Historic moment for Chinese CAR-T biotech

by Alexey Bersenev on June 6, 2017 · 0 comments

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The biggest and the most prestigious conference in clinical oncology (ASCO) could be a turning point for Chinese CAR-T biotech. Yesterday, presentation of preliminary data from CAR-T trial in multiple myeloma by China’s company Nanjing Legend Biotech (Legend), was a bomb! Repercussions of this success could be historic for perception of Chinese CAR-T biotech by “Western world”.

First of all, ASCO committee recognized the importance of Legend’s data and accepted their late-breaking abstract. Right after presentation, ASCO issued an immediate press release. A buzz was rapidly escalated by big media outlets (Reuters, NBC, CBS and others) as well as by coverage of specialized biothech/ medical news journalists (see: EP Vantage, Endpoints, FierceBiotech and STAT).

The data are spectacular – 100% response rate with 74% CR at 4 months (n=19). Much anticipated data release from very similar trial, run by US-based bluebird bio, was overshadowed by Chinese Nanjing Legend, presented in the same day.

Why is it a big deal for Chinese CAR-T biotech? Well, I don’t remember so much attention from “western word” to any CAR-T data (and even for any cell therapy data), coming from China, before. China has a lot of CAR-T trials going on and it has published their results (see here, here and here) and presented on prestigious conference (for example, ASH 2016 – see here and here). Despite quite good (comparable to “western world”) results, it had never got covered by western media and biotech analysts. The common perception of data from China among “westerners” was something like “it is unreliable” and “untrusted”. Would Legend’s ASCO success be a game changer for Chinese CAR-T biotech? I hope so. Well, at least now we got to know what city of Nanjing is.

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About two years ago I attempted to analyze published results of regenerative medicine clinical studies. It was very hard and time consuming thing to do, so I’ve ditched my efforts. Recently, I was very happy to find a study by Tania Bubela’s group from University of Alberta, published in Stem Cell Reports. This is the first detailed and the most complete study of published results of clinical trials in the field of regenerative medicine.

The study captures all trials, registered in international databases until end of 2012. The authors allowed 2.5 years time lag from registration to beginning of their analysis in mid-2015. Besides cell-based regenerative medicine trials, search criteria also included agents to (1) stimulate stem/ progenitor cells in vivo and (2) mobilize stem/ progenitor cells for for regenerative purposes. The authors captured many parameters, but the most important were number of publications (reported results), time to publication from trial completion, completeness (quality) of trial reporting and results of published trials.
To me, the most important thing from methodology was to learn how to perform comprehensive search for publications of trial results. It was done by the search of 3 databases: PubMEd, Embase and Google Scholar for –

  • trial ID (for example, NCT #);
  • investigator names, indicated in registry;
  • key words from trial title.

Using this search strategy, the authors identified 357 publications, 74.2% of which linked to trial registration ID.

The study has a lot of interesting data, which you can use to make graphs for your presentations. Here is one graph I made:

bubela_2017

Now, some interesting quotes and my comments.

About publication rate:

Of 1,052 novel trials in our dataset, 393 were completed, 81 were terminated or suspended, 22 were withdrawn, and the remaining 556 were in progress, including trials with unknown status. Of the trials completed, 179 (45.4%) had published results in 205 associated publications with English-language abstracts…

For clinical trials of novel stem cell interventions, a publication rate of 45.5% for completed trials is consistent with other studies of publication rates. However, it remains problematic because the stem cell field combines high patient expectations, patient advocacy, strong political support, and therapeutic promise with regulatory concerns over safety and limited evidence of efficacy…

Interestingly, “publicability” does not increase with progression of trials from Phase 1 to 3/4. Thus, % of publications in Phase 1 trials was 27.7%, in Phase 2 – 27.2% and in Phase 3/4 – 25%.

On trials results:

Safety was reported by 91.2% of publicly funded and 93.0% of industry-funded trials; a higher proportion of industry-funded than publicly funded trials reported positive efficacy (77.2% versus 67.2%); fewer industry-funded than publicly funded trials reported no efficacy (14.0% versus 22.7%); more publications advocating for further or continuing studies reported on industry-funded compared with publicly funded trials (82.4% versus 75.6%).

No surprises here. I was very curious to learn anything about trials failure rate in from phase-to-phase. According to table 2 from the study, positive outcomes of Phase 1 and 1/2 were reported in 125/167 (74.8%) publications, of Phase 2 and 2/3 in 59/93 (63.4%), of 3 and 3/4 in 3/12 (25%). However, difference was insignificant:

No trial characteristic had a significant overall effect on the publication of positive results, although phase III and phase III/IV trials were less likely to report positive results than phase I and phase I/II trials (odds ratio [OR] 0.11; p < 0.004).

It seem to me that “positive outcome” was “as reported” in publications, but not assessed by Bubela’s group. 63.4% of success rate in Phase 2 looks too high to me. Two years ago, I was trying to assess trials outcome myself, since many reports, which contained mixed (some end points were met some were not) or incomplete results, were presented as “positive” by authors in publications. That’s why, I think, these numbers are overestimated. Also, these numbers do not allow us to calculate “failure rate” precisely, since all “incomplete/ mixed/ inconclusive/ failed” could fall under “other than positive”. According to Bubela’s study, trial status has significant effect of the completeness of reporting (I understood that completeness of reporting was worse with progression of trial phase).

On publication bias:

Our result of 67.3% publications reporting positive outcomes is concerning when combined with the early stage of most, and incomplete status of many, novel stem cell clinical trials.

On “unproven stem cell therapies”:

We identified 48 clinical trials with registration numbers on both ClinicalTrials.gov and the International Clinical Trials Registry Platform (ICTRP) from known clinics in North America, Eastern Europe, and Asia that offer unproven stem cell therapies (Table S1). Trials of adipose-derived stem cells or umbilical cord mesenchymal stem cells predominated for a range of conditions in both adult and pediatric participants. Most were recruiting or “enrolling by invitation.” None reported results.

This kind of analysis was performed for the first time. The obvious question here is how did authors identify clinics with “unproven stem cell therapies” in databases? The explanation is in methods:

…we searched our dataset for the names of clinics that provide unproven stem cell therapies identified from the stem cell tourism literature (Li et al., 2014, Master et al., 2014, Master and Resnik, 2011, Levine, 2010, Lau et al., 2008, Turner and Knoepfler, 2016, Goldring et al., 2011, von Tigerstrom, 2008, Sipp and Turner, 2012, Ogbogu et al., 2013)…

It is very very interesting to observe how datasets like Knoepfler/ Turner on “stem cell clinics” became a reference for the other analytical studies.

Overall, this study provides very unique and useful information for all of us in the field. I’d highly recommend you to read it and utilize their data in your work. It will be important to continue to track publications and trial results after 2012 and see how data will evolve over time. Because we cannot calculate “trials failure rate” precisely, based on data from this study, it will be important to perform such analysis in the future.

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2017 marks 20 years since the first regulatory approval of cell-based therapeutic product on a market. In 1997 Carticel (manufactured by Genzyme Corp.) was approved by FDA for US market. One year before Carticel approval, 2 cell-based products were launched and marketed for the first time in Europe (Italy) – Laserskin and Hyalograft by Fidia Advanced Biopolymers. I was curious to learn about other approved and marketed cell-based products worldwide in the last 20 years. I also wanted to learn what happen to the first products, marketed 15-20 years ago. It took me almost a year to investigate this topic, collecting bits of information from public sources and conferences. Today, I’m sharing some of my data analysis.

Methodology:
I searched published literature, company press releases, mass media coverage, books (via Google books), patents, presentations from conferences and meetings, information from regulatory agencies. Also, I’ve learned some unique information from multiple conferences and from personal communications.

Inclusion criteria:

  • the product must contain alive cells and used for therapeutic purpose;
  • the product must be marketed and/ or approved by regulatory agency;
  • cord blood products for homologous use, obtained BLA as FDA requirement in US;
  • traceable public information is available.

Exclusion criteria:

  • absence of traceable public information when and where product was marketed;
  • tissues for transplantation without brand name (not a product);
  • More than 3000 therapeutic products marketed in Japan, as Specific Processed Cellular Products under the Act on the Safety of regenerative Medicine (ASRM) – Class III Regenerative Medicine products (not regulated under the PMDA). In this case, individual institutions (hospitals) submit a “Plan to Provide Regenerative Medicine” and seek for approval from Japanese Ministry of Health, Labour and Welfare (MHLW). Information about 3 ASRM products was publicly available and searchable. These 3 products were included in the dataset as an exception.

For historical analysis I was trying to capture the earliest available data. Some early approvals and self-launches happened before defining regulatory framework for cell/ tissue products. So, some cell-based products were approved as devices. The following data were captured: name of the product, name of the manufacturer, year of approval and/ or when it was launched on the market, where it was marketed, name of regulatory agency (if it was approved), indication, cell type, traceable changes (off market, manufacturer went for bankruptcy…). The whole dataset is available on Cell Trials Data.

Results:
(1) As of March 2017, I was able to identify 90 marketed cell-based products. There were mentions of few products, without traceable information of when it was launched (for example, Cartogen in Australia). 61% (55/90) of marketed products were approved by regulatory agencies; 12% (11/90) were self-launched with manufacturing license, issued by governmental agency; 27% (24/90) were self-launched without information about manufacturing license.

marketed products

Figshare link
How to cite this figure: Bersenev, Alexey (2017): Self-launched versus approved cell-based products, marketed worldwide. figshare. https://doi.org/10.6084/m9.figshare.4829452
DOI: 10.6084/m9.figshare.4829452

(2) Most of cell-based products were marketed for 3 major groups of indications: skin defects (31%), cartilage repair (24%) and oncology (19%).

marketed products indications

By the time of writing this post, at least 12 products (13%) were off market. This number is underestimated, since there was no public information available about current status of many products, marketed earlier. At least 5 manufacturers went to bankruptcy, some were acquired or outlicensed products to other companies.

(3) Since 1997, there were 58 regulatory approvals of 55 cell-based products by 13 different jurisdictions. 3 products were approved by more than one jurisdiction (Provenge, Prochymal and MACI).

58 approvals
Figshare link
How to cite this figure: Bersenev, Alexey (2017): Regulatory approvals of cell-based therapeutic products by jurisdiction. figshare. https://doi.org/10.6084/m9.figshare.4829182.v1
DOI: 10.6084/m9.figshare.4829182

(4) Historical trend for approvals is slowly going up with some volatility. Number of approvals per year was ranging from 0 to 8.

58 approvals trend

Figshare link
How to cite this figure: Bersenev, Alexey (2017): Historical trend in regulatory approvals of cell-based therapeutic products worldwide. figshare.
https://doi.org/10.6084/m9.figshare.4829503.v1
DOI: 10.6084/m9.figshare.4829503

How to cite this post:
Bersenev Alexey. Historical analysis of cell-based therapeutic products marketed and approved worldwide. CellTrials blog. April 7, 2017. Available: http://celltrials.info/2017/04/07/marketed-approved

Get raw data

PS: I’d like to thank Colin Lee Novick for clarifying information about regulation in Japan.

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CAR cell therapy trials in China

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Presentation: CELL THERAPY – Definitions, Classifications and Trends

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Here is my talk that I gave on August 15 this year during annual BioProcessing Summit in Boston. Cell Therapy – Definitions and Classifications from nanog Link Transcript: 2. Cell therapy is mostly experimental field right now. So, one of the best ways to track activities in this field is to look at number of […]

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