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Since the reform of the drug review and approval system in 2015, the development of the domestic innovative drug industry has changed with each passing day, and finally in 2021, when the new crown epidemic is still ending, innovation policies are frequent, and the international situation changes, it has reached an inflection point
of differentiation.
At present, more and more local pharmaceutical companies are no longer limited to the domestic market, but are actively participating in the global market competition in accordance with international standards by increasing investment in research and development, and stepping out of the road of
internationalization.
So what should local companies do to successfully go overseas? Some experts pointed out that in addition to strengthening communication with regulatory agencies, it is also necessary to have enough understanding of international clinical trials, not internationalization for the sake of internationalization, but from the very top level design, even before the product enters the clinic
.
In the face of the ever-changing and fiercely competitive industry situation, how can domestic CROs help improve the efficiency of clinical research and development of innovative drugs and expand the opportunities for the internationalization of innovative drugs?
On October 14th, five industry experts from Northscope were invited in the live broadcast room: Dr.
Chen Gang, Chief Scientific Officer of Northscope, Professor Hu Bei, Chief Clinical Pharmacology Scientist of Northscope, Dr.
He Kun, Chief Statistician of Northscope, Mr.
Li Jigang, Chief Medical Officer of Northscope, and Mr.
Wang Tao, Senior Vice President of Northscope, around the theme of "how to maximize the clinical value of innovative drugs and international opportunities", to bring you wonderful analysis and discussion.
For gourmet readers, please watch
the full replay in the video version.
Chen Gang, Chief Scientific Officer of NorthscopeDr.
Chen Gang, Chief Clinical Pharmacologist of Northscope, Professor Hu Bei, Chief Statistician of NorthscopeDr.
He Kun, Chief Medical Officer of Northscope, Mr.
Li Jigang, Senior Vice President of NorthscopeMr.
Wang Tao"How to maximize the clinical value and internationalization opportunities of innovative drugs"
A single arm is still a single arm, but the rules are not loopholes
A single arm is still a single arm, but the rules are not loopholes Chen Gang: First of all, whether supervision is becoming stricter cannot be one-sidedly defined
.
In the 90s in the US FDA, there was already a very full discussion about single-arm testing, when is it allowed to do single-arm? There are two necessary conditions, the first is clinical urgent need, these patients must be incurable, then any promising drug can be given a conditional approval, also called accelerated approval
in the United States.
Second, the drug should reflect the corresponding efficacy
.
Can surrogate endpoints be used? Discuss
as appropriate.
Most of the applicable scenarios are terminal-line patients, and from the regulatory perspective, surrogate endpoints are allowed to initially determine whether the drug can bring benefit
to patients.
These two are the most basic conditions, more than 20 years later
.
The basic interpretation of this rule should still be consistent
.
But now the situation is the same as in the 90s, and it is different
.
The same is that the situation of clinical urgent need still objectively exists
.
But what's different is that the patient's potential choice is no longer unique
.
So from a regulatory point of view, in this case, it is still hoped that there will be a control group and potential options to do a comparison, rather than simply doing a single arm and then giving a conditional approval
.
In the late 90s, there was a great deal of discussion between the US FDA and the European Union, and that was the most famous theme of the Helsinki Declaration - the highest goal
must be to maximize the interests of patients.
This derives the concept of non-inferiority, whether the control group can use placebo, whether to use weaker standard treatment, completely from the perspective of maximizing patient benefit, then we must give patients the best treatment plan in clinical trials, even the control group must choose the best quality
.
So today, instead of stricter regulation, it is better to return to international standards
.
DH: The single arm has been used
by the FDA since the 90s.
This is for the consideration of maximizing the interests of patients, giving the rules a tilt, but we can't treat the rules as loopholes, so in 2006, when an ODAC meeting was held, the conditional approved drugs pulled out a list to see what were the supplementary tests that were not originally promised, and it turned out that many of them were not done, after all, the control means of drugs after the market are relatively limited, and since then there has been a rule, conditional approval research needs to be basically completed, or follow-up plans must reach consensus with supervision
。 Second, due to the lack of drugs or the lack of randomized trials in patients with fewer patients, the one-arm began from the end line in the early years, but now this rule has a generalization trend, which has led to a change in the FDA's caliber, although not unacceptable, but most tend to randomized trials
.
In addition, there is a trend change, which used to be small molecule drugs, and theoretically the efficacy of large doses is relatively good
.
Now that biological drugs are breaking out, the dosage is very different from chemical drugs, so
.
Doses that are too high can cause some problems
.
In fact, in 2010 and 11, the FDA did a statistic that about 80% of the approved drugs were high doses, and there were problems
with PMC (post-marketing commitment) or PMR (post-marketing requirements).
Hu Bei: From the perspective of clinical pharmacology, this question is essentially what data are the regulatory authorities based on when approving a new drug? Isn't confidence very sufficient? That is to say, the drugs you approve through single-arm trials are later confirmed to no longer need more trials, or some clinical problems have not been fully solved, because single-arm trials are relatively classical randomized controlled clinical trials and are an accelerated approval, so whether some clinical pharmacological studies of single-arm trials are sufficient, it is particularly important, because the essence of clinical pharmacology research is to confirm the dose and effect
of drugs.
Effects include the construction
of a relationship between clinical efficacy and safety signals.
Then, such a relationship construction is a research that needs to be carried out throughout clinical research and development, and more adequate data support is needed, because various indicators are mutated in the population, and the dose-effect relationship obtained in a smaller population in the single-arm trial, whether the relationship between some indicators is not stable enough because of the deviation of the sample size, all need to be confirmed
in a relatively large population 。 Therefore, for different drug studies, for the construction of quantitative relationships between different indicators, how large is the sample size? It is necessary to conduct large-scale confirmatory randomized controlled clinical trials to confirm that the work of dose selection and dose optimization has been sufficient, and specific cases are needed
.
Li Jigang: The review of supervision is not scripted, but keeps pace with the times, and sometimes there is a certain degree of flexibility
in mastering a standard.
In 2014, Gilead's Edrani was granted one-arm conditional approval
.
But until 2021, there are new companies that are approved
with one arm for the same indication.
From 14 to 17 years, 3 products for the same indication have been approved
.
So from the perspective of keeping pace with the times, this is a possible potential vulnerability
.
Second, at that time these products were doing randomized controlled confirmatory studies, the results have proved that there is no clinical benefit in terms of survival, and may even have clinical harm, at the beginning of the selection of the dose, everyone is using the maximum tolerable dose to enter the second phase to obtain the greatest efficacy, but this dose for different groups of people or different patients, now seems to be a significantly higher dose, so there will be relatively large toxicity and damage, so in the regulatory review process, can not be carved into the sword, think that five years ago, Standards from seven years ago still apply
today.
Therefore, it is necessary to judge the trial design plan
in combination with the clinical needs.
If there is a very large unmet need at the time, regulators may be more willing to use alternative endpoints to review and approve a product, and if the relevant treatment needs have been well addressed, more corroborative evidence may be required to approve the product
.
Medicine Cube
Maintaining communication is the key to advancing clinical trials together with regulators
Maintaining communication is the key to advancing clinical trials together with regulators Gang Chen: Now there are more and more strategies to file in the United States or the European Union, and then use bridging tests in China or Japan, and with the development of the trend, MRCT (international multi-center) is becoming more and more inevitable
.
ICH E17 and E5 have given clear guidelines on what kind of test results can be accepted
by global regulatory authorities.
E5 is local first, for example, after the European and American experiments are completed, you have to find local to redo
it in Japan and China.
E17 requires MRCT to meet certain conditions, and the recent ODAC meeting also commented on the issue of
single patient population.
Therefore, we are going international, and the guidelines and regulations related to ICH must be very familiar.
He Kun: Now seeking declaration in the FDA, the previous standards will definitely not work, but it is not to say stricter or tighter, more is to unify the standards, to consider the diversity of MRCT, but also to understand the local market situation, the size of the indications, whether the clinical urgent need, comprehensive judgment
.
For sponsors, they must attach importance to the opportunity to communicate with the regulator, actively prepare, and understand in advance the issues that the regulator may be concerned about, as well as the views they want to express and the issues
to consult.
Hu Bei: Now the globalization of innovative drugs is also a trend, and Chinese pharmaceutical companies will also go global in the future, and will face exchanges
with reviewers from European and American regulators.
In the face of regulatory issues, whether it is product establishment, R&D strategy or program design, as the sponsor, we should pay great attention to providing evidence and providing the basis
for data selection from different dimensions.
In this way, the efficiency of
communication can be improved.
In addition, you should be particularly familiar with the regulatory authorities you are talking to, the usual requirements for drug development in the corresponding therapeutic area, or some general standards; Third, we should also be familiar with similar products and the specific requirements of regulatory authorities, so we should attach great importance to the collection and concretization
of data and evidence.
Li Jigang: In the past two years, CDE has intensively issued many guiding principles, 71 the year before last and 87 last year
.
These guidelines are important references
for project establishment, including design.
Therefore, clinical research should start with the end, and the entire registration path should be considered
for a long time during phase I clinical trials.
Medicine Cube
Draining the value of every piece of data is to reduce costs and increase efficiency
Draining the value of every piece of data is to reduce costs and increase efficiency Wang Tao: From the perspective of clinical operation, there are two main levels to reduce costs and increase efficiency, and all costs of clinical operation are divided into direct costs and indirect costs
.
The direct cost is actually very simple, everyone can see, that is, we want to do a clinical trial, we need all the labor, hospital, suppliers, experimental drug costs, direct costs to improve efficiency and reduce costs, on the one hand, rely on more reasonable, scientific clinical design, such as sample size, follow-up arrangements, etc
.
The second level is the implementation level
of clinical operations.
Deliver greater efficiency
from the executive level of clinical operations.
Hidden costs, such as the speed of research that determines market share, the potential quality problems that determine the success or failure of research, etc.
, are difficult to measure directly and require experienced estimates
.
At the same time, we must also objectively realize that whether it is direct or indirect costs, part of which is rigid costs, which exist objectively and cannot be avoided, and such costs also determine the quality and efficiency
of clinical research.
Li Jigang: Product strategy is very important in reducing costs and increasing efficiency, relying on scientific top-level design, avoiding competition, shortening cycles, controlling sample size, improving progress, and meeting patients
on the clinical demand side.
At the same time, it is necessary to flexibly grasp the preferential policies of supervision, such as priority review, breakthrough progress, exemption from clinical trials, accelerated review, etc
.
Clinical trial design is not only a medical issue, but also a comprehensive effort
of various departments and specialties.
Chen Gang: The efficiency of clinical trials should be understood
from multiple angles.
In a sense, cost control should be put last, the first thing to consider is efficiency, and the most important thing is to improve the probability of trial success, because the measurement of cost is based on success
rate and efficiency.
Therefore, the most avoidable mistake is due to mistakes
in the design process.
Leads to the failure of clinical studies of
effective drugs.
There are only two reasons for the failure of clinical trials, one is natural disasters and the other is man-made disasters
.
Under the premise of translational medicine and precision medicine, even if natural disasters are rarely harvested, it is still possible to find a precise small range of people to benefit
.
But man-made disasters, unsuitable designs lead to failure, which is irreparable in all dimensions
.
Hu Bei: The success of clinical trials actually requires that the benefit-risk ratio of each patient participating in the study can be maximized
.
Considering individual differences, achieving this is still complex and requires a clear interpretation
of the variation between the various parameters of the population, as well as the variation between the parameters.
It's about squeezing out the value
contained in every piece of data.
In the data obtained in good quality control clinical research, the existence of each observation value has its inevitability, how can the inevitability behind each data be analyzed? As a clinical pharmacology research that runs through the whole process of drug development, it pays special attention to and constructs the dose-efficacy relationship
of drugs under investigation.
And the research results will be translated into cost-effectiveness and implemented into specific clinical research experiments
.
In this way, clinical outcomes can be controlled
by maximizing the benefit-risk ratio for each patient.
Li Jigang: Risk prevention is also one of
the important considerations for reducing costs and increasing efficiency.
For example, copying clinical design is likely to encounter problems that are not easy to detect in advance, such as racial differences and regional differences, so clinical design should pay attention to many details of the program elements to achieve risk prevention
.
The above is our summary of the essence of this live broadcast for you, for more dry goods, please watch the video version of the replay
.
【Friends of the Cube】In the live broadcast room, we will pass on more professional medical information knowledge with big coffee, and we will continue to bring you more insights from industry experts, so stay tuned
.
