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"It is important for biopharmaceutical companies to reach consensus with regulators in the process of promoting their biopharmaceutical products globally" - Interview with Dr. Liu Juhong, former FDA CMC Review Director

 Last Update: 2022-11-15
 Source: Internet
 Author: User

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The Bai Ao Gu & Biopharmaceutical Xiaobian team has a special "Bai Jiayan" column, focusing on the upstream and downstream of the biopharmaceutical industry, focusing on business and technology, focusing on humanities and society, and paying attention to your concerns
.
Your recommendations and suggestions are
welcome.
In the 33rd issue, you are presented with a fascinating interview
with Dr.
Liu Juhong.

Bai Ao Gu Biopharmaceutical Xiaobian Biopharmaceutical Xiaobian team has a special "Bai Jiayan" column "Bai Jiayan" column, focusing on the upstream and downstream of the biopharmaceutical industry, Focus on business and technology, focus on people and society, pay attention to your concerns
.
Your recommendations and suggestions are
welcome.
Issue 33 33 presents you with a wonderful interview
with Dr.
Liu Juhong and Dr.
Liu Juhong.

Dr.
Juhong Liu received his Ph.
D.
in biochemistry and molecular biology from Peking Union Medical College in 1990 and began his postdoctoral research
in the same year.
Since 1995, he has been a researcher in the Pathology Laboratory of the National Cancer Institute, engaged in cancer molecular biology research
.
He joined the U.
S.
Food and Drug Administration in 2008 The Department of Biopharmaceuticals (OBP) (FDA) is engaged in the review of
biopharmaceutical applications.
He has worked as a CMC reviewer and review team leader
.

In 2015, Dr.
Liu became the CMC Review Director of OBP Division II and received FDA's highest technical title – The chief review manager is responsible for managing the CMC review
of more than 50 kinds of BLA approved for commercial production and more than 400 kinds of biological drug IND under the division.
He has managed and reviewed regulatory requirements for multiple protein product types, including monoclonal antibodies, ADCs, bispecific antibodies, FC fusion proteins, enzyme replacement therapy products, cytokines and hormones
.

In addition, Dr.
Liu is experienced
in strategic planning for orphan products and breakthrough product development.
He was repeatedly invited to leave the FDA for Dr.
Liu Juhong in 2018 Become a biopharmaceutical CMC R&D consultant is committed to assisting biopharmaceutical companies to promote their biopharmaceutical products
globally.
He successfully led the listing filings
of Yiyi Biologics in the US FDA, EMA and CDE.

"This is the most critical! Whether domestic enterprises vigorously develop and produce biological drugs, small molecule drugs, if they want to go international, this step is inseparable! Dr.
Juhong Liu, who has more than 10 years of experience in biopharmaceutical application review at the FDA, said
.

In China, the products produced by enterprises must meet China's minimum requirements and meet the requirements of
the Chinese Pharmacopoeia.
Similarly, when you go abroad, you must meet local requirements, such as those of
the United States Pharmacopeia.
If domestic companies want their products to be sold commercially worldwide, there is a lot of preparation for listing from IND to listing application
.
Dr.
Liu told us, "This is a step-by-step process, how to integrate the requirements in the process of product production and development, from phase III clinical trial to marketing, to achieve a product sales globally is an important part
.
" ”

This is a step-by-step process, how to integrate various requirements in the process of product production and development, from phase III clinical trial to market, to achieve a product sales worldwide is an important part
.
”

Dr.
Juhong Liu has been a researcher in the Pathology Laboratory of the National Cancer Institute since 1995, engaged in cancer molecular biology research
.
He joined the U.
S.
Food and Drug Administration (FDA) Division of Biopharmaceuticals in 2008 (OBP) Engaged in biopharmaceutical application and review, experienced CMC reviewer, review team leader
.
In 2015, Dr.
Liu became the CMC Review Officer of OBP Division II and obtained the FDA's highest technical title, Lead Reviewer, responsible for managing the CMC review
of more than 50 BLAs approved for commercial manufacturing and more than 400 biological drug INDs under the division.

Dr.
Liu has managed and reviewed regulatory requirements for multiple protein product types, including monoclonal antibodies, ADCs, bispecific antibodies, FC fusion proteins, enzyme replacement therapy products, cytokines and hormones, are particularly experienced
in the strategic planning of orphan products and breakthrough product development.
At the invitation of the 4th Bio-ONE Annual Bioprocess Industry Summit, Bai Jiayan had the honor to conduct an interview
with Dr.
Juhong Liu.

At the invitation of the 4th Bio-ONE Annual Bioprocess Industry Summit, Bai Jiayan had the honor to conduct an interview
with Dr.
Juhong Liu.

Supervision is not a fixed black and white line, enterprises need to find a balance between effective safety and quality stability of products

This year marks the fifth year of China's accession to the ICH, and the ICH Guiding Principles
have been fully implemented in China.
"At the time of listing, whether it is CDE, FDA or EMA, the difference between the materials required for listing is not particularly large, because now everyone uses CTD format, and some of the content required in CTD is clearly
written.
" Dr.
Liu continued, "But the requirements at the IND stage are quite different
.
”

"At the time of listing, whether it is CDE, FDA or EMA, the difference between the materials required for listing is not particularly large, because now everyone uses CTD format, and some of the content required in CTD is clearly
written.
" Dr.
Liu continued, "But the requirements at the IND stage are quite different
.
”

Generally speaking, the company's candidate products can meet the requirements of CDE, then there will not be much gap with the requirements of FDA and EMA, from the perspective of products going overseas is a good for Chinese enterprises, but in the IND stage of national regulatory authorities will have different requirements, these differences also reflect the understanding of different things and the degree of tolerance for safety of regulatory authorities in various countries
.

In the IND stage, the regulatory authorities of various countries will have different requirements, and these differences also reflect the understanding of different things and the degree
of tolerance of the regulatory authorities in various countries.

Take antibodies as an example, Since the first antibody drug "Rituximad" was launched in 1997, the FDA has monitored such products for more than 20 years and has accumulated rich experience
.
Based on these experiences, FDA can exempt many unwanted regulatory programs
.
Returning to the perspective of CDE, one is that there are not so many items declared in China, and the second Chinese Pharmacopoeia has some testing requirements that must be done, and the change cycle of the pharmacopoeia is relatively long
.
Therefore, CDE does have some requirements according to the pharmacopoeia, which is very important
for Chinese biopharmaceutical companies that need to be internationalized.

In addition, the FDA strictly follows the concept of phased product development during the IND, and the requirements for product marketing can be very different
from those during clinical trials.
It can be said that in clinical phase I and II, the FDA's requirements for product CMC are not particularly high, and it will not require product consistency, and the FDA mainly relies on the company to manage
itself.
Because when the company is doing clinical work, if there is a problem with the product that causes injury to the patient, this responsibility is extremely serious
.
Therefore, in general, enterprises will take the initiative to put forward very strict control
over product quality in the first and second phases of clinical trials.
"So the difference is not only between regulators, but also in the environment of the company or clinical research, the risk assessment of the environment and the company's tolerance for risk
.
" It's a common thing, so the difference isn't just in regulators
.
”

In addition, the FDA strictly follows the concept of phased product development during the IND, and the requirements for product marketing can be very different
from those during clinical trials.

Dr.
Liu continued, "Regulators and companies consider issues from different angles
.
”

"Regulators and companies don't
think about things from the same angle.
"

From the perspective of regulators, the first consideration for applying for BLA products is safety, the second is effectiveness, and the third is product consistency
.
"For example, after the product is approved for marketing, this drug can be sold for more than ten or twenty years
.
More than a dozen batches are produced every year, a total of more than 100 batches, like PD-1 antibodies may be hundreds of batches
.
How to ensure the consistency of this product, what kind of information the company gives to the regulatory authorities, to ensure that each batch can be produced in the future, are comparable to the phase III clinical batch, which is what the regulatory authorities are concerned about
.
”

Regulators will not supervise the commercial operation of products, but companies must maximize commercial returns
while ensuring that products are safe and effective.
For manufacturers, the consideration of product pipelines, the first is to speed up the listing declaration, and the second is to control costs
.
Both of these are very critical, but many companies do not realize that in the eyes of the FDA or CDE, the most important thing is to ensure the effective safety and quality stability
of products.
"How to find a balance here is very important
.
"

Regulators will not supervise the commercial operation of products, but companies must maximize commercial returns
while ensuring that products are safe and effective.

Dr.
Liu went on to give an example of a pharmaceutical company that obtained an FDA breakthrough product in 2017, but the marketing application three years ago was not approved because its production was unstable
at that time.
From this point of view, whether it is a breakthrough product or an orphan drug, the regulator looks at whether the company can produce the product stably
.
Therefore, companies can choose to adopt some more effective and rapid methods to provide clinical data in the clinic, but CMC must keep up
.

"The regulatory authorities must approve the product, not the clinical
trial.
Clinical trials can fail, 1 out of 10 trials are successful, regulatory agencies can approve them, but there is only one
product.
Enterprises need to consider the whole picture, clinical trials, CMC and other aspects of any place can not be on the market
.
Dr.
Liu said
.

Businesses need to know when not to do something

People who deal with the FDA a lot often hear the phrase "it.
" Depends", it seems that they are answering perfunctory questions, but it makes a lot of sense, because each product and every process has some unique characteristics
.
The results of the study of product characterization and process characterization during the R&D process are how to effectively answer the FDA's "it.
" depends", which is also a key point
worth thinking about for Chinese companies.

The results of the study of product characterization and process characterization during the R&D process are how to effectively answer the FDA's "it.
" depends", which is also a key point
worth thinking about for Chinese companies.

Both studies are time-consuming, taking process characterization as an example, which generally takes a year if it is fast, and a year and a half is possible
if it is slightly more complicated.
Therefore, many companies wonder if it is worth the time.
"In fact, it is very necessary, this year, one and a half years will contribute greatly to the stability of the company's products and processes in the future, and can also greatly increase the possibility
of approval.
" Dr.
Liu told us, "After seeing more BLAS and more late-stage INDs, you will understand that doing these two representations well can really lay a good foundation
for enterprises in the 10 years and 20 years after the product is launched.
" ”

"After seeing more BLA and more late-stage IND, you will understand that doing these two characterizations well can really lay a good foundation
for the company in 10 years and 20 years after the product is launched.
"

Returning to clinical phase I and phase II production, it is often heard whether to pay special attention to process consistency
.
In fact, the products and processes of clinical phase I and phase II can be changed, and there are many
more opportunities for change than unchanged.
Therefore, process stability
can be ignored before the third phase of clinical practice.
This goes back to "IT Depends", all products have their own process characteristics, just look at the use of a technology platform, but according to the product of different MOA, the focus is different
.
Dr.
Liu said, "Although it comes from similar platforms, it is more focused on which points of the platform, which parameters, which quality standards, so it will be very different
.
" ”

"Although it comes from a similar platform, it will be very different
if it focuses more on which points of the platform, which parameters, which quality standards.
"

Or take antibodies as an example, the biological activity of some antibodies has a strong correlation with the level of glycosylation, so when enterprises do process verification or process characterization, they must strive to find out how to maintain the conditions
of glycosylation level of antibodies.
For other antibodies, the level of glycosylation has nothing to do with its activity, and it is much
simpler for companies to do product characterization and process characterization.
"So not all monoclonal antibodies are the same, some products require eleven or two release tests, and some monoclonal antibodies have only five or six
release tests.
" So this monoclonal antibody is not equal to that monoclonal antibody
.
So the FDA would say 'it.
' depends”.

So is there some experience that companies can refer to, how to make a drug from IND to market faster? On this issue, Dr.
Liu said, "A lot of biopharm experience comes from actual combat, first take some detours, and finally start to go straight"
.
This is one approach, but it is not for Chinese companies to advocate each striving for a decade, which may be a lost decade
.

So is there some experience that companies can refer to, how to make a drug from IND to market faster?

And "there is nothing new under the sun", so if you can find a group of experienced participants, consider these things from a relatively wide dimension, and do a good job of overall planning, it is completely possible to accelerate from IND to listing
.
Everyone now knows that K drug sales are very high, in fact, the manufacturer's previous experience in antibodies is relatively general, when they saw the potential of this drug invited a large number of experienced people to come, and the final facts did prove that the manufacturer's injection pressure was
correct.

"I thought it was interesting when I saw this, and that's one of the reasons
why I left the FDA.
" Dr.
Liu said
.
During the FDA period, you will find that many companies are developing valuable products, but from the perspective of experts, companies have actually taken a lot of wrong paths
in the early days.
For example, in the first phase of clinical practice, MCB and WCB did a good job first, which took a lot of time
.
However, from the actual situation, from the perspective of regulatory requirements for approval, WCB is not clinical phase III, and enterprises do not need to do it
.
So we will see that some companies have done a lot of unnecessary work in the early stage of clinical practice, and then in the later clinic, especially after the phase III clinical trial, they have missed a lot of work necessary for listing, because the company has not listed the product, it is not very clear about what must be done and what can be done or not
.

"Adding these two things together will delay a product from clinical to market to an infinite amount of time
.
" Dr.
Liu said, "The impact on when and when not to do what a pipeline should do, especially when not to do it, has a great
impact on the development speed of the enterprise.
So I felt that these things were not too difficult to solve, and if the enterprise side could have a better long-term plan, such as a 3 to 5-year plan, then the time could be accelerated a lot
.
This is also a lot of experience for me, so I feel that I can come out and do something for the company
.
”

"Adding these two things together will delay a product from clinical to market to an infinite amount of time
.
"

Time is of the essence, and it is important to fully communicate and reach consensus

When it comes to the issue of time, we will also consider the use of some new technologies, such as continuous perfusion this culture method is now more common, unlike the FDA approved only three or four
in 2018.
Dr.
Liu said, "I think it's like all new technologies before, but in fact, regulators really like it, that is, companies need to come up with new technologies, and then the two sides will discuss and move forward, and everyone will learn
together.
" "So the biggest obstacle to the adoption of a new technology is not really not the large-scale use by enterprises, but how the new technology can reach consensus
with regulators.
"

In addition, the regulator has the most basic requirement, which is that it is impossible to change for the sake of a new technology ICH requirements for recommendations
.
Therefore, how to communicate with regulators to achieve the ability to use new technologies without violating the requirements of ICH is a point
that everyone needs to work on.
Or take perfusion as an example, everyone knows that it will increase the yield, but how to ensure the quality of the product? Continuous perfusion for more than 200 days, so is the quality of the product on the first day of harvest consistent with the quality of the last day, and how to prove that the product quality is close to the requirements of the regulatory agency? "I think the biggest obstacle is not in technology, but in terms of communication and finally reaching consensus, how to reach a consensus is difficult
.
" Dr.
Liu added
.

The regulator also has the most basic requirement, which is that it cannot be changed for a new technology ICH requirements for recommendations
.
Therefore, how to communicate with regulators to achieve the ability to use new technologies without violating the requirements of ICH is a point
that everyone needs to work on.

Consensus at the specific operational level, timely discovery of some problems, such as the prescribed 220 days, suddenly 110 days when the problem is found, what should I do? How to deal with this situation? There are actually some consensus that has not yet been reached
.
In fact, regulators are actually advancing with manufacturers in most cases, such as CDE still could not be produced in batches many years ago, and slowly small grading can also be used, and branch production and local production can also be used
.
Dr.
Liu said, "Will it be a few years before biological macromolecules can also be produced separately?" This slow possibility will always achieve global agreement, but it will take time
.
”

Coordination and communication between companies and regulators is critical
to how to achieve the most effective development pathway.
Domestic companies and FDA communication does have relatively large defects, in fact, do not need to worry about communicating with the FDA, in fact, a manufacturer produces several drugs, but the FDA has contacted hundreds of products, manufacturers encounter problems, FDA may have seen, so they can not only help manufacturers evaluate a certain practice is right, they may even provide some suggestions to the company, so meeting communication is very critical
.

Coordination and communication between companies and regulators is critical
to how to achieve the most effective development pathway.

"The communication with CDE in China is also very scientific, and the decisions made by CDE are also well-founded, so the same needs to be communicated with CDE," Dr.
Liu said
.

Summary - orphan drugs

"Someone once asked such a question, is it to spend 250,000 US dollars to treat a patient, this rare disease patient does not have this 250,000 US dollars, I am afraid that in a few years people will die? Or $250,000 to treat 1,000 other patients? "This is indeed a philosophically unsolvable problem
.
" "But we believe that with the progress of technology and the efforts of all parties to find a good business model for products, there will be more and more products that effectively benefit patients, especially rare disease patients, which is also the original intention
of all pharmacists.
"

However, we believe that with the progress of technology and the efforts of all parties to find a good business model for products, there will be more and more products that effectively benefit patients, especially patients with rare diseases, which is also the original intention
of all pharmacists.

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