Since 2015, my country has initiated the process of in-depth reform of the drug review and approval system. “Improving the quality of generic drugs and accelerating the quality consistency evaluation of generic drugs” has become one of the five major goals of the reform. Before the end of 2018, the completion of the quality consistency evaluation of the oral solid preparations of chemical drugs in the “National Essential Drug List” approved before October 1, 2007 has become the specific task of the first stage. In March 2016, the State Food and Drug Administration forwarded the “Opinions on Carrying out the Quality and Efficacy Consistency Evaluation of Generic Drugs” issued by the General Office of the State Council, and the curtain of consistency evaluation was officially opened.
Realizing the clinical substitution of original research drugs, reducing the overall drug price level, and carrying out the quality and efficacy consistency evaluation of generic drugs have been placed high expectations by all parties in the society. But experts said in the interview that the consistency evaluation of generic drugs is not as simple as it seems.
What are original research drugs and generic drugs
From the perspective of drug development, drugs on the market can be simply divided into original research drugs and generic drugs.
Zhu Xinbo, professor of pharmacology at the School of Pharmacy of Wenzhou Medical University, introduced that the original research drug refers to the original new drug that has been screened for thousands of compounds and passed rigorous preclinical and clinical trial verification before being approved for marketing; its research and development usually requires It takes about 10 years and an investment of about 1 billion US dollars. Generic drugs are those that have the same active ingredients, dosage composition, route of administration, effects, and indications as the original drug, but can be different in terms of shape, release mechanism, and inactive ingredients.
During the patent protection period, the original research drugs are usually more expensive, so as to provide manufacturers with an economic return on investment and encourage them to continue to research and introduce new drugs. Due to the high price of the original patented drugs, which has brought a greater burden of medical expenses, after the patents of the original researched drugs expire, governments of various countries will actively promote and encourage the introduction of generic drugs on the market.
Experts said that in the United States, where the pharmaceutical industry is well-developed, the approval policy for generic drugs has also gone through a process of exploration from loose to tight to moderate. Before 1962, generic drugs could be developed and submitted for approval based solely on published medical scientific literature, and many low-quality generic drugs were also produced; after 1962, the drug regulatory authority required generic drugs to be as safe and effective as the original drugs. Sexual clinical trials have greatly increased the development and production costs of generic drugs, leading to a reduction in drug varieties and an increase in prices.
“The development and approval of generic drugs cannot be too easy or too difficult. Finally, a moderate method was found.” Zhu Xinbo introduced that in 1984, the United States promulgated the “Drug Price Competition and Patent Term Restoration Act” (Hatch-Waxman Amendment), creating The modern approval system for generic drugs has been established, which stipulates that generic drugs do not need to repeat a series of clinical trials of the original drug, but only need to prove the bioequivalence of the generic drug and the reference drug. The amendment is regarded as a milestone in the modern generic drug industry. “The main purpose of the Hatch-Waxman amendment is to balance the goals of two important public policies, not only to ensure that the original research drug manufacturers are encouraged to develop more valuable new drugs; at the same time, to ensure that their imitations can be quickly marketed to benefit consumers. “
Where is the gap between domestic generic drugs
Since the start of the new round of medical reform, my country has gradually established a basic medical security system that covers the entire population. With the continuous improvement of the medical insurance protection level, medical and health expenditures are also increasing rapidly year by year, which brings both the safe operation of the medical insurance fund and the personal burden of patients. It’s a lot of pressure.
“Under this reality, it is very meaningful to encourage the clinical substitution of generic drugs to the original research drugs. However, the generic drugs produced in my country are indeed somewhat overwhelming.” Zhu Xinbo said that my country’s generic drug approvals have also gone through a tortuous process. Of the nearly 190,000 existing drug production approval document numbers, more than 90% were approved from 2002 to 2006. “Behind the crazy approval is the low quality of the drug”. Zhu Xinbo said that the quality of generic drugs approved for marketing before 2007 in my country is worrying. The main reason is that bioequivalence (BE), the most critical indicator, was not done well in the development process.
Experts said that the degree of drug absorption is a key indicator in the BE test. As long as the absorption degree of the imitation product can reach 80% of the reference product, the two can be basically determined to be bioequivalent. Therefore, the quality of the reference preparation directly affects the reliability of the BE test results. According to previous policies and regulations, the reference preparation should generally be an original drug of the same dosage form that has been approved for marketing in China, but it may also be considered to use a leading product that has been marketed. In actual examination and approval, drugs that meet my country’s drug standards and that are already on the market can become generic targets; in order to save costs, generic drug manufacturers generally use the lower limit of the generic targets for development approval, assuming that the absorption level of the first generic drug can reach the original research drug 80% of the second generic drug is the first generic drug, so its absorption may only be 64% compared with the original drug.” By analogy, before the reform of drug review and approval, the quality and efficacy of most domestic generic drugs in my country can be imagined.
Experts frankly said that most of the drugs currently produced in my country are generic drugs, but most generic drugs have not been evaluated for consistency with the original formulations.
What is the focus of consistency evaluation
Since the quality and efficacy of most generic drugs are far less than those of the original research drugs, they themselves cause a certain amount of waste of medical expenses; moreover, the “incompetence” of generic drugs also makes it difficult to effectively challenge the clinical use and price of the original drugs. The original research drug that has passed the patent period can still maintain the original sales price in my country.
To this end, my country has started the reform of drug review and approval since 2015, and adjusted generic drugs from the current “drugs imitating existing national standards” to “drugs with the same quality and efficacy as the original drugs”. The review and approval must use the original research drug as the reference preparation. For the huge stock of marketed generic drugs on the market, the consistency evaluation shall be carried out in phases and batches in accordance with the principle of consistency with the quality and bioequivalence of the original drug.
According to Chen Hao, Center for Pharmaceutical Policy and Management, Tongji Medical College, Huazhong University of Science and Technology, since generic drugs are still difficult to form a comprehensive and real challenge to the original drugs in the short term, it is an indisputable fact that there is a certain degree of inflated prices in the pharmaceutical field in my country. Many people have high hopes for promoting the formation of full competition in the drug market through the consistency evaluation of generic drugs, thereby reducing drug prices.” However, Chen Hao believes that the primary task of the consistency evaluation of generic drugs is to eliminate those drugs that are in fact unqualified. The possible competition and price reduction effects should not be overemphasized “, let alone the review process. , Otherwise it will lose the meaning of consistency evaluation.”
Chen Hao emphasized that the quality and efficacy consistency evaluation of generic drugs should not only focus on the product itself. It is not difficult to produce a batch of high-quality drugs through consistency evaluation. What is more worthy of attention is the one behind the production of drugs. The construction of the entire quality management system still requires the regulatory authorities to strengthen supervision in accordance with the new regulatory requirements, and resolutely avoid the consistency evaluation from being reduced to a “one-off evaluation”, to promote the entire industry to fully meet the standards and high requirements, and to promote the true formation of the industry’s self-discipline culture” .
How to correctly understand BE test
Zhu Xinbo introduced that the BE test of general drugs is designed according to the principles of two preparations, two sequences, two cycles, single times, and crossovers. Most of them recruit a certain number of healthy subjects, take reference preparations and imitations one after another, and measure various parameters such as blood drug concentration at specified time points. After substituting the relevant data into the software, compare the dissolution curves and other indicators of the two for evaluation.
“In fact, the BE test itself has certain natural defects.” Zhu Xinbo said that in order to reasonably control the development and production costs of generic drugs, it can only be assumed that bioequivalence is a good substitute for drug safety and effectiveness. It is assumed that the research data obtained in healthy people is equivalent to real-world patient research.
According to the relevant regulations of my country’s drug supervision, clinical trials should be conducted for innovative drugs that have not been marketed at home and abroad. The minimum number of cases in the trial group is 20-30 cases in phase I clinical trials, 100 cases in phase II clinical trials, and 300 in phase III clinical trials. Cases, 2000 cases in phase IV clinical trials. The BE test is required for the approval and registration of generic drugs, and the number of participants in the test is required to be 18 to 24 cases.
According to the principle of selection of subjects in BE trials, the age should be over 18 years old, covering the characteristics of the general population. If the drug is mainly applied to the elderly, as many elderly subjects 60 years and older should be selected as possible. “For the safety of subjects, in reality, very few BE trials enroll elderly people; children are even more important. Not allowed to be subjects.” Zhu Xinbo said that due to various reasons, college students have become the “main force” of the BE test. The scientific research model has replaced the clinical model. It is a natural academic loophole in the BE test, which also determines the BE test and the There are certain differences in the use of drugs in the real world.
What to watch out for when replacing generic drugs
“BE research conducted by generic drugs in healthy subjects cannot replace clinical patient pharmacokinetic data, especially for special populations, such as organ transplant patients, patients with comorbidities, and patients with combined application of multiple drugs, etc. “Zhu Xinbo said, because the difference in pharmacokinetics and bioavailability may be masked by a small number of samples and large individual errors, it is not easy to find differences outside of this type of experiment.
Zhu Xinbo said that in addition to the limitations of the BE trial itself, there are many problems that can also lead to differences in the clinical efficacy of generic drugs and original drugs. For example, the production of new and unconfirmed related substances after changing the production process may have a curative effect. The crystal form changes caused during the synthesis of raw materials and the preparation process can also cause changes in the efficacy of the drug, and the interaction of excipients is also difficult. aware.
“Generic drugs that do not meet certain standards in process, quality control, and crystal form cannot well improve patient symptoms and prolong survival time. On the contrary, they may delay the patient’s condition, cause the patient to miss the best treatment time, and lose the opportunity to improve the quality of life.” According to Zhu Xinbo, in view of this, countries around the world have different policy attitudes towards the substitution of generic drugs for original research drugs. In the United Kingdom, France, Italy and other countries, if the prescription issued by a doctor is an original research drug, it is not allowed to substitute a generic drug.
Zhu Xinbo believes that in most routine cases, generic drugs that pass the consistency evaluation can be used instead of the original drugs, but there are also special cases that are not suitable for substitution. “Critically ill patients, drugs with high toxicity and narrow therapeutic index, Hematological diseases, cardiovascular and cerebrovascular diseases, severe infections and other diseases are difficult to control patients, elderly, children, pregnant women and other high-risk patient groups. Under these circumstances, it is necessary to be extra cautious to substitute generic drugs for original research drugs.”
“There are certain differences in tablet hardness, dissolution, excipients, and preparation processes between generic drugs and original drugs. These influencing factors may not be reflected in healthy people; but in elderly patients, due to the degradation of physiological functions and the impact of disease The process of different preparations in the body may have significant differences.” Zhu Xinbo particularly emphasized that due to the decline in metabolism in the body of elderly patients and the frequent use of multiple drugs, it is very difficult to evaluate the bioequivalence of generic drugs and original drugs. “In the United States, experts have suggested to the drug regulatory authorities that before conducting BE studies in a large number of elderly patients, it is not advisable to substitute generic drugs for the original drugs in the treatment.”