Strategy for Cell Therapy In Regenerative Medicine With CDMO

For related consulting services or further request, please search (LinkedIn, FB)：Delon Hsueh (Reviewer, Scientist, ex-TFDA official)

1. Cell Therapy is booming, with the FDA recently approving 10-20 drug licenses per year. So far, Taiwan authority (TFDA) has also approved two drug licenses related to this field, one for gene therapy (Zolgensma) and the other for immune CAR-T cells  (Kymriah), and the rest are in clinical development, as in other countries. Statistically, there are 80 cell therapy INDs and 30 gene therapy INDs, most of which are in Phase I & Phase II. However, most companies, nearly 80 % small-medium business, considering their time, proof of concept and financial situation, as well as the impact of COVID-19, have resorted to the assistance of contract development and manufacturing organizations (CDMOs), nearly CAGR 7 % , especially in the mass production stage of entering clinical trials. The following are perspectives and recommendations.
2. Regulatory points (立法者觀點)：

（1）Definition: Understanding the definition of a new drug for ATP (such as  stem cell, CAR-T cell exosome, and other derivatives). How to define a drug, similar to a medical device, is extremely important, especially in the early stages of development. Generally speaking, we can judge from main/active ingredients, content, dosage form, administration, and claims (intended use) of the product. Sometimes, It brings the industry and authority a challenge to define it.

（2）Compliance with the regulation (e.g. Pharmaceutical Act in Taiwan such as GXP (PIC/S GMP, GVPP) during the R&D to NDA/BLA (new drug approval/Biologic License Application) stage.

（3）Harmonization of regulation: Under the The International Council for Harmonisation (ICH) framework, the country who participated in the Association will have to harmonize the regulation. Both Safety and Efficacy are essential for the approval of a new drug.

（4）Accessibility of drugs: In general, Cell therapy is usually used to treat intractable diseases, such as hematologic cancers, so governments have accelerated the approval of drugs based on safety and efficacy in order to speed up access to medicines, especially for the patient group of local population with critical or difficult-to-treat conditions. A little bit similar to the philosophy of vaccine availability against COVID-19, once the drug is substitutable, the speed of approval to market may also be reduced, however, it is not a prerequisite. So have a deep survey on the market where you are going to.

（5）Dual-track regulatory framework (雙軌管理制) : Owing to the attribute of such kind treatment, that means that cell therapy is regulated both as an advanced technology and as a drug, with the former subject being the health care provider (hospital) and the latter subject being the license holder (company).

a. This technology is a part of cell therapy management. Cell therapy technology that has been performed overseas for specific indications with low risk, or has been implemented in human trials for a certain number of cases, and whose safety can be confirmed and whose effectiveness can be expected, is included in the management of specific medical technologies.  * US and Europe: No pre-approval is required for a single autollogous procedure

b. Being a drug: you have to follow the rules, from GXP, IND to a final NDA registration. check the conditional approval and time limit for your product no matter in any kind of indication.

（6）Post-marketing surveillance（PMS）: Indeed, a “long term follow-up” (LTFU) shall be conducted following exposure to the investigational cell therapy product.  For example, The FDA has recommended that subjects be monitored for delayed adverse events for up to 15 years at the time of exposure to investigational gene therapy (GT) products. Annual examinations for the first 5 years, followed by 10 years of continuous annual follow-up, including inquiries or questionnaires. Besides five years for adeno-associated virus vectors (AAV)  vectors, the rest of gene therapy product will be up to 15 years, including gammaretroviral and lentiviral vectors, herpes virus vectors, microbial vectors, genome editing products. The preparation is usually five years.

3. Delon Hsueh’s perspective to Cell Therapy industry plus CDMO：

（1）D (development) is greater than R (research)：Owing to the advance of biomedicine as well as COVID-19, as I always tell start-up companies, D (development) is much greater than R (research), and the commercialization process requires a lot of manpower, capital, and resources. If small-medium companies can leverage CDMO as a resource (partner) to support their business (namely, successful route to commercialization), it will greatly reduce the time and the development cost. Development Strategy is important. 

（2）Get Serious about Your Product Indications：About 50 % of these are focused on cancer, with the rest, in descending order, being degenerative arthritis, hard-to-heal wounds, and spinal injuries in Taiwan.

（3）How to find a CDMO：It depends. For the top ten CDMO in the world it is thus it should be from your R&D to GXP to CRO to CDMO. The One of the largest contract manufacturers in the world, Switzerland's Lonza,  followed by the Wu Xi Biologics (Cayman) Inc. in China, Catalent in the U.S., FAREVA in France, Recipharm AB from Sweden etc. So it seems that trying to find a CDMO cleverly and locally may be better than finding a foreign one. 

（4）Technical issues to think

a. For cell therapy, it suggests that  Xenograft is the marketing trend. the market will accept the Xenograft more than allograft In terms of donor availability, flexibility and convenience.

b. Whether you have the key special  technologies: you may research start from a technology transfer or develop certain cell by your own Lab. Such as serum-free culture media for cell therapy, have been developed and are available due to some of the disadvantages of containing serum ( such as serum batches, contamination, serum components issue), and it costs lots when used in a long-term period. 

c. Beware of Adverse Drug Reaction for cytokine release syndrome (CRS) or get warning letter

* Cytokine release syndrome (CRS) is an acute systemic inflammatory condition that is characterized by fever and organ dysfunction in association with CAR-T cell therapy, as well as biological antibodies, and allogeneic transplantation.

d. Mass production without OSS (out of specification ) is still a critical technical issue.

How to deal with the OOS situations with regulators is a real world challenge. Applying the rigorous process controls to cell therapy manufacturing is not always smart and suitable, due to the fact that manufacturing variability does not always make a negative impact on clinical response. For example, when your product has been approved in one country without local manufacture and needs to be sent back for cell cultivation, it may happen during the logistics or end use. Understanding the root cause of the OOS condition and providing feedback to the regulatory authority or manufacturer will allow this treatment to better predict, manage, or address the problem.

（5）Regulation issue: Every country has its own management of regulations on cell therapy. The most important thing is to be compliant with the regulations.

（6）Key Success Factor:

a. Due diligence to choose a CDMO partner and cooperate intensely with a reliable CDMO where you want to market. Generally speaking, It includes the gap analysis, mass production (preclinical/clinical use), and the fill-in process.

b. Shall be compliant with the regulation and communicate with the local authority intensely. 

c. Be mindful about the related regulations where you are going to have the product marketing on, especially in China.

d. Due to the COVID-19, there is an impact of delay on logistics either sea or flight. therefore, it could greatly influence your research and the schedule which is going to be completed.

（7）Obligation: at present, it still usually belongs to the medical implementation side, as in the case of MDR management for medical devices in the EU, where the allocation of responsible persons needs to be carried out.

Finally, cellular therapy is an emerging patient treatment with high selling prices and conditional/time-limited approvals that have attracted investment from many pharmaceutical companies. Unlike "orphan" drugs, the market is much larger and is still expanding.

Also See: 

1. The top 10 manufacturers in the fight against COVID-19
2. Pharmaceutical Affairs Act  (Taiwan)
3. Pharmaceutical and Medical Device Act, PMD Act (Japan)
4. Long Term Follow-up After Administration of Human Gene Therapy Products (US FDA)
5. Is the FDA Slow-Walking Authorization of Novavax's COVID Vaccine?