Take your neighbor as your teacher ｜ Take the wrong road less, and the secret of drug success in the sea!
With the development of biopharmaceutical industry in China, more and more pharmaceutical companies are actively seeking the sea route to break through the bottleneck of drug commercialization by opening the door to emerging markets. howeverThe fullness of dreams can’t sometimes replace the realistic bone feeling. At present, there are not many drugs that really have the ability to stand on the international market.It is a long way to go for drug research and development to move from the level of innovation in China to the level of international innovation. The change of innovative ideas, the improvement of innovative ability and the incubation of innovative technology all require great efforts and enough patience. Every pharmaceutical enterprise must go through many tests in the process of achieving overseas success.
How to make an international R&D route to stand out and go to sea successfully?On this issue, Dr. Mann Fung, founder/CEO of Tuochuang Bio, summed up some experiences from several international R&D failure cases for your reference.
"Learning from neighbors" is an excellent column of Dr. Mann Fung on sharing his clinical experience.Dr. Mann Fung holds medical licenses from four states in the United States, and has been an expert in drug evaluation of FDA. He has more than 30 years of experience in drug research and development, clinical and management of multinational pharmaceutical companies. Dr Fung was the medical director of Lilly in Japan and Greater China, and has presided over the clinical development of Lilly’s heavy drugs. Later, he joined Johnson & Johnson as the global vice president of cancer drug research and development, and was fully responsible for the commercial evaluation of cancer drug research and development and innovation projects of Johnson & Johnson Asia-Pacific Innovation Center, and presided over the clinical development and successful listing of a new generation of small molecule BTK inhibitor irutinib and other drugs. Dr Fung also worked as a venture partner at Fidelity’s Stowe Capital. In 2019, Dr. Fung, with his profound insight and rich experience in the pharmaceutical industry, and Dr. Mark Chiu jointly founded Tavotek, a company focusing on protein’s engineering transformation and multi-drug development.
01
Clinical failure for a pharmaceutical company,
Apart from the frustration of scientific research and the huge cost, what other important negative effects are there?
The failure of the costly drug in Phase III clinical trial or its failure to be approved by the FDA not only means that the drug may die, but may even have a fatal blow to the whole company. Recently, there have been several well-known cases in the industry. For example, the company’s share price dropped by 64% after the treatment of anemia caused by chronic kidney disease was not approved by the FDA. Rafael’s drug for treating pancreatic cancer and AML failed to reach the end of phase III clinical trials, and its valuation was immediately cut by 78%.
In addition, clinical failure may also directly lead to the company’s massive layoffs. For example, Beyond Spring Company plinabulin’s CIN indications failed to pass the FDA’s approval, and the company had to lay off 34% of its employees in the United States quickly. However, this kind of failure does not only happen to small companies, but also to large pharmaceutical companies. At the beginning of this year, Pfizer and Merck failed to obtain FDA approval for new drugs respectively, which also caused a small drop in share prices.
Generally speaking, any major late clinical trial failure or failure to be approved by the FDA for listing will directly lead to the company’s stock price decline, a large number of layoffs, and significant financial losses, so we have to be cautious.
02
Why do stones from other mountains attack jade?
Through the regression analysis of some clinical failure cases in Europe and America, we may find some strategies to improve the success rate. In fact, most of the drugs born in the laboratory can’t be fully verified for their efficacy and side effects, and drug evaluation agencies won’t even receive clinical applications for new drugs. Even if the drugs are pushed to the clinical stage, many will face failure. Most of the reasons for failure are deeply hidden in the complex mechanism of pharmacology and efficacy. At present, we humans do not have a mature scientific path to explain and reveal the secret perfectly.
howeverThe failure of research and development of some new drugs is due to the mistakes in the design and implementation of clinical programs.. This may be the direction we can work hard to avoid bad luck and fall into the deep pit that other companies have fallen into. Generally speaking, starting from here may be a good start to improve the internationalization ability of drugs.
03
Whether the clinical success rate is high or low,
Is there any corresponding reference data to prove it?
There are many such statistical studies, which can be found everywhere in literature and on the Internet. Among them, Paraxel has published some reference data a few years ago. The data show that the success rate of the first phase is about 2/3, the second phase is 1/3, and the third phase is also 2/3. After the success of Phase III clinical trial, the success rate of NDA/BLA application finally approved for listing can reach 90%. It can be seen that the most likely to fail is the second-phase clinic, andThe whole process can be completed, and the overall success rate is about 1-2%.
In addition, these data also compare tumor drugs with non-tumor drugs.Non-tumor drugs seem to be more likely to succeed.For small molecule drugs and macromolecular antibody drugs,The success rate of antibody drugs seems to be higher.
Of course, these data are the results of analysis several years ago, and they have changed in recent years, but the general trend is still the same, that is,The early clinical success rate is high, and the late clinical success rate is relatively low.
04
Successfully passed the second phase of clinical drugs,
Will clinical phase III still fail?
The FDA published a regression analysis in 2017 and found that many drugs that were successful in the second phase still failed in the third phase. According to the analysis report, 22 drugs, vaccines and medical devices all showed positive results in the second phase of clinical practice, but they suffered from waterloo in the third phase of clinical practice. Some of the second-phase clinics are still quite large in scale, and even other indications have been successfully approved, but their third-phase clinics are still unsuccessful.
Two obvious failures are:
1) Short-term therapeutic effect cannot be confirmed in long-term clinical trials;
2) The side effects that can’t be seen in the short term will appear in the long-term clinical trials.Generally speaking, among these 22 new medical products, the third phase of 14 products did not run out of the second phase, and the toxic and side effects of 1 product were more obvious, while the curative effects and toxic and side effects of 7 products were not up to standard. In two of them, the patient’s condition did not improve after taking the medicine, but it was more serious. These cases confirmed the necessity of phase III clinical practice, and also provided some information resources to enhance the success of phase III clinical practice. See the table below for details:
The FDA’s approval cases show that there are inconsistent test results between phase 3 clinical and phase 2 clinical of 22 medical products.
In another report released by Paraxel, we also summarized 38 drugs that did not run out of the clinical positive efficacy data of Phase II in Phase III, and some of the data were also very interesting: the most failed drugs were tumor drugs, with a total of 18 drugs, and the average number of people enrolled in each drug was about 1,000; However, the clinical trials with the largest average number of participants are for the treatment of cardiovascular diseases, with as many as 10,000 people in each project.
This information shows that,The research and development of cancer drugs is risky, but the research and development cost of new drugs for cardiovascular diseases and diabetes is even higher. The number of people enrolled in the third phase of clinical trials is tens of thousands, which is not easy for ordinary small companies to try.
05
"uncontrollable" reasons leading to different test results in Phase III and Phase II
First of all, the factors of human illness are quite complicated. If we only treat some patients with a specific pathogenic factor, there is no guarantee that it will have a curative effect. Moreover, the interaction between drugs and patients’ bodies is also very complicated. No matter how beautiful the previous "pharmacological hypothesis" is, sometimes the expected clinical treatment effect may not be obtained. Secondly, although Biomarker have been widely used, most of them still can’t predict the clinical outcome reliably. Trapped by the limited scientific knowledge of human beings, many clinical failures generally have one or more of the following manifestations:
Pre-clinical results cannot be converted into clinical results;
Although the target is bound by drugs, it fails to achieve the expected effect on the disease or the force is not enough;
The research object is in the stage of gene composition and disease condition, so that there are many subject variability)； in other potential diseases;
Different levels of "anti-drug antibodies" (ADA) produced by biological agents.
06
"Controllable" Causes of Other Phase III Clinical Failure
Paraxel’s research report has summarized the controllable reasons of clinical failure, which can be divided into the following five categories:
These controllable factors can generally be predicted before the clinical start, such as:
The understanding of disease pathway is not complete enough;
Lack of strict and rigorous experimental design scheme;
Wrong control group
Inappropriate entry criteria;
Insufficient drug dosage was used;
Lack of reliable biomarkers;
Improper design of "salvage therapy" after initial treatment failure;
Jump directly from phase I clinical stage to phase III, or insist on entering phase III despite poor data in phase II;
Through careful pre-clinical planning and efficient clinical implementation, most clinical failures caused by these "controllable" factors can be avoided. In practice, many pharmaceutical companies are trying their best to avoid unnecessary failure risks in the whole process of drug research and development, including pre-clinical and post-clinical.valueThere are two well-known research and development frameworks for new drugs. One is Pfizer’s "Three Pillars of Drug R&D Survival Framework": 1) Accurately deliver drugs to the target position; 2) tightly bind the drug to the target; 3. Effectively regulate the function of pharmacological pathway after target binding.
In addition, AstraZeneca has also put forward the R&D 5R framework, that is, the right target, the right organization, the right safety, the right patient and the right business potential. The specific details are as follows for your reference:
AstraZeneca’s R&D Cheats-"R&D 5R Framework"
07
For a drug that has achieved clinical success in Phase III,
Why did NDA/BLAs fail miserably?
An article in November 2021BioSpace newsIn terms of analysis, the company releasedThree drugs that have not been approved by FDA recently.They are rejected for different reasons, but they are quite representative., the details are as follows:
1. Iterum Company was informed by FDA that its sulopenem antibiotic was not approved for urinary tract infection. The reason for rejection was that the FDA did not agree with the control group drugs it chose. In addition, the FDA also suggested that Iterum should redo new clinical trials.Choose the dosage carefully.
2. The NDA of a dehydrated alcohol drug from Eton Company used to treat methanol poisoning was also rejected becauseThe quality of their European drug manufacturers is not recognized by FDA.
3. A drug named Nuplazid from Acadia Company has been approved for mental disorders related to Parkinson’s disease, but FDA thinks it is applied for mental disorders related to Alzheimer’s disease.Phase 3 clinical research is ineffective, especially some subgroups are rejected because of the lack of obvious statistical differences..
Famous medical media Fierce Biotech On its website, a number of new drugs that have not been approved by FDA recently are listed, for your reference:
In addition, in February, 2022, the People’s Daily Health Client also summarized the reasons for the refusal of 17 FDA drugs in the past year as follows:1) The safety data is in doubt; 2) Single clinical data of patients; 3) The clinical benefit is not clear; 4) There are defects in production facilities.Among them, the single clinical data has been repeatedly mentioned in many rejected cases, because most of the listing applications only have a phase 3 clinical data. To be honest, if the data is bright, only one phase 3 or even phase 2 clinically approved drugs are everywhere. However, if the data is average, or the data source is only a single region rather than a global multi-center experiment, then it is of course relatively difficult.
You may wonder whether this kind of FDA refusal case has been rising in recent years, and it is still relatively stable. Evaluate Vantage, a well-known medical media, made a research on this last year and found that from 2017 to 2020, more than 30 drugs failed to pass the FDA’s approval and listing every year. Although the number increases or decreases slightly every year, we can see that the number of failed projects has been relatively stable in recent years, so you don’t have to worry too much.
08
Take your neighbor as your teacher and take the wrong path less.
If we know how to avoid all kinds of "big pits and small pits" in the whole drug development process, the success rate of listing application can naturally be improved and the internationalization ability of drugs can be established.Learning from the failure cases of other overseas countries is one of the only ways to avoid the pit.
Generally speaking, these experiences can be summarized as follows:1) Taking the evaluation standard of the national regulatory agency of the target country as a work benchmark, considering the characteristics of the industry, the evaluation standard of FDA is relatively worth learning; 2) It is very important to keep close communication with the regulatory authorities, especially when there is a problem, we must immediately cooperate with the regulatory authorities to solve it; 3) The focus of clinical research and development should be on curative effect, research scheme design, safety and CMC quality.
In a word, close communication with regulators and following their requirements and suggestions are the golden rules to ensure the smooth progress of R&D and improve the success rate of approval.
09
tag
It is the strategic goal that every biotechnology company actively pursues to base itself on its own country and realize its scientific and technological value in the vast international market.Whether the strategy of going to sea is successful or not depends on its own scientific research ability and clinical development ability.Only by studying and working hard in practice and giving yourself enough time can you hear the sound of the last flower. And in all the learning paths,Learning from the R&D failure cases of international pharmaceutical companies can be described as a good path.
To sum up, based on the subtle and difficult nature of science itself, it is difficult for us pharmaceutical manufacturers to grasp all the factors that determine the success or failure of each drug, but what we can grasp must be done as we can.