China CDE Q&A | BE Study, Reference Listed Drug, and Quality & Therapeutic Equivalence Evaluation

A1: The applicant should prove the drug's BCS (biopharmaceutics classification system) class according to the Guidelines on the Waiver of Bioequivalence Studies in Humans. 

• For BCS Class I drugs, the applicant should conduct solubility, dissolution, and intestinal permeability researches.

• For BCS Class III drugs, in addition to the aforementioned researches, the applicant should ensure the proposed drug and the reference drug contain the same types of ingredients, and the ingredients in the proposed drug should be quantitatively similar to those in the reference drug.

The applicant should submit the application according to the drug's characteristics and documentation requirements.

A2: We advise that permeability data should be based on in vivo human data, and the relevant data in the originator drug's medication package insert, if any, can be used a reference. If the human data is insufficient, then in vitro permeability data can serve as supporting data.

A3: We advise the applicant to follow the Technical Guidelines on Technical Guidelines on Generic Drug Bioequivalence Studies in Humans with Pharmacokinetic Endpoints, which allows the use of non-highest strength in BE studies if the highest strength has safety risks. Also, the test drug should meet the following conditions:

1. The test product has a linear pharmacokinetic profile;

2. For the test product and the reference product, their highest strengths and non-highest strengths have similar ingredient ratios*.

*Similar ingredient ratio refers to the following situations:

1) The ratios between all the active ingredient(s) and the inactive ingredient(s) are similar for different strengths;

2) For highly active drugs, where active ingredient(s) take a low percentage (e.g., the active ingredient(s) account for＜5% in the tablet core or the capsule contents);

i. The weights of different strengths are the same, with deviation rate lower than 10%;

ii. All the strengths use the same type of inactive ingredient(s);

iii. The differences between strengths lie in the different amounts of active ingredient(s) and the different amounts of one or more inactive ingredients.

3. According to the dissolution test, the test product has a similar dissolution profile to that of the reference product's highest strength.

A4: According to Technical Guidelines on Generic Drug Bioequivalence Studies in Humans with Pharmacokinetic Endpoints, the applicant can skip the fed bioequivalence study if the reference drug's medical package insert specifies that the drug can only be taken in an unfed state (1 hour before meal or 2 hours after meal).

For immediate-release oral drugs, it is recommended that the applicant should conduct both unfed and fed bioequivalence studies, unless the unfed one has severe safety risks.

If there is sufficient data proving the severe safety risks with the unfed dose, the applicant only needs to conduct the fed bioequivalence study.

A5: In general, the approval document remains effective if NMPA doesn't give special requirements in the document.

A6: According to the current regulations and technical guidelines, investigational drug samples should be manufactured on the drug's actual production line or in middle or larger scale GMP-compliant factories for trial production. The investigational drug's production scale should be middle or larger, with the same manufacturing techniques used in mass production and the manufacturing process following the GMP.

A7: The answers to the three questions are as follows.

1. For BCS Class I drugs applying for biowaivers, the applicant should submit the solubility and permeability data according to Guidelines on Waiving Bioequivalence Studies in Humans.

2. Human pharmacokinetic study is the most direct and effective method for proving high permeability. Pharmacokinetics data in the originator drug's medical package insert can support the permeability. If there is in vivo human pharmacokinetic data, whether sufficient or not, it should be submitted.

When in vivo human pharmacokinetic data is insufficient, in vitro permeability data, e.g., Caco-2 assay data, can also be the evidence for permeability. When necessary (e.g. there is no in vivo human pharmacokinetic data or any other data for proving high permeability), the applicant should submit extra literature to prove the permeability.

3. For BCS Class I drugs which apply for biowavers and are different in excipient type and amount from the reference drug, the applicant should submit data to prove the excipient's effect on the absorption.

A8: The applicant can design the study according to the reference-scaled average bioequivalence (RSABE) statistical method recommended by US FDA's guidance. But before adopting the RSABE method, the applicant should analyze the reason for the drug's high variability, and evaluate and demonstrate the applicability of the method in the BE study based on the existing researches and literature. In addition, the applicant should specify the statistical method in the clinical trial plan and the statistics plan.

A9: According to the BE study filing regulations, the stability research data should cover at least three batches of self-made samples from the mid-or-above size trial production, including but not limited to samples from mid-to-larger-size trial production and samples produced for the BE study. The accelerated and long-term stability research on the samples should last for at least three months before the bioequivalence study with recorded experimental data, and continue during the study.

A10: No, the reference listed drugs / test drugs to be used in the same bioequivalence study should come from the same batch.

A1: According to China NMPA's Announcement on Conducting Quality and Therapeutic Equivalence Evaluations of Generic Versions of Injectable Chemical Drugs, the MAH should select RLD from the RLD Catalog issued by NMPA, conduct therapeutic equivalence researches, and apply for the equivalence evaluation.

A2: From the perspectives of drug lifecycle management and risk control, the applicant should decide whether to buy a new RLD based on the research result and the situation after the changes.

A3: According to former CFDA's Application Documentation Requirements for Chemical Drugs Under the New Registration Classifications (Trial), the applicant should summarize the samples' conditions in the stability study as well as the study's conditions, indicators, and result, analyze the changing trend, and propose the drug's storage conditions and expiration date. The applicant should also compare the generic drug with its originator version and the drug with the same nonproprietary name listed in the Chinese Pharmacopoeia (ChP). The generic drug should have no lower stability than the originator drug and ChP-listed drug.

A4: The applicant does not have to choose RLDs from the RLD lists released by former CFDA. Instead, the applicant can choose the product considered to be equivalent to the RLD to perform as the reference drug according to NMPA's Statement on the Published RLDs (hereafter referred to as the Statement).

If the equivalence is too difficult to be proved / is wrong according to the Statement, but there is enough evidence to support the equivalence, the applicant can submit an official document, including the chosen drug's detailed information and relevant materials, to specify the difficulty to prove the equivalence and propose a solution to the Equivalence Evaluation Office, then the Office will discuss the matter with the applicant.

A5: For drugs without recommended RLDs, CDE will regularly discuss the proposed RLDs with experts according to the RLD selection principles in the former CFDA's Announcement on the Work Items about Quality and Therapeutic Equivalence Evaluations of Generic Drugs (No. 100 Announcement in 2017). Based on expert's opinions and the review of new generic versions under the same nonproprietary name, CDE will publish the official RLD lists regularly.

A1: There are three situations:

1. If the solution injection and the RLD have the same concentration rate but different volumes, the solution injection can be accepted for the evaluation. After clinical review, NMPA will conduct the equivalence evaluation of the strength within the permitted scope, and approve the equivalence evaluation if the strength meets the requirements.

2. Solution injection which has a different concentration rate from the RLD can be accepted for the equivalence evaluation. The technical review should cover whether the strength is proper considering the clinical usage and dosage. The recognized strength should be reviewed according to the quality improvement requirements. The strength that passes the technical review will not be considered as having passed the equivalence evaluation.

3. Powder injection, in which the strength is equivalent to the volume, can refer to the first situation above.

A2: As equivalence evaluation is administered under the nonproprietary names of different drugs, the applicant can directly submit the equivalence evaluation application for adding a new strength to the drug under the same nonproprietary name. To prevent the misuse of the strengths, the new strength should be within the scope for reasonable clinical usage and dosage, and equivalent with the originator drug or the RLD.

A3: According to the Announcement on Filing Bioequivalence Studies on Chemical Drugs, the drugs belong to the following five categories*, to seek equivalence evaluation, should first submit supplemental applications. With the approved supplemental application, the applicant can conduct the clinical research, then apply for equivalence evaluation after completing the research.

*Five categories:

1. Radioactive drugs, anesthetics, class 1 and class 2 psychoactive drugs, and chemical precursors.

2. Cytotoxic drugs.

3. Drugs not applicable to be verified the quality and therapeutic equivalence to RLDs by BE tests.

4. Drugs used in BE tests not aiming for drug registration in China or the quality and therapeutic equivalence evaluation of generic drugs.

5. Drugs considered by the applicant to have potential safety risks in the BE tests and need technical evaluation.  

A4: For new drugs applying for approval under the new registration classifications, they already have safety and efficacy evidence. For generic drugs applying for approval under the new registration classifications, they will be accepted and reviewed according to the principle that they are equivalent to the originator drug in quality and therapeutic effect.

For new drugs and generic drugs mentioned above, they don't need to go through equivalence evaluations. After approval, they will be included in China Marketed Drug Catalog.

A5: The applicant can submit a supplemental application for the waiver.  

A6: We advise the applicant to conduct stability study on the proposed drug according to stability study's guidelines. It is not mandatory to conduct the stability comparison study on both the proposed drug and the RLD.

A7: The tests are required if the manufacturing technique changes, but are not required if the injections already have clinical safety data.