From Bench to Bedside For Pharmaceutical Industries
Spaker: Ruimei (Linda) Li, MD. PhD., CEO, GCP Clinical Service.
Intro: Linda Li focused on the new drug development process and the timeline to go through regulatory approval, and how to develop and build a successful team and manage the budget for the clinical trials.
New Drug Development Process and Timeline
The approval process for innovative new drugs can be time consuming. The average approval process takes about 7-8 years. In some cases, this can go up to more than 20 years. Typically, the pre-IND (Investigational New Drug) (investigational new drug application) stage can take up to five years within the lab. The IND (Investigational New Drug) approval process can take anywhere between zero to two years. In some cases, companies may license in new products that may have failed the IND approval. The companies may refine the application and can speed up the approval process. This is a strategic consideration. The IND approval will take average two years. The clinical trial typically includes three phases of clinical trials, and a post marketing phase study in the Risk Evaluation and Mitigation Strategies (REMS). Take a cancer treatment as an example. Typically, in the U.S., the Phase I clinical trial may require 12 to 20 cases of First In Human (FIH) or Proof of Concept experiments. In China, the CDE (Center for Drug Evaluation) may require at least 22 cases in Phase I. The objective at this stage is to test the safety at different dose levels and PK/PD (pharmacokinetic/ pharmacodynamic). The successful rate is high. About 70%~80% of the applications can moved to Phase II. In Phase II, the objective is to look at the efficacy of the product and further evaluation of safety information. In Phase II the sample size should be over 50 subjects at least for cancer. It is exceedingly difficult to move from Phase II to Phase III, with only about 30% applications can successfully proceed. Many experiments are designed to combine Phase I and II to save regulatory time. In Phase III, it is testing the efficacy in a larger population. The population can range from 300 cases for cancer to over 3000 cases for AIDS(Acquired Immune Deficiency Syndrome). Some vaccines may require a population size of over 30,000. The patient reported outcome is an important measurement in phase 3. The data collection on PK/PD will continue about 10% of the population.
Many cell and genetic based drugs may be approved based on the Phase II data (serval hundreds of cases) due to limited subjects.
Path to IND (Investigational New Drug Application)
Amongst FDA’s six key review departments, Center for Drug Evaluation & Research and Center for Biologics Evaluation & Research are the most relevant to new drug application.
The interaction with FDA (Food and Drug Administration) for a new drug will be throughout the Product Lifecycle. Some key steps include Pre-IND Phase, IND Review Phase, Marketing Application Phase, and Post Marketing Phase.
The Pre IND phase includes the development of new chemical molecules and early animal experiments. In the States, there is a Pre Pre -IND meeting and Pre IND meeting. Once the IND application is submitted, the review of application takes 30 days. In China and Europe this process takes 60 days. This process will answer your questions regarding the application and experimental design.
There are some strategic considerations at the Pre IND stage, for example the design of investigator
Initiated trials, and the applications of Orphan Drug Designations (ODD).
After the initial IND review, the company can focus on the Clinical Trials. At the end of the Phase II, there is an End of Phase 2 Meeting with FDA to discuss the results from the previous stages and plan for the Phase III. There is another meeting after Phase III before the launch to the market. Once the drug is approved, FDA will review the safety of the drug at the posting marketing phase. Occasionally, drugs may be discounted due to the discovery of toxicity within the larger population.
Clinical Development Plan (CDP)
If the application of the drug may include pediatric population, it is important to include the clinical study for pediatric applications in the Clinical Development Plan (CDP). This is called Pediatric Indication Plan (PIP) in Europe.
CBER Regulated Products
Biological products may include Cell & Gene Therapies, Xenotransplantation, Whole Blood, Blood Components, Blood Products, and Vaccines. The good news in the CBER side is since December 2020, FDA allows for an Interact Meeting (Pre-Pre IND-Meeting). It is intended for innovative drugs. This meeting can be held during the chemistry discovery stage. The meeting may discuss aspects such as chemistry, manufacturing, and control (CMC), pharmacology/ toxicology, and clinical studies. This is a unique opportunity. Linda shared her experience when she worked with a vaccine company in China. They finished the development process and animal studies, they discovered that the drug cannot be approved for clinical trial due to its chemical structure with no prior record. The advantage of this early meeting is to limit the risk early and get feedback from FDA early.
IND Filling Process
There are three types of IND in the States. Linda focused on the Treatment IND. This includes the Animal pharmacology and toxicology, Manufacture information, Protocol and Informed Consent Form, Clinical Development Plan, Investigator brochure, Leading Investigator, FDA Inspection.
It is important to check the regulatory requirements, and CRO qualification if company use CRO to conduct pre-clinical studies at early stage, and GMP manufacture, some CROs were recognized by FDA and passed FDA inspection with GLP and GMP qualification. Otherwise, it is possible to hire the third-party examiner CRO without the proper qualification recognized by FDA. The result of the animal studies may not be validated for the IND process.
In Europe, the manufacturing process is very important. It requires the Qualified Person (QP) to examine the manufacturing facilities. It is extremely difficult and can take up more than two years to obtain a QP certification. The only country does not require QP in EU is Ukraine.
As mentioned above, it is important to include pediatric plan in your Clinical Development Plan at the beginning. It is worth to note that sometimes FDA may require a separate Risk Control Plan.
FDA requires a contract with the investigator (FDA1572). FDA list all the information regarding the past investigators. It is important to verify the potential investigator’s history of potential warning letters and audit history, FDA report (Debarment list) is public information, company can find out the investigator’s information.
It is also important to understand the Ethic Review Board, whether you will need the Local Institutional Review Board in the universities or the central one.
For experimental drugs, the Pre IND meeting is extremely important. The FDA offers a 21-day response. The meeting is offered for free but take 6-8 weeks to schedule. In this meeting, FDA may identify areas of the application that needs improvement. Common problems may include inadequate CMC information, lack of information on selection of dosage, and unacceptable clinical trial design.
During the CMC review process, FDA may give hundreds of questions to be addressed by sponsor and mandated for feedbacks. It is an opportunity for sponsor to improve its process. It is important to have the Pre IND meeting to minimize the potential questions at the IND stages and avoid run into the risk of clinical holding .
IIT (Investigator Initiated Trials)
It is important to conduct Investigator Initiated Trials early to gather data. In Europe, data generated from IIT can only be used for publication and cannot be used for IND applications. It can be included in the IND safety data in the States and China. It is easy to go through in China. It is even easier in Australia as it does not require IND. It is an advantage as it can speed up the process and gather population data. Furthermore, a tax credit of 40% is offered in Australia that may lower the cost to comparable to China. It is also a good idea to do this early before the company is on the public market (IPO). After IPO, the China regulatory process is much stricter.
Orphan drug is targeting rate disease, which is defined differently in different countries. In the States it is defined as any disease or condition that affects fewer than 200,000 people in the United States. In Europe it is defined as life-threatening or chronically debilitating diseases which are of such low prevalence that special combined efforts are needed to address them. In Japan, rare disease is the one that affects about 1 in 2,500 people. There is no rare disease definition currently in China.
There are advantages for being recognized as an orphan drug. First, the expense for clinical trials may receive up to 50% deduction in tax. The application fee for BLA is also waived ($ 3 million). There are also other supports throughout the process.
Orphan drug designation is easy to obtain compared to IND.
Key Success Factors
Some of the key success factors may include the budget for clinical trial and build up of the clinical teams.
Clinical research is a complex systematic process. It is much more complicated than the pre-clinical stage. It is common to outsource the clinical stage to CRO (Contract research organization). The expense on CRO can take up to 30% to 40% of the clinical research. It is also not easy to manage the CRO. It is possible to build your own team to reduce the cost of clinical studies, however, the cost on team management is high.
The clinical study can cost more than 5-10 times than the pre-clinical study. Many scientist founders may allocate majority of their budgets at the pre-clinical studies, as a result, the company has little resources to complete the clinical studies. A good strategic consideration is to allocate adequate resources to the clinical stages.
The last consideration is the clinical study team. This will include MD, regulatory, Clinical Operations (CO), Data Management (DM), Pharmacovigilence (PV), and pharmacokinetic/pharmacodynamic (PK/PD) CMC. In China, the company tends to start with CO. However, the MD is the head of the team. If you can identify the MD, the MD will be able form and build the team. It is recommended that the company to start with MD, even a part time MD.
To build a high-performance team will take time. It takes more than nine months to form a productive team. It is important to strategically plan early before the IND stage.
Pre-Market Approval for Medical Device
Spaker: Ellen Jiang, General Manager. Ramed (Beijing) Medical Technology Co.,Ltd.
Intro: Ellen focused on the changing landscape of the regulatory in medical device.
An Overview of Medical industry
Medical device industry is one of the fastest growing industries in the last five years. As a result, medical device companies are favored by the investors. However, one challenge lay before the investors and innovators is the regulatory process. To obtain regulatory approval is a key milestone.
We shall estimate the intuitional cost of the regulatory approval process. The cost is associated with the level of medical device industry development. The most innovative medical device industry is in the States, then Europe. China is now the most promising market. Most of the import medical devices go to China through Shanghai Port.
The history of China’s medical device regulation started in 1996 as Registration Provision. In 2000 it started as regulation. The Emergency approval started in 2009. By 2014, there is Innovative device approval. The process is now electrical based process, making the process easier and more accessible. In the last five years, there are a few amendments that is advantageous for innovative medical devices to export to China.
In Europe, the medical device was not regulated by law until recently. Since its recent introduction of IVDR (2022) and MDR (2021) (European Union Medical Device Regulations), it is moving away from the self-declared CE process.
Based on the level of the industry development, there are about 3 million products approved in the States. To date China has 137,000 active regulations.
Traditionally China classifies the medical devices based on its clinical application and has limited categories. It has now revised to near 7,000 categories, comparable with FDA’s over six thousand categories. The regulatory bodies are now learning from each other and become more consistent in different countries.
In terms of the approval process, traditionally China has only one path for all kinds of medical devices. It introduced an innovation Path for innovative products. In this path, there is dedicated resources and timelier response. Traditionally clinical trials are required to enter China. Recent changes will recognize the data collected overseas.
In Europe, the regulatory approval is done through CE certification. The clinical Evaluation will follow ISO20916. The newly introduced MDR and IVDR will significantly increase the cost of the regulatory approval process.
In the States, the most common approval is 510(k). PMA (Premarket Approval) has about 8% of the total applications.
China’s Medical Device Market Size
China’s medical device industry is impacted by the pandemic, it still surpassed the USD$70M. In this market, there are about 2,000 companies that produce Class III devices, 14,000 companies that produce Class II devices, and 16,000 companies that produce Class I devices.
China ranks the third place in the medical device industry, following the States and Japan. Currently the ratio of clinical usage of drug to device in China is 1:0.14. There is a lot of room for future growth. Especially since the recent change in the pharmaceutical procumbent process. The regulatory body oversees the manufacturers, distributors, logistics providers, medical institutions, as well as research institutions.
A significant difference exists in the market value of the Top 30 medical device companies in both China and the States. It shows that the Chinese companies can improve both in the technological innovation and market compatibility. There are still good opportunities for the scientists and entrepreneurs with innovative ideas to develop in China.
In China, medical device is classified in three classes based on the risks. The Class I device has the lowest risk. The Class II does not differentiate between a and b where Europe does differentiate between a and b. The Class II a is managed at the provincial level. The Class III and all imported Class II devices are centrally managed. In China, Class I makes up 16% of the devices, where in the States it makes up about 46% of the devices. As result, the Class II or Class III devices in China may be classified as Class I devices in the States. Similarly, a class II device from the States is likely to be classified as Class III. A key consideration is the capability of the provincial regulatory body.
The regulatory body oversees the entire medical device life cycle throughout R&D, Manufacturing, Premarket Approval (PMA), Storage and Distribution, as well as Use. Since 2018, the expansion of the intended use beyond the registration is forbidden by law.
NMPA MD Registration Approaches
There are some important updates on the registration process. Traditionally, there is only one path for medical device registration. The company must obtain PMA in the country of origin and apply for CNDA (China National Drug Administration) import registration. The company needs to either secure their own GMP (Good Manufacturing Practice) plants in China or develop partnership with China GMP qualified plant for manufacturing.
One of the important updates is that the company does not have to build their own GMP plants. Companies can be manufactured by the OEMs (Original Equipment Manufacturers). This change will allow the specialization in the company’s capabilities and improve the industry’s competitiveness.
To be recognized as Innovative Medical Device, two criteria must be met: a valid invention patent and recognized contribution in clinical needs. There must be clear link between the patent and the clinical needs. If these are met, there will be dedicated specialist to support throughout the registration process.
The registration process is now simplified. In the past, all medical devices must be evaluated by third parties, which takes about six months. The companies can now self-declare if qualification is proven. This will allow the import companies to substitute the third-party report.
Despite the official process time is ninety working days. Most companies cannot obtain the registration within this ideal time. The average process time was 277 working days for year 2020, and 295 working days for year 2021.
Path to Get COVID19 IVDs (In Vitro Diagnostics) Approved
For COVID19 related devices, there are two pathways: emergency or normal. Currently there are many equivalent products obtained approval, however there are very few innovative products, especially in the Home Use Tests. There are many opportunities for the innovative companies to enter Chinese market. The difficulty is that there are fewer COVID19 positive cases in China for clinical studies. The requirement for clinical study is the same (one thousand cases) or both the emergency and normal registration.
Many companies obtained CE registration instead of the Chinese NMPA because of its self-declaration. Companies now focus on the antigen diagnostic development.
Registered AI (Artificial Intelligence) & Challenges
AI is a hot topic. However, it is difficult to define AI. It is not a strict requirement. Typically, AI means a recommendation, a baseline or a range based on big data. Most of the AI products are image based. Most of the common applications focus on navigation and spatial registration.
If the product is cloud based, there are many considerations for the data management. For example, where the data should be hosted in the hospital.
China adopted many FDA guidelines in the technical requirements. If a product is developed based on FDA guidelines, it would be registered in other countries due to the harmonization in technical requirements.
Approved CDx (Companion Diagnostics) & Solution for Clinical Evaluation
Another new area is the reagents industry for testing. Right now, in China it is classified as cancer related. Nineteen products have been approved. There are two ways to obtain the approvals. Ideally, the studies should be done simultaneously with the antitumor drugs. It will be accepted by the regulatory body. However, if it is not possible, the company shall consider three different approaches if the Cancer Drug has been launched. First, the company may conduct a comparison study with codeveloped CDx. Second, to conduct a bridging study using the same compound. If neither approach works, the company may conduct observational studies on the efficacy of antitumor drugs on the market.
In comparison, FDA has approved a total of 46 CDx reagents for over 137 diverse types of intended use.
Panel Discussion
For a Class IV medical device (invasive) developed in Canada and targeting both US and Canada, would it make sense to apply for approval in FDA first or Health Canada first
Ellen: Because Canadian market is smaller, it is recommended to obtain FDA approval first then to obtain Health Canada registration. If the company wants to enter China market, it is important to obtain the approval from the country of origin. Many processes can be done concurrently.
For lab developed tests (LDT), for example genetic tests for rare disease, sometimes no FDA clearance is needed; what is requirement in EU (European Union) and China?
Ellen: LDT does not need to be approved by FDA. In China this is not allowed. It is possible the registration and regulatory requirements will change soon. In Europe, the LDT does not require CE certification in the past. Under IVDR, the lab use does not require CE certification.
For therapeutics and medical device being developed, can data from Chinese clinical trials acceptable for FDA and EU?
Ellen: The data can be used for FDA and EU if the racial and lifestyle does not affect the safety of the product.
Linda: For example, lever cancer is considered as rare disease but a common disease in China.
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