Original research, imitation of the "same" survival "difference"

When you search on the Internet with "imported" and "domestic" as keywords, there will be a phenomenon of "asking the same question", from milk powder, snacks, drugs to cars, furniture, electrical appliances... Every field has the same question - is it better to import or domestic to produce?

In order to answer questions, some people used disassembling the machine, analyzing the ingredients, tasting and other ways to "personally" control, which attracted a lot of attention...

But putting aside the essence of the problem, what the people really care about may not be the difference between "import" and "domestic production", but higher quality.

So, what is the difference between domestic and imported quality? Today, Xiaobian uses the example of cancer drugs that are closely related to life, from the most important aspects of efficacy and price, and analyze with you what is the matter of imported original drugs and domestic generic drugs?

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Efficacy: The same or the same

In 2016, the implementation of the consistency evaluation of generic drugs was officially introduced in a programmatic document, requiring that the generic drugs and the imitated original drugs must be consistent in quality and efficacy, and the evaluation method is to confirm the efficacy of generic drugs through bioequivalence tests [1].

How to determine whether a generic drug has a qualified bioequivalence?

The criteria for judging bioequivalence are based primarily on several important parameters of the drug concentration curve: area under the drug concentration-time curve (AUC), peak concentration (Cmax), and peak time (tmax)[1].

According to the 2018 consistency evaluation training instructions of the Drug Evaluation Center of the State Drug Administration, the numerical range of the 90% confidence interval of the above parameters is 80% to 125% of the reference preparation, which can be judged as biological equivalent [1].

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The bioavailability of generic drug A is 80% of the original drug C, then A can pass the consistency evaluation;

However, it is interesting that generic drug A is considered to be biologically equivalent to the original drug C and has passed the consistency evaluation, but there is actually a 20% difference between A and C, how much will this be clinically magnified, and does the bioequivalence of the generic drug mean that it is really equivalent? It's worth pondering.

Below, we take the original research and discontinuinib and the imitation of the original research and the imitation of the rootvatinib as an example, to see the similarities and differences between the imported original drugs and the domestic generic drugs.

same? different? Let's look at the pH first

pH is a very important influencing factor in bioequivalence testing of generic drugs. In bioequivalence testing, the consistency of the dissolution curve of the generic drug and the original drug in different pH media needs to be measured as an important consideration for evaluating the bioequivalence of the drug.

(Dissolution curve refers to the relationship curve between drug dissolution and time in the drug dissolution test, which will directly affect the bioavailability of the drug.) ）

Why do I need to measure in different pH media?

The reason is simple, the pH of people with different ages and different physical conditions is different (the pH value here refers specifically to the pH in stomach acid). People with normal stomach acid have a lower pH; people with lack of stomach acid have a higher pH, which is also the stomach acid environment of most elderly people.

It is precisely because of such differences that the determination of the dissolution curve of generic drugs in a variety of pH media and the comparison of the dissolution curve of the original drug are extremely important, and only when the dissolution curves of different media are consistent, is the consistency of high standards.

With the above concepts in mind, let's take a look at the consistency of the remvatinib imitation and the original research lunvatinib dissolution curve in different pH media.

According to public data, when the generic products of a certain enterprise 1 are consistent with the dissolution curve of the original research lunvatinib, the pH of the dissolution medium is 4.5, that is, the stomach acid environment of young people; and in the elderly with a dense concentration of liver cancer patients, the dissolution curve data of pH of 6.8 is not disclosed, and whether it is consistent with the original research and research lunvatinib cannot be determined.

In the dissolution medium with a pH of 6.8, the dissolution curve is not consistent with the original research lunvatinib, as mentioned above, the dissolution curve will directly affect the bioavailability of the drug, in other words, in the dissolution medium with a pH of 6.8, that is, in the stomach acid environment of the elderly, it is impossible to obtain the rumination curve that the rumination curve is consistent with the bioavainib of the original research lunvatinib.

On the above public data, it is not difficult for us to find that although the imitation of renvatinib has completed the consistency evaluation, whether it can obtain all-round consistency in many aspects needs further verification.

equivalent? Same effect? Look at the clinical data

The original research lenvatinib liver cancer indications have been on the market for 13 years (2005-2018), from phase I to phase III clinical studies, with a cumulative enrollment of nearly thousands of patients. The Global Multicenter Phase III Clinical Study (REFLECT study) shows that in the Chinese subgroup, renvatinib achieved a historic breakthrough in the treatment of liver cancer. The median overall survival (mOS) of the renvatinib group was 15.0 months, the median progression-free survival (mPFS) was 9.2 months, and the objective response rate (ORR) was as high as 43.8 percent (mRECIST)[3].

Since its listing, as of December 2021, there have been nearly 200,000 liver cancer patients worldwide, of which nearly 130,000 are from China. Data from real-world studies show that the efficacy and safety of proto-lamvatinib are highly consistent with the results of its phase III clinical studies.

Because of the lack of key clinical research data, the data on practical application in the real world are also lacking, and the efficacy and safety still need time to prove.

copy? imitate? Look at the craftsmanship

Excipients and preparation processes are parts of the original drug that will not be disclosed to the public.

Original research and development process of lumphavatinib in the research and development process has spent two and a half years to explore the most suitable ratio of excipient calcium carbonate and the most suitable particle diameter to achieve the best dissolution rate and stability, this is called the perfect "gold ratio", in the case of key preparation process data is not public, lunvatinib imitation is indeed difficult to completely copy. More importantly, differences in formulation processes can also lead to differences in efficacy and safety [1].

With the introduction of the consistency evaluation in 2016 and the strengthening of national supervision, the quality of generic drugs has been significantly improved. However, in order to achieve complete consistency between efficacy and safety and the original drug, further verification of clinical data is expected.

Price: Good value or genuine

In the past, we regarded "low price" as the "advantage" of generic drugs, and found a way out for them to compete in the market with the original drugs. Today, with the introduction of national policies and the promotion of medical insurance, the original research drugs are more and more accessible to patients.

Recently, a number of lunvatinib imitation products for sale, the price of 2100-2800 yuan, and the original research lunvatinib price is not much difference, after medical insurance reimbursement after the price difference is even more minimal. Combined with clinical data and price, the original research and lenvatinib is indeed worthy of the real price, is a more cost-effective choice.

"Is it better to import or domestic?" The topic has been hotly discussed for half a century, and in today's rapid development of material civilization, what we care about is not the identity of import and domestic production, but the quality behind it. In other words, we prefer to pay for quality.

At the same time, the era of "quality determines everything" rather than "low price determines everything" in China's pharmaceutical market has arrived. If there is no obvious advantage in the price of the drug, and the efficacy has not been verified by large-scale clinical studies, then the real thing is the wiser choice, especially for tumor patients with a short treatment window. After all, there is no chance of trial and error in life.

We are fortunate to be born in a good era of choice, and we look forward to the advent of more and more drugs with "close to the people" price on the basis of quality assurance, and better serve patients in China and even around the world.

bibliography

Shen Lingling. Interpretation of the consistency evaluation policy of generic drugs[J].Herald of Medicine. 2020(05):722-727.

Xie Mufeng. Dissolution curve with discriminating force. China Journal of Pharmaceutical Industry.2014,45(7)

[3] Instructions for lumphavatinib mesylate capsules

Author | Wang An School of Medicine

Source | Find a pharmacopoeia