochloride Tablets,Codeine Phosphate Tablets,Morphine Sulfate Tablets and Morphine Hydrochloride Sustained-Release Tablets that are under investigation.In addition,the reference preparation for Sodium Aminosalicylate Enteric-coated Tablets is also under investigation.Diclofenac Sodium Sustained Release Tablet (V)has no valid approval number and filing for one specification,but the other specification is a modified one without filing too.

In summary,the reference preparations of the 289 list are basically clear.Ten of them are not recommended for reference preparations due to the lack of filings.Some varieties have published their reference preparations but they have no filings,which delays the progress of the consistency evaluation.The following analysis is on the varieties that are not put on file.

3 Analysis of unfiled varieties

3.1 Forty two unfiled varieties

Since the filing of reference preparations from enterprises released by National Institutes for Food and Drug Control has not been updated since November 20,2017,the latest information of reference preparations can only be got from the Basic Situation Table for Reference Preparations of 289 List issued by CDE on February 14,2018.A total of 42 varieties without filing of reference preparations are studied as of February 14,2018[11].See Table 2 below.

Table 2 Varieties of reference preparations without filing

Continued Table 2

Continued Table 2

3.2 Analysis of the reasons for unfiled varieties

A total of 16 varieties with modified dosage(base)forms have the filing from other dosage form of same generic names except Tegafur Tablets.Therefore,it is probable that enterprises will give priority to the evaluation of original dosage form of same generic names.Reference preparations of 11 varieties have been published but there are no filings from any enterprises.According to Announcement on the Consistency Evaluation of the Quality and Efficacy of Generic Drugs (No.100)issued by CFDA in August 2017,the published reference preparations don't need to be filed by enterprises.So there may be consistency evaluation that is not filed or enterprises give priority to the evaluation of the original dosage form of the same generic names.In addition,there are 18 varieties that have no other dosage form of same generic drug names filing either.

According to Announcement on the Consistency Evaluation of the Quality and Efficacy of Generic Drugs (No.102)[12]issued by National Medical Products Administration (NMPA)on December 28,2018,the National Essential Drugs List (Edition of 2018)set up a dynamic adjustment mechanism on November 1,2018, that was linked to the generic drug consistency evaluation.Those passing the consistency evaluation will be included in the list in priority while those failing to pass the evaluation will be gradually removed from the list.According to the statistics of the National Essential Drugs List (Edition of 2018),11 drugs with the same generic names (13 varieties)were removed from the list.See Table 3 below.

Table 3 Varieties removed from the National Essential Drug List (Edition of 2018)

Continued Table 3

4 Suggestions

Four of the 18 varieties without other dosage form of same generic drug names filing had been removed from the National Essential Medicine List(Edition of 2018).It means they can be replaced by other preparations.Otherwise,these four varieties should be retained and enterprises should be encouraged to conduct their consistency evaluation.The remaining 14 varieties include 5 birth control drugs,3 anti-tumor drugs,2 hormones and endocrine drugs,2 anti-microbial drugs,1 procoagulant drug,1 antipsychotic drug,and 1 ophthalmology drug.Some may not be suitable for bioequivalence tests.For example,anti-tumor drugs should not be used in healthy humans.Some may be highly competitive in the market,such as antimicrobial drugs.It is recommended that the drug regulatory authority further evaluate the substitutability of these varieties and avoid low-cost drugs to be removed from the National Essential Medicine List due to the lack of consistency evaluation[13].

At the same time,some varieties with dosage forms that cannot pass the consistency evaluation should be replaced by other dosage forms that will pass the consistency evaluation and meet the clinical needs.If they can meet the needs,the unreasonable dosage forms should be gradually removed from the National Essential Medicine List.

In addition,before releasing the eighth batch of reference preparations on July 21,2017,the majority of reference preparations in the list were confirmed.Most of the reference confirmed in the follow-up was the original drugs manufactured and marketed in China or the supplementary ones.It can be concluded that the confirming time of the reference preparations in the list is relatively early,but by the end of 2018,only 38 varieties passed the consistency evaluation.The regulatory authorities should further improve the availability of reference preparations,speed up the issuance of guidelines,provide targeted technical guidance,and improve incentives to stimulate enterprises for the generic drug consistency evaluation.